Urothelial Origin Research Articles

Adenocarcinoma at Anastomotic Site of Ureterosigmoidostomy Potentially of Urothelial Origin Spreading to the Upper Urinary Tract.

Ureterosigmoidostomy is associated with the risk of several late complications including cancer development at anastomotic sites. We present an unusual case with adenocarcinoma of the anastomotic site associated with multiple adenocarcinoma lesions in the upper urinary tract. A 69-year-old man complained of persistent melena and hematuria. He had undergone radical cystectomy for high-grade bladder cancer and ureterosigmoidostomy 30 years before. Colonoscopy showed a tumor at the right ureterocolonic anastomosis, which was endoscopically resected and histologically diagnosed as adenocarcinoma. Seven years later, a tumor of the left ureterocolonic anastomosis associated with hydronephrosis was found. He underwent temporal percutaneous nephrostomy followed by sigmoidectomy and left ureterocutaneostomy. Eighteen months after the operation, computed tomography (CT) detected left renal pelvic tumor with a mass along the former nephrostomy tract. Left nephroureterectomy and resection of the nephrostomy tract tumor revealed adenocarcinoma with multiple lesions of adenocarcinoma in the ureter. These tumors showed atypical immunohistochemistry as a colonic adenocarcinoma: positive for cytokeratin 7, negative for cytokeratin 20, and negative for β-catenin nuclear accumulation. Anastomotic site adenocarcinoma of the present case is potentially of urothelial origin because of unusual clinical manifestation and immunohistochemistry as a colon cancer.

Clinicopathological features of carcinoma of the distal penile urethra.

Distal urethral carcinomas are very rare and are similar in their pathology and behaviour to tumours of the glans penis and foreskin. Similarly they are associated with penile intraepithelial neoplasia (PeIN) of both differentiated and undifferentiated types. Current management is mainly surgical, but increasingly involves specialist penile-preserving techniques. Handling and dissection of the specimens is broadly the same as other primary penile tumours. The prognosis of distal urethral lesions is believed to be worse than penile tumours and better than prostatic urethral tumours, but the evidence is sparse. The staging system for urethral tumours does not distinguish between proximal and distal, apart from prostatic urethra, and has led to much confusion in the literature. Although the subtypes of tumours seen in the distal urethra are the same as those on the glans and foreskin, there is an increased proportion of basaloid squamous carcinoma and malignant melanoma whereas the majority of tumours seen in the proximal and prostatic urethra are of urothelial origin. In future, distal urethral tumours should be separately designated with site-specific staging/TNM and reporting system and pathologically classified in the same way as penile and foreskin tumours. Ultimately, this will improve the quality of data and produce evidence to inform management.

Uroplakin II is a more sensitive immunohistochemical marker than uroplakin III in urothelial carcinoma and its variants.

Uroplakin (UP) II and UPIII are highly specific immunohistochemical markers for urothelial differentiation. Here we studied the sensitivity of UPII and UPIII in conventional and variant urothelial carcinomas (UCs). Immunohistochemical staining for UPII and UPIII was performed on tissue microarray slides, including 105 conventional bladder UCs (BUCs), 90 upper urinary tract UCs (UUTUCs), and 47 micropapillary, 16 plasmacytoid, 22 small cell carcinoma, and 41 sarcomatoid UC variants. UPII expression was significantly higher than UPIII expression in conventional BUC (44% vs 17%, P < .001) and UUTUC (67% vs 46%, P = .045). UPIII expression was significantly higher in UUTUC than in BUC (P < .001). In UC variants, UPII expression was significantly higher than UPIII expression in micropapillary (91% vs 25%, P < .001), plasmacytoid (63% vs 6%, P < .001), and sarcomatoid (29% vs 5%, P = .032) variants. Only rare cases of the small cell carcinoma variant had focal UPII and UPIII expression. Compared with conventional UC, the sarcomatoid variant had significantly lower UPII expression, whereas the micropapillary variant had significantly higher UPII expression (P < .001). UPII demonstrates a significantly higher sensitivity than UPIII in conventional and variant UCs. Thus, UPII is a more valuable marker than UPIII in immunohistochemical analyses for confirming the urothelial origin of carcinomas.

