Shuji Mikami

Lymphovascular Invasion Predicts Clinical Outcomes in Patients With Node-Negative Upper Tract Urothelial Carcinoma

PURPOSE To assess the association of lymphovascular invasion (LVI) with cancer recurrence and survival in a large international series of patients treated with radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC). PATIENTS AND METHODS Data were collected on 1,453 patients treated with RNU at 13 academic centers and combined into a relational database. Pathologic slides were rereviewed by genitourinary pathologists according to strict criteria. LVI was defined as presence of tumor cells within an endothelium-lined space. RESULTS LVI was observed in 349 patients (24%). Proportion of LVI increased with advancing tumor stage, high tumor grade, presence of tumor necrosis, sessile tumor architecture, and presence of lymph node metastasis (all P < .001). LVI was an independent predictor of disease recurrence and survival (P < .001 for both). Addition of LVI to the base model (comprising pathologic stage, grade, and lymph node status) marginally improved its predictive accuracy for both disease recurrence and survival (1.1%, P = .03; and 1.7%, P < .001, respectively). In patients with negative lymph nodes and those in whom a lymphadenectomy was not performed (n = 1,313), addition of LVI to the base model improved the predictive accuracy of the base model for both disease recurrence and survival by 3% (P < .001 for both). In contrast, LVI was not associated with disease recurrence or survival in node-positive patients (n = 140). CONCLUSION LVI was an independent predictor of clinical outcomes in nonmetastatic patients who underwent RNU for UTUC. Assessment of LVI may help identify patients who could benefit from multimodal therapy after RNU. After confirmation, LVI should be included in staging of UTUC.

Adrenocortical Zonation in Humans under Normal and Pathological Conditions

CONTEXT Aldosterone synthase (CYP11B2) and steroid 11 beta-hydroxylase (CYP11B1) catalyze the terminal steps for aldosterone and cortisol syntheses, respectively, thereby determining the functional differentiation of human adrenocortical cells. Little is known, however, about how the cells expressing the enzymes are actually distributed in the adrenals under normal and pathological conditions. OBJECTIVE The objective of the study was to determine the localization of CYP11B2 and -B1 in human adrenal specimens by using developed antibodies capable of distinguishing the two enzymes from each other. RESULTS Under normal conditions, CYP11B2 was sporadically detected in the zona glomerulosa, whereas CYP11B1 was entirely detected in the zonae fasciculata-reticularis. Adrenocortical cells lacking both enzymes were observed in the outer cortical regions. In addition to conventional zonation, we found a variegated zonation consisting of a subcapsular cell cluster expressing CYP11B2, which we termed aldosterone-producing cell cluster, and a CYP11B1-expressing area. Aldosterone-producing adenomas differed in cell populations expressing CYP11B2 from one another, whereas CYP11B1-expressing and double-negative cells were also intermingled. Adenomas from patients with Cushings syndrome expressed CYP11B1 entirely but not CYP11B2, resulting in atrophic nontumor glands. The nontumor portions of both types of adenomas bore frequently one or more aldosterone-producing cell clusters, which sustained CYP11B2 expression markedly under the conditions of the suppressed renin-angiotensin system. CONCLUSION Immunohistochemistry of the human normal adrenal cortex for CYP11B2 and CYP11B1 revealed a variegated zonation with cell clusters constitutively expressing CYP11B2. This technique may provide a pathological confirmatory diagnosis of adrenocortical adenomas.

Impact of Lymph Node Dissection on Cancer Specific Survival in Patients With Upper Tract Urothelial Carcinoma Treated With Radical Nephroureterectomy

PURPOSE We examined the impact of lymphadenectomy on the clinical outcomes of patients with upper tract urothelial cancer treated with radical nephroureterectomy. MATERIALS AND METHODS Data were collected on 1,130 consecutive patients with pT1-4 upper tract urothelial cancer treated with radical nephroureterectomy at 13 centers worldwide. Patients were grouped according to nodal status (pN0 vs pNx vs pN+). The choice to perform lymphadenectomy was determined by the treating surgeon. All pathology slides were reevaluated by dedicated genitourinary pathologists. Univariable and multivariable Cox regression models measured the association of nodal status (pN0 vs pNx vs pN+) with cancer specific survival. RESULTS Overall 412 patients (36.5%) had pN0 disease, 578 had pNx disease (51.1%) and 140 had pN+ disease (12.4%). The 5-year cancer specific survival estimate was lower in patients with pN+ compared to those with pNx disease (35% vs 69%, p <0.001), which in turn was lower than that in those with pN0 disease (69% vs 77%, p = 0.024). In the subgroup of patients with pT1 disease (345) cancer specific survival rates were not different in those with pN0 and pNx. In pT2-4 cases (813) cancer specific survival estimates were lowest in pN+, intermediate in pNx and highest in pN0 (33% vs 58% vs 70%, p = 0.017). When adjusted for the effects of standard clinicopathological features pN+ was an independent predictor of cancer specific survival (p <0.001). pNx was significantly associated with worse prognosis than pN0 in pT2-4 upper tract urothelial cancer only. CONCLUSIONS Nodal status is a significant predictor of cancer specific survival in upper tract urothelial cancer. pNx is significantly associated with a worse prognosis than pN0 in pT2-4 tumors. Patients expected to have pT2-4 disease should undergo lymphadenectomy to improve staging and thereby help guide decision making regarding adjuvant chemotherapy.

