Clinical significance of lymphovascular invasion in upper urinary tract urothelial cancer

OBJECTIVES

To clarify the significance of lymphovascular invasion (LVI) in patients with pT3N0M0 upper urinary tract (UUT) urothelial carcinoma (UC) relative to prognosis in terms of disease‐specific survival, as LVI, which implies both blood vessel and lymph vessel involvement, is reportedly a poor prognostic factor in patients with UUT‐UC.

PATIENTS AND METHODS

The clinical records of 90 patients who had surgery for UUT‐UC were reviewed retrospectively. The median patient age was 71 years and the median follow‐up was 42 months. The prognostic significances of LVI (with vs without), T stage (<1 vs 2–4), grade (1–2 vs 3), N stage (0 vs 1–2), age (≤70 vs >70 years), gender and tumour location (renal pelvis vs ureter) for survival time were evaluated.

RESULTS

LVI of UUT‐UC was found in 34 patients (37.8%). There were significantly higher frequencies of LVI with advancing stage and lymph node metastasis. Kaplan‐Meier analysis showed that LVI was strongly associated with disease‐specific survival in all patients (P < 0.001) and in patients with pT3N0M0 disease (P < 0.001). Univariate analyses showed that LVI, T stage, N stage and tumour grade were significantly related to disease‐specific survival in all patients (P < 0.001, <0.001, 0.003 and 0.007, respectively). Multivariate analysis using Cox proportional hazards model showed that LVI was the only prognostic factor with independent significance for disease‐specific survival (P < 0.001).

CONCLUSIONS

LVI appears to be an important and independent prognostic factor for UUT‐UC in patients treated by nephroureterectomy. Our data suggest that the LVI status might be a predictive marker for disease‐specific survival in patients with T3N0M0 UTT‐UC.     

Comparison of type I and II papillary renal cell carcinoma (RCC) and clear cell RCC

OBJECTIVE

To compare the pathological features of clear cell renal cell carcinoma (ccRCC) with papillary RCC (pRCC) and further differentiate type I and II pRCC as independent prognosticators for survival.

PATIENTS AND METHODS

From September 1994 to February 2007 557 RCCs were treated and reviewed. All patients underwent radical nephrectomy or nephron‐sparing surgery. We reviewed patient data and correlated RCC subtypes to tumour size, pathological stage, nuclear grade, and 5‐year cancer‐specific survival (CSS). pRCC was re‐evaluated in to type I and II. The 2002 Tumour‐Node‐Metastasis and Fuhrman classifications were used.

RESULTS

In all, 391 (70%) patients had ccRCC, 96 (17%) had pRCC, 34 (6%) had chromophobe RCC, seven (1%) had ductus Bellini RCC and 29 (5%) had unclassified RCC. Upon re‐evaluation 34 patients had type I pRCC and 62 had type II. The pRCCs were significantly smaller than the ccRCCs, at a mean (sd ) of 4.5 (2.5) cm vs 5 (2.9) cm (P = 0.013), and multifocal (25% vs 12%, P = 0.001). Whereas patients with ccRCC had significantly more primary metastases (12% vs 3%, P = 0.014). The mean (sd ) follow‐up was 42.3 (41.4) months. The 5‐year CSS for M0 patients was 84% for ccRCC and 90% for pRCC (P = 0.573). At multivariate analyses predictors for 5‐year CSS were only tumour size (hazard ratio, HR 2.6, P < 0.001), pathological stage (HR 3.9, P < 0.001) and nuclear grade (HR 2.7, P < 0.001). The type I and II pRCCs had significantly different lymphovascular invasion (LVI) and 5‐year CSS rates (94% vs 74%, P = 0.03).

CONCLUSIONS

The ccRCCs were significantly larger at diagnosis than the pRCCs. The histological subtype (pRCC vs ccRCC) had no impact on the 5‐year CSS in multivariate analyses. The type I and II pRCCs had similar histopathological features except for a significant difference in LVI. However, the 5‐year CSS was significantly different in type I and II pRCC.     

Impact of several histopathological prognosticators and local tumour extension on oncological outcome in pT3b/c N0M0 renal cell carcinoma

OBJECTIVE

To investigate the prognostic relevance of different histopathological features and local tumour extension in patients with pT3b/c N0M0 renal cell carcinoma (RCC), as recently new proposals of reclassifying tumour fat invasion in pT3b/c RCC have been made but the effect of other histopathological tumour characteristics and combinations thereof with tumour invasion has yet to be determined in these patients.

PATIENTS AND METHODS

Between 1990 and 2006, 1943 patients underwent surgical treatment for renal tumours in our institution, of which 175 patients (8.7%) had pT3b/c RCC. After exclusion of 57 patients (32.6%) with lymph node and/or distant metastases at the time of diagnosis, 118 (67.4%) remained for retrospective analysis. Different histopathological features and local tumour extension were studied for their association with cancer‐specific‐survival (CSS) and progression‐free‐survival (PFS) by univariate and multivariate analyses. Histopathology was reviewed and revised according to the 2002 Tumour‐Nodes‐Metastasis (TNM) classification system by one pathologist (S.B.). CSS and PFS were estimated by the Kaplan–Meier method.

