5076

PAX2

paired box 2;PAX2;paired box 2

paired box homeotic gene 2|paired box protein Pax-2

10q24

protein-coding

PAX-2 is a homeogene expressed during kidney development. Although immunohistochemical expression of PAX-2 has been described in a variety of primary renal cell carcinoma (RCC) subtypes and in metastatic RCC, its specificity as a marker of renal lineage in a metastatic setting has not been fully evaluated. In addition, its utility has not been directly compared with the most widely used antibody in this setting, renal cell carcinoma marker (RCCma). We studied PAX-2 expression in metastatic clear cell renal cell carcinoma (CC-RCC) and in a variety of nonrenal neoplasms with clear cytoplasm that may potentially mimic CC-RCC. Archival material from 27 CC-RCCs metastatic to various organs and 50 close morphologic mimics of CC-RCC were retrieved. Immunohistochemistry with PAX-2 and RCCmapi antibodies was performed on each case. Nuclear staining (PAX-2) or membranous staining (RCCma) was scored semiquantitatively. Twenty-three of 27 (85%) metastatic CC-RCCs showed nuclear immunoreactivity for PAX-2, whereas RCCma reactivity was found in 19 of 27 (70%). The immunoprofiles of the metastatic CC-RCC were PAX-2+/RCCma+: 19 of 27 (70%), PAX-2+/RCCma-: 5 of 27 (19%), PAX-2-/RCCma+: 2 of 27 (7%), and PAX-2-/RCCma-: 1 of 27 (4%). Five of the 50 mimics of CC-RCC (10%) had at least focal nuclear reactivity with PAX-2, including 1 of 3 parathyroid carcinomas (33%), 3 of 7 clear cell carcinomas of the ovary (43%), and the 1 clear cell papillary cystadenoma of the epididymis. Membranous RCCma reactivity was identified in 26 of the 50 mimics (52%). We conclude that PAX-2 is a useful marker for distinguishing metastatic CC-RCC from its potential morphologic mimics, but caution must be used in certain differential diagnostic settings where nonrenal tumors such as parathyroid carcinoma, ovarian clear cell carcinoma, and clear cell papillary cystadenoma of the epididymis were shown to express both PAX-2 and RCCma.

PAX2 and PAX8 are transcription factors that are essential in embryonic development of mullerian organs. They may also play a role in tumor development in these organs. The diagnostic utility of PAX2 and PAX8 relative to one another has not been comprehensively studied. Archival tissue samples for normal or non-neoplastic tissue (251), primary epithelial neoplasms (316 for PAX2 and 357 for PAX8), and metastatic epithelial neoplasms (16), all of mullerian origin, were subjected to PAX2 and PAX8 immunostaining. The staining frequency, extent, and intensity for these markers were compared. Virtually identical PAX2 and PAX8 expressions were noted in non-neoplastic tissue. They were constantly seen in most epithelial cells (but not in stromal cells) of the endocervix, endometrium, fallopian tube, paratubal cyst, endosalpingiosis, endometriosis, and endometrial polyp. Within the primary epithelial neoplasms, PAX2 and PAX8 expression was noted in 55% and 98% of serous tumors, 25% and 94% of endometrioid tumors, 19% and 100% of clear cell tumors, 11% and 67% of transitional/undifferentiated tumors, and 10% and 22% of mucinous tumors, respectively. Regardless of histologic subtypes, PAX2 staining was noted in fewer cells and with less staining intensity compared with PAX8. No tumor showed only PAX2 staining. Within the metastatic carcinomas, PAX2 and PAX8 expression was noted in 38% and 98% of cases, respectively, with a diffuse and strong staining for PAX8, contrasting with a patchy and weak PAX2 expression. PAX2 and PAX8 are constantly expressed in normal or non-neoplastic tissue of mullerian origin. For primary and metastatic mullerian epithelial tumors, PAX8 shows strong and diffuse staining in most cases of all histologic subtypes, except in mucinous tumors. In contrast, PAX2 expression is always less than PAX8, and exclusive staining for PAX2 is not seen. PAX8 supersedes PAX2 as probably the best epithelial marker hitherto for primary or metastatic mullerian epithelial tumors.

PAX transcription factors play an important role during development and carcinogenesis. In this study, we investigated PAX2 protein levels in melanocytes and melanoma cells by Western Blot and immunofluorescence analysis and characterized the role of PAX2 in the pathogenesis of melanoma. In vitro we found weak PAX2 protein expression in keratinocytes and melanocytes. Compared to melanocytes increased PAX2 protein levels were detectable in melanoma cell lines. Interestingly, in tissue sections of melanoma patients nuclear PAX2 expression strongly correlated with nuclear atypia and the degree of prominent nucleoli, indicating an association of PAX2 with a more atypical cellular phenotype. In addition, with chromatin immunoprecipitation assay, PAX2 overexpression and PAX2 siRNA we present compelling evidence that PAX2 can regulate ADAM10 expression, a metalloproteinase known to play important roles in melanoma metastasis. In human tissue samples we found co-expression of PAX2 and ADAM10 in melanocytes of benign nevi and in melanoma cells of patients with malignant melanoma. Importantly, the downregulation of PAX2 by specific siRNA inhibited the anchorage independent cell growth and decreased the migratory and invasive capacity of melanoma cells. Furthermore, the downregulation of PAX2 abrogated the chemoresistance of melanoma cells against cisplatin, indicating that PAX2 expression mediates cell survival and plays important roles during melanoma progression.