Simultaneous immunostaining with anti-S100P and anti-SV40 antibodies revealed the origin of BK virus-infected decoy cells in voided urine samples.

Methods for determining the origin of BK virus (BKV)-infected cells (decoy cells) in clinical urine samples have not been established although they could enhance the diagnosis of BKV infection in immunocompromised patients. We performed simultaneous immunostaining with anti-S100P (a urothelial marker) and anti-SV40 antibodies in 66 clinical urine samples exhibiting SV40 positivity and a decoy-cell appearance on Papanicolaou staining. The clinical voided urine samples included seven cases of renal transplantation, 47 cases of cancer therapy and 12 cases of non-neoplastic disease. SurePath(™) liquid-based cytology was used for the urine samples. BKV-infected cells were categorized as SV40(+)/S100P(+) and SV40 (+)/S100p(-). SV40(+)/S100P(-) cells were found in 55 cases (83.4%); nine cases (13.6%) carried both SV40(+)/S100P(-) and SV40(+)/S100P(+) cells. The former were identified as BKV infection in renal tubules and the latter in both the renal tubules and urothelial epithelia. The remaining two cases (3.0%) had only SV40(+)/S100P(+) cells of urothelial origin. Simultaneous immunostaining with anti-S100P and anti-SV40 is a useful method for determining the origin of BKV-infected cells in clinical urine samples from immunocompromised patients such as renal transplantation recipients.

Metastatic Transitional Cell Carcinoma Masquerading as Cholangiocarcinoma

Introduction: An 85-year old female presented with a 3-week history of RUQ pain radiating to the back. She reports intermittent nausea, nonbilious/nonbloody vomitus, anorexia, weight loss, and was found to have abnormal liver function tests. Her past medical history was significant for a stage II urothelial tumor of the left ureter treated with a left nephrectomy 1 year prior. On exam she was noted to have icterus, mild jaundice, and tenderness to palpation of the RUQ. No masses palpated and no organomegaly was noted. Laboratory findings showed elevated total bilirubin, alkaline phosphatase, AST, and ALT. Sonogram suggested acute cholecystitis and biliary ductal dilatation, and HIDA scan confirmed cystic duct obstruction. An MRI/MRCP was performed that suggested a malignant obstructive process in the RUQ, consistent with a cholangiocarcinoma. The patient underwent ERCP, which revealed a long smooth common bile duct stricture and brush cytology was obtained. A plastic stent was placed across the stricture with biliary drainage. EUS suggested gallbladder carcinoma without evidence of vascular invasion. She then underwent laparascopic investigation with intent to resect the tumor but was found to have encasement of the hepatic artery. An open cholecystectomy was performed and biopsy results were consistent with transitional cell origin (IHC was diffusely positive for GATA-3, p63 and focally positive for uroplakin-2). This was an unexpected finding of metastatic disease from her previous left renal pelvis tumor. More than 90% of ureter and renal pelvis tumors are of urothelial origin. Histologically these represent transitional cell carcinoma (TCC) of the bladder. In the United States and Western Europe, approximately 90% of bladder cancers are TCC. Much less commonly, urothelial cancers can arise in the renal pelvis, ureter, or urethra. TCC rarely spreads to distant sites and this occurs in less than 5% of cases. The most common sites of TCC metastasis are lymph nodes, bone, lung, liver, and peritoneum. Metastasis causing biliary obstruction is extremely rare; there has been only 1 report which described bile duct wall metastasis due to TCC mimicking primary hilar cholangiocarcinoma and 1 case in which TCC metastasized to the gallbladder. Furthermore, to our knowledge, there has not been a case in which TCC not only caused biliary obstruction but also cystic duct obstruction. This is the first case in which a TCC caused common bile duct and cystic duct obstruction. This is an extremely uncommon scenario in the literature. Therefore, physicians should consider, in the appropriate setting, metastatic TCC causing biliary obstruction. The patient in this case was successfully palliated with a cholecystectomy and CBD SEMS placement. She was planned to begin outpatient chemotherapy.

