Metastasis Of Urothelial Carcinoma Research Articles

Non-Muscle Invasive Papillary Urothelial Carcinoma Metastatic to the Mandible.

Urothelial carcinoma, the most common histologic subtype of bladder cancer in the United States, most frequently presents as non–muscle invasive disease. Initially, therapy involves transurethral endoscopic resection and subsequent intravesical therapies with extended surveillance for high-risk disease. Even with the best treatments, recurrence and progression can occur. However, metastasis of non–muscle invasive bladder cancer to distant sites without evidence of progression or regional metastasis is rare. In this article, we present the case of a patient with high-grade papillary urothelial carcinoma who developed an unusual metastasis to the mandible, confirmed by GATA-3 immunostaining, over 4 years after initial transurethral resection. Prior to the development of metastatic disease, this patient had no evidence of local recurrence during maintenance Bacillus Calmette-Guerin intravesical therapy and concurrent surveillance. Positron emission tomography-computed tomography taken after presentation with mandibular metastasis did not show any evidence of regional metastasis. This case highlights an unusual location for distant metastasis of urothelial carcinoma occurring in a patient without evidence of muscle invasive disease or regional metastasis. We additionally highlight the utility of GATA-3 immunostaining in identifying urothelial carcinoma histologically.

To oophorectomy or not to oophorectomy: Practice patterns among urologists treating bladder cancer

ObjectivesClassically, radical cystectomy (RC) involves hysterectomy and bilateral salpingo-oophorectomy (BSO). Current understanding of ovarian cancer pathogenesis and effect of premature oophorectomy has lead to a shift within gynecology toward risk-reducing salpingectomy without oophorectomy in the absence of gynecologic malignancy. The purpose of this study was to assess knowledge base and practice patterns of urologic oncologists with regard to management of the gynecological organs at the time of RC. Materials and methodsAn anonymous and voluntary electronic survey was distributed to members of the Society of Urologic Oncology (SUO). Demographic data, training, practice setting and duration, experience, rationale for BSO, and knowledge assessment of ovarian cancer pathogenesis/risks associated with BSO was collected. ResultsA total of 159/660 (24%) SUO members responded of whom 110 (69%) were academic urologists and 58 (36%) involved in training urologic oncology fellows. Of all, 75% had performed an ovarian-sparing RC. Furthermore, 14% were aware that salpingectomy alone reduces the risk of ovarian cancer, whereas 95%, 66%, and 26% were aware that BSO increases the risk of osteoporosis, cardiovascular disease, and all-cause mortality, respectively. Reasons for BSO at the time of RC included concern for urothelial carcinoma metastasis (54%), development of future gynecologic pathology (50%), and facilitation of pelvic lymph node dissection (36%). ConclusionsMany urologic oncologists remain unaware of the benefits of risk-reducing salpingectomy and the risks associated with BSO, identifying a potential area for further education in the urologic community.

Nested variant of urothelial carcinoma metastatic to the parotid gland

Parotid metastasis from urothelial carcinoma is extremely rare. We present an example of a nested variant of urothelial carcinoma metastasis to the parotid with well‐documented cyto‐ and histomorphologic features.

Expression of GFRα3 correlates with tumor progression and promotes cell metastasis in urothelial carcinoma.

Urothelial carcinoma (UC) is a major health problem in the general population. We aimed to evaluate the function of GFRα3 and unravel its underlying molecular mechanism to develop novel treatment options equivalent to UC. To evaluate the function of GFRα3, a group of 60 pairs of UC patients were recruited in for this study. UC tissues and their adjacent normal control tissues (NCTs) were collected between 2012 and 2015. We used immunohistochemistry to analyze the correlation between GFRα3 expression and clinicopathologic variables and patient survival. The role of regulation of GFRα3 in UC was applied in vitro. In addition, we further investigated the signaling pathway of GFRα3 in UC progression. The expression level of GFRα3 was remarkably upregulated in 49.3% (19/60) patients and downregulated in 25.0% (15/60) patients. The GFRα3 protein expression was upregulated in UC tissues. GFRα3 promotes UC cell migration and invasion in vitro. GFRα3 also promotes UC cell metastasis in vitro. High level of GFRα3 promotes UC cell migration via upregulation of MMP9 expression. Our results demonstrate that increased GFRα3 expression is significantly correlated with poor prognosis of patients with UC. Thus, GFRα3 might be an important marker and a therapeutic target for UC.