The extent of lymphadenectomy seems to be associated with better survival in patients with nonmetastatic upper-tract urothelial carcinoma: how many lymph nodes should be removed?

BACKGROUND The role and extent of lymphadenectomy in patients with upper-tract urothelial carcinoma (UTUC) is debated. OBJECTIVE To establish whether the number of lymph nodes (LNs) removed might be associated with better cause-specific survival in patients with UTUC. DESIGN, SETTING, AND PARTICIPANTS The study included 552 consecutive patients who underwent radical nephroureterectomy (RNU) and lymphadenectomy between 1992 and 2006. INTERVENTION Patients were treated with RNU and lymphadenectomy. MEASUREMENTS Univariable and multivariable Cox proportional hazards regression models addressed the association between the number of LNs removed and cause-specific mortality (CSM). The number of LNs removed was coded as a cubic spline to allow for nonlinear effects. Finally, the most informative cut-off for the number of removed LNs was identified. RESULTS AND LIMITATIONS In the entire population, the number of LNs removed was not associated with CSM in univariable (hazard ratio [HR]: 0.99; p=0.16) or in multivariable (HR: 0.97; p=0.12) analyses. In contrast, in the subgroup of pN0 patients (n=412), the number of LNs removed achieved the independent predictor status of CSM (HR: 0.93; p=0.02). Eight LNs removed was the most informative cut-off in predicting CSM (HR: 0.42; p=0.004). The inclusion of the variable defining dichotomously the number of removed LNs (< 8 vs > or = 8) in the base model (age, Eastern Cooperative Oncology Group performance status, pathologic stage, grade, architecture, and lymphovascular invasion) significantly increased the accuracy in predicting CSM (+1.7%; p<0.001). CONCLUSIONS The extension of the lymphadenectomy in pN0 UTUC patients seems to be associated with CSM. Longer survival was observed in patients in whom at least eight LNs had been removed.

Renal angiomyolipoma: a radiological classification and update on recent developments in diagnosis and management

Angiomyolipoma is the most common benign solid renal neoplasm observed in clinical practice. Once thought to be a hamartoma and almost always diagnosed by the imaged-based detection of fat, angiomyolipomas are now known to consist of a heterogeneous group of neoplasms. Although all are considered perivascular epithelioid cell tumors, many display different pathology, imaging features, and clinical behavior. The importance of understanding this group of neoplasms is emphasized by the fact that many types of angiomyolipoma contain little to no fat, and despite being benign, sometimes escape a pre-operative diagnosis. These types of angiomyolipomas can all be considered when encountering a renal mass that is both hyperattenuating relative to renal parenchyma on unenhanced CT and T2-hypointense, features that reflect their predominant smooth muscle component. We review recent developments and provide a radiological classification of angiomyolipomas that helps physicians understand the various types and learn how to both diagnose and manage them.

Loss of Syndecan‐1 and Increased Expression of Heparanase in Invasive Esophageal Carcinomas

Heparan sulfate proteoglycans play important biological roles in cell‐cell and cell‐matrix adhesion, and are closely associated with growth factor actions. Loss of syndecan‐1, a cell surface‐bound heparan sulfate proteoglycan, has been reported for advanced head and neck carcinomas, and expression of endoglycosidic heparanase, which cleaves heparan sulfate glycosaminoglycans (HS‐GAGs), is associated with invasion and metastatic potential of malignant tumors. Paraffin sections of 103 primary esophageal squamous cell carcinomas were immunohistochemically examined for the expression of syndecan‐1 core protein, HS‐GAGs and heparanase protein, and the results were compared with various clinicopathological parameters, such as invasion depth. For 16 cases, fresh tumor samples were quantitatively analyzed for heparanase and syndecan‐1 mRNA expression by real‐time RT‐PCR in addition to the immunohistochemical studies. Syndecan‐1 core protein and HS‐GAGs expression was significantly decreased in pT2 and pT3 cases compared with their pTis and pTl counterparts. Decreased expression of core protein and HS‐GAGs was correlated with the incidence of lymphatic invasion, and venous involvement. Furthermore, decreased expression of HS‐GAGs was correlated positively with the incidence of nodal metastasis and distant organ metastasis, and negatively with the grade of tumor cell differentiation. The percentage of cytoplas‐mic heparanase protein‐positive cases increased significantly in pT2 and pT3 cases compared to that in pTis and pTl cases, and this was associated with lymphatic invasion, and venous and lymph nodal involvement. The level of heparanase mRNA was inversely correlated with the degree of HS‐GAGs expression rather than core protein. In conclusion, loss of syndecan‐1 and heparanase overexpression in esophageal squamous cell carcinomas are closely associated with malignant potential. Regarding the mechanism of loss of HS‐GAGs, heparanase upregulation appears to play an important role.

