Difficulty in differential diagnosis for renal cancer with microscopic papillary architecture: overlapped pathological features among papillary renal cell carcinoma (RCC), mutinous tubular and spindle cell carcinoma, and unclassified RCC. Lessons from a Japanese multicenter study.

OBJECTIVES: In our multicenter study evaluating metastatic papillary renal cell carcinoma (PRCC), 29% of tumors diagnosed as PRCC in collaborative institutes were finally diagnosed as other RCCs under central review. In those tumors, mucinous tubular and spindle cell carcinoma (MTSCC) was the leading histology, followed by unclassified RCC (ucRCC). We focused on those patients with MTSCC or ucRCC. METHODS: We reviewed the processes for the pathological diagnoses of nine tumors and reviewed their clinical features. RESULTS: All of the MTSCCs and ucRCCs were positive for AMACR, which is frequently positive in PRCC. Mucin was demonstrated in 80% of the MTSCCs, and its presence is important for their diagnoses. One MTSCC was diagnosed as a mucin-poor variant. The presence of spindle cells with low-grade nuclei was suggestive of MTSCC, but the diagnosis of high-grade MTSCC was difficult. Four tumors were diagnosed as ucRCC by histological and immunohistochemical findings. Three of the four tumors were suspicious of ucRCC in the initial review due to atypical findings as PRCC. Sunitinib and interferon-α were effective for one MTSCC patient who survived for >5 years. Two MTSCC patients who were Memorial Sloan-Kettering Cancer Center poor risk had unfavorable prognoses. One patient with mucin-poor MTSCC had an indolent clinical course. Two of four ucRCC patients showed durable stable disease with targeted agents (TAs) and survived >3 years. CONCLUSION: Some MTSCC metastases progressed very slowly and poor-risk tumors progressed rapidly. Systemic therapies including TAs showed some efficacies. Some patients who have metastatic ucRCC with microscopic papillary architecture can benefit from TAs.

Angiogenic, inflammatory and immunologic markers in predicting response to sunitinib in metastatic renal cell carcinoma.

The objective of this prospective study was to identify baseline angiogenic and inflammatory markers in serum as well as the baseline levels of immune cells in whole blood to predict progression-free survival in patients with metastatic renal cell carcinoma treated with sunitinib. Blood samples were collected at baseline in all 90 patients to analyze serum angiogenic and inflammatory markers together with peripheral blood immunological marker. The association between each marker and sunitinib efficacy was analyzed. Univariate and multivariate Cox proportional model analyses were used to assess the correlation between those markers with survival. Baseline levels of interleukin-6, interleukin-8, high sensitivity C-reactive protein and myeloid-derived suppressor cells were significantly higher in patients who progressed when compared with those with clinical benefit. Analysis by the Cox regression model showed that baseline interleukin-8, high sensitivity C-reactive protein and percentage of T helper type 1 cells were significantly associated with progression-free survival in univariate analysis. Furthermore, in multivariate analysis, those three markers were independent indices to predict progression-free survival. In conclusion, angiogenic (interleukin-8), inflammatory (interleukin-6, high sensitivity C-reactive) and immunologic (myeloid-derived suppressor cells, percentage of T helper type 1 cells) markers at baseline would predict the response to sunitinib therapy and/or disease progression in patients with metastatic renal cell carcinoma.

Clinical efficacy and prognostic factors of tumor progression in Japanese patients with advanced renal cell carcinoma treated with sorafenib.