PAX2 and PAX8 are transcription factors that are essential in embryonic development of mullerian organs. They may also play a role in tumor development in these organs. The diagnostic utility of PAX2 and PAX8 relative to one another has not been comprehensively studied. Archival tissue samples for normal or non-neoplastic tissue (251), primary epithelial neoplasms (316 for PAX2 and 357 for PAX8), and metastatic epithelial neoplasms (16), all of mullerian origin, were subjected to PAX2 and PAX8 immunostaining. The staining frequency, extent, and intensity for these markers were compared. Virtually identical PAX2 and PAX8 expressions were noted in non-neoplastic tissue. They were constantly seen in most epithelial cells (but not in stromal cells) of the endocervix, endometrium, fallopian tube, paratubal cyst, endosalpingiosis, endometriosis, and endometrial polyp. Within the primary epithelial neoplasms, PAX2 and PAX8 expression was noted in 55% and 98% of serous tumors, 25% and 94% of endometrioid tumors, 19% and 100% of clear cell tumors, 11% and 67% of transitional/undifferentiated tumors, and 10% and 22% of mucinous tumors, respectively. Regardless of histologic subtypes, PAX2 staining was noted in fewer cells and with less staining intensity compared with PAX8. No tumor showed only PAX2 staining. Within the metastatic carcinomas, PAX2 and PAX8 expression was noted in 38% and 98% of cases, respectively, with a diffuse and strong staining for PAX8, contrasting with a patchy and weak PAX2 expression. PAX2 and PAX8 are constantly expressed in normal or non-neoplastic tissue of mullerian origin. For primary and metastatic mullerian epithelial tumors, PAX8 shows strong and diffuse staining in most cases of all histologic subtypes, except in mucinous tumors. In contrast, PAX2 expression is always less than PAX8, and exclusive staining for PAX2 is not seen. PAX8 supersedes PAX2 as probably the best epithelial marker hitherto for primary or metastatic mullerian epithelial tumors.

Ovarian serous papillary carcinoma, although rarely metastasizing to the breast, is often challenging based on morphology alone, particularly from the micropapillary variant of breast carcinoma. Gross cystic disease fluid protein-15, although a specific marker, can be negative in up to 50% of breast carcinomas. Wilms tumor gene 1 (WT-1) has been identified as a useful marker to differentiate metastatic ovarian serous papillary carcinoma from primary breast carcinoma; however, it has recently been shown in the micropapillary variant of the primary breast carcinoma making it a less specific marker. PAX 2, a nuclear transcription factor, was recently observed in ovarian serous papillary carcinomas. In this study of 89 breast carcinoma cases, 26 micropapillary carcinoma, and 63 nonmicropapillary carcinoma types were retrieved from our pathology archives, represented on a single tissue microarray (TMA) with a 3-fold redundancy (TMA-1, TMA-2). In addition, whole tissue sections of a variety of benign and neoplastic mullerian tissues were surveyed with the PAX 2 immunostain. All cases were stained with rabbit polyclonal PAX 2 antibody and, in addition, the 5 metastatic ovarian serous carcinoma cases were stained with WT-1 as well for comparison. Only nuclear staining was considered positive. All primary breast carcinomas represented on TMA-1 and TMA-2 were entirely negative for PAX 2 100% (89/89), whereas 100% (5/5) of all metastatic ovarian serous carcinomas showed moderate-to-strong staining. PAX 2 expression was comparable with WT-1 as well in the metastatic ovarian serous carcinoma group. We therefore conclude that PAX 2 is a promising new, sensitive, and specific mullerian immunomarker for ovarian serous carcinomas (primary and metastatic).

BACKGROUND: metastasis is a consequence of many biological events, during which cancer stem cells are shifted into a malignant state. Among these events, invasion of prostate cancer cells into host tissues is possible to be assessed by means of an in vitro invasion model, and is thought to be coupled to altered expression of membrane proteins. Dysregulated functions of the factors regulating organogenesis during embryogenesis are known to facilitate metastasis of many types of cancers. PAX2 (paired box 2) is a member of the PAX transcription factor family, which regulates prostatic ductal growth and branching in organogenesis of mammalian prostates. However, the role of PAX2 in prostate cancer development remains to be determined. METHODS: PAX2 expression in human prostate cancers and normal prostate epithelium were examined by quantitative RT-PCR and immunohistochemistry. Matrigel invasion assay and a gene array analysis were performed using prostate cancer cell lines transfected with either control or PAX2 siRNA. RESULTS: In human prostate cancers, PAX2 was hyper-expressed in metastatic cancers, but was expressed at lower levels in non-metastatic cancers. Consistent with this, PAX2 knockdown repressed cell growth and invasion in a Matrigel invasion assay. Gene ontology analysis revealed that many cell membrane proteins were downregulated after PAX2 knockdown. CONCLUSIONS: Our data suggested that PAX2 hyper-expression promotes the development of the metastatic state in prostate cancer cells, presumably through upregulating the expression of cell membrane proteins.