Rare Case of Acute Liver Failure Caused by Diffuse Liver Metastases in a Patient With Non-Muscle Invasive Transitional Cell Carcinoma of the Bladder

Introduction: Acute liver failure (ALF) secondary to infiltration of the liver by malignant cells is unusual, and hematological malignancies are the most common underlying etiology. ALF secondary to liver infiltration from transitional cell bladder cancer is extremely rare. Case Report: A 70-year-old woman with a 2008 history of non-muscle invasive (Stage T1) transitional cell cancer of bladder, treated with transurethral resection of the bladder tumor, presented to the hospital with right upper quadrant pain, fever, and vomiting. Labs showed WBC 12,000, lactate 6.2 mmol/L, and abnormal liver parameters (AST, 416 U/L; ALT, 147 U/L, total/direct bilirubin, 6.1/4 mg%, alkaline phosphatase, 268 U/L, INR, 1.5). Abdominal ultrasound showed multiple gallstones and non-dilated CBD. ERCP showed no CBD stone or evidence of cholangitis. Viral hepatitis, autoimmune serologies, and other laboratory studies for other causes of acute liver failure were negative or non-reactive. A CT scan showed numerous low attenuation masses in the liver and enlarged retroperitoneal lymph nodes, and the bladder appeared normal. A liver biopsy showed sheets of malignant cells. P63 stain was positive, suggestive of metastatic carcinoma of urothelial origin. The patient’s liver synthetic parameters continued to worsen. She developed hepatic coma and expired 6 days after presentation. Discussion: ALF secondary to infiltration of the liver by malignant cells is a well-described entity, with hematological malignancies, including lymphoma and leukemias, being the most common causes. Other metastatic malignancies that rarely can cause ALF include adenocarcinomas and melanoma. ALF secondary to liver infiltration from transitional cell bladder cancer is extremely rare, with only 3 previous cases reported, all with documented muscle invasive (Stage T2) disease. Conclusion: To our knowledge, we report the first case of ALF secondary to non-muscle invasive (Stage T1) transitional cell bladder cancer occurring 5 years after original presentation and presumptive cure.

Prostate pointers and pitfalls: the 10 most prevalent problems in prostate biopsy interpretation.

As small volumes of prostate cancer are being detected with ever-increasing frequency, the pathologist is challenged to make more diagnostically out of less. This photoessay explores ten diagnostic problems that are noted with regularity by a provider of second opinions in prostate biopsy interpretation. These include: suboptimal submission of prostate cores, atypia with small size of the focus of concern, cytologic ambiguity of the focus of concern, issues with ordering and interpreting immunostains, atypia arising with high-grade prostatic intraepithelial neoplasia, benign mimics of cancer, omitting mention of extraprostatic tumor extension or of Gleason pattern 5, not recognizing intraductal carcinoma, and the differential diagnosis of cancer of urothelial versus prostatic origin.

Differential expression of GATA-3 in urothelial carcinoma variants.

GATA binding protein 3 (GATA-3) is a novel immunohistochemical marker for urothelial carcinoma (UC); however, few studies have investigated GATA-3's role as a marker for UC variants. We used immunohistochemistry to assess GATA-3 expression in different UC variants, including micropapillary (n = 46), sarcomatoid (n = 43), small cell carcinoma (n = 22), and plasmacytoid (n = 16) variants, and we also compared GATA-3 expression in conventional bladder UC (n = 103) to that in squamous cell carcinoma (n = 14). GATA-3 expression was present in 70% (72/103) of conventional bladder UCs and highly concordant between matched primary and metastatic UCs. The GATA-3 expression levels of the micropapillary variants (57%; 26/46) and plasmacytoid variants (44%; 7/16) were not significantly different from that of conventional UC. However, the GATA-3 expression levels of the sarcomatoid variants (16%; 7/43) and small cell carcinoma variants (5%; 1/22), which only weakly expressed the protein, were significantly lower than that of conventional UC (P < .001). Only 7% of squamous cell carcinomas (1/14) expressed GATA-3, and it was also significantly lower than that of conventional UC (P < .001). GATA-3 expression was not significantly associated with tumor stage or patients' clinical outcomes. In conclusion, GATA-3 expression differed among UC variants. GATA-3 is a useful marker for confirming the urothelial origin of micropapillary and plasmacytoid UC variants but not that of sarcomatoid or small cell carcinoma variants. GATA-3 can also be used in differentiating UC from squamous cell carcinoma.

