Prognostic value of micrometric substaging in pT1 bladder cancer patients treated with en-bloc transurethral resection.

AIMS: We aimed to assess the oncological impact of micrometric extent of invasion in patients with pT1 bladder cancer (BCa) who underwent en-bloc resection for bladder tumour (ERBT). METHODS AND RESULTS: We retrospectively analysed the records and specimens of 106 pT1 high-grade BCa patients who underwent ERBT. The extent of invasion, such as depth from basal membrane, number of invasive foci, maximum width of invasive focus, muscularis mucosae invasion and infiltration pattern (pattern A: solid sheet-like, nodular or nested growth, pattern B: trabecular, small cluster or single-cell pattern) were evaluated by a single genitourinary pathologist. The end-points were recurrence-free (RFS) and progression-free survival (PFS). Within a median follow-up of 23 months, overall, 36 patients experienced recurrence and 13 patients experienced disease progression. The 2-year PFS differed significantly depending on depth from basal membrane (< 1.3 mm: 94.8% versus ≧ 1.3 mm: 65.2%, P = 0.005), maximum width of invasive focus (< 4 mm: 91.7% versus ≧ 4 mm: 62.3%, P < 0.001), muscularis mucosae (MM) invasion (above MM = 96.1% versus into or beyond MM = 64.8%, P = 0.002) and infiltration pattern (pattern A: 100% versus pattern B: 83.3%, P = 0.037). In a multivariable analysis, MM invasion [hazard ratio (HR) = 4.54, 95% confidence interval (CI) = 1.25-16.5] and maximum width of invasive focus ≧ 4 mm (HR = 4.79, 95% CI = 1.25-16.5) were independent prognostic factors of progression. CONCLUSIONS: En-bloc resection facilitates the evaluation of pathologic variables that might be useful in predicting disease recurrence and progression. In particular, not only the MM invasion but also the maximum width of invasion focus, reflecting the invasive volume, appear to be reliable prognosticators for disease progression.

pT1 Subclassification Predicts Progression-Free Survival in En Bloc Resection of Bladder Tumor Specimens.

CONTEXT.­: The pathologic diagnosis of pT1 substage in conventional transurethral resection of bladder tumor specimens is inaccurate and has low interobserver reproducibility owing to fragmentation and cauterization of the specimens. En bloc resection of bladder tumor is a novel surgical procedure that improves diagnostic feasibility and accuracy in the pathologic diagnosis of bladder cancer, including depth and extent of invasion. OBJECTIVE.­: To examine the prognostic value of multiple pT1 subclassification methods, using only en bloc resection specimens. DESIGN.­: We examined 106 patients with T1 bladder cancer who underwent en bloc resection. The pT1 substages were assigned by 3 different subclassification methods by using the muscularis mucosae or stalk of the papillary lesion as diagnostic landmarks or millimetric depth of invasion. Intergroup differences in progression-free survival and recurrence-free survival rates were analyzed. The prognostic values of clinicopathologic factors for progression/recurrence were analyzed by using multivariate analysis. RESULTS.­: The pT1 substage was evaluable in all cases. Tumors with invasion into/beyond the muscularis mucosae and those beyond the stalk of the papillary lesion were associated with worse progression-free survival (P = .002 and P = .01, respectively). Notably, no patient with invasion confined to the stalk had disease progression during the 23-month median follow-up period. Only the pT1 subclassification method using the muscularis mucosae was an independent prognosticator of progression in multivariate analysis (P = .03). CONCLUSIONS.­: Precise pathologic subclassification of invasion using en bloc resection specimens may enable accurate prognosis and assessment in patients with bladder cancer with suspicious shallow invasion.

Clinical impact of detrusor muscle in en bloc resection for T1 bladder cancer.

