Molecular Screening of PAX2 Gene Polymorphism in Primary Vesicoureteral Reflux Patients in Taif Governorate, KSA.

<b>Background and Objective:</b> Primary Nonsyndromic Vesicoureteral Reflux (PVUR) is a widespread genetic malformation and considered a prevalent Congenital Abnormality of the Kidney and Urinary Tract (CAKUT). Mutations in the <i>PAX2 </i>gene have been associated with abnormalities in the kidney extending from CAKUT to oncogenic processes. The present study analyzes the <i>PAX2</i> polymorphisms and their association with primary VUR in Saudi children patients from the Taif governorate. <b>Materials and Methods:</b> Fifteen children with primary VUR were identified and screened for gene mutations in the <i>PAX2</i> gene by direct sequencing method of purified Polymerase Chain Reaction (PCR) products of all exons to elucidate the correlation between <i>PAX2</i> gene and VUR. <b>Results:</b> Seven new variants have been defined. Three polymorphic missense variants in homozygous genotype form were found in intron 8 and detected in eight patients, One missense mutation was found in exon 10 in the site of transactivation domain and detected in ten patients and <i>in-silico</i> analysis predicted it as a pathogenic one, Three mutations were found in exon 11 and detected in all patients as a compound homozygous. <b>Conclusion:</b> <i>PAX2</i>is important for normal kidney development and mutations in the gene possibly lead to disturbance in the protein structure and could be non-functional thus mutations in <i>PAX2</i> may be one of the causes of PVUR in Saudi Arabia. Further investigation is necessary to understand the aetiology of disease and maybe other genes implicated in VUR.

Immunohistochemical expression of PAX8, PAX2, and cytokeratin in melanomas.

BACKGROUND: Deviations from the classic melanocytic immunophenotype in melanoma can present a diagnostic challenge. PAX8 and PAX2 are common markers for renal or Müllerian differentiation. While most PAX8+ or PAX2+ carcinomas are seldom confused with melanoma, some cases may show a more ambiguous immunophenotype, especially when MiTF family altered renal cell carcinoma (MiTF-RCC) is in the differential diagnosis. Neither PAX8 nor PAX2 expression has been reported in melanoma to date. We aimed to better characterize PAX8, PAX2, and cytokeratin immunoreactivity in a large series of melanomas. METHODS: Tissue microarrays consisting of 263 melanomas were immunostained for PAX8, PAX2, and cytokeratin and graded by an h-score. RESULTS: PAX8 expression was seen in 7.9% of melanomas and was significantly associated with spindle cytomorphology. PAX2 was positive in one (0.4%) melanoma. Cytokeratin positivity was seen in three (1.2%) cases and was associated with metastases. CONCLUSIONS: PAX8 is expressed in a subset of melanomas and may be strong/extensive. As PAX8 positivity does not exclude a diagnosis of melanoma, it should be used in conjunction with other immunohistochemical markers, such as cytokeratin and PAX2, when melanoma, MiTF-RCC, and other PAX8+ tumors are in the differential diagnosis.

Specific Biomarker Expression Patterns in the Diagnosis of Residual and Recurrent Endometrial Precancers After Progestin Treatment: A Longitudinal Study.

