Dilek Ertoy

PAX8 (+)/p63 (−) Immunostaining Pattern in Renal Collecting Duct Carcinoma (CDC): A Useful Immunoprofile in the Differential Diagnosis of CDC Versus Urothelial Carcinoma of Upper Urinary Tract

BackgroundCollecting duct carcinoma (CDC) is a relatively rare but aggressive type of renal malignancy with variable morphologic features. One of the World Health Organization diagnostic criteria for CDC is the exclusion of urothelial carcinoma of renal pelvis from the differential diagnosis. PAX8 is a novel lineage restricted transcription factor expressed in renal tubules. We investigated the expression pattern of PAX8 in CDC and its utility, in combination with p63, in resolving the differential diagnosis of CDC versus upper tract urothelial carcinoma (UUC). DesignArchival tissues from 21 CDC and 34 UUC were retrieved from our institutional files. Immunohistochemistry for PAX8 and p63 were performed on routine and tissue microarray sections using standard immunohistochemistry protocol. Intensity of nuclear staining was evaluated for each marker and assigned an incremental 0, 1+, 2+, and 3+ score. Extent of staining was categorized as focal (<25%), nonfocal (25% to 75%), or diffuse (>75%). ResultsCDC: All 21 (100%) CDC were positive for PAX8. Intensity of expression was moderate to strong (2+/3+) in 19 cases (90%). Extent of staining was diffuse in 13 of 21 tumors. The p63 was positive in 3 of 21 (14%) CDC cases (PAX8+/p63+). UUC: The 34 UUC included 5 pT1, 4 pT2, and 25 pT3/pT4 tumors. Thirty-one of 34 (91.2%) UUC were negative for PAX8, whereas 33 of 34 (97%) were p63 positive. Staining intensity was moderate in 15 cases (44%), of which 12 were nonfocal or diffuse. The unique p63-negative UUC was a pT1 tumor that was also negative for PAX8 (PAX8−/p63−). ConclusionsWe propose the use of the combination of PAX8 and p63 in the diagnosis of poorly differentiated renal sinus epithelial neoplasms where the differential diagnosis includes CDC versus UUC. The immunoprofile of PAX8+/p63− supports the diagnosis of CDC with a sensitivity of 85.7% and a specificity of 100%. In contrast, a (PAX8−/p63+) profile supports the diagnosis of UUC with a sensitivity of 88.2% and a specificity of 100%. The inverse PAX8/p63 expression seen in CDC and UUC supports a renal tubular rather than an urothelial differentiation in CDC given the nephric lineage restriction of PAX8.

POSTOPERATIVE TOPICAL MITOMYCIN C IN CONJUNCTIVAL SQUAMOUS CELL NEOPLASIA

PURPOSE To report the efficacy of topical mitomycin C in preventing local recurrences after incomplete surgical excision of conjunctival squamous cell neoplasia. METHODS Four patients presented with unilateral conjunctival tumors. Excisional biopsy results revealed conjunctival intraepithelial neoplasia with an intact basement membrane. Neoplastic cells were present in at least one of the surgical borders of the excised conjunctiva in all four cases. Patients were treated with topical mitomycin C 0.02% three times daily for 2 weeks to prevent recurrences. RESULTS All four patients were free of clinically detectable tumors after a mean follow-up period of 20 months (range, 16-23 months). Side effects included mild discomfort, redness, photophobia, and punctate epithelial keratopathy that subsided on discontinuation of the medication. CONCLUSION Postoperative topical mitomycin C application may be a useful adjunct to prevent recurrences in patients with incompletely excised conjunctival squamous cell neoplasia.

Preventive effect of pentoxifylline on renal scarring in rat model of pyelonephritis