PAX-2 is a homeogene expressed during kidney development. Although immunohistochemical expression of PAX-2 has been described in a variety of primary renal cell carcinoma (RCC) subtypes and in metastatic RCC, its specificity as a marker of renal lineage in a metastatic setting has not been fully evaluated. In addition, its utility has not been directly compared with the most widely used antibody in this setting, renal cell carcinoma marker (RCCma). We studied PAX-2 expression in metastatic clear cell renal cell carcinoma (CC-RCC) and in a variety of nonrenal neoplasms with clear cytoplasm that may potentially mimic CC-RCC. Archival material from 27 CC-RCCs metastatic to various organs and 50 close morphologic mimics of CC-RCC were retrieved. Immunohistochemistry with PAX-2 and RCCmapi antibodies was performed on each case. Nuclear staining (PAX-2) or membranous staining (RCCma) was scored semiquantitatively. Twenty-three of 27 (85%) metastatic CC-RCCs showed nuclear immunoreactivity for PAX-2, whereas RCCma reactivity was found in 19 of 27 (70%). The immunoprofiles of the metastatic CC-RCC were PAX-2+/RCCma+: 19 of 27 (70%), PAX-2+/RCCma-: 5 of 27 (19%), PAX-2-/RCCma+: 2 of 27 (7%), and PAX-2-/RCCma-: 1 of 27 (4%). Five of the 50 mimics of CC-RCC (10%) had at least focal nuclear reactivity with PAX-2, including 1 of 3 parathyroid carcinomas (33%), 3 of 7 clear cell carcinomas of the ovary (43%), and the 1 clear cell papillary cystadenoma of the epididymis. Membranous RCCma reactivity was identified in 26 of the 50 mimics (52%). We conclude that PAX-2 is a useful marker for distinguishing metastatic CC-RCC from its potential morphologic mimics, but caution must be used in certain differential diagnostic settings where nonrenal tumors such as parathyroid carcinoma, ovarian clear cell carcinoma, and clear cell papillary cystadenoma of the epididymis were shown to express both PAX-2 and RCCma.

CONTEXT: The diagnosis of metastatic renal cell carcinoma (RCC) remains problematic. OBJECTIVE: To evaluate the role of PAX-2, a renal tubular cell transcription factor, in the diagnosis of metastatic RCC. PAX-2 expression in metastatic RCC was compared with that of the renal cell carcinoma marker antigen (RCCM) and kidney-specific cadherin (KSC), which are 2 known markers for RCC. DESIGN: Immunostaining for PAX-2, RCCM, and KSC was performed on consecutive tissue sections of 95 metastatic RCCs (77 clear cell, 8 papillary, 5 sarcomatoid, and 5 collecting duct) and 183 metastatic tumors other than RCC. RESULTS: For PAX-2, positive immunoreactivity was detected in 77% clear cell, 75% papillary, 100% collecting duct, and 0% sarcomatoid metastatic RCCs. For RCCM, positive immunoreactivity was detected in 49% clear cell, 75% papillary, 0% collecting duct, and 0% sarcomatoid metastatic RCCs. For KSC, only 2 metastatic clear cell RCCs (3%) were positive. In combination, all markers were positive in 0% of cases; all markers were negative in 23% of cases (17 clear cell, 1 papillary, and for all 5 sarcomatoid); and at least 1 marker was positive in 76% of cases (PAX-2 only in 28% of cases [21 clear cell, 1 papillary, and 5 collecting duct] and RCCM only in 3% of cases [2 clear, 1 papillary]). Of 183 metastatic tumors other than RCC, 14 were positive for PAX-2 (nodal metastasis of carcinoma of colon [1], breast [1], endometrium [1], and ovary [1]; and omental metastasis of carcinoma of uterus or ovary [10]). CONCLUSIONS: PAX-2 is a sensitive and specific marker for metastatic RCC. The diagnostic yield would be marginally increased by adding RCCM, but not KSC, as an immunomarker.

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), mullerian carcinoma (21 cases) or non-mullerian carcinoma (41 cases). RESULTS: PAX2 stained 0% (0/18) of controls, 100% (8/8) of RCCs, 35% (7/20) of mullerian carcinomas, and 2% (1/41) of non-mullerian carcinomas. PAX8 stained 6% (1/18) of control cases, 100% (9/9) of RCC cases, 100% (20/20) of mullerian carcinomas, and 5% (2/41) of non-mullerian carcinomas. PAX2 was 35% sensitive and 95% specific for mullerian carcinoma and 100% sensitive and 95% specific for RCC. PAX8 was 100% sensitive and 95% specific for mullerian carcinoma and 100% sensitive and 95% specific for RCC. CONCLUSIONS: PAX8 is more sensitive than PAX2 for metastatic effusions from mullerian 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 mullerian carcinomas and RCCs in effusion cytology. PAX8 is superior for carcinomas of mullerian origin.