BACKGROUND: Conservative management with progestin is a treatment option for atypical hyperplasia (AH). However, pathologic diagnosis of residual/recurrent lesions is often problematic because of the profound morphologic changes induced by progestin and the lack of established diagnostic criteria for progestin-treated residual AH. METHODS: We conducted a longitudinal study of 265 endometrial biopsies from 54 patients with a history of AH on progestin therapy. Patient outcomes were divided into 3 categories after morphologic review and immunohistochemical staining with phosphatase and tensin homolog (PTEN) and paired box 2 (PAX2): (1) persistent or residual disease; (2) recurrent disease; (3) complete response. All specimens were classified into 3 categories based on morphology: (1) persistent/recurrent disease (nonresponse), (2) morphologically uncertain response, (3) optimally treated (complete response). The staining patterns of PTEN/PAX2 were tracked over time in individual patients and correlated with morphologic findings before and after progestin therapy. RESULTS: Our data showed that aberrant expression patterns of PTEN and/or PAX2 were identified in 48 (88.9%) of the 54 primary biopsies and persisted in persistent/recurrent AH across serial endometrial biopsies (n=99, P<0.00001), while normal PTEN and PAX2 expressions were consistently observed in optimally treated cases (n=84, P<0.00001). More importantly, follow-up biopsies that showed a morphologically uncertain response but a PTEN/PAX2 expression pattern identical to the initial biopsy were significantly correlated with persistent or recurrent disease (n=18, P=0.000182), as evidenced by areas with morphologic features diagnostic of AH on subsequent biopsy. CONCLUSIONS: Biomarker PTEN/PAX2 signatures offer a valuable diagnostic aid to identify residual AH in progestin-treated endometrial samples for which the biomarker status from preprogestin treated AH is known. The findings of this study are promising for a possible future change of diagnostic practice.

Endometrioid Tubal Intraepithelial Neoplasia (E-TIN) of the Fallopian Tube: A Case Series.

Although serous tubal intraepithelial carcinoma has been well described in the distal fallopian tube as precancers of pelvic high-grade serous carcinoma, endometrioid precancers have drawn less attention. Recently, endometrioid precursor lesions have been identified and reported to have a specific immunophenotype (PAX2-, ALDH1+, diffuse nuclear beta-catenin), as well as an association with both uterine and ovarian endometrioid carcinomas. These have been referred to as endometrioid (or type II) secretory cell outgrowths. A subset of endometrioid secretory cell outgrowths show architectural complexity resembling hyperplasia of the endometrium and have been referred to as endometrioid tubal intraepithelial neoplasia. We report 4 cases of endometrioid tubal intraepithelial neoplasia with clinical correlation and morphologic differential diagnosis.

CRISPR-Cas9-Mediated Correction of the G189R-PAX2 Mutation in Induced Pluripotent Stem Cells from a Patient with Focal Segmental Glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is defined by focal (involving few glomeruli) and segmental sclerosis of the glomerular tuft that manifests with nephrotic syndrome. Mutations in genes involved in the maintenance of structure and function of podocytes have been found in a minority of these patients. A family with adult-onset autosomal dominant FSGS was recently found to carry a new germline missense heterozygous mutation (p.G189R) in the octapeptide domain of the transcription factor PAX2. Here, we efficiently corrected this point mutation in patient-derived induced pluripotent stem cells (iPSCs) by means of CRISPR-Cas9-based homology-directed repair. The iPSC lines were differentiated into podocytes, which were tested for their motility. Editing the PAX2 p.G189R mutation restored podocyte motility, which was altered in podocytes derived from patient iPSCs.

PAX2 expression is correlated with better survival in tamoxifen-treated breast carcinoma patients.

PAX2 (paired box gene 2) is a transcription factor, which is involved in both cell proliferation and carcinogenesis. This study aimed to investigate PAX2 expression in tamoxifen resistant (TAM-R) and tamoxifen sensitive (TAM-S) breast carcinoma patients and analyze its correlation with clinicopathological characteristics and survival. Immunohistochemical analysis was performed to evaluate PAX2 protein expression in 36 TAM-R and 36 TAM-S formalin-fixed paraffin-embedded (FFPE) breast tumor tissues. Data analysis indicated that PAX2 expression was significantly higher in TAM-S group in comparison to TAM-R (P = 0.014). Overexpression of PAX2 was significantly correlated with perineural invasion (PNI) (P = 0.025). Kaplan-Meier survival analysis showed significant association between high expression of PAX2 and better disease-free survival (P < 0.001) and also overall survival (P = 0.031). Multivariate cox regression analysis demonstrated that patients with increased expression of PAX2 have a trend toward improved disease free survival (OR = 0.065, 95% CI: 0.009-0.476; P = 0.007) and overall survival (OR = 0.147, 95% CI: 0.020-1.105; P = 0.062). Our data suggested that high expression of PAX2 could be associated with better survival in estrogen receptor positive tamoxifen-treated breast carcinoma patients.

