Comparative analyses define differences between BHD-associated renal tumour and sporadic chromophobe renal cell carcinoma.

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome, caused by germline alteration of folliculin (FLCN) gene, develops hybrid oncocytic/chromophobe tumour (HOCT) and chromophobe renal cell carcinoma (ChRCC), whereas sporadic ChRCC does not harbor FLCN alteration. To date, molecular characteristics of these similar histological types of tumours have been incompletely elucidated. METHODS: To elucidate renal tumourigenesis of BHD-associated renal tumours and sporadic renal tumours, we conducted whole genome sequencing (WGS) and RNA-sequencing (RNA-seq) of sixteen BHD-associated renal tumours from nine unrelated BHD patients, twenty-one sporadic ChRCCs and seven sporadic oncocytomas. We then compared somatic mutation profiles with FLCN variants and RNA expression profiles between BHD-associated renal tumours and sporadic renal tumours. FINDINGS: RNA-seq analysis revealed that BHD-associated renal tumours and sporadic renal tumours have totally different expression profiles. Sporadic ChRCCs were clustered into two distinct clusters characterized by L1CAM and FOXI1 expressions, molecular markers for renal tubule subclasses. Increased mitochondrial DNA (mtDNA) copy number with fewer variants was observed in BHD-associated renal tumours compared to sporadic ChRCCs. Cell-of-origin analysis using WGS data demonstrated that BHD-associated renal tumours and sporadic ChRCCs may arise from different cells of origin and second hit FLCN alterations may occur in early third decade of life in BHD patients. INTERPRETATION: These data further our understanding of renal tumourigenesis of these two different types of renal tumours with similar histology. FUNDING: This study was supported by JSPS KAKENHI Grants, RIKEN internal grant, and the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research.

Single-cell transcriptomes underscore genetically distinct tumor characteristics and microenvironment for hereditary kidney cancers.

Our understanding of how each hereditary kidney cancer adapts to its tissue microenvironment is incomplete. Here, we present single-cell transcriptomes of 108,342 cells from patient specimens including from six hereditary kidney cancers. The transcriptomes displayed distinct characteristics of the cell of origin and unique tissue microenvironment for each hereditary kidney cancer. Of note, hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated kidney cancer retained some characteristics of proximal tubules, which were completely lost in lymph node metastases and present as an avascular tumor with suppressed T cells and TREM2-high macrophages, leading to immune tolerance. Birt-Hogg-Dubé (BHD)-associated kidney cancer exhibited transcriptomic intratumor heterogeneity (tITH) with increased characteristics of intercalated cells of the collecting duct and upregulation of FOXI1-driven genes, a critical transcription factor for collecting duct differentiation. These findings facilitate our understanding of how hereditary kidney cancers adapt to their tissue microenvironment.

[A Case of Lymphoepithelioma-Like Carcinoma of the Ureter].

Lymphoepithelioma-like carcinoma (LELC) of the ureter is very rare and only 14 previous cases have been reported. Here, we report a case of LELC of the ureter. A 76-year-old woman was admitted to our hospital complaining of gross hematuria. Left ureteral cancer was suspected by the imaging examination, and laparoscopic left total nephroureterectomy was performed. Histopathological examination showed pure type of LELC in the ureter. She is alive without disease recurrence at fifteen months after surgery.

FLCN alteration drives metabolic reprogramming towards nucleotide synthesis and cyst formation in salivary gland.