OBJECTIVE: Result of clinical trial for registration purpose is often difficult to generalize because of its limited population in number and inclusion criteria. METHODS: To understand the efficacy of sorafenib under daily medical practice, we retrospectively investigated therapeutic outcomes of 175 Japanese patients with advanced renal cell carcinoma treated with sorafenib at 15 centers. RESULTS: The objective response rate and disease control rate were 15.4 and 77.1%, respectively, being similar to those in the Phase II study in Japanese patients (19.4 and 73.6 months). Any tumor shrinkage was observed with 53% of patients, while tumor control without growth was in 61%. Lung lesions were more sensitive to sorafenib than other lesions, in terms of any tumor shrinkage (54%) and the extent of maximal shrinkage, while tumor control was better in lymph node metastases (77%) than in lung (69%). Liver was worse in any tumor shrinkage (35%), tumor control (55%) and the extent of tumor growth. Slightly, shorter median overall survival of 21.1 months compared with Phase II clinical trial (25.3 months) is likely to be attributable to different patient population, because median overall survival was improved to 26.4 months when the population was matched to that in Phase II trial. Univariate and multivariate analyses identified prognostic factors for worse overall survival, including intermediate and poor Memorial Sloan-Kettering Cancer Center risk, Eastern Cooperative Oncology Group performance status ≥1, the presence of non-clear cell component and the presence of liver metastasis. CONCLUSIONS: In conclusion, the present study confirmed the efficacy of sorafenib in the real-world setting on advanced renal cell carcinoma.

[Pseudosarcomatous myofibroblastic proliferation of the bladder-case report].

A 66-year-old man with a history of sporadic von Recklinghausen' s disease was treated for pseudosarcomatous myofibroblastic proliferation in the bladder. The patient had a history of repetitive recurrence of bladder carcinoma requiring transurethral resection (TUR) 4 times and 1 course of intravesical BCG instillation. Three months after the fourth TUR, an intravesical solid mass 4 cm in diameter was detected. Suspicion of recurrent bladder carcinoma led to a fifth TUR procedure. Pathological findings showed submucosal growth of myofibroblasts with myxoidal stroma and we made a diagnosis of Pseudosarcomatous myofibroblastic proliferation. The patient was well with no evidence of recurrence after 1 year.

[Neobladder-rectal fistula as early postoperative complication of radical cystectomy and orthotopic neobaldder construction].

We report a case of neobladder-rectal fistula that developed as an early postoperative complication of radical cystectomy and orthotopic neobladder construction procedures. A 75-year-old man underwent a radical cystectomy and orthotopic neobladder construction using Studer's method for locally invasive bladder cancer (cT2N0M0). The patient had severe watery diarrhea on postoperative day 20, and was diagnosed with a neobladder-rectal fistula based on cystography findings. We inserted a Foley catheter into the neobladder, and performed conservative treatment. Four months after development of the fistula, cystography revealed that it had spontaneously closed. A neobladder-rectal fistula is an extremely rare complication, with no other known reports. Herein, we present this case of neobladder-rectal fistula and discuss its formation, diagnosis and treatment, along with reference to previous reports of neobladder-vaginal fistulas.

A study of plasma bicalutamide concentrations in hemodialysis patients.

Bicalutamide is an anti-androgen that is used worldwide to treat prostate cancer (CaP). However, there are no data on blood bicalutamide concentrations in hemodialysis (HD) patients with CaP. Therefore, we investigated the plasma levels of bicalutamide during the peridialysis period in this population. The study group included 5 HD patients with CaP who had been treated with bicalutamide (80 mg/day) for at least 3 months. Blood samples were taken during and between HD sessions and the plasma concentrations of the active R enantiomer (R-bicalutamide) were assessed using an HPLC assay. The plasma R-bicalutamide levels on the non-dialysis day were measured in 2 patients (patients 1 and 2) immediately before dosing and 8 and 24 h after dosing. These levels were 18,730, 19,090 and 19,420 ng/ml (patient 1), and 4,522, 4,581, and 5,296 ng/ml (patient 2), respectively. The mean plasma levels of R-bicalutamide in all 5 subjects just before HD, and 2 and 4 h after the start of HD were 8,726, 9,354 and 10,068 ng/ml, respectively. These results show that bicalutamide does not accumulate and is not diluted in the blood circulation of HD patients when given at the normal dosage used in the general population.

[Renal epithelioid angiomyolipoma with malignant behavior].

The patient was a 22-year-old woman with a history of tuberous sclerosis who complained of abdominal distention. Computed tomography showed bilateral renal masses with minimal fat tissue that were unlike classical angiomyolipoma (AML), as well as enlargement of the paraaortic lymph nodes, pleural effusion, and ascites, similar to other advanced malignant neoplasms such as renal cell carcinoma and renal sarcoma. We performed a left nephrectomy to relieve the symptoms. A pathological examination revealed that the tumor was composed of polygonal epithelioid cells positive for both αSMA and HMB-45, as well as spindle-shaped cells, while immunoreactivity proved the tumor to be an eAML, a subtype of AML with malignant potential. Although the patient was scheduled for postoperative adjuvant chemotherapy, her condition worsened and she died on postoperative day 24 before receiving chemotherapy. We discuss this case with reference to previous reports.