Immunophenotypic comparison of testicular sclerosing Sertoli cell tumors and Sertoli cell tumors not otherwise specified.

Testicular Sertoli cell tumors (SCTs) are rare, and most fall into the category of SCT-not otherwise specified (SCT-NOS). Only a few additional types of SCT are recognized. Sclerosing SCT (S-SCT), originally described in 1991, comprises a small fraction of SCTs and was considered a specific entity until the 2016 revision of the World Health Organization classification of non-germ cell tumors, where it was classified as a morphologic variant of SCT-NOS. In a recent study, differences in expression of PAX2/PAX8, inhibin, androgen receptor, and S100 protein between SCT-NOS and S-SCT were noted in a small number of cases. In this interinstitutional study, we compared the expression of these markers and ß-catenin in 11 cases each of SCT-NOS and S-SCT to determine if differences exist that could justify keeping a separate classification of these neoplasms. PAX2/PAX8 cocktail was the only marker that was significantly overexpressed in S-SCT. Expression of androgen receptors was strong in S-SCT and variable in SCT-NOS but did not reach statistical significance. Expression of ß-catenin was common in both, whereas inhibin was infrequent. The available material was insufficient for a conclusive evaluation of S100 protein expression. Overall, our results support the inclusion of S-SCT as a morphologic variant of SCT-NOS. Expression of PAX2/PAX8 in S-SCT may reflect an overactive epithelial-to-mesenchymal transition as has been shown in experimental models of acute and chronic seminiferous tubular injury and might be related to the process generating the stroma in these tumors.

[Clinicopathologic study of primary renal hemangioblastoma].

OBJECTIVE: To study the clinicopathologic characteristics of primary renal hemangioblastoma. METHODS: The morphologic features, immunophenotype and molecular findings of 3 cases of primary renal hemangioblastoma were studied, with review of literature. RESULTS: The age of patients ranged from 43 to 57 years. There were 2 women and a man. The patients often presented with renal mass. Histologically, the tumors were surrounded by thick fibrous capsule and composed of epithelioid or spindle cells. Two cases had a prominent stromal component and the other one was rich in capillary network. Lipid vacuoles were observed in all cases. Features of hemorrhage were demonstrated in 2 cases. Capsular invasion and necrosis were seen in 1 case. Immunohistochemical study showed that the stromal cells were positive for alpha-inhibin (3/3), S-100 protein (3/3), EGFR (2/2), PAX-2 (2/2), PAX-8 (2/2) and CA9 (2/2) but negative for CKpan (2/2) and HMB45 (2/2). Focal membranous staining for CD10 (3/3) was noted. No VHL gene mutations or chromosome 3p deletion were detected in the 2 cases studied. CONCLUSIONS: Renal hemangioblastoma shows distinctive morphologic appearance with a wide range of variation. The unexpected positive staining for PAX-2, PAX-8 and CD10 in renal hemangioblastoma needs to be aware. Immunohistochemical study may be helpful in differential diagnosis of these renal tumors.

The significance of Pax2 expression in the ureter epithelium of children with vesicoureteric reflux.

Vesicoureteral reflux (VUR) is the retrograde passage of urine from the bladder to the urinary tract; this leads to renal scarring and end-stage renal disease in children. Pax2 is a nuclear transcription factor that is involved in urinary system development. We measured the expression of Pax2 in the ureters of 47 patients with VUR. The messenger RNA expression and the protein level of Pax2 were significantly increased in patients with VUR, suggesting a correlation with VUR. Further studies demonstrated that Pax2 was hypomethylated, and Dnmt3a messenger RNA expression was significantly lower than in the control group. We speculate that the low level of Dnmt2a might decrease PAX2 gene methylation and up-regulate the Pax2 protein. The high level of Pax2 might be related to cellular apoptosis and functional lesions in ureters. In conclusion, our results revealed that the level of Pax2 is correlated with VUR; thus, Pax2 represents a possible target for VUR therapy.