FLCN is a tumor suppressor gene which controls energy homeostasis through regulation of a variety of metabolic pathways including mitochondrial oxidative metabolism and autophagy. Birt-Hogg-Dubé (BHD) syndrome which is driven by germline alteration of the FLCN gene, predisposes patients to develop kidney cancer, cutaneous fibrofolliculomas, pulmonary cysts and less frequently, salivary gland tumors. Here, we report metabolic roles for FLCN in the salivary gland as well as their clinical relevance. Screening of salivary glands of BHD patients using ultrasonography demonstrated increased cyst formation in the salivary gland. Salivary gland tumors that developed in BHD patients exhibited an upregulated mTOR-S6R pathway as well as increased GPNMB expression, which are characteristics of FLCN-deficient cells. Salivary gland-targeted Flcn knockout mice developed cytoplasmic clear cell formation in ductal cells with increased mitochondrial biogenesis, upregulated mTOR-S6K pathway, upregulated TFE3-GPNMB axis and upregulated lipid metabolism. Proteomic and metabolite analysis using LC/MS and GC/MS revealed that Flcn inactivation in salivary gland triggers metabolic reprogramming towards the pentose phosphate pathway which consequently upregulates nucleotide synthesis and redox regulation, further supporting that Flcn controls metabolic homeostasis in salivary gland. These data uncover important roles for FLCN in salivary gland; metabolic reprogramming under FLCN deficiency might increase nucleotide production which may feed FLCN-deficient salivary gland cells to trigger tumor initiation and progression, providing mechanistic insight into salivary gland tumorigenesis as well as a foundation for development of novel therapeutics for salivary gland tumors.

[A CASE REPORT OF FUNGUS BALL FOUND DURING TRANSURETHRAL URETEROLITHOTOMY].

Herein we report the confirmation of fungus balls (circular collections of C.tropicalis) during a transurethral ureterolithotomy, which is as far as we know the first reported instance. A-61-year old man was referred to the urology department with bilateral ureteral calculi. Initially a transurethral ureterolithotomy was attempted but residual stones existed. During the second operation, we found numerous white fluffy material in the renal pelvis. Because of them, we were unable to have a clear field of vision to complete operation. During the third operation, we found the fungus balls again and cultured them. Cultures yielded C.tropicalis.

[NON-SPECIFIC GRANULOMATOUS PROSTATITIS: A CASE REPORT].

We report non-specific granulomatous prostatitis in a 58-year-old man who visited a Urology clinic with fever and dysuria. Digital rectal examination revealed prostatic tenderness, and laboratory examination of the urinary sediment revealed pyuria. Thus, he was diagnosed with acute bacterial prostatitis and treated with antibiotics. He remained symptomatic despite treatment; therefore, he was referred to our hospital. A second digital rectal examination (performed at our hospital) revealed stony hard nodules in the prostate and an irregularity of its surface. Moreover, magnetic resonance imaging (MRI) suggested a prostate cancer. We performed a transperineal needle biopsy, which revealed only non-specific inflammatory cells without any evidence of neoplasm in the specimen. Therefore, a definitive diagnosis could not be established. Nevertheless, he continued to show a high index of suspicion for prostatic malignancy based on his clinical findings. Therefore, we performed a transurethral resection of the prostate and a transrectal biopsy to obtain more specimens. Microscopic findings revealed granulomatous prostatitis without any evidence of prostate carcinoma. Notably, an MRI demonstrated remarkable shrinkage of the prostate 3 months after the diagnosis. Non-specific granulomatous prostatitis is a rare inflammatory disease. Because it is difficult to differentiate this disease from prostatic neoplasms based on clinical findings or imaging modalities such as MRI, a few reports have described performing a radical prostatectomy in patients. This disease usually demonstrates a good prognosis as was noted in our patient. We conclude that establishing a preoperative histopathological diagnosis is important to avoid invasive procedures.

Squamous Cell Carcinoma in a Calyceal Diverticulum Detected by Percutaneous Nephroscopic Biopsy.