A combination of p40, GATA-3 and uroplakin II shows utility in the diagnosis and prognosis of muscle-invasive urothelial carcinoma

Recently developed antibodies against uroplakin II and ΔNp63 (p40) show utility in diagnosing primary bladder urothelial carcinoma, although application in metastatic bladder cancer and patient outcomes has been less well defined. We evaluated these antibodies by immunostain intensity and H-score, in conjunction with GATA-3 immunoreactivity, in 89 patients with muscle-invasive urothelial carcinoma and 35 paired metastasis. The maintenance of immunoreactivity in metastatic lesions and the association to disease recurrence and survival was assessed. Bladder urothelial carcinoma showed immunoreactivity for GATA-3 in 99% (88/89), p40 in 87% (77/89) and uroplakin II in 80% (71/89) of cases, with a positive correlation between GATA-3 and uroplakin II H-score (0.44; p<0.0001). All lesions were positive for at least one marker, reinforcing the use of these markers as a panel. In 35 patients with paired lymph node metastasis, uroplakin II and GATA-3 were retained in 90% and 75% of patients, respectively, suggesting these markers may have relatively high sensitivity in diagnosing metastatic urothelial carcinoma. High intensity p40 immunostain (3+), however, was significantly associated with reduced patient survival (p=0.03). These results suggest that whereas GATA-3 and uroplakin II may be most useful in the diagnosis of urothelial carcinoma metastasis, p40 may be additionally suited as a prognostic marker.

Abstract 1616: Galectin-4 interferes with the integrin β4/Src/FAK cascade and attenuates metastasis in urothelial carcinoma

Abstract Galectin-4 (Gal-4), a multifunctional lectin, is presented at both intracellular and extracellular sites. Recent studies have shown that Gal-4 plays certain role in attenuating cancer progression and metastasis. We have also observed that patients with urothelial carcinoma (UC) with the lower Gal-4 expression were at higher grade and stage. In addition, the Gal-4 expression is inversely associated with lymph node invasion and prognosis. Since how Gal-4 attenuates the cancer metastasis in UC has not been well investigated, the goal of the present study is to understand the role of Gal-4 in UC progression. We ectopically expressed Gal-4 in UC cells and found that increased Gal-4 significantly inhibits cell proliferation, colony formation, migration, and invasion. We also demonstrated that Gal-4 overexpression leads to a significant decrease the adhesion of UC cells to the basement membrane substrate laminin. Mechanistically, we found that Gal-4 overexpression significantly reduces the expression of the laminin receptor integrin α6β4. Besides to downregulation of integrin β4, Gal-4 overexpression also reduces phosphorylation of Src and focal adhesion kinase (FAK) and promotes anoikis. Together, the present results revealed that Gal-4 reduces the metastasis activity of UC cells by interfering integrin β4/Src/FAK cascade, which are of essential to prevent the suspended cells from anoikis. These results suggest that Gal-4 could be considered as a pivotal factor in the migration and invasion of UC cells. Key words: Galectin-4, integrin β4, migration, invasion, metastasis, anoikis, urothelial cancer Citation Format: Li-Fang Lin, Meei-Maan Wu, Te-Chang Lee. Galectin-4 interferes with the integrin β4/Src/FAK cascade and attenuates metastasis in urothelial carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1616.

18F-FDG PET/CT Findings of Metastasis to Spongy Body of Penis From Urothelial Carcinoma of Bladder

The spongy body of the penis metastasis from other primary sites is a rare clinical entity. It is frequently associated with widespread metastatic disease and poor prognosis clinically. We report a case of a 61-year-old man with a previous history of cystectomy due to infiltrating urothelial carcinoma of the bladder 12 months ago and presented with penile shaft swelling pain and hematuria for 3 months. The restaging F-FDG PET/CT scan demonstrated a hypermetabolic mass at his penile shaft. This lesion was confirmed on phallectomy to be infiltrating urothelial carcinoma metastasis from the known primary bladder tumor.