Clinical results and pharmacokinetics of sorafenib in chronic hemodialysis patients with metastatic renal cell carcinoma in a single center.

OBJECTIVE: We investigated the safety and feasibility of sorafenib in patients with end-stage renal disease undergoing hemodialysis by examining the influence of pharmacokinetic parameters to their benefit and also the occurrence of drug-related adverse events of sorafenib. METHODS: Ten patients with metastatic renal cell carcinoma undergoing hemodialysis received sorafenib. Initial dose was 200 mg once daily, and the dose was increased up to the maintenance dose of 200 mg twice daily. The pharmacokinetic study was performed after a steady state was reached with 200 mg twice daily in six patients. RESULTS: Complete response occurred in one patient, partial response in three, stable disease in four and progressive disease in two. Median progression-free survival was 6.3 months. Serious adverse events were found in nine patients, including a Grade 5 subarachnoid hemorrhage and a Grade 4 cerebellar hemorrhage. In the pharmacokinetic study, the geometric mean of maximum concentration and area under the curve from 0 to 10 h of plasma concentration were similar on the day of hemodialysis and the day off hemodialysis. These data were lower than those from Japanese people with healthy kidneys and normal kidney function. There was no association between objective response or the occurrence of serious adverse events and pharmacokinetic parameters. CONCLUSIONS: Treatment with sorafenib of patients with metastatic renal cell carcinoma undergoing hemodialysis appears to be feasible, but we express some concern about the higher incidence of serious adverse events even with the reduced dose. However, clinical efficacy was not compromised.

Postoperative renal function after partial nephrectomy for renal cell carcinoma in patients with pre-existing chronic kidney disease: a comparison with radical nephrectomy.

We assessed whether adequately functioning parenchyma is preserved in patients with pre-existing chronic kidney disease (CKD) after partial nephrectomy (PN) compared with those who underwent radical nephrectomy (RN). A total of 95 patients with pre-existing CKD who underwent curative surgery for pathological T1a-T2N0M0 renal cell carcinoma with a follow-up period of 12 months or more were the subject of the present study. Of these, 51 patients underwent RN, and 44 PN. Renal function was assessed by using the estimated glomerular filtration rate (e-GFR). We classified the subjects into two groups according to the preoperative e-GFR: preoperative e-GFR 45-59 mL/min/1.73 m(2) (68 patients); and 30-44 mL/min/1.73 m(2) (27 patients). In the former group, the probability of freedom from new onset of e-GFR <45 mL/min/1.73 m(2) stemmed from the significant difference between the PN and RN groups (P = 0.006; PN: 2 years 64%; RN: 2 years 22%). In contrast, in the latter group, the probability of freedom from new onset of e-GFR <30 mL/min/1.73 m(2) was not associated with a significant difference between PN and RN group (P = 0.80). Overall survival and the number of the patients who went on to develop end-stage renal disease requiring renal replacement therapy between PN and RN were not significantly different in each group. Death from renal cell carcinoma was not noted in either group. PN could significantly prevent development to late-stage CKD in patients with preoperative e-GFR 45-59 mL/min/1.73 m(2) compared with RN. Patients with preoperative e-GFR 30-44 mL/min/1.73 m(2) should be reviewed in a more strict study.

Template-based lymphadenectomy in urothelial carcinoma of the upper urinary tract: impact on patient survival.