A 73-year-old woman was referred to our department with a complaint of asymptomatic gross hematuria. Dynamic computed tomography revealed a complicated (Bosniak type IIF) cyst in the upper pole of her right kidney, which was diagnosed as a calyceal diverticulum. The diagnosis was confirmed by ureteroscopy. The diverticulum was filled with a soft protein matrix that was difficult to completely remove from the inner surface of the calyceal diverticulum. Endoscopy combined with intrarenal surgery (ECIRS) was performed to completely remove the matrix. Percutaneous nephroscopy further revealed papillary lesions on the surface of the diverticulum, confirmed as squamous cell carcinoma on pathological assessment. A laparoscopic right radical nephroureterectomy was performed, with curative intent. Pathological assessment confirmed a high-grade squamous cell carcinoma with renal parenchymal invasion (pT3). Although carcinomas in a calyceal diverticulum are highly uncommon, when present, these tend to be high-grade neoplasms that deeply invade the parenchymal wall. As the effective management of these lesions is difficult, early-stage diagnosis is required for curative treatment. We report the case of squamous cell carcinoma in a calyceal diverticulum that was difficult to diagnose on preoperative computed tomography, urinal cytology examination, and ureteroscopy but was found during ECIRS.

Time-dependent change in relapse sites of renal cell carcinoma after curative surgery.

We investigated time-dependent changes in the relapse features of renal cell carcinoma (RCC) after curative surgery. Between 1985 and 2015, 1398 patients with RCC (1226 clear cell RCC, 89 papillary RCC, and 53 chromophobe RCC) underwent curative surgery at Yokohama City University Hospital and its affiliated hospitals. We retrospectively reviewed the clinicopathologic factors of patients with relapse after surgery. Median follow-up was 56.3 months. Recurrence occurred in 245 patients (217 clear cell RCC, 12 papillary RCC, and 3 chromophobe RCC). Papillary RCC and chromophobe RCC had no recurrence beyond 5 years after surgery, but 20 cases of clear cell carcinoma had recurrence beyond 10 years after surgery. The typical recurrence sites of clear cell RCC were lung (46.6%), bone (17.9%), liver (7.6%), and lymph nodes (6.5%). The proportion of recurrences at these typical sites was 83.9% for recurrences within 5 years, 76.3% between 5 and 10 years, and 40.0% beyond 10 years. In contrast, the proportion of retroperitoneal organ recurrence, including contralateral kidney, pancreas, and adrenal glands, increased with increasing time after surgery. Interestingly, the hazard ratio of typical site relapse decreased whereas that of retroperitoneal organ relapse increased in a time-dependent manner. In summary, clear cell RCC showed potential to relapse beyond 10 years after surgery. Recurrence at typical sites decreased whereas retroperitoneal organ recurrence increased in a time-dependent manner. Clinicians should check for recurrence at various sites beyond 10 years, especially in clear cell RCC.

[GIANT BLADDER CALCULI TREATED WITH SINGLE-STAGE SIMULTANEOUS PERCUTANEOUS SUPRAPUBIC AND TRANSURETHRAL CYSTOLITHOTRIPSY: A CASE REPORT].

An 82-year-old man presented with lower abdominal pain and general malaise. Noncontrast computed tomography revealed a remarkably enlarged prostate and a full bladder with a giant stone 80 mm in diameter causing bilateral hydroureteronephrosis. Laboratory data demonstrated systemic inflammation and renal dysfunction with hyperkalemia. Acute postrenal dysfunction caused by urinary retention was diagnosed. A urethral catheter was inserted and emergent dialysis was initiated. After renal function recovered, we performed lithotripsy for the urinary bladder calculi. To achieve stone free status with a single-stage procedure, we performed simultaneous percutaneous suprapubic and transurethral cystolithotripsy. The procedure was successfully performed without significant complications.The patient was discharged 9 days after surgery, although clean intermittent catheterization was required.Giant bladder calculi are often treated with cystolithotomy because transurethral cystolithotripsy requires time to remove all fragments. In this case, we achieved stone free status in acceptable operative time by performing simultaneous percutaneous suprapubic and transurethral cystolithotripsy. In conclusion, the endourological management is an effective treatment choice, even in a case with a giant bladder calculus.

[Renal Cell Carcinoma with Retroperitoneal Metastases and Renal Invasion from Breast Cancer : A Case Report].