Identification of novel immunomodulatory tumor biology through comprehensive characterization of a metastases-specific epigenome in patients with metachronous primary and metastatic urothelial carcinoma (UC) tumor pairs.

452 Background: The Cancer Genome Atlas project identified a distinct cluster of hypermethylated muscle-invasive UC tumors in one third of patients. It is unknown if this epigenetic biology persists or changes in UC metastases. The present study aimed to identify uniquely hypermethylated regions in UC metastases compared to their matched primary tumors. Methods: UC patients with paired formalin fixed paraffin embedded tissue samples ( &gt; 75% tumor) from primary and metachronous metastatic tumors were identified. DNA methylation was analyzed on the Illumina HiSeq platform by double-enzyme reduced representation bisulfite sequencing (dRRBS). Results were analyzed by BS-seq within BSmooth open source software. Alignment and methylation estimation was done using Bismark open source software. CpG regions with coverage &lt; 2 in more than 66% of samples were removed to reduce false positive results. Differentially methylated regions (DMRs) in metastases compared to primary tumors were determined by paired t-test. Gene set enrichment analysis (GSEA) of the top 5% DMRs was performed utilizing multiple gene set collections including c7IMMUNO. A false discovery rate of &lt; 10% defined significant DMRs. Results: 15 UC primary/metachronous metastases pairs were analyzed. After filtering for low coverage, 1,781,762 loci remained for analysis. After merging loci within 2500 bp of each other, the top 5% DMRs resulted in 18,452 DMRs. GSEA including the c7IMMUNO gene set identified multiple previously undescribed hypermethylated genes modulating immune function through TGF-beta and Treg signaling including: TGFBR2, TGFBR3, SMAD1, SMAD3, SMAD4, BACH1, BACH2, and VDR all q &lt; 0.05. Conclusions: We identified numerous genes with immunomodulatory functions significantly hypermethylated in UC metastases compared to their matched primary tumors. Our findings provide rationale to examine epigenetic approaches as a means to improve clinical outcomes of UC patients treated with immunotherapy. Our small sample size limits definitive conclusions and warrants validation in independent data sets.

Concomitant Occurrence of Psoas Muscle and Splenic Metastasis from Squamous Cell Carcinoma of the Urinary Bladder: A Case Report

Introduction: Skeletal muscle is a rare localization of bladder cancer metastasis. Very few cases of urothelial carcinoma metastasis in psoas muscle were reported in the literature. We report concomitant psoas muscle tumor metastasis and splenic metastasis originated from urinary bladder squamous cell carcinoma. This association was never, described in earlier medical literature. Case report: The patient was 45 years old Moroccan male. He underwent trans-urethral bladder tumor resection (TURB). The diagnosis was done a month earlier in the emergency department while consulting for side pain and right leg swelling. The patient was feverish and showed an advanced general state deterioration. The CT-scan revealed a typical aspect of right psoas abscess associating a metastatic splenic localization. The ultrasound of the right leg showed an extended thrombophlebitis. The patient underwent a surgical drainage of psoas abscess and biopsies. The histopathological and immunohistochemistry studies demonstrated squamous carcinoma of the psoas muscle with very low differentiation. These tumors were originated from metastasis of this abscess. Despite the anticoagulant treatment, the patient died of pulmonary embolism after 3 weeks of surgical treatment. Conclusion: The reported psoas squamous carcinoma was originated in the bladder with splenic metastasis. It is the first report in the literature. Considering the possible metastatic origin of the psoas abscess, it is recommended to avoid a useless surgical drainage.

External Validation of Models for Prediction of Lymph Node Metastasis in Urothelial Carcinoma of the Bladder.