PURPOSE: Detrusor muscle (DM) in the resected specimen of patients with pT1 bladder cancer (BCa) is a quality-of-care criteria. We aimed to assess whether obtaining adequate DM is dependent on surgeon's experience, whether is a surrogate for resection quality, and whether the degree of DM thickness is related to postoperative outcomes in en bloc resection for bladder tumors (ERBT). MATERIALS AND METHODS: We retrospectively analyzed the records of 106 pT1 high-grade BCa patients who underwent ERBT at several institutions. All specimens were reviewed by a single pathologist who assessed the presence or absence of DM and its thickness measured by a micrometer, when present. Early recurrence, defined as pathologically confirmed BCa on repeat resection or tumor recurrence at the first follow-up cystoscopy (within 3 months), was the endpoint reflective of the resection quality. RESULTS: Of 106 patients, DM was detected in 99 (93%), and the median DM thickness was 1.8 mm. Large tumor size (>30 mm) was associated with adequate DM sampling (>1.8mm) (odds ratio [OR]: 6.10, 95% confidence intervals [CIs]: 2.08-17.9, P = 0.001), while surgeon's experience was not. DM presence and DM thickness were both not associated with early recurrence, while positive surgical margin was an independent prognosticator for early recurrence (OR: 3.38, 95% CI: 1.12-10.2, P = 0.031). Excessive DM sampling (>2.1 mm) was associated with prolonged urethral catheterization (OR: 28.8, 95% CI: 3.36-248, P = 0.002). CONCLUSIONS: In ERBT, surgeon's experience seems irrelevant to obtain DM. Resection quality relies on surgical margin status, not the degree of DM. Obtaining excessive DM incurs adverse events/unnecessary medical care.

En Bloc Resection Versus Conventional TURBT for T1HG Bladder Cancer: A Propensity Score-Matched Analysis.

BACKGROUND: We aimed to assess the clinical, oncological, and pathological impact of en bloc resection of bladder tumors (ERBT) compared with conventional transurethral resection of bladder tumors (cTURBT) for pT1 high-grade (HG) bladder cancer. PATIENTS AND METHODS: We retrospectively analyzed the record of 326 patients (cTURBT: n = 216, ERBT: n = 110) diagnosed with pT1 HG bladder cancer at multiple institutions. The cohorts were matched by one-to-one propensity scores based on patient and tumor demographics. Recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS), and perioperative and pathologic outcomes were compared. The prognosticators of RFS and PFS were analyzed using the Cox proportional hazard model. RESULTS: After matching, 202 patients (cTURBT: n = 101, ERBT: n = 101) were retained. There were no differences in perioperative outcomes between the two procedures. The 3-year RFS, PFS, and CSS were not different between the two procedures (p = 0.7, 1, and 0.7, respectively). Among patients who underwent repeat transurethral resection (reTUR), the rate of any residue on reTUR was significantly lower in the ERBT group (cTURBT: 36% versus ERBT: 15%, p = 0.029). Adequate sampling of muscularis propria (83% versus 93%, p = 0.029) and diagnostic rates of pT1a/b substaging (90% versus 100%, p < 0.001) were significantly better in ERBT specimen compared with cTURBT specimen. On multivariable analyses, pT1a/b substaging was a prognosticator of disease progression. CONCLUSIONS: In patients with pT1HG bladder cancer, ERBT had similar perioperative and mid-term oncologic outcomes compared with cTURBT. However, ERBT improves the quality of resection and specimen, yielding less residue on reTUR and yielding superior histopathologic information such as substaging.

Do we need repeat transurethral resection after en bloc resection for pathological T1 bladder cancer?

OBJECTIVES: To assess the clinical significance of repeat transurethral resection (reTUR) and surgical margin status after en bloc resection of bladder tumour (ERBT) for pathological T1 (pT1) bladder cancer. PATIENTS AND METHODS: We retrospectively analysed the record of 106 patients with pT1 high-grade bladder cancer who underwent ERBT between April 2013 and February 2021 at multiple institutions. All specimens were reviewed by a genitourinary pathologist. The primary outcome measures were recurrence-free survival (RFS) and progression-free survival (PFS) between patients with and those without reTUR. We also analysed the predictive value of surgical margin on the likelihood of residual tumour on reTUR. RESULTS: A reTUR was performed in 50 of the 106 patients. The 2-year RFS and 3-year PFS were comparable between patients who underwent reTUR and those who did not (55.1% vs 59.9%, P = 0.6, 80.6% vs 82.6%, P = 0.6, respectively). No patient was upstaged to pT2 on reTUR. Regarding the surgical margin status, there were no recurrences at the original site in 51 patients with negative horizontal margins. Cox proportional hazard analysis revealed that a positive vertical margin was an independent prognostic factor of worse PFS. On reTUR, six pTa/is residues were detected in patients with a positive horizontal margin, and three pT1 residues were detected in one patient with a positive vertical margin or other adverse pathological features. CONCLUSIONS: A reTUR after ERBT for pT1 bladder cancer appears not to improve either recurrence or progression. Surgical margin status affects prognosis and reTUR outcomes. A reTUR can be omitted after ERBT in patients with pT1 bladder cancer and negative margins; for those with positive horizontal or vertical margins, reTUR should remain the standard until proven otherwise.