OBJECTIVES: The benefit of lymphadenectomy (LND) in patients with urothelial carcinoma of the upper urinary tract (UCUUT) has remained controversial. The aim of this study was to examine the influence of the LND template and the total number of lymph nodes (LN) when increasing the number of patients undergoing complete dissection of regional nodes (CompLND). METHODS: A total of 109 UCUUT patients with clinically negative nodes underwent nephroureterectomy with concomitant lymphadenectomy at our center. Patients' survival was examined according to the type of LND and the number of removed LN. Univariate analysis was performed to find the cut-off value of LN influencing survival. RESULTS: Seventy-eight patients underwent CompLND. Incomplete lymphadenectomy was performed in an additional 41 patients. In the patients with pT2 or higher who were clinically negative for nodal metastasis, any cut-off value for the total number of LN removed showed no statistical significance. In contrast, CompLND had a significant impact on patient survival. The Cox proportional hazard model showed that CompLND was a significant factor after adjusting for adjuvant chemotherapy. The total number of removed LN was not significant. CONCLUSIONS: In patients with muscle-invasive clinical node-negative UCUUT, the number of LN removed shows minimal influence on their survival. In contrast, the influence of the particular type of lymphadenectomy is statistically significant. These findings suggest that the extent of lymphadenectomy should be determined by the template and not by the number of removed LN.

Contralateral metachronous tumor occurrence is more frequently associated with distant metastases or postoperative intrarenal recurrence in renal cell carcinoma patients.

OBJECTIVE: To analyze the prognosis of patients with sporadic bilateral renal cell carcinoma (RCC). METHODS: From January 1979 to December 2007, 984 patients with sporadic RCC underwent surgery at our department. Of these, 53 patients (5.7%) presenting with bilateral RCC were included in this retrospective analysis. RESULTS: Thirty-one of the 53 bilateral RCC patients had synchronous RCC, and 22 had metachronous RCC. Distant metastases by the time of the bilateral tumor occurrence were found in four patients (13%) in the synchronous group and in 10 patients (48%) in the metachronous group. No difference was found between the two groups in terms of overall survival. In contrast, survival after the second surgery in the metachronous group was significantly lower than that after the first surgery (P < 0.001) in the synchronous group (P = 0.02). In addition, the incidence of local recurrence after partial nephrectomy was higher in the metachronous group (26%) compared to the synchronous group (4%, P = 0.04) or the unilateral RCC patients (0.4%, P < 0.01). CONCLUSIONS: Metachronous occurrence of RCC in the contralateral kidney is associated with an unfavorable prognosis, suggesting that metachronous contralateral tumors might be metastasis of the original tumors. A stricter follow-up schedule is advisable for metachronous bilateral RCC patients.

Computed tomographic appearance of urachal carcinoma associated with urachal diverticulum misdiagnosed by cystoscopy.

Urachal carcinoma associated with the urachal diverticulum is rare. We present a surgical case of this condition that was initially diagnosed as bladder urothelial carcinoma by cystoscopy, but was then correctly diagnosed by computed tomography (CT). Whereas the CT appearance mimicked that of bladder cancer, accurate localization of the lesion and identification of the median umbilical ligament clarified diagnosis.

Penile malignant melanoma in a hemodialysis patient.

A patient who was receiving hemodialysis treatment developed melanotic macules on the surface of the penis in 2002 and showed a tumor-like mass in the same region in July 2006. The patient presented with a pedunculated tumor of 3 cm in diameter on the right side of his penis. The tumor was resected for biopsy and was diagnosed as malignant melanoma. The melanoma was in stage IIIB with pT4 N1 M0. The patient received interferon-beta for a total of three courses. A computed tomography scan in the 10th postoperative month did not find any additional metastatic foci or recurrence of the tumor. In the present case, side effects caused by interferon were not observed. Therefore, particularly in dialysis patients, immune therapy might be favored over anticancer drug treatment.

Spermatic cord abscess with concurrent prostatic abscess involving the seminal vesicle.

Prostatic abscess involving the seminal vesicle has become rare following the development of effective antibiotic treatments. To our knowledge, we report the first case in the English-language literature of a patient with a spermatic cord abscess and a concurrent prostatic abscess. We examined an 81-year-old man for swelling and pain in the left inguinal region and performed computed tomography (CT) that later confirmed the suspected diagnosis of left inguinal hernial strangulation. We performed urgent surgical drainage of a left spermatic cord abscess; and under the correct diagnosis by CT, he was successfully treated further with antibiotics and transperineal drainage of a prostatic abscess extending to the seminal vesicle. We highlight that familiarity with such a rare condition is overwhelmingly essential for patient management and that CT is the most valuable imaging procedure for diagnosing such cases.