Risk stratification of patients with nodal involvement in upper tract urothelial carcinoma: value of lymph-node density

To determine the risk factors associated with clinical outcome in patients with lymph node (LN)‐positive urothelial carcinoma of the upper urinary tract (UTUC) treated with radical nephroureterectomy (RNU) and lymphadenectomy, focusing on the concept of LN density (LND).

Tumor cell-derived angiopoietin-like protein ANGPTL2 is a critical driver of metastasis

Strategies to inhibit metastasis have been mainly unsuccessful in part due to insufficient mechanistic understanding. Here, we report evidence of critical role for the angiopoietin-like protein 2 (ANGPTL2) in metastatic progression. In mice, Angptl2 has been implicated in inflammatory carcinogenesis but it has not been studied in human tumors. In patients with lung cancer, elevated levels of ANGPTL2 expression in tumor cells within the primary tumor were associated with a reduction in the period of disease-free survival after surgical resection. Transcription factors NFATc, ATF2, and c-Jun upregulated in aggressive tumor cells promoted increased Angptl2 expression. Most notably, tumor cell-derived ANGPTL2 increased in vitro motility and invasion in an autocrine/paracrine manner, conferring an aggressive metastatic tumor phenotype. In xenograft mouse models, tumor cell-derived ANGPTL2 accelerated metastasis and shortened survival whereas attenuating ANGPTL2 expression in tumor cells-blunted metastasis and extended survival. Overall, our findings showed that tumor cell-derived ANGPTL2 drives metastasis and provided an initial proof of concept for blockade of its action as a strategy to antagonize the metastatic process.

Increased RANKL expression is related to tumour migration and metastasis of renal cell carcinomas

Receptor activator of NF‐κB ligand (RANKL) and its receptor, receptor activator of NF‐κB (RANK), play a key role in osteoclastogenesis, and osteoprotegerin (OPG) acts as a decoy receptor for RANKL. We investigated the role of the RANKL–RANK–OPG system in renal cell carcinomas (RCCs), which frequently metastasize to bones. Real‐time quantitative PCR revealed that RANKL mRNA expression was higher in clear cell RCCs than in papillary and chromophobe RCCs. Similarly, RANKL protein expression level in clear cell RCCs was higher than that in papillary and chromophobe RCCs, showing positive correlations with the primary tumour stage and distant metastasis. There was no significant association between the expression level of RANK, OPG and histological subtypes of RCC. RANKL and RANK expression was observed in metastatic RCCs in the bone and other organs, suggesting that they play a role in metastasis to the bone and other organs. Recombinant RANKL protein stimulated migration of a clear cell RCC cell line, Caki‐1, in vitro, and this enhanced migration was inhibited by the administration of recombinant OPG protein. Furthermore, multivariate Cox analysis revealed that elevated RANKL and RANK expression with low‐OPG expression was a significant and independent predictor of recurrence, bone metastasis and a poor prognosis. These data suggest that the RANKL–RANK–OPG system is involved not only in the bone metastasis of RCCs but also in metastasis to other organs through the stimulation of cancer cell migration. Copyright

Preoperative Hydronephrosis Grade Independently Predicts Worse Pathological Outcomes in Patients Undergoing Nephroureterectomy for Upper Tract Urothelial Carcinoma

PURPOSE We analyzed the prognostic impact of hydronephrosis grade on disease specific survival and evaluated whether hydronephrosis grade could preoperatively predict worse pathological outcomes in cases of upper tract urothelial carcinoma treated surgically. MATERIALS AND METHODS We identified and retrospectively reviewed the records of 91 patients who were evaluated by multidetector computerized tomography and/or magnetic resonance imaging preoperatively, and treated with nephroureterectomy at our institution from 2000 to 2009. Ipsilateral hydronephrosis was graded 0 to 4 by 2 urological radiologists blinded to clinical outcomes. We analyzed the associations between hydronephrosis grade, and pathological findings and patient outcomes. RESULTS Preoperatively 67 patients (73.6%) had ipsilateral hydronephrosis. Grade was 1 to 4 in 3 (3.3%), 17 (18.7%), 23 (25.3%) and 24 cases (26.4%), respectively. Higher hydronephrosis grade was significantly associated with a ureteral tumor (p = 0.0307), higher pT stage (p = 0.0002) and lymphovascular invasion (p = 0.0014). Higher hydronephrosis grade was not associated with disease specific or metastasis-free survival. On preoperative multivariate analysis high hydronephrosis grade predicted pathological T stage (T3 or greater) (HR 4.98, p = 0.0228), positive lymphovascular invasion (HR 6.37, p = 0.0022) and grade 3 (HR 2.98, p = 0.0311). CONCLUSIONS On image analysis preoperative hydronephrosis grade was associated with features of aggressive disease and predicted an advanced pathological outcome in patients with upper tract urothelial carcinoma. This information could prove useful to select candidates for neoadjuvant chemotherapy and make decisions concerning surgical options.