PurposeTo externally validate models to predict LN metastsis; Karakiewicz nomogram, clinical nodal staging score (cNSS), and pathologic nodal staging score (pNSS) using a different cohortMaterials and MethodsClinicopathologic data from 500 patients who underwent radical cystectomy and pelvic lymphadenectomy were analyzed. The overall predictive values of models were compared with the criteria of overall performance, discrimination, calibration, and clinical usefulness.ResultsPresence of pN+ stages was recorded in 117 patients (23.4%). Agreement between clinical and pathologic stage was noted in 174 (34.8%). Based on Nagelkerke’s peudo-R2 and brier score, pNSS demonstrated best overall performance. Area under the receiver operating characteristics curve, showed that pNSS had the best discriminatory ability. In all models, calibration was on average correct (calibration-in-the-large coefficient = zero). On decision curve analysis, pNSS performed better than other models across a wide range of threshold probabilities.ConclusionsWhen compared to pNSS, current precystectomy models such as the Karakiewicz nomogram and cNSS cannot predict the probability of LN metastases accurately. The findings suggest that the application of pNSS to Asian patients is feasible.

Primary apocrine adenocarcinoma of scrotum suspected as urothelial carcinoma metastasis: A clinical and pathological dilemma

A 78-year-old man presented with an enlarging, tender mass in the scrotum separate to the testes. This was on the background of radical cystoprostatectomy, urethrectomy, and ileal conduit formation for high-grade urothelial carcinoma of the bladder invading submucosa 3 years prior. Examination revealed a 4 × 5 cm lesion, which was hard, fixed to the overlying skin and nodular to palpation. Ultrasound confirmed a solid mass in the scrotum extending into the perineum. Computerized tomography of the chest, abdomen, and pelvis revealed enlargement of inguinal lymph nodes but no other metastases. Complete resection of the scrotal lesion and selective removal of regional lymph nodes was performed. Rather than a cutaneous scrotal metastasis from the bladder urothelial carcinoma, histological examination suggested a primary apocrine adenocarcinoma of the scrotum. This case report explores the clinical and pathological features associated with both of these unusual differential diagnoses.

Vulvar metastasis from bladder cancer.

Vulvar metastasis of urothelial carcinoma of the bladder is a very rare entity; few cases are reported in the English literature. In this paper, we describe the clinical and pathological characteristics, evolution, and treatment of a patient with vulvar metastasis of urothelial carcinoma of the bladder followed by a brief review of the reported cases in the literature.

The Effectiveness of Cytologic Evaluation of Urinary Diversion Specimens and UroVysion Assay as Surveillance Tests in the Detection of Recurrent Bladder Cancer

Introduction: Different surveillance protocols exist for the detection of urothelial carcinoma recurrence in patients that have undergone radical cystectomy (RC) and each protocol varies in choice of test and frequency of testing. Cytologic examination of urinary diversion specimens and UroVysion assay are two surveillance tests that may be used to detect recurrent disease. The cytologic interpretation of urinary diversion specimens is suboptimal since they contain abundant degenerate glandular cells, histiocytes, bacteria, acute inflammation and non-specific debris. In this milieu recurrent disease can be obscured and identification made difficult, if not impossible. The purpose of this study is to evaluate the effectiveness of cytology and UroVysion assay in this subset of patients. Materials and Methods: A Retrospective chart review of 97 patients who underwent RC with cutaneous diversion or orthotopic neobladder reconstructions for bladder cancer andwho also had a LIS (Laboratory Information System) word search result containing “ileal conduit urine” between January 2001 and January 2012was performed. The cytopathology reports for urinary diversion specimens and any UroVysion assays from these patients were reviewed. Cytologic results were divided into positive, suspicious, atypical, negative and unsatisfactory. The atypical category did not imply malignancy or the potential for malignancy, but was used to indicate some degree of variation from cytology seen in traditional urine specimens. Results: A total of 355 urinary diversion cytology reportswere reviewedwith diagnoses as follows: positive e 0, suspicious e 3 (0.8%), atypical e 136 (38.3%), negative e 213 (60%) and unsatisfactory e 3 (0.8%). A total of 56 Urovysion molecular tests were reviewed with interpretations as follows: positive e 3 (5.3%), negative e 39 (69.6%), indeterminate e 2 (3.6%), insufficient e 12 (21.4%). Four of 97 patients (4.1%) had at least one abnormal cytologic result. One cytologic diagnosis of atypical showed no abnormality on pouch biopsy. The remaining 3 patients with abnormal cytologies had no subsequent biopsies at our institution. Two patients had positive Urovysion assays and both these patients had orthotopic neobladder reconstructions. One patient had two subsequent positive Urovysion assay results which are accounted for by the presence of residual transitional cell carcinoma in-situ (TCIS) in the urethra as this patient had a positive urethral margin at the time of his cystoprostatectomy. The second patient with a positive UroVysion assay result occurred in a patient with 5 normal urinary diversion cytologies who was ultimately diagnosed with Stage 4 urothelial cancer (urothelial carcinomametastasis to skin). Thiswas deemed to be a false positive test result based on clinical assessment. None of the four patientswith abnormal cytology results were found to have recurrent disease. Conclusion: The results of this study question the effectiveness of cytologic evaluation of urinary diversion specimens and UroVysion assay as surveillance tests for detecting recurrent bladder cancer.We did not detect any upper tract/urethral recurrence in our series. Furthermore, the UroVysion assay is not FDA-approved for testing urine specimens derived from patients