Intravesical mitomycin C (MMC) and MMC + cytosine arabinoside for non-muscle-invasive bladder cancer: a randomised clinical trial.

OBJECTIVES: To compare the urinary pH, recurrence-free survival (RFS), and safety of adjuvant intravesical therapy in patients with non-muscle-invasive bladder cancer (NMIBC) receiving mitomycin C (MMC) therapy and MMC + cytosine arabinoside (Ara-C) therapy. PATIENTS AND METHODS: A total of 165 patients with NMIBC from six hospitals were randomly allocated to two groups: weekly instillation of MMC + Ara-C (30 mg/30 mL + 200 mg/10 mL) for 6 weeks and the same instillation schedule of MMC (30 mg/40 mL). The primary outcome was RFS, and secondary outcomes were urinary pH and toxicity in the two groups. RESULTS: A total of 81 and 87 patients were randomised into the MMC and MMC + Ara-C groups, respectively. Overall, the RFS in the MMC + Ara-C group was significantly longer (P = 0.018) than that in the MMC group. A similar significant difference was detected in patients with intermediate-risk NMIBC, but not in those with high-risk NMIBC. The mean (SD) urinary pH was significantly higher in the MMC + Ara-C group than in the MMC group, at 6.56 (0.61) vs 5.78 (0.64) (P < 0.001), and the frequency of a urinary pH of >7.0 in the MMC and MMC + Ara-C groups was 6.3% and 26.7%, respectively (P < 0.001). Multivariate analysis models including clinicopathological features and second transurethral resection demonstrated that increased urinary pH was associated with better outcomes (hazard ratio 0.18, 95% confidential interval 0.18-0.038; P < 0.001). In all, there were 14 and 10 adverse events in the MMC and MMC + Ara-C groups, respectively, without a significant difference (P = 0.113). CONCLUSIONS: Our randomised clinical trial suggested that intravesical therapy with MMC and Ara-C is useful and safe for patients with intermediate-risk NMIBC. Increase in urinary pH with Ara-C is speculated as a mechanism for increased anti-cancer effects.

A pilot study to assess the safety and usefulness of combined transurethral endoscopic mucosal resection and en-bloc resection for non-muscle invasive bladder cancer.

BACKGROUND: Transurethral resection (TUR) is the standard operation used for non-muscle invasive bladder cancer (NMIBC). Although most solid tumors are principally removed via single block resection without incising the mass, disruption of the lesion is unavoidable in traditional TUR. Furthermore, pathological diagnosis is often difficult due to heat-related denaturation of tissues in TUR. Although transurethral en-bloc resection is useful for judging tumor invasion, it is associated with a prolonged operative duration. We attempted to show the safety and usefulness of combined endoscopic mucosal resection (EMR) and en-bloc resection in NMIBC patients. METHODS: We investigated 39 patients with clinical NMIBC who were treated using our original EMR + en-bloc resection technique, which involved removal of the tumor mass that protruded from the mucosa, using a polypectomy snare similar to that used for EMR. The residual lesion was removed using en-bloc resection. The operative period, duration of hospitalization, and recurrence rates were compared with those of conventional TUR (n = 31). RESULTS: The mean (standard deviation, range) time interval for EMR and total operative duration were 1.6 (1.1, 1-5) min and 18.3 (10.5, 3-48) min, respectively. The total operative duration was comparable to that of TUR (17.3 min, p = 0.691). The mean duration of catheterization in the EMR + en-bloc resection group (4.2 days) was also similar to that in the TUR group (3.7 days; p = 0.285). No severe complications were observed with EMR + en-bloc resection. The pathologists were able to determine tumor invasiveness with considerable certainty in all specimens obtained via the EMR + en-bloc procedure than via TUR, and the difference in the ease of diagnosis was statistically significant (p = 0.016). Recurrence rates were comparable (p = 0.662) between the EMR + en-bloc (15.4%) and TUR groups (19.4%). CONCLUSIONS: Our results demonstrated that the EMR + en-bloc resection technique is feasible, safe, and useful for treating patients with NMIBC. Furthermore, this technique helps provide a more accurate pathological diagnosis.