OBJECTIVES To evaluate the efficiency of pentoxifylline (PTX), a methyl xanthine derivative, in preventing renal scar formation after the induction of pyelonephritis in an experimental rat model with delayed antimicrobial therapy. METHODS An inoculum of 1 x 10(9) colony-forming units/0.1 mL of the K-12 strain of Escherichia coli, which has both type 1 and P pili, was injected directly into both renal parenchyma of Wistar rats (n = 40). Group 1 (control) received isotonic saline instead of bacterial solution (n = 10). Four equal groups were then formed: group 2 was not treated and group 3 was treated only with ciprofloxacin for 5 days, starting 3 days after bacterial inoculation; in group 4, 50 mg/kg of PTX, and in group 5, PTX (50 mg/kg) and ciprofloxacin (15 mg/kg) together were administered intraperitoneally for 5 days, starting 3 days after bacterial inoculation. Six weeks after bacterial inoculation, all the rats were killed, and both kidneys were examined histopathologically for renal scarring. RESULTS Delayed treatment with antibiotics had no effect on scarring compared with the untreated controls. However, the addition of PTX to the delayed antibiotic therapy significantly inhibited renal scarring compared with the untreated or antibiotic-only groups (P <0.05). CONCLUSIONS These results suggest that PTX is effective in preventing renal scar formation in pyelonephritis when the initiation of antimicrobial treatment is delayed in this rat model of pyelonephritis.

Testicular teratoma and anti-N-methyl-D-aspartate receptor-associated encephalitis

We report a patient with a testicular teratoma and seminoma, who developed treatment-responsive encephalitis associated with antibodies to NMDA receptor, but not antibodies to Ma2 protein. A 30-year-old male was admitted to hospital with a 1-week history of personality changes, confusion, agitation and recurrent generalised tonic-clonic seizures. His past medical history was unremarkable, except for the presence of generalised fatigue and sore throat a few days before symptom onset. On physical examination, the only pathological finding was bilateral testicular enlargement. He was agitated and disoriented to time, place and person; his speech was incoherent, and he had persecutory and erotic delusions. The rest of the neurological examination was normal. The initial laboratory studies, including complete blood count, biochemistry, EEG and brain MRI, were normal. The CSF examination was significant for an elevated protein concentration (113 mg/dl) with normal glucose content and mild leukocytosis (25 cells/μl); bacterial and viral studies, including PCR for herpes simplex virus, were negative. Testicular ultrasound revealed the presence of a left testicular mass and right testicular torsion. Computerised tomography of the chest, abdomen and pelvis demonstrated the presence of a retroperitoneal lesion, which was suggestive of metastasis. These findings led us to consider the diagnosis of paraneoplastic encephalitis. Accordingly, CSF …

Clinicopathological implication of cripto expression in early stage invasive cervical carcinomas

This study evaluates the expression of cripto (CR-1) protein in matched sets of non-neoplastic cervical epithelium, primary cervical carcinoma and metastatic tumours in the lymph nodes to investigate its role in uterine cervical cancer development and progression. Ninety-four primary cervical carcinomas in an early clinical stage and having the same surgical treatment modality were analysed. Immunoreactivity in the primary tumour was compared with that of non-neoplastic cervical epithelium and metastatic lymph nodes. The conventional clinicopathological prognostic variables for cervical carcinomas such as grade, tumour size, depth of invasion, parametrial and endometrial extension, lymphovascular space involvement and lymph node metastasis status were also compared with CR-1 expression of the primary tumour. Strong CR-1 immunopositivity was significantly correlated with tumour size and lymphovascular space involvement (P < 0.05). Furthermore, a significant relationship was found between CR-1 immunoreactivity and endometrial extension as well as parametrial involvement (P < 0.05). Interestingly, the CR-1 expression level was increased in metastatic lymph nodes compared with their primary tumours. These results suggest that CR-1 may contribute to disease progression in cervical carcinomas.

Benign familial hematuria associated with a novel COL4A4 mutation.

Abstract. We describe a father and three offspring with hematuria. The father and one girl also complained of flank pain. Renal function tests and ophthalmological examinations were normal in all. The father had very mild neural deafness. The renal biopsy samples of two affected siblings showed changes compatible with thin basement membrane disease. Genetic analysis revealed a novel missense mutation in exon 32 of COL4A4 to be responsible for the phenotype in this family. We suggest that thin basement membrane disease may have overlapping clinical features with other causes of hematuria; genetic analysis may help in the differential diagnosis and help us further understand the disease processes.