A 67-year-old female was hospitalized with back pain. Computed tomography (CT) incidentally revealed a tumor in her left kidney tumor (33 mm) and bilateral breast tumors. She underwent a breast biopsy and was diagnosed with breast cancer (invasive lobular cancer, cT2N0M0). The renal tumor was suspected to be clear cell carcinoma, cT1aN0M0, based on contrast-enhanced CT. Surgery was considered necessary for both the breast cancer and renal tumor. First, laparoscopic radical nephrectomy was performed for the renal tumor. However, the lateroconal fascia adhered strongly to the perirenal fat, and so simple nephrectomy was carried out after conversion to open surgery. The perirenal fat was also excised after the nephrectomy. A histopathological examination revealed clear cell carcinoma and renal invasion by invasive lobular cancer cells. Also, scattered metastases were detected in the perirenal fat and the lateroconal fascia. So, it was considered that retroperitoneal metastases from the breast cancer had directly invaded the kidney. After the operation, the patient received hormonal therapy for her breast cancer, and she was still alive and symptom-free 5 months after the operation.

Measurement of serum isoform [-2]proPSA derivatives shows superior accuracy to magnetic resonance imaging in the diagnosis of prostate cancer in patients with a total prostate-specific antigen level of 2-10 ng/ml.

OBJECTIVE: More accurate diagnostic procedures for prostate cancer are needed to avoid unnecessary biopsy due to the low specificity of prostate-specific antigen (PSA). Recent studies showed that the percentage of serum isoform [-2]proPSA (p2PSA) to free PSA (%p2PSA), the Prostate Health Index (PHI) and magnetic resonance imaging (MRI) were more accurate than PSA. The aim of this study was to test the accuracy of %p2PSA, PHI and MRI in discriminating patients with and without prostate cancer. MATERIALS AND METHODS: The subjects were 50 consecutive men with a PSA level of 2.0-10.0 ng/ml, who underwent prostate biopsy from October 2012 to July 2014. These patients underwent multiparametric MRI before biopsy, and their serum samples were measured for PSA, free PSA and p2PSA. The sensitivity, specificity and accuracy of PHI, %p2PSA and MRI were compared with PSA in the diagnosis of biopsy-confirmed prostate cancer. RESULTS: In a univariate analysis, %p2PSA [area under the curve (AUC): 0.811] and PHI (AUC 0.795) were more accurate than MRI (AUC: 0.583) and PSA (AUC: 0.554) for prostate cancer detection. At 60% sensitivity, the specificity of PHI (76.5%) was higher than that of MRI (52.9%). For significant cancer detection, %p2PSA (AUC: 0.745), PHI (AUC: 0.791) and MRI (AUC: 0.739) were marginally more accurate than PSA (AUC: 0.696). At 85% sensitivity, the specificity of MRI (62.1%) was higher than that of PHI (34.5%). CONCLUSION: PHI and %p2PSA can be used for screening the general population and MRI can be used for detection of significant cancer in patients suspected, from screening tests, of having prostate cancer.

Bilateral renal lymphoma: rapid recovery from an acute kidney injury after open renal biopsy.

Renal lymphoma as an initial lesion is relatively rare. Bilateral renal lymphoma frequently presents as acute kidney injury. With systematic chemotherapy for the lymphoma, patients usually recover their kidney function. However, in the case we describe here, the patient's kidney function recovered greatly after an open renal biopsy. Here, we review and discuss this unique case.

Mucinous cystadenoma of a horseshoe kidney: A case report and literature review.

A 45-year-old man complained of a palpable mass in his left abdomen. Computed tomography showed a horseshoe kidney with a Bosniak type II complicated cyst from a left segment. Three years after his initial examination, due to the growing cystic lesion and the compression imposed on the urinary collecting system and surrounding organs, we performed a left heminephrectomy. The diagnosis was mucinous cystadenoma of the kidney. No recurrence was observed 6 months after surgery. The histopathology was unique since the inner surface of the cyst was covered by a mucin-positive columnar epithelium connected to a urothelium, with continuous transition between the two. This suggests that the mucinous tumour may have originated from a sequestered segment of the renal pelvic epithelium in the renal parenchyma.