Bladder Cancer in Males: A Comprehensive Review of Urothelial Carcinoma of the Bladder

Bladder cancer is the second most common genitourinary malignancy after prostate cancer. It is a disease most commonly encountered in the elderly, particularly males, and has several well-established risk factors, including smoking and occupational exposures to certain chemical carcinogens. Roughly 90% of all bladder cancers are urothelial in origin; that is, they arise from the epithelial lining of the bladder. The remainder, including squamous cell carcinoma and adenocarcincoma, are nonurothelial. This review will focus solely on bladder cancer of urothelial origin, commonly referred to as urothelial carcinoma (UC) of the bladder. Bladder cancer can be divided into three distinct clinical entities: nonmuscle-invasive bladder cancer (NMIBC), muscle-invasive bladder cancer (MIBC), and metastatic bladder cancer. Each entity calls for different management. NMIBC, which accounts for roughly 70% of bladder cancer diagnoses, usually can be managed with transurethral resection, intravesical chemotherapy/immunotherapy, and aggressive surveillance protocols to monitor for recurrence and progression. MIBC calls for radical cystectomy (RC) with urinary diversion and bilateral pelvic lymph node dissection. Although it is often underutilized, neoadjuvant chemotherapy with platinum-based regimens improves survival. Data on adjuvant chemotherapy are less robust, but it remains an option for those who are medically fit and considered to be at high risk for recurrence and progression. Bladder-preserving strategies, including partial cystectomy and trimodality therapy, can provide adequate cancer control in appropriately selected patients with MIBC. Stringent surveillance is required. Metastatic bladder cancer is often lethal and the standard of care remains platinum-based chemotherapy regimens. Renal insufficiency is a common comorbidity that prevents patients from receiving chemotherapy in all settings. Currently, there are no recommended second-line chemotherapy regimens. Given the high rate of recurrence and progression, better prognostic variables should help to identify those who should be targeted in clinical trials. As bladder cancer affects a large number of men every year and significantly contributes to healthcare expenditures, prompt diagnosis and appropriate management are critical.

GATA3

GATA3 is a transcription factor important in the differentiation of breast epithelia, urothelia, and subsets of T lymphocytes. It has been suggested to be useful in the evaluation of carcinomas of mammary or urothelial origin or metastatic carcinomas, but its distribution in normal and neoplastic tissues is incompletely mapped. In this study, we examined normal developing and adult tissues and 2040 epithelial and 460 mesenchymal or neuroectodermal neoplasms for GATA3 expression to explore its diagnostic value in surgical pathology, using monoclonal antibody (clone L50-823) and Leica Bond automated immunohistochemistry. GATA3 was expressed in trophoblast, fetal and adult epidermis, adult mammary and some salivary gland and sweat gland ductal epithelia, urothelia, distal nephron in developing and adult tissues, some prostatic basal cells, and subsets of T lymphocytes. It was expressed stronger in fetal than in adult mesothelia and was absent in respiratory and gastrointestinal epithelia. In epithelial neoplasms, GATA3 was expressed in >90% of primary and metastatic ductal and lobular carcinomas of the breast, urothelial, and cutaneous basal cell carcinomas and trophoblastic and endodermal sinus tumors. In metastatic breast carcinomas, it was more sensitive than GCDFP. Among squamous cell carcinomas, the expression was highest in the skin (81%) and lower in cervical (33%), laryngeal (16%), and pulmonary tumors (12%). Common positivity was found in skin adnexal tumors (100%), mesothelioma (58%), salivary gland (43%), and pancreatic (37%) ductal carcinomas, whereas frequency of expression in adenocarcinomas of lung, stomach, colon, endometrium, ovary, and prostate was <10%. Chromophobe renal cell carcinoma was a unique renal tumor with frequent positivity (51%), whereas oncocytomas were positive in 17% of cases but other types only rarely. Among mesenchymal and neuroectodermal tumors, paragangliomas were usually positive, which sets these tumors apart from epithelial neuroendocrine tumors. Mesenchymal tumors were only sporadically positive, except epithelia of biphasic synovial sarcomas. GATA3 is a useful marker in the characterization of not only mammary and urothelial but also renal and germ cell tumors, mesotheliomas, and paragangliomas. The multiple specificities of GATA3 should be taken into account when using this marker to detect metastatic mammary or urothelial carcinomas.