Clinical Outcomes in Patients With Metastatic Papillary Renal-Cell Carcinoma: A Multi-Institutional Study in Japan.

BACKGROUND: Standard treatments have not been established in metastatic papillary renal-cell carcinoma (PRCC). We aimed to investigate treatment outcomes in patients with mPRCC. PATIENTS AND METHODS: This study included 51 patients who were diagnosed with PRCC at 14 institutions. Pathologic slides were reviewed by pathologists. The associations between clinical factors and overall survival (OS) were analyzed. RESULTS: Final pathologic diagnoses could be determined in 50 patients. Thirty-five tumors were diagnosed as PRCC (type 2 PRCC, 91.4%), and 15 were diagnosed as other histologic types. Targeted therapies (TTs) were provided to 25 mPRCC patients. Patients treated with TT survived significantly longer than those treated before the era of TT (median OS, 22.5 vs. 6.3 months; P = .0035). Median OS of patients who experienced stable disease for ≥ 9 months using single TT was 43.1 months. Patients treated with a tyrosine kinase inhibitor (TKI) as first-line TT survived longer after TT initiation than those treated with an mTOR inhibitor (median, 22.4 vs. 11.7 months; P = .2684). Patients treated with TKIs in both first- and second-line settings had significantly better survival after TT initiation than those treated with a TKI in one therapy line and an mTOR inhibitor in the other (31.4 vs. 12.9 months, P = .0172). Patients treated with a TKI as second-line TT survived significantly longer after second-line TT initiation than did those treated with an mTOR inhibitor (16.2 vs. 7.4 months, P = .0016). CONCLUSION: Prognoses of patients with mPRCC were improved by TT, and TKIs appeared to be the treatment of choice in both the first- and second-line settings.

Rapid Progressive Disease After Nivolumab Therapy in Three Patients with Metastatic Renal Cell Carcinoma.

BACKGROUND/AIM: Rapid progressive disease (RPD), accelerated tumour growth immediate after the initiation of immune checkpoint inhibitor therapy, has been reported in melanoma and lung cancer. Herein, we describe 3 cases of RPD during the initial phase of nivolumab treatment for metastatic renal cell carcinoma. PATIENTS AND METHODS: The first and second patients received nivolumab in the fourth-line setting. The third patient received nivolumab therapy as third-line treatment. RESULTS: The first patient developed severe respiratory failure due to carcinomatous lymphangiosis 14 days after initiation of nivolumab therapy. The second patient developed leg paraplegia due to rapid growth of the metastatic tumour at the sixth thoracic vertebrae 5 days later. The third patient developed grade 4 hypercalcemia due to RPD on day 3. CONCLUSION: Clinicians should be aware of RPD during the initial phase of nivolumab therapy, especially in patients with critical lesions in the late-line setting.

[Clinico-pathological investigation of upper urinary tract tumors in patients with normal renal function and in patients with end stage renal disease].

AIMS: To clinically investigate upper urinary tract tumors in end stage renal disease (ESRD) patients. PATIENTS AND METHODS: Between 1988 and 2003, a study was made of 153 patients who underwent surgical treatment for upper urinary tract tumors in the Department of Urology, Tokyo Women's Medical University. Of these, 10 had ESRD while 143 had normal renal function. Comparisons were made of the following variables between the two groups: patient's background, clinical findings, surgical procedures, pathological findings, prognosis, depth of tumor cell invasion, tumor grades, postoperative survival rates, cancer-specific survival rates, and complications. RESULTS: Ten ESRD patients with upper urinary tract tumors were comprised of 5 males and 5 females with a median age of 59 (40-71) years and an average hemodialysis period of 71 (0-279) months. Macroscopic hematuria appeared in seven cases (70%) at the onset, and tumors occurred at the renal pelvis in nine cases (90%). As to the T stage, seven cases (70%) were pT2 or more and all 10 cases (100%) exhibited grade 2 or higher in ESRD patients, yielding no significant differences with the cases of normal renal function. In addition, there was no significant difference in both groups with respect to postoperative survival rates and cancer-specific survival rates in cases with curative resection. CONCLUSION: Although upper urinary tract tumors had been considered to exhibit higher grades and stages of malignancy in ESRD cases than in those with normal renal function, the present results showed that the clinico-pathological features are similar in both patients groups. Given that there was no significant difference in postoperative survival rates and cancer-specific survival rates, radical surgery should be also indicated, if possible, for the ESRD patients with upper urinary tract tumors as well as the patients with normal renal function.