RESULTS

Follow‐up data were obtained from 110 patients at a median (range) of 3.2 (0.3–16.1) years. In univariate analysis, microvascular invasion (MVI) and capsular invasion increased the risk of tumour progression by 2.05‐ and 2.72‐times (P = 0.037 and P < 0.001). Overall, tumour fat invasion (TFI) and the presence of areas composed by cells with eosinophilic cytoplasm were associated with a higher risk of progression (P = 0.001 and P = 0.011) and reduced CSS (P = 0.037 and P = 0.017). In multivariate analysis, MVI and capsular invasion were associated with a two‐fold increased risk of dying from cancer (hazard risk ratio, HR 2.22, P = 0.045 and HR 2.31, P = 0.011). TFI in general (P = 0.004) and specifically coexistent perirenal fat invasion (PFI) and renal sinus fat invasion (RSFI) were associated with a three‐fold increased risk of developing tumour progression (HR 3.36, P = 0.001). The 10‐year CSS and PFS rates were 39% and 36% for all patients, 47% and 45% for pT3b/c RCC with no PFI or RSFI, and 25% and 10% for PFI + RSFI.

CONCLUSION

Patients with pT3b/c RCC with MVI, capsular invasion, TFI and especially PFI + RSFI, have a markedly reduced prognosis compared with patients with pT3b/c RCC without these features. When these results are corroborated by additional studies and external validation, modification of the TNM classification system would be a sensible consequence.     

Lymphovascular invasion is an independent predictor of oncological outcomes in patients with lymph node‐negative urothelial bladder cancer treated by radical cystectomy: a multicentre validation trial

Study Type – Prognosis (inception cohort)
Level of Evidence 1b

OBJECTIVES

To validate the association of lymphovascular invasion (LVI) with disease recurrence and cancer‐specific survival (CSS) in a multicentre cohort of patients treated with radical cystectomy (RC) for urothelial bladder cancer (UBC).

PATIENTS AND METHODS

We collected pathological and clinical data on 1099 lymph node‐negative patients treated with RC at six German institutions. LVI was defined as the presence of tumour cells within an unequivocal endothelium‐lined space in haematoxylin and eosin‐stained sections.

RESULTS

LVI was present in 295 (26.8%) patients; the presence of LVI correlated significantly with increasing tumour stage, i.e. pT1, 65 (29.4%); pT2, 88 (31.5%); pT3 110 (31.8%); and pT4 32 (38.1%) (P= 0.002) and grade (P < 0.001). In univariable analysis the presence of LVI was significantly associated with reduced recurrence‐free survival (P= 0.008) and reduced CSS (P= 0.039). On multivariable Cox regression analysis tumour stage (P < 0.001), age (>75 vs ≥75 years; P= 0.018) and LVI (P < 0.001) were identified as independent predictors of CSS.

CONCLUSIONS

Our large multicentre study confirms the independent prognostic value of LVI in patients with node‐negative UBC. LVI can be regarded as a surrogate variable for lymphatic micrometastasis in node‐negative UBC. Assessment of LVI might improve the selection of patients who are likely to benefit from adjuvant therapy after RC. The identification of factors involved in the process of LVI could reveal new therapeutic targets for UBC.     

Analysis of renal cell carcinoma with subdiaphragmatic macroscopic venous invasion (T3b)

OBJECTIVE

To review our institutional experience of surgery for renal cell carcinoma (RCC) with subdiaphragmatic macroscopic venous invasion (T3b) and to assess variables associated with cancer‐specific survival (CSS), as the stratification of RCC with venous involvement (T3b and T3c) is subject to debate.

PATIENTS AND METHODS

We retrospectively reviewed the hospital records of patients who underwent a radical nephrectomy with resection of subdiaphragmatic tumour thrombus (T T) between October 1990 and May 2006. The log‐rank and Cox uni‐ and multivariate regression analysis were used to evaluate predictive factors for CSS.

RESULTS

In all, 101 cases were identified. In the N0M0 group, univariate Cox regression analysis confirmed that ipsilateral adrenal gland invasion, Mayo Clinic level of T T, histological subtype and fat invasion were significantly associated with worse CSS. In multivariate Cox regression analysis, only Mayo Clinic level of T T was an independent predictor for CSS. In the subgroup with renal vein involvement only, the median CSS was not reached. In the subgroups with level I, II and III T T involvement, the median CSS was 69, 26 and 21 months, respectively. In the N+ and/or M+ group, only tumour size and type were independent predictors of CSS, while the level of T T was not. Radical nephrectomy yielded poor results with a median CSS of 13 months.

CONCLUSION

The Mayo Clinic level of T T is an independent prognostic predictor for CSS in non‐metastatic T3b RCC. We strongly support the need for re‐classification of the currently applied 2002 Tumour‐Node‐Metastasis staging system, which in its present form does not discriminate between levels of subdiaphragmatic venous invasion.     