3. Clear cell adenocarcinoma of urinary tract: 2 cases involving urethra and bladder

<h3>Background</h3> Adenocarcinoma of urothelial tract is considered primary when conventional urothelial carcinoma component is not identified. Cases with co-existing urothelial carcinoma are regarded as differentiation of urothelial origin. Clear cell adenocarcinoma is a rare variant that needs to be discriminated from primary adenocarcinoma of urinary tract, urothelial carcinoma with glandular differentiation and metastatic tumours. <h3>Methods</h3> We report two cases of clear cell adenocarcinoma of urinary tract, involving urethra (Case 1) and urinary bladder (Case 2). Histological features, immunohistochemical profile and clinical outcome are summarised. <h3>Results</h3> Case 1 (urethral tumour): A 64-year-old Chinese female presented with anterior vaginal wall mass. Biopsy showed clear cell adenocarcinoma and she underwent neoadjuvant chemotherapy. Resection showed urethral tumour involving bladder neck and one lymph node. Histologically, tumour showed tubulopapillary and glandular architecture, hobnail nuclei and clear cytoplasm. Immunohistochemically, tumour cells were CK7 and CA125 positive, thrombomodulin and HMWCK weak positive, and CK20 and p63 negative. Patient is under follow-up. Case 2 (bladder tumour): A 56-year-old Chinese female underwent surgery for bladder mass. Tumour showed tubulopapillary and glandular architecture, hobnail nuclei and clear cytoplasm. Two lymph nodes were positive. Immunohistochemical profile was CK7 positive and CK20 negative. Patient expired following peritoneal carcinomatosis. Conclusions: Clear cell adenocarcinoma of urinary tract can be identified by a constellation of features: (1) presence of tubulo-papillary/glandular architecture, high grade hobnail nuclei and clear cytoplasm, (2) absence of primary adenocarcinoma of urinary tract, conventional urothelial carcinoma with glandular differentiation and metastasis, and (3) immunohistochemical profile of positive CK7 and CA125, weak positive HMWCK and CK5/6, negative CK20 and p63 and negative staining for potential metastatic tumour (e.g., CDX2 negative). Clinical behaviour is aggressive. Correct identification can aid in trial of neoadjuvant chemotherapy.

Immunohistochemistry for the Novel Markers Glypican 3, PAX8, and p40 (ΔNp63) in Squamous Cell and Urothelial Carcinoma

To examine squamous cell carcinomas (SCCs) from diverse anatomic sites and invasive urothelial carcinomas (UCs) for expression of the oncofetal antigen glypican 3 (GPC3), the paired box transcription factor PAX8, and the ΔN isoform of p63 (p40). Immunohistochemistry for GPC3, PAX8, and p40 was performed on whole sections of 107 SCCs from 11 anatomic sites and 49 UCs; evaluation included extent and intensity of staining. GPC3 was detected in 20% of SCCs and 12% of UCs and PAX8 in 3% of SCCs, limited to the uterine cervix, and 10% of UCs. p40 Was found in 99% of SCCs and 96% of UCs. GPC3 expression is frequent in SCC/UC, awareness of which should guard against an incorrect diagnosis of hepatocellular carcinoma, while PAX8, limited in distribution, may have some use in suggesting a cervical or urothelial tract origin in a metastatic squamotransitional carcinoma of unknown primary. There is no drop-off in sensitivity for the diagnoses of SCC or UC with ΔNp63-specific immunohistochemistry, and if this performance can be extended to other applications, p40 may supplant the dominant "pan-p63" antibody clone.