[Intravesical therapy of heparin and lidocaine for interstitial cystitis : a case report].

Interstitial cystitis (IC) is a chronic inflammatory condition of the urinary bladder, and its treatment has many uncertainties. We report a case of IC treated with intravesical instillation of heparin and alkalized lidocaine. A 64-year-old woman presented with urinary frequency and urgency with suprapubic pain. She underwent intravesical treatment with combined heparin and alkalinized lidocaine for IC, since prior medical treatments (imipramine, solifenacin, suplatast tosilate, and kampo extracts) and hydrodistention of bladder had little or no effect on her symptoms. A 50 ml solution containing 20,000 units of heparin, 200 mg of lidocaine and 7% sodium bicarbonate was administered intravesically twice a week for 12 months. The O'Leary-Sant IC symptom index score and IC problem index score improved from 20 to 8 and from 16 to 8, respectively, and her bladder capacity increased from 90 ml to 300 ml. Intravesical instillation of combined heparin and lidocaine was useful in the treatment of IC.

[Case of complete androgen insensitivity syndrome].

Androgen insensitivity syndrome, gonadectomy, estrogen supplementation a 23-year-old single female visited our gynecological clinic because of primary amenorrhea. The patient's breast development was good. However the patient had thin pubic hair and blind-ending vagina. Serum levels of estrogen E2, testosterone, luteinizing hormone (LH) and follide stimulating hormone (FSH) were 37.0, 497 pg/ml, 22.0 and 8.7 mIU/ml, respectively. Chromosomal analysis was a karyotype of 46, XY. There was no uterus and no ovaries. However, there were bilateral inguinal elastic masses which were gonads. The patient was diagnosed with complete androgen insensitivity syndrome and bilateral gonadectomy was performed. The postoperative course was good and the patient is receiving estrogen replacement therapy.

Calreticulin represses E-cadherin gene expression in Madin-Darby canine kidney cells via Slug.

Calreticulin (CRT) is a multifunctional Ca(2+)-binding molecular chaperone in the endoplasmic reticulum. In mammals, the expression level of CRT differs markedly in a variety of organs and tissues, suggesting that CRT plays a specific role in each cell type. In the present study, we focused on CRT functions in the kidney, where overall expression of CRT is quite low, and established CRT-overexpressing kidney epithelial cell-derived Madin-Darby canine kidney cells by gene transfection. We demonstrated that, in CRT-overexpressing cells, the morphology was apparently changed, and the original polarized epithelial cell phenotype was destroyed. Furthermore, CRT-overexpressing cells showed enhanced migration through Matrigel-coated Boyden chamber wells, compared with controls. E-cadherin expression was significantly suppressed at the protein and transcriptional levels in CRT-overexpressing cells compared with controls. On the other hand, the expression of mesenchymal protein markers, such as N-cadherin and fibronectin, was up-regulated. We also found that the expression of Slug, a repressor of the E-cadherin promoter, was up-regulated by overexpression of CRT through altered Ca(2+) homeostasis, and this led to enhanced binding of Slug to the E-box element in the E-cadherin promoter. Thus, we conclude that CRT regulates the epithelial-mesenchymal transition-like change of cellular phenotype by modulating the Slug/E-cadherin pathway through altered Ca(2+) homeostasis in cells, suggesting a novel function of CRT in cell-cell interaction of epithelial cells.

Tumor lymphangiogenesis in transitional cell carcinoma of the upper urinary tract: association with clinicopathological features and prognosis.