The role of GATA binding protein 3 in the differential diagnosis of collecting duct and upper tract urothelial carcinomas

Differential diagnosis of collecting duct carcinoma (CDC) from invasive upper tract urothelial carcinoma (UTUC) can be challenging. PAX8 and p63 are 2 markers often used in this setting. GATA binding protein 3 (GATA3) is a marker of urothelial differentiation. We investigated GATA3 expression in CDC and UTUC and its use in this differential. Eighteen CDC and 25 UTUC cases were used to build 2 tissue microarrays. GATA3, p63, and PAX8 nuclear expression was evaluated using standard immunohistochemistry. Staining intensity and percentage of positive cells were assessed. Sensitivity, specificity, and positive and negative predictive values of the markers and their combination were also evaluated. We found GATA3 positivity in 22 (88%) of 25 UTUCs and 1 (6%) of 18 CDCs. The median GATA3 extent of expression was higher in UTUC than in CDC (74% versus 0%, P = .00). We found p63 positivity in 23 (92%) of 25 UTUCs and 2 (11%) of 18 CDCs. PAX8 was positive in 3 (12%) of 25 UTUCs and all (100%) CDCs. GATA3 sensitivity and specificity for UTUC were 88% and 94%, respectively. p63 sensitivity and specificity for UTUC were 92% and 89%, respectively. The p63+/PAX8- profile showed higher sensitivity for UTUC than did the GATA3+/PAX8- profile (80% versus 76%). Both showed a specificity of 100% for UTUC. GATA3+ or p63+/PAX8- sensitivity and specificity for UTUC were 84% and 100%, respectively. Immunohistochemical expression of GATA3 was higher in UTUC, suggesting a potential role for distinguishing UTUC from CDC. Adding this marker to the combination panel of p63 and PAX8 might improve its performance in the diagnosis of epithelial neoplasms involving the renal sinus.

Insights derived from ACE knockout mice

The evaluation of ACE knockout mice has illustrated the tremendous physiologic importance of the RAAS. We have discussed how interruption of this system influences blood pressure, renal function, renal development, serum and urine electrolyte composition, haematocrit and male reproductive capacity. This body of data underlines the modelling of the RAAS as a type of biological machine that is positioned to respond to environmental insult and to maintain a homeostasis of blood pressure, blood volume and electrolyte composition. These data also emphasise Harry Goldblatts seminal observation that the kidney and the RAAS are intimately linked in the regulation of normal blood pressure.

High prevalence of TERT promoter mutations in primary squamous cell carcinoma of the urinary bladder

TERT promoter mutations (TERT-mut) are detectable in the majority of urothelial carcinomas. The detection of TERT-mut in urine is under investigation as a potential urine-based molecular-screening assay for bladder cancer. A small but significant number of bladder carcinomas are pure squamous cell carcinoma. We sought to assess the incidence of TERT-mut in squamous cell carcinoma of the urinary bladder. A retrospective search of the institutional pathology archives yielded 15 cystectomy specimens performed for squamous cell carcinoma (2000–2014). Histologic slides were reviewed by a senior urologic pathologist to confirm the diagnosis and select a representative formalin-fixed paraffin-embedded tissue block for mutational analysis. All cases yielded adequate material for DNA analysis. Sequencing for TERT-mut was performed using previously described SafeSeq technique. We detected TERT-mut in 12/15 (80%) of bladder squamous cell carcinomas. TERT promoter mutations, commonly found in conventional urothelial carcinoma, are also highly prevalent in urinary bladder squamous cell carcinoma suggesting a common tumorigenesis and potential utility as a molecular urine-based-screening assay.

Detection of TERT promoter mutations in primary adenocarcinoma of the urinary bladder.

TERT promoter mutations (TERT-mut) have been detected in 60% to 80% of urothelial carcinomas. A molecular urine-based screening assay for the detection of TERT-mut is currently being pursued by our group and others. A small but significant number of bladder carcinomas are adenocarcinoma. The current study assesses the incidence of TERT-mut in primary adenocarcinomas of urinary bladder. A retrospective search of our institutional pathology records identified 23 cystectomy specimens with a diagnosis of adenocarcinoma (2000-2014). All slides were reviewed by a senior urologic pathologist to confirm tumor type and select a representative formalin-fixed, paraffin-embedded block for mutational analysis. Adequate material for DNA testing was available in 14 cases (7 enteric type and 7 not otherwise specified). TERT-mut sequencing analysis was performed using previously described SafeSeq technique. Overall, 28.5% of primary adenocarcinoma harbored TERT-mut. Interestingly, 57% of nonenteric adenocarcinomas were mutation positive, whereas none of the enteric-type tumors harbored mutations. Similar to urothelial carcinoma, we found a relatively higher rate of TERT-mut among nonenteric-type adenocarcinomas further supporting the potential utility of TERT-mut urine-based screening assay for bladder cancer.