HOXB13 is a sensitive and specific marker of prostate cells, useful in distinguishing between carcinomas of prostatic and urothelial origin

The origin of a primary or metastatic carcinoma in the pelvic area is sometimes difficult to establish, in particular the distinction between those originating in the bladder and the prostate. A candidate marker is the HOXB13 gene, essential for prostate development. Some studies have shown expression of HOXB13 protein by immunohistochemistry in the nuclear compartment of benign prostate luminal epithelium and prostate carcinoma. Forty-two cases of biopsies and resection specimens of the prostate and urinary bladder, metastatic lymph nodes, and pelvic masses were retrieved from our databases. In all cases, doubt persisted regarding prostatic versus urothelial origin. All cases were stained for CK7, p63, p504s, PSA, CK20, and HOXB13. Chromogranin A, CD56, and synaptophysin were used when neuroendocrine differentiation was suspected. HOXB13 staining was negative or only weakly positive in all carcinomas of urothelial origin. Three of four carcinomas with neuroendocrine differentiation did not express HOXB13. The fourth carcinoma, in a patient with a history of prostate carcinoma, was positive. In two cases with a synchronous prostatic and urothelial carcinoma, HOXB13 was exclusively expressed in the prostatic carcinoma. Our results demonstrate that HOXB13 expression identifies prostatic origin of a carcinoma with good sensitivity (89 %) and very good specificity (100 %). HOXB13 is a specific and sensitive marker for prostate cells and a valuable diagnostic tool, especially when poorly differentiated or neuroendocrine tumors are encountered. These results justify testing of HOXB13 as a prostate-specific carcinoma marker in larger cohorts for a more thorough evaluation of its sensitivity and specificity.

Incidentally detected squamous cell carcinoma of the renal pelvis in patients with staghorn calculi – A case report and literature review

Squamous cell carcinomas of the renal pelvis (renal squamous cell carcinoma, RSCC) are rare. They are highly malignant tumors of urothelial origin and have a poor prognosis owing to misleading clinical presentations and difficulty in early diagnosis. We present a case of incidentally detected RSCC in patients with staghorn calculi and discuss this entity.

Mutation Spectra of Kras and Tp53 in Urethral and Lung Neoplasms in B6C3F1 Mice Treated with 3,3′,4,4′-Tetrachloroazobenzene

3,3',4,4'-tetrachloroazobenzene (TCAB) is a contaminant formed during manufacture of various herbicide compounds. A recent National Toxicology Program study showed B6C3F1 mice exposed to TCAB developed a treatment-related increase in lung carcinomas in the high-dose group, and urethral carcinomas, an extremely rare lesion in rodents, in all dose groups. As the potential for environmental exposure to TCAB is widespread, and the mechanisms of urethral carcinogenesis are unknown, TCAB-induced urethral and pulmonary tumors were evaluated for alterations in critical human cancer genes, Kras and Tp53. Uroplakin III, CK20, and CK7 immunohistochemistry was performed to confirm the urothelial origin of urethral tumors. TCAB-induced urethral carcinomas harbored transforming point mutations in K-ras (38%) and Tp53 (63%), and 71% displayed nuclear TP53 expression, consistent with formation of mutant protein. Transition mutations accounted for 88% of Tp53 mutations in urethral carcinomas, suggesting that TCAB or its metabolites target guanine or cytosine bases and that these mutations are involved in urethral carcinogenesis. Pulmonary carcinomas in TCAB-exposed animals harbored similar rates of Tp53 (55%) and Kras (36%) mutations as urethral carcinomas, suggesting that TCAB may induce mutations at multiple sites by a common mechanism. In conclusion, TCAB is carcinogenic at multiple sites in male and female B6C3F1 mice through mechanisms involving Tp53 and Kras mutation.

