Hepatocyte nuclear factor-1β expression in clear cell adenocarcinomas of the bladder and urethra: Diagnostic utility and implications for histogenesis

Department of Pathology, Johns Hopkins Hospital Medical Institutions, Baltimore, MD 21287, USA.
Human pathology (Impact Factor: 2.77). 04/2011; 42(11):1613-9. DOI: 10.1016/j.humpath.2011.01.007
Source: PubMed


The histogenesis of clear cell adenocarcinoma of the bladder/urethra is uncertain. Hepatocyte nuclear factor-1β is a homeodomain protein that has been reported to be frequently overexpressed in ovarian clear cell adenocarcinoma in comparison with rare or no expression in other types of epithelial ovarian tumors. We assessed the expression of hepatocyte nuclear factor-1β in a series of 18 clear cell adenocarcinomas of the bladder and urethra and compared it with that of invasive high-grade transitional/urothelial carcinoma (n = 35); adenocarcinomas of the bladder, urethra, and paraurethral glands (n = 21); as well as nephrogenic adenomas of the bladder (n = 8). Staining intensity and extent were evaluated using a 4-tiered grading system (0-3). A case was considered positive for hepatocyte nuclear factor-1β if 10% or more of tumor cells showed at least weak nuclear staining or if any moderate or strong nuclear staining was observed. All 18 clear cell adenocarcinomas exhibited nuclear staining in at least 50% of tumor cells (16 strong, 1 moderate, and 1 weak with focal strong nuclear staining) in comparison with positive nuclear staining (moderate) in 1 of 21 bladder adenocarcinoma, 1 of 35 invasive high-grade transitional/urothelial carcinoma (weak to moderate staining), and 2 of 8 nephrogenic adenomas (1 weak and 1 moderate to strong staining). We concluded that hepatocyte nuclear factor-1β is a useful marker in differentiating clear cell adenocarcinomas of the bladder/urethra from invasive high-grade transitional/urothelial carcinoma and other types of bladder adenocarcinomas and to a lesser extent from nephrogenic adenomas. Hepatocyte nuclear factor-1β is of no diagnostic utility in discriminating primary bladder/urethral clear cell adenocarcinomas from metastatic clear cell adenocarcinomas of the female genital tract to the bladder/urethra. From a histogenesis standpoint, although the expression of hepatocyte nuclear factor-1β in both gynecologic and urologic tract clear cell adenocarcinomas may point to a Müllerian derivation/differentiation, this immunohistochemical evidence is insufficient to completely exclude an urothelial association.