A rare cause of testicular metastasis: upper tract urothelial carcinoma.

Metastatic testicular cancers are rare. Primary tumor sources are prostate, lung, and gastrointestinal tract for metastatic testicular cancers. Metastasis of urothelial carcinoma (UC) to the testis is extremely rare. Two-thirds of upper tract urothelial carcinoma (UTUC) is of invasive stage at diagnosis and metastatic sites are the pelvic lymph nodes, liver, lung, and bone. We report a rare case of metastatic UTUC to the testis which has not been reported before, except one case in the literature. Testicular metastasis of UC should be considered in patients with hematuria and testicular swelling.

First Experience Using Peptide Receptor Radionuclide Therapy in a Patient With Urothelial Carcinoma

A 78-year-old man with urothelial carcinoma metastasis after surgical resection of the right kidney, part of the ureter, and urinary bladder in May 2003 and 3 cycles of chemotherapy with cisplatin-gemcitabine was referred for peptide receptor radionuclide therapy (PRRT). Somatostatin-receptor profile was assessed by 68Ga-labeled lanreotide PET, and PRRT was performed using 3738 MBq (101 mCi) of 90Y-DOTA-lanreotide. Because of adequate PRRT response confirmed with MRI and 18F-FDG PET, surgical resection of the solitary cervical metastasis was feasible. Treatment was well tolerated, and the patient remains in complete remission from his urothelial carcinoma.

Invasionsmechanismen und Metastasierung des Urothelkarzinoms

Local invasion of cancer cells occurs early during the progression of urothelial carcinoma. Micrometastatic disease and the presence of nodal metastases are major causes of cancer-specific mortality following radical surgery. Only surrogate markers for aggressive and micrometastatic disease have been identified. The metastatic cascade is complex, including multiple steps from initial invasion to colonization and proliferation at distant sites. The initial mechanisms of cancer cell dissemination in urothelial carcinoma are poorly understood. Various proteases, chemokines and growth factors are involved in this process and alterations of the lymphatic system may promote systemic spread. There is a high demand for therapeutic targeting of the metastatic process. Functional preclinical studies in representative models are therefore required to better elucidate the multiple steps of progression. We review the current knowledge on factors associated with metastasis in urothelial carcinoma. Preclinical approaches to identify key player molecules for invasion and to develop new therapeutic strategies are discussed.

Gemcitabine and docetaxel, an effective second-line chemotherapy for lung metastasis of urothelial carcinoma

The objective of this study was to evaluate the efficacy of a gemcitabine and docetaxel (GD) combination as a second-line treatment for patients with metastatic urothelial carcinoma (UC) after failure of first-line treatment with platinum-based chemotherapy. From June 2006 to January 2012, 38 patients with metastatic UC previously treated with platinum-based chemotherapy received GD therapy. This consisted of gemcitabine 800 mg/m(2) and docetaxel 40 mg/m(2) on days 1 and 8 of each 21-day cycle as second-line chemotherapy. All the patients were evaluated for toxicity and assessed every cycle by imaging. We analyzed the efficacy of GD as second-line chemotherapy in the follow-up study. The median number of GD treatment cycles was 4 (range 2-9); the objective response rate was 47.4 %; and the median progression-free survival and median overall survival were 4.1 and 10.8 months, respectively. Univariate and multivariate analyses on the GD treated group showed that the existence of lung metastases was the only prognostic factor for tumor response. Grade 3 treatment-related toxicity included neutropenia (31.6 %) and thrombocytopenia (15.8 %), and only one patient with grade 4 toxicity had thrombocytopenia (2.6 %). The GD regimen as second-line chemotherapy was especially effective for lung metastatic UC and yielded favorable results in patients whose first-line platinum-based chemotherapy had failed. Given the safety and benefit profile seen in this study, a large prospective study is warranted to consider the potential utility of GD chemotherapy as a second-line for UC.