The Groucho-associated phosphatase PPM1B displaces Pax transactivation domain interacting protein (PTIP) to switch the transcription factor Pax2 from a transcriptional activator to a repressor.

Pax genes encode developmental regulatory proteins that specify cell lineages and tissues in metazoans. Upon binding to DNA through the conserved paired domain, Pax proteins can recruit both activating and repressing complexes that imprint distinct patterns of histone methylation associated with either gene activation or silencing. How the switch from Pax-mediated activation to repression is regulated remains poorly understood. In this report, we identify the phosphatase PPM1B as an essential component of the Groucho4 repressor complex that is recruited by Pax2 to chromatin. PPM1B can dephosphorylate the Pax2 activation domain and displace the adaptor protein PTIP, thus inhibiting H3K4 methylation and gene activation. Loss of PPM1B prevents Groucho-mediated gene repression. Thus, PPM1B helps switch Pax2 from a transcriptional activator to a repressor protein. This can have profound implications for developmental regulation by Pax proteins and suggests a model for imprinting specific epigenetic marks depending on the availability of co-factors.

Diagnostic utility of PAX2 and PAX5 in distinguishing non-small cell lung cancer from small cell lung cancer.

Lung cancer is the leading cause of cancer-related death in both men and women and consists of different histological types. Histopathological examination and accurate subtype diagnosis has become increasingly important in guiding patient management and, as such, is the most important currently available lung cancer "biomarker". In this study, we examined the expression of PAX2 and PAX5 by immunohistochemistry in 47 cases of lung cancer and 13 cases of pneumonia. The results demonstrated that PAX2 were detected in 82.8% (24/29) of NSCLC, 0% (0/18) of SCLC and 7.7% (1/13) of pneumonia, respectively; However, PAX5 were detected in 15/18 cases (83.3%) of SCLC, 6.8% (2/29) of NSCLC and 7.7% (1/13) of pneumonia. Further, the samples with lymphatic metastasis had remarkable higher positive PAX2 or PAX5 than that without metastases. Overall, our data indicated that PAX2 and PAX5 differentially expressed in NSCLC and SCLC. Thus, PAX2 and PAX5 are useful biomarker in the differential diagnosis of lung cancer.

Evaluation of PAX2 and PAX8 expression in salivary gland neoplasms.

PAX2 and PAX8 are transcription factors involved in embryogenesis that have been utilized as immunohistochemical indicators of tumor origin. Specifically, PAX2 is a marker of neoplasms of renal and müllerian origin, while PAX8 is expressed by renal, müllerian, and thyroid tumors. While studies examining these transcription factors in a variety of tumors have been published, data regarding their expression in salivary gland neoplasms are limited. The goal of this study was to assess expression of PAX2 and PAX8 in a large cohort of salivary gland tumors. Utilizing tissue microarrays, samples of normal salivary glands (n = 68) and benign and malignant salivary gland neoplasms (n = 442) were evaluated for nuclear immunoreactivity with PAX2 and PAX8. No expression was observed with either marker in the normal salivary glands, and PAX8 was negative in all neoplasms. Focal expression of PAX2 was observed in one example each of oncocytoma and acinic cell carcinoma. These results indicate that evaluation of PAX2 and/or PAX8 expression would be valuable in differentiating primary salivary gland tumors from metastases known to express PAX2 and/or PAX8.

The glomerular parietal epithelial cell's responses are influenced by SM22 alpha levels.