Multiple joint metastasis of a transitional cell carcinoma in a dog

An 8-year-old castrated male hound mix was referred to the Purdue University Veterinary Teaching Hospital for severe lameness, pollakiuria, and dyschezia. On presentation, the dog was nonweight bearing on the right rear limb and the right carpus was diffusely swollen. Synovial fluid analysis from the right carpus revealed a population of epithelial cells displaying marked anisocytosis, anisokaryosis, multinucleation, and prominent, variably sized nucleoli. A metastatic carcinoma with presumed prostatic or urothelial origin was diagnosed based on cytomorphology. Subsequent cytologic evaluation of peripheral lymph nodes revealed the presence of a similar neoplastic population. The dog was euthanized and synovial fluid from both stifle joints, as well as impression smears of the prostate gland, were collected. Carcinoma cells were identified in each stifle joint and in the prostate gland. Immunocytochemistry was performed on synovial fluid smears from 2 of the joints (right stifle and right carpus) and on impression smears of the prostate gland. The neoplastic population in the joints and prostate gland showed strong immunoreactivity to uroplakin III, a urothelial marker, indicating metastasis of a transitional cell carcinoma to multiple joints. In addition, evidence for epithelial to mesenchymal transition was identified using cytokeratin, an epithelial marker, and vimentin, a mesenchymal marker. A necropsy was performed and histopathology confirmed the presence of metastatic transitional cell carcinoma in various tissues. This case illustrates the importance of considering metastatic disease when a patient is presented with severe lameness and joint pain, and the clinical utility of synovial fluid cytology for diagnosis of metastasis in these cases.

GATA3 Immunohistochemical Expression in Salivary Gland Neoplasms

GATA3 is a zinc finger transcription factor that regulates the normal development of many tissues and cell types. Recent studies have shown that immunohistochemical nuclear staining for GATA3 among tumors is highly restricted to carcinomas of breast and urothelial origin; however salivary gland tumors have not been tested. Given that breast and salivary gland tissues are very similar with respect to embryologic development and structure, we performed GATA3 staining on a spectrum of salivary gland neoplasms. GATA3 immunohistochemistry was performed on a diverse collection of 180 benign and malignant salivary gland neoplasms including 10 acinic cell carcinomas, 2 adenocarcinomas not otherwise specified, 41 adenoid cystic carcinomas, 2 epithelial-myoepithelial carcinomas, 1 low grade cribriform cystadenocarcinoma, 15 mammary analogue secretory carcinomas, 7 metastatic squamous cell carcinomas, 27 mucoepidermoid carcinomas, 2 oncocytic carcinomas, 5 oncocytomas, 34 pleomorphic adenomas, 4 polymorphous low grade adenocarcinomas, 25 salivary duct carcinomas, and 5 Warthin tumors. Staining for GATA3 was observed in 92/180 (51%) of salivary gland tumors. GATA3 staining was observed in most of the tumor types, but diffuse immunolabeling was consistently seen in salivary duct carcinoma (25 of 25) and mammary analogue secretory carcinoma (15 of 15)-the two tumor types that most closely resemble breast neoplasia. Background benign salivary gland tissue was also usually weakly positive in both acini and ducts. GATA3 immunostaining is not restricted to tumors of breast and urothelial origin. Rather, it is expressed across many different types of salivary gland neoplasms. As a result, salivary gland origin should be considered in the differential diagnosis of a GATA3-positive carcinoma, particularly in the head and neck. Although GATA3 immunohistochemistry is not helpful in resolving the differential diagnosis between a primary salivary gland neoplasm and metastatic breast cancer, it may have some utility in subtyping salivary gland tumors, particularly salivary duct carcinoma and mammary analogue secretory carcinoma.

Abstract 2404: Prognostic significance of FGFR-2 immunohistochemical expression in breast and prostate adenocarcinomas.