Hypermethylation of the CpG island of connexin 32, a candiate tumor suppressor gene in renal cell carcinomas from hemodialysis patients.

Long duration of patients on hemodialysis is a large risk for the development of renal cell carcinoma (RCC) compared to general patients. However, the carcinogenic process is still unclear. On the other hand, we have reported that connexin (Cx) 32, a molecule of gap junction, is a new tumor suppressor gene in human RCC. In this study, we investigated the clinical significance of methylation-dependent silencing of Cx32 gene in the development of the RCC from the hemodialysis patients. As the result, we found that the inactivation of Cx32 through hypermethylation of the promoter regions frequently occurred in non-cancerous regions as well as cancerous regions of kidneys from hemodialysis patients. However, the hypermethylation of Cx32 occurred only in cancerous regions but not non-cancerous regions of kidneys from the general patients without hemodialysis. Furthermore, the hypermethylation of RASSAF1A, a representative tumor suppressor gene in human RCC, occurred in cancerous regions but not non-cancerous regions of kidneys from the hemodialysis and general patients. These results suggest that Cx32 is a promising tumor suppressor gene relating to the early stage of renal carcinogenesis in the hemodialysis patients.

[A case of focal xanthogranulomatous pyelonephritis difficult to differentiate from renal cell carcinoma].

A 34-year-old female with left flank pain persisting for 3 months consulted us on 19 Feb, 2001. Ultrasonography (US), computerized tomography (CT), magnetic resonance imaging (MRI) and renal angiography revealed a cystic renal tumor in the upper pole of the left kidney invading the spleen, and paraaortic lymph node swelling. Left radical nephrectomy combined with splenectomy and partial diaphragmectomy was performed under a tentative diagnosis of renal cell carcinoma. However, histopathological findings revealed xanthogranulomatous pyelonephritis (XGP). XGP is a rare, severe, chronic inflammatory disease characterized by accumulation of lipid laden macrophages. XGP is classified as diffuse or focal type. Preoperative diagnosis of focal XGP is difficult because of radiological similarities to renal cell carcinoma. Our case was more difficult to diagnose because she showed few signs of inflammation and had no history of urinary tract infection or stones.

[The clinical efficacy of Bladder Chek NMP22 in urothelial cancer].

The purpose of this study is to investigate the clinical efficacy of a quick test for NMP22 (Nuclear Matrix Protein 22), Bladder Chek NMP22, as a screening test for urothelial cancers. The subjects include 51 cases(43 cases with pathologically confirmed bladder cancer, and 8 cases with upper urothelial cancer). Bladder Chek NMP22 revealed false positive in the urine with more than 1 x 10(5)/microliter of erythrocytes and 1 x 10(3)/microliter of white blood cells. Thus, showing that Bladder Chek NMP22 was not relatively affected by the contaminated erythrocytes and white blood cells, compared with other conventional methods to detect urinary malignant disease. In 51 cases diagnosed of having pathologically urothelial cancers, the sensitivity of Bladder Chek NMP22 was 56.8%. Bladder Chek NMP22 demonstrated more excellent sensitivity than the other methods. The positivity of Grade3 patients was 68.4%, 68.4% and 63.2% by Bladder Chek NMP22, NMP22 ELISA and urinary cytology. In contrast, the positivity rate for the patients with Grade1 stage was 58.3%, 33.3% and 8.3%. There is no significance of positivity rate between each examination in patients with high grade cancer. However Bladder Chek NMP22 demonstrated the higher positivity in patients with low grade cancer. Bladder Chek NMP22 test could be an easy and confidential method to detect urothelial cancers, especially with low grade, as a screening examination.