BACKGROUND: Studies have shown in several diseases initially affecting podocytes, that the neighboring glomerular parietal epithelial cells (PECs) are secondarily involved. The PEC response might be reparative under certain circumstances, yet injurious under others. The factors governing these are not well understood. We have shown that SM22α, an actin-binding protein considered a marker of smooth muscle differentiation, is upregulated in podocytes and PECs in several models of podocyte disease. However, the impact of SM22α levels on PECs is not known. METHODS: Experimental glomerular disease, characterized by primary podocyte injury, was induced in aged-matched SM22α+/+ and SM22α-/-mice by intraperitoneal injection of sheep anti-rabbit glomeruli antibody. Immunostaining methods were employed on days 7 and 14 of disease. RESULTS: The number of PEC transition cells, defined as cells co-expressing a PEC protein (PAX2) and podocyte protein (Synaptopodin) was higher in diseased SM22α-/-mice compared with SM22α+/+mice. WT1 staining along Bowman's capsule is higher in diseased SM22α-/-mice. This was accompanied by increased PEC proliferation (measured by ki-67 staining), and an increase in immunostaining for the progenitor marker NCAM, in a subpopulation of PECs in diseased SM22α-/-mice. In addition, immunostaining for vimentin and alpha smooth muscle actin, markers of epithelial-to-mesenchymal transition (EMT), was lower in diseased SM22α-/-mice compared to diseased SM22α+/+mice. CONCLUSION: SM22α levels may impact how PECs respond following a primary podocyte injury in experimental glomerular disease. Absent/lower levels favor an increase in PEC transition cells and PECs expressing a progenitor marker, and a lower EMT rate compared to SM22α+/+mice, where SM22 levels are markedly increased in PECs.

Mesonephric carcinosarcoma involving uterine cervix and vagina: report of 2 cases with immunohistochemical positivity For PAX2, PAX8, and GATA-3.

Mesonephric carcinomas are rare tumors predominantly arising in the uterine cervix from mesonephric remnants. Although the tumor has classic morphologic features, some cases can mimic Müllerian adenocarcinoma and be misdiagnosed, especially those with significant ductal pattern. Moreover, there is an overlap in immunohistochemical results with endometrial and endocervical carcinomas. In this study, we report 2 cases of mesonephric carcinosarcoma, originally diagnosed as Müllerian carcinomas, 1 presenting in the vagina; review immunohistochemical results including positivity for GATA-3, not previously reported and comment on the proposed panel of PAX8, p16, and estrogen receptors as discriminators of Müllerian adenocarcinoma (endocervical or endometrial) versus mesonephric carcinoma.

PAX2 and PAX8: useful markers for metastatic effusions.

OBJECTIVE: It was the aim of this study to determine the utility of PAX2 and PAX8 in cytology effusions with metastatic tumor. STUDY DESIGN: PAX2 and PAX8 immunohistochemical staining was performed on cell blocks of 89 pleural, pericardial and peritoneal effusions with benign diagnoses (18 cases), or secondary to renal cell carcinoma (RCC; 9 cases), müllerian carcinoma (21 cases) or non-müllerian carcinoma (41 cases). RESULTS: PAX2 stained 0% (0/18) of controls, 100% (8/8) of RCCs, 35% (7/20) of müllerian carcinomas, and 2% (1/41) of non-müllerian carcinomas. PAX8 stained 6% (1/18) of control cases, 100% (9/9) of RCC cases, 100% (20/20) of müllerian carcinomas, and 5% (2/41) of non-müllerian carcinomas. PAX2 was 35% sensitive and 95% specific for müllerian carcinoma and 100% sensitive and 95% specific for RCC. PAX8 was 100% sensitive and 95% specific for müllerian carcinoma and 100% sensitive and 95% specific for RCC. CONCLUSIONS: PAX8 is more sensitive than PAX2 for metastatic effusions from müllerian carcinomas (100 vs. 35%), while also having a higher intensity of staining than PAX2. However, PAX2 and PAX8 are both highly sensitive and specific for RCCs. PAX2 and PAX8 are valuable diagnostic markers for metastatic müllerian carcinomas and RCCs in effusion cytology. PAX8 is superior for carcinomas of müllerian origin.

Sporadic hemangioblastoma of the kidney with PAX2 and focal CD10 expression: report of a case.