Prognostic Role of KiSS-1 and Possibility of Therapeutic Modality of Metastin, the Final Peptide of the KiSS-1 Gene, in Urothelial Carcinoma

The KiSS-1 gene has been reported to be a metastasis suppressor gene in human melanoma. The gene product was isolated from human placenta as the ligand of GPR54, a G protein-coupled receptor, and the C-terminally amidated peptide of 54 amino acids is called metastin. The binding of metastin to GPR54 has been shown to inhibit tumor metastasis in some tumor cells; however, its function remains unclear in urothelial carcinoma. We first evaluated KiSS-1 expression and GPR54 expression in 151 patients with upper urinary tract urothelial carcinoma to determine their prognostic significance. Next, we examined the role of metastin in the invasiveness and lung metastasis of MBT-2 variant (MBT-2V), which is a highly metastatic murine bladder cancer cell. Multivariate analysis revealed that KiSS-1 expression was an independent predictor of metastasis and overall survival. However, GPR54 expression was not selected. Hematogeneous metastasis had a significantly lower level of KiSS-1 expression compared with lymph node metastasis. Metastin treatment significantly reduced the invasiveness of MBT-2V cells and inhibited the DNA-binding activity of NF-κB by blocking its nuclear translocation, leading to a reduction in the expression and activity of matrix metalloproteinase-9. Metastin treatment dramatically prevented the occurrence of lung metastatic nodules (6.3 ± 2.3, n = 15) compared with controls (30.4 ± 5.1, n = 15; P < 0.01), as well as had survival benefit. KiSS-1 plays an important role in the prognosis of upper tract urothelial carcinoma and metastin may be an effective inhibitor of metastasis in urothelial carcinoma through its blockade of NF-κB function.

Long-Term Survival after Adrenalectomy for Asynchronous Metastasis of Bladder Cancer to the Bilateral Adrenal Glands

Isolated adrenal metastasis of bladder cancer, particularly the bilateral, is quite rare. Systemic chemotherapy is the treatment of choice for metastatic urothelial carcinoma. However, despite initially promising response rates of approximately 45%–71%, most tumors eventually show progression, and the median survival time following chemotherapy regimen is approximately 14-15 months. Recently, favorable results of surgery for metastatic urothelial carcinoma have been reported. Here, we report a rare case of asynchronous metastasis of bladder cancer to the bilateral adrenal glands with long-term survival after bilateral adrenalectomy. A 69-year-old man underwent radical cystoprostatectomy and ileal conduit urinary diversion for invasive bladder cancer. Ten months later, left adrenalectomy was performed for a left adrenal tumor, revealing metastatic urothelial carcinoma. After adjuvant chemotherapy, a tumor in the right adrenal gland was detected. Right adrenalectomy was done, and the tumor was also found to be metastatic urothelial carcinoma. The patient had an uneventful recovery after starting steroid replacement therapy. Three years later, he was doing well and had no evidence of recurrence. Adrenalectomy for isolated adrenal metastasis of urothelial carcinoma may be a reasonable option, even if such metastases are bilateral.

Fine‐needle aspiration diagnosis of metastatic urothelial carcinoma: A review

Urothelial carcinoma (UC) is the most common malignant neoplasm of the urinary tract. Metastases of UC are most common in the regional lymph nodes, lungs, liver, bone, and adrenal glands. Fine-needle aspiration cytology diagnosis of such metastases can be difficult, particularly in the setting of incomplete clinical history or when multiple primary neoplasms may be present. This review focuses on the cytologic features helpful in differentiating UC from its potential mimics, as well as ancillary studies that may be helpful in the distinction.