PURPOSE: Lymph node metastasis is an important prognostic factor in many types of cancer. Recently several specific markers for lymphatic endothelium were developed that facilitate the quantification of lymphangiogenesis in human cancer tissues. We investigated the clinical and prognostic significance of lymphangiogenesis in patients with transitional cell carcinoma of the upper urinary tract. MATERIALS AND METHODS: We measured lymph vessel density and relative lymphatic vascular area in 125 specimens by quantitative immunohistochemical staining for D2-40 antibody (DakoCytomation, Glostrup, Denmark). These parameters were examined in the intratumor and peritumor areas, and measured using image analysis software. RESULTS: Peritumor lymph vessel density and peritumor lymphatic vascular area correlated with lymph node metastasis and tumor grade. In the intratumor area lymphatic vessels were detected in only 16.0% of specimens. However, the presence of intratumor lymphatic vessels was associated with lymph node metastasis (p = 0.002). Multivariate analysis identified high peritumor lymphatic vascular area and the presence of intratumor lymphatic vessels as significant and independent factors of metastasis-free survival after surgery (OR = 5.11, p = 0.020 and OR = 2.92, p = 0.025, respectively). Multivariate analysis also identified the presence of intratumor lymphatic vessels as the only independent predictive factor of cause specific survival (OR = 3.89, p = 0.049). CONCLUSIONS: Lymphangiogenesis may have important roles in tumor metastasis and survival in patients with transitional cell carcinoma of the upper urinary tract. Quantification of lymphatic vessels, especially peritumor lymphatic vascular area and intratumor lymphatic vessels, was useful for predicting metastasis-free survival. In addition, the presence of intratumor lymphatic vessels was an independent predictor of cause specific survival.

Lymphangiogenesis and angiogenesis in bladder cancer: prognostic implications and regulation by vascular endothelial growth factors-A, -C, and -D.

PURPOSE: Lymph vessel density (LVD) and microvessel density (MVD) correlate with the malignant potential of tumors and patient survival. Vascular endothelial growth factors (VEGF)-A, VEGF-C, and VEGF-D could modulate LVD and MVD. We investigated the clinical and prognostic significance of LVD and MVD on lymphangiogenic and angiogenic function of VEGF-A, VEGF-C, and VEGF-D in human bladder cancer. EXPERIMENTAL DESIGN: We reviewed tissue samples from patients with nonmetastatic bladder cancer who had undergone transurethral resections (n = 126). The densities of D2-40-positive vessels (LVD) and CD34-positive vessels (MVD) were measured by a computer-aided image analysis system. Expression of VEGF-A, VEGF-C, and VEGF-D was examined by immunohistochemistry; survival analyses and their independent roles were investigated using multivariate analysis models. RESULTS: LVD was associated with tumor grade but not with pT stage. LVD was associated with metastasis-free survival (log rank P = 0.039), but was not an independent prognostic factor. Although MVD affected survival, the combination of high LVD and high MVD in tumors was an independent predictor of metastasis-free survival. Although VEGF-C expression was positively associated with both LVD and MVD, VEGF-D was associated only with LVD. VEGF-A expression was associated with MVD in univariate analysis, however, it was not an independent factor. CONCLUSIONS: Lymphangiogenesis and angiogenesis influence metastasis-free survival, and are regulated by VEGF-C and/or VEGF-D. Our results suggest that LVD and MVD are useful tools for the selection of postoperative management and treatment strategies in patients with bladder cancer.

[A case of renal pelvic squamous cell carcinoma accompanied with humoral hypercalcemia of malignancy (HHM)].

A 78-year-old male was urgently admitted to our hospital because of consciousness disturbance. Laboratory data showed marked hypercalcemia (17.0 mg/dl), hypophosphatemia, low intact PTH level, high PTH relating peptide (PTHrP) level, normal osteocalcin and normal 1-25(OH)2D level. Computed tomography revealed a right renal tumor with extracapsular extension. Bone scintigram appeared normal. We performed right nephrectomy under the diagnosis of right renal tumor. Pathological diagnosis was poorly differentiated squamous cell carcinoma (SCC) of the right pelvis. Immunohistochemical study of the resected specimen for PTHrP was positive. Therefore, we diagnosed it as renal pelvic SCC with humoral hypercalcemia of malignancy (HHM). After nephrectomy, serum calcium returned to normal, but 5 months after nephrectomy, local recurrence appeared and serum calcium was re-elevated. She died 7 months after nephrectomy.