In this study, we presented an additional case of renal hemangioblastoma, which demonstrates PAX2 and focal CD10 expression. Histologically, the tumor consisted of sheets of oval or polygonal cells and a prominent vascular network. The tumor cells varied in size, and possessed pale or eosinophilic cytoplasm that sometimes contained sharply delineated fine vacuoles. The tumor cell nuclei with inconspicuous nucleoli showed moderate nuclear atypia and pleomorphism. Focal areas of stromal hyalinization and sclerosis were detected. On account of its strong or moderate immunoreactivity for the a-inhibin, S100, NSE, and EGFR, the diagnosis of renal hemangioblastoma was established. For further evidence of VHL deficiency, the tumor was subjected to VHL sequence analysis of all three exons and fluorescence in situ hybridization (FISH) detection for chromosome 3p deletion. None of the VHL gene mutations and chromosome 3p deletion was detected in the tumor. Because of several shared morphological and immunophenotypic features, renal hemangioblastoma may be underrecognized and should be included in the differential diagnosis of primary renal tumors, in particular clear cell renal cell carcinoma. The unexpected positive staining of PAX2 and CD10 in renal hemangioblastoma should be particular concerned. Using a combination of immunoprofile may be helpful to the differential diagnosis of these renal tumors.

Fallopian tube intraluminal tumor spread from noninvasive precursor lesions: a novel metastatic route in early pelvic carcinogenesis.

Pelvic serous carcinoma is usually advanced stage at diagnosis, indicating that abdominal spread occurs early in carcinogenesis. Recent discovery of a precursor sequence in the fallopian tube, culminating in serous tubal intraepithelial carcinoma (STIC), provides an opportunity to study early disease events. This study aims to explore novel metastatic routes in STICs. A BRCA1 mutation carrier (patient A) who presented with a STIC and tubal intraluminal shedding of tumor cells upon prophylactic bilateral salpingo-oophorectomy (PBSO) instigated scrutiny of an additional 23 women who underwent a PBSO and 40 patients with pelvic serous carcinoma involving the tubes. Complete serial sectioning of tubes and ovaries of patient A did not reveal invasive carcinoma, but subsequent staging surgery showed disseminated abdominal disease. STIC, intraluminal tumor cells, and abdominal metastases displayed an identical immunohistochemical profile (p53/WT1/PAX8/PAX2) and TP53 mutation. In 16 serous carcinoma patients (40%) tubal intraluminal tumor cells were found, compared with none in the PBSO group. This is the first description of a STIC, which plausibly metastasized without the presence of invasion through intraluminal shedding of malignant surface epithelial cells in the tube and subsequently spread throughout the peritoneal cavity. These findings warrant a reconsideration of the malignant potential of STICs and indicate that intraluminal shedding could be a risk factor for early intraperitoneal metastasis. Although rare in the absence of invasive cancer, we show that intraluminal shedding of tumor cells in the fallopian tubes from serous carcinoma cases are common and a likely route of abdominal spread.

Podocyte repopulation by renal progenitor cells following glucocorticoids treatment in experimental FSGS.

Prednisone is a mainstay of treatment for patients with focal segmental glomerulosclerosis (FSGS), a disease characterized by reduced podocyte number and glomerulosclerosis. Although the systemic immune-modulatory effects of prednisone are well-known, direct tissue effects on glomerular cells are poorly understood. Experimental FSGS was induced in mice with a cytotoxic anti-podocyte antibody, resulting in an abrupt decrease in podocyte number by day 3, proteinuria, and the development of glomerulosclerosis. Administering daily prednisone to mice with FSGS, beginning at day 3, significantly increased podocyte number at weeks 2 and 4. Podocyte number did not increase in control mice with FSGS given DMSO. The increase in podocyte number in prednisone-treated mice correlated significantly with reduced glomerulosclerosis. Prednisone reduced podocyte apoptosis measured by synaptopodin⁺/caspase-3⁺ double staining. Additionally, the number of podocyte progenitors, defined as cells expressing both a parietal epithelial cell protein and a podocyte protein, was significantly increased in prednisone-treated mice with FSGS at weeks 2 and 4. This was associated with increased phospho-ERK staining in both parietal epithelial cells (PAX2⁺/p-ERK⁺) and in podocyte progenitors (WT-1⁺/p-ERK⁺ lining Bowman's capsule). These data show that in this model of experimental FSGS, prednisone augments glomerular repair by increasing podocyte number through direct effects on both glomerular epithelial cells. Prednisone limits podocyte loss by reducing apoptosis, and it increases regeneration by augmenting the number of podocyte progenitors. The data support a direct glomerular cell action for prednisone in improving outcomes in FSGS.