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    • "Hepatocyte nuclear factor-1β was tested in clear cell adenocarcinomas of the bladder and urethra by Brimo and colleagues in 18 cases and was found to be a useful marker in differentiating clear cell adenocarcinomas from invasive high-grade urothelial carcinoma and other types of bladder adenocarcinomas [14]. It would be interesting to apply the marker to clear cell urothelial carcinoma to learn about the staining pattern of the tumor and, possibly, for diagnostic utility. "
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    ABSTRACT: Introduction The occurrence of clear cell tumors in the bladder is not uncommon. Clear cell dysplasia is well-described and characterized by focal replacement of transitional mucosa by cells with abundant clear cytoplasm, nuclear enlargement, and a granular chromatin pattern. Clear cells can also be seen in clear cell adenocarcinoma, which is rare, comprising 0.5% to 2.0% of the reported bladder carcinomas. Other clear cell tumors found in the bladder to be considered in the differential diagnosis are tumors of Müllerian origin and metastatic lesions, such as renal cell carcinoma, clear cell sarcoma, and malignant melanoma. Clear cell urothelial carcinoma is exceedingly rare, with only nine clinical cases described in the literature. Case presentation We report the case of a 75-year-old Caucasian man who presented with intermittent hematuria, in whom a bladder tumor was identified. A final histopathology examination of a cystoprostatectomy specimen revealed a pT3b, G3 urothelial carcinoma of clear cell type (>90% clear cells) and a prostatic adenocarcinoma of Gleason grade 3+3 (score=6). The bladder tumor consisted of sheets of malignant cells with severe nuclear atypia and abundant clear cytoplasm; no glandular or tubular structures were identified. Tumor cells were periodic acid-Schiff positive and negative after diastase treatment; additional mucicarmine and oil red O stains were negative. Immunohistochemical stains showed the tumor cells positive for cytokeratin 7 (CK7), p63 (>80% nuclei), p53 (about 30% nuclei), vimentin, E-cadherin, cluster of differentiation (CD10), and Ki-67 (>70% nuclei). Stains for cell adhesion molecule 5.2 (CAM 5.2), CD117, cytokeratin 20 (CK20), human melanoma black 45 (HMB-45), paired box protein (PAX 8), placental alkaline phosphatase (PLAP), prostate specific antigen (PSA), renal cell carcinoma (RCC), cancer antigen 25 (CA25), leukocyte common antigen (LC), S-100 protein, and uroplakin III were all negative. Conclusions The tumor marker profile was consistent with clear cell type carcinoma of urothelial origin. Within the differential diagnoses, we ruled out other possible tumor types such as urothelial carcinoma with focal clear cell differentiation, clear cell adenocarcinoma, Müllerian tumors, and metastatic disease.
    Journal of Medical Case Reports 08/2014; 8(1):275. DOI:10.1186/1752-1947-8-275
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    • "Summary of immunohistochemical stains in the differential diagnosis of clear cell adenocarcinoma in the urinary tract [5, 6, 10–14]. "
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    ABSTRACT: Carcinoma of the renal pelvis is an uncommon renal neoplasm. Clear cell adenocarcinoma in the urinary tract is rare and has a histomorphology resembling that of the female genital tract. We herein present a case of clear cell adenocarcinoma of the renal pelvis, which is the first example in a male patient to our knowledge. A 54-year-old man presented with right flank pain. The tumor was associated with renal stones and hydronephrosis and invaded into the peripelvic fat tissue with regional lymph node metastasis. The patient died of metastatic disease six months postoperatively. Histologically, the tumor showed complex papillary architecture lined with clear and hobnail cells. Clear cell adenocarcinoma of the renal pelvis may pose a diagnostic challenge on histological grounds, particularly in the distinction from renal cell carcinoma. The immunohistochemical stains could help confirm the diagnosis. Due to its rarity, an effective treatment regimen remains to be determined.
    12/2013; 2013:494912. DOI:10.1155/2013/494912
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    • "Overexpressed in ovarian clear cell adenocarcinoma (OCCC); reduction of HNF-1β expression by RNA interference induces apoptotic cell death in ovarian OCCC cells; HNF-1β is hypomethylated in OCCC and can thus be targeted in ovarian cancers. [276] [277] [278] [279] [280] HE4 A glycoprotein highly expressed in ovarian cancers that might have a role in ovarian carcinogenesis; HE4 expression is highest in endometrioid and serous ovarian cancer [214] [281] [282] OPN A glycophosphoprotein cytokine secreted by activated T-lymphocytes, macrophages, and leukocytes at the inflammation site; higher levels occur in patients with ovarian cancer versus normal control; correlates significantly with tumor response to surgery, chemotherapy, and disease recurrence; implicated in tumorigenesis, tumor invasion, metastasis, and poor prognosis; binding of OPN as an ECM component to integrin and CD44 receptors in the tumor microenvioronment regulates signaling cascades associated with adhesion, migration, invasion, chemotaxis, and cell survival; alternative splicing of OPN leads to 3 isoforms, OPNa, OPNb, and OPNc; the latter possess ovarian protumorigenic properties mediated by PI3K/Akt signaling pathway which serves as a critical cancer molecular target. [14, 111, 283– 285] MES Binding of MUC16 to MES, a GPI-anchored glycoprotein, is thought to facilitate cell adhesion and peritoneal metastasis of ovarian tumors; this function can be exploited as a molecular targeting strategy, for example, anti-MES antibodies, to limit the metastatic spread of the tumor; MES is an attractive candidate for adenoviruses-mediated gene therapy of ovarian cancers; diffuse mesothelin expression is associated with prolonged survival in patients with high-grade ovarian serous carcinoma. "
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    ABSTRACT: The hallmarks of ovarian cancer encompass the development of resistance, disease recurrence and poor prognosis. Ovarian cancer cells express gene signatures which pose significant challenges for cancer drug development, therapeutics, prevention and management. Despite enhancements in contemporary tumor debulking surgery, tentative combination regimens and abdominal radiation which can achieve beneficial response rates, the majority of ovarian cancer patients not only experience adverse effects, but also eventually relapse. Therefore, additional therapeutic possibilities need to be explored to minimize adverse events and prolong progression-free and overall response rates in ovarian cancer patients. Currently, a revival in cancer drug discovery is devoted to identifying diagnostic and prognostic ovarian cancer biomarkers. However, the sensitivity and reliability of such biomarkers may be complicated by mutations in the BRCA1 or BRCA2 genes, diverse genetic risk factors, unidentified initiation and progression elements, molecular tumor heterogeneity and disease staging. There is thus a dire need to expand existing ovarian cancer therapies with broad-spectrum and individualized molecular targeted approaches. The aim of this review is to profile recent developments in our understanding of the interrelationships among selected ovarian tumor biomarkers, heterogeneous expression signatures and related molecular signal transduction pathways, and their translation into more efficacious targeted treatment rationales.
    Journal of Oncology 02/2012; 2012(6):737981. DOI:10.1155/2012/737981
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