Abstract Background: The fibroblast growth factor receptors (FGFR) are tyrosine kinase receptors with a well established role in angiogenesis and tumorigenesis, mediating transformation and progression in animal and human tumors. Their oncogenic role is well documented in human tumors of colonic, renal, urothelial, pancreatic, pulmonary and oral origin. Although a few reports of FGF/FGFR have demonstrated their influence in breast and prostate carcinogenesis, this is the first clinical study demonstrating the prognostic significance of FGFR-2 expression in these tumors. Design: Formalin-fixed, paraffin-embedded tissue sections from 126 breast [102 ductal carcinomas (IDC) and 24 lobular carcinomas (ILC)] and 136 prostate cancers were immunostained by a manual method using rabbit polyclonal FGFR-2 antibody (sc 122; Santa Cruz Biotech, Santa Cruz, CA). Cytoplasmic and nuclear immunoreactivity was semiquantitatively scored based on staining intensity and distribution and the results were correlated with morphologic and prognostic variables. Results: In breast, intense diffuse cytoplasmic FGFR-2 overexpression was observed in 35/126 (28%) tumors and correlated overall with tumor type (46% ILC vs 24% IDC, p=0.028), disease recurrence (p=0.031) and shortened survival (p=0.048); within the IDC subgroup, with disease recurrence (p=0.001) and shortened survival (p=0.018); and within the ER negative subgroup, with advanced stage (p=0.027) and disease recurrence (p=0.002). On multivariate analysis, early age at diagnosis (p&amp;lt;0.0001), metastatic disease (p&amp;lt;0.0001) advanced stage (p=0.004), and intense diffuse cytoplasmic FGFR-2 overexpression (p=0.013) independently predicted disease recurrence; while advanced stage (p&amp;lt;0.0001) and metastatic disease (p&amp;lt;0.0001) independently predicted overall survival. In prostate, intense diffuse cytoplasmic FGFR-2 overexpression found in 46/136 (34%) correlated with high tumor grade (p=0.003) and advanced tumor stage (p=0.006). Nuclear expression found in 78/136 (57%) cases correlated with high tumor grade (p=0.005). On multivariate analysis of clinicopathologic parameters and FGFR-2 overexpression, advanced tumor stage (p=0.0002) independently predicted biochemical disease recurrence. Conclusion: Cytoplasmic overexpression of the FGFR-2 protein is an independent prognostic factor in breast cancer and correlates with poor prognostic variables in prostate cancer. Further study of FGFR-2 expression, including comprehensive genomic profiling to understand the genomic basis of FGFR-2 overexpression, and to further define its potential role as a target of therapy in breast and prostate cancers appears warranted. Citation Format: Bhaskar VS Kallakury, Christine E. Sheehan, Jeffrey S. Ross. Prognostic significance of FGFR-2 immunohistochemical expression in breast and prostate adenocarcinomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2404. doi:10.1158/1538-7445.AM2013-2404

Oxidative Status and Lipofuscin Accumulation in Urothelial Cells of Bladder in Aging Mice

Age-related changes in various tissues have been associated with the onset of a number of age-related diseases, including inflammation and cancer. Bladder cancer, for instance, is a disease that mainly afflicts middle-aged or elderly people and is mostly of urothelial origin. Although research on age-related changes of long-lived post-mitotic cells such as neurons is rapidly progressing, nothing is known about age-related changes in the urothelium of the urinary bladder, despite all the evidence confirming the important role of oxidative stress in urinary bladder pathology. The purpose of this study was thus to investigate the oxidative status and age-related changes in urothelial cells of the urinary bladder of young (2 months) and aging (20 months) mice by means of various methods. Our results demonstrated that healthy young urothelium possesses a powerful antioxidant defence system that functions as a strong defence barrier against reactive species. In contrast, urothelial cells of aging bladder show significantly decreased total antioxidant capacity and significantly increased levels of lipid peroxides (MDA) and iNOS, markers of oxidative stress. Our study demonstrates for the first time that ultrastructural alterations in mitochondria and accumulation of lipofuscin, known to be one of the aging pigments, can clearly be found in superficial urothelial cells of the urinary bladder in aging mice. Since the presence of lipofuscin in the urothelium has not yet been reported, we applied various methods to confirm our finding. Our results reveal changes in the oxidative status and structural alterations to superficial urothelial cells similar to those of other long-lived post-mitotic cells.

The relationship of cancer stem cells in urological cancers

Numerous studies are ongoing to identify and isolate cancer stem cells from cancers of genito-urinary tracts. Better understanding of their role in prostate, urothelial and kidney cancer origin, growth and progression opens new pathways in development of more effective treatment methods. However there are still many issues before advances in this field can be introduced for clinical application. This review addresses current achievements in cancer stem cells research in uro-oncology.