Flat pattern of nephrogenic adenoma: previously unrecognized pattern unveiled using PAX2 and PAX8 immunohistochemistry.

Nephrogenic adenoma is a benign lesion of the urinary tract, particularly the urinary bladder. It is a gross and microscopic mimicker of urothelial neoplasm or metastatic carcinoma. Several histological patterns (tubular, tubulocystic, polypoid, papillary, fibromyxoid) have been recognized, but a flat pattern has not been described. Histologically, nephrogenic adenoma consists of tubules, cysts or papillae lined by flat to polygonal cells with frequent hobnail appearance. The stroma is often edematous or has a granulation tissue-like appearance with acute or chronic inflammation. By immunohistochemistry, nephrogenic adenomas are positive for renal epithelial markers CK7, CD10 and alpha-methylacyl-coenzyme A racemase, and negative for bladder urothelium or prostate markers. Recent studies have shown that nephrogenic adenomas are positive for PAX2 and PAX8. We encountered an interesting case of tubular nephrogenic adenoma with adjacent areas suspicious of flat urothelial atypia. Immunohistochemistry for PAX2 and PAX8 were positive in these areas, unveiling a flat pattern of nephrogenic adenoma. This case prompted us to study 15 cases of nephrogenic adenoma to determine additional instances of flat pattern and to assess the value of PAX2 and PAX8 immunoreactivity to diagnose nephrogenic adenoma. PAX2 and PAX8 immunostaining was positive in 14/15 and 15/15 cases, respectively. The flat pattern was present at least focally adjacent to tubular, polypoid and papillary areas, in 8/15 cases of nephrogenic adenoma. In conclusion, the flat pattern is a common finding in nephrogenic adenomas, but easily under recognized by morphologic examination and may be confused with flat urothelial lesions with atypia. Immunostains for PAX2 and PAX8 are useful in the detection of nephrogenic adenomas and particularly unveil those nephrogenic adenomas with flat pattern.

Value of PAX8, PAX2, claudin-4, and h-caldesmon immunostaining in distinguishing peritoneal epithelioid mesotheliomas from serous carcinomas.

Distinguishing between peritoneal epithelioid mesotheliomas and papillary serous carcinomas involving the peritoneum can be difficult on routine histological preparations, but this differential diagnosis can be facilitated by the use of immunohistochemistry. Recent investigations have indicated that PAX8, PAX2, claudin-4, and h-caldesmon are immunohistochemical markers that can assist in distinguishing between these two malignancies; however, much of the information published on the value of these markers is either insufficient or contradictory. The purpose of this study is to resolve some of the existing controversies and to fully determine the practical value of these markers for assisting in the differential diagnosis between peritoneal mesotheliomas and serous carcinomas. In order to do so, a total of 40 peritoneal epithelioid mesotheliomas and 45 serous carcinomas (15 primary, 30 metastatic to the peritoneum) were investigated. PAX8 and PAX2 nuclear positivity was demonstrated in 42 (93%) and 25 (56%) of the serous carcinomas, respectively, whereas none of the mesotheliomas expressed either marker. Forty-four (98%) of the serous carcinomas exhibited claudin-4 reactivity along the cell membrane, whereas none of the mesotheliomas were positive for this marker. All of the serous carcinomas and mesotheliomas were negative for h-caldesmon. Based on these results, it is concluded that PAX8 and claudin-4 have a higher sensitivity and specificity for assisting in discriminating between peritoneal epithelioid mesotheliomas and serous carcinomas when compared with all of the other positive carcinoma markers that are, at present, recommended to be included in the immunohistochemical panels used in this differential diagnosis. Even though it is highly specific, PAX2 has little practical value in the diagnosis of peritoneal epithelioid mesotheliomas as its sensitivity is low. The h-caldesmon is not useful.