Long-term effects of bacille Calmette-Guérin perfusion therapy for treatment of transitional cell carcinoma in situ of upper urinary tract.

OBJECTIVES: To report our experience with bacille Calmette-Guérin (BCG) perfusion therapy for transitional cell carcinoma in situ of the upper urinary tract. BCG perfusion therapy is widely used to treat transitional cell carcinoma in situ of the upper urinary tract. However, it has not yet been established as a standard treatment. METHODS: Ten patients diagnosed with transitional cell carcinoma in situ of the upper urinary tract were treated with BCG perfusion therapy from January 1990 to May 2002. BCG was instilled weekly for 6 weeks, with a median dose of 65 mg at 1.17 mg/mL (Tokyo 172 strain, dissolved in normal saline). RESULTS: The mean follow-up period was 50.9 months (range 12 to 134). The initial response to therapy was excellent, and cytology became negative in all patients after one course of BCG perfusion. Five patients developed recurrence after 5, 11, 24, 26, and 45 months, and all died after 46, 12, 41, 134, and 79 months, respectively. The mortality rate was 50% and was 100% in those with recurrence. The mean recurrence-free period was 22.2 months (range 5 to 45). Complications included bladder irritation-related symptoms in all patients, fever greater than 38 degrees C (n = 9), hematuria (n = 2), hydronephrosis (n = 2), and lumbago (n = 1) but all were transient and did not affect long-term prognosis. CONCLUSIONS: BCG perfusion therapy for carcinoma in situ of the upper urinary tract is safe, and the short-term response is excellent. However, the long-term results were not satisfactory. Therefore, this therapy should be considered experimental, although it may have potential benefits in delaying progression and possibly providing local control for patients in poor condition. Long-term studies are required for additional evaluation of BCG therapy.

[A case of prostate cancer with invasion to the middle ureter].

A 69-year-old male was diagnosed as having prostate cancer with ureter invasion. His serum prostate specific antigen level was not so high (19.6 ng/ml) before treatment, but clinical stage was D2, poorly differentiated adenocarcinoma of prostate. He was treated with chemoendocrine therapy. Prostate cancer with continuous invasion to the middle ureter is rare. To the best of our knowledge, this is the 6th case report of such an unusual invasion of prostate cancer.

Expression of metalloproteinase-2, metalloproteinase-9, and tissue inhibitor of metalloproteinase-1 in transitional cell carcinoma of upper urinary tract: correlation with tumor stage and survival.

OBJECTIVES: To investigate the relationship between the expression of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 and pT stage or survival in patients with transitional cell carcinoma of the upper urinary tract. MMP-2 and MMP-9 are associated with tumor invasion in several malignancies. TIMPs exert an anti-invasive effect by blocking MMP activity. Recent studies have shown, however, that TIMPs can also stimulate cell proliferation and angiogenesis. METHODS: Tumor sections surgically removed from 91 patients were examined for expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 by immunohistochemistry. We also determined the proliferation index and microvessel density in each tumor and investigated the independent roles of these factors in tumor stage and survival using multivariate analysis. RESULTS: Of 91 tissue samples, 50, 51, 45, and 39 were positive for MMP-2, MMP-9, TIMP-1, and TIMP-2 expression, respectively. Tumors positive for MMP-2, MMP-9, and TIMP-1 exhibited a greater proliferation index than tumors with negative expression (P <0.001, P = 0.013, and P <0.001, respectively). The microvessel density of tumors positive for MMP-2 and TIMP-1 was greater than that of negative tumors (P <0.001). The expression of MMP-2, MMP-9, and TIMP-1 was an independent predictor of high pT stage. Cox proportional hazard analysis identified TIMP-1 expression as an independent factor for cause-specific survival (odds ratio 5.2, P = 0.011), similar to microvessel density, pT4, and lymph node metastasis. CONCLUSIONS: TIMP-1 expression correlated with pT stage and was an independent predictor of cause-specific survival. Our results suggest that TIMP-1 expression is a potentially useful tool for the selection of postoperative observation strategies in patients with transitional cell carcinoma of the upper urinary tract.