Frequency and predictors of axillary lymph node metastases in invasive breast cancer

Background: The objectives of the present study were to evaluate the incidence and predictors of axillary lymph node metastases (ALNM) in patients with breast cancer, and to identify if axillary surgery could be safely omitted in selected patients. Methods: Between January 1996 and May 2000, 492 patients underwent 501 axillary lymph node dissections (ALND). The incidence of ALNM was correlated with clinical and pathological characteristics by univariate and multivariate analyses. Results: Axillary lymph node metastases were found in 41% (207/501) of cases. Univariate analysis showed that palpability of primary and axillary lymph node (ALN), pathological tumour size, grade, lymphovascular invasion (LVI) and multifocality or multicentricity were significant predictors of ALNM. By multivariate analysis, palpability of ALN, pathological tumour size, LVI and multifocality or multicentricity remained as independent predictors. Among the 431 cases without palpable ALN, no ALNM were found if the tumour was ≤ 5 mm, non‐multifocal or multicentric, and without LVI, or the tumour was a tubular or mucinous car­cinoma ≤ 15 mm (n = 21). The frequency of ALNM in the absence of the other risk factors was 11% (7/64) if the tumour size was > 5–10 mm, and 17% (19/113) if the tumour was > 10–20 mm. However, the incidence of ALNM was 72% for the 32 clinically node‐negative cases with multifocal or multicentric tumour ≥ 10 mm and LVI. Those patients with palpable ALN (n = 66) had a greater than 50% risk of ALNM. Conclusions: Routine ALND could be omitted in clinically node‐negative patients with either a ≤ 5‐mm, LVI‐negative tumour, or a ≤ 15‐mm tubular or mucinous carcinoma. Axillary lymph node dissection is still useful for determining pathological nodal status in all other cases, and in most cases with palpable ALN, as a therapeutic manoeuvre.     

Comparison of oncological outcomes after segmental ureterectomy or radical nephroureterectomy in urothelial carcinomas of the upper urinary tract: results from a large French multicentre study

Study Type – Therapy (multi‐centre retrospective cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Upper urinary tract urothelial carcinomas (UUT‐UCs) are rare tumours. Because of the aggressive pattern of UC, radical nephroureterectomy (RNU) with bladder cuff removal remains the ‘gold‐standard’ treatment. However, conservative strategies, such as segmental ureterectomy (SU) or endourological management, have also been developed in patients with imperative indications. Some teams are now advocating the use of conservative management more commonly in cases of elective indications of UUT‐UCs. Due to the paucity of cases of UUT‐UC, only limited data are available on the oncological outcomes afforded by conservative management. We retrospectively investigated the oncological outcomes after SU and RNU in a large multi‐institutional database. Overall, 52 patients were treated with SU and 416 with RNU. There was no statistical difference between the RNU and SU groups for the 5‐year probability of cancer‐specific survival, recurrence‐free survival and metastasis‐free survival. The type of surgery was not a significant prognostic factor in univariate analysis. The results were the same in a subgroup analysis of only unifocal tumours of the distal ureter with a diameter of <2 cm and of low stage (≤T2). Our results suggest that oncological outcomes after conservative treatment with SU are comparable to RNU for the management of UUT‐UC in select cases.

OBJECTIVE

• ? To compare recurrence‐free survival (RFS), metastasis‐free survival (MFS) and cancer‐specific survival (CSS) after segmental ureterectomy (SU) vs radical nephroureterectomy (RNU) for urothelial carcinoma (UC) of the upper urinary tract (UUT‐UC) located in the ureter.

PATIENTS AND METHODS

• ? We performed a multi‐institutional retrospective review of patients with UUT‐UC who had undergone RNU or SU between 1995 and 2010.
• ? Type of surgery, Tumour‐Node‐Metastasis status, tumour grade, lymphovascular invasion and positive surgical margin were tested as prognostic factors for survival.

RESULTS

• ? In all, 52 patients were treated with SU and 416 with RNU. The median (range) follow‐up was 26 (10–48) months.
• ? The 5‐year probability of CSS, RFS and MFS for SU and RNU were 87.9% and 86.3%, respectively (P= 0.99); 37% and 47.9%, respectively (P= 0.48); 81.9% and 85.4%, respectively (P= 0.51).
• ? In univariable analysis, type of surgery (SU vs RNU) failed to affect CSS, RFS and MFS (P= 0.94, 0.42 and 0.53, respectively).
• ? In multivariable analyses, pT stage and pN stage achieved independent predictor status for CSS (P= 0.005 and 0.007, respectively); the positive surgical margin and pT stage were independent prognostic factors of RFS and MFS (P= 0.001, 0.04, 0.009 and 0.001, respectively).
• ? The main limitation of the study is its retrospective design, which is due to the rarity of the disease.

CONCLUSIONS

• ? Short‐term oncological outcomes after conservative treatment with SU are comparable to RNU for the management of UUT‐UC in select cases and should be considered an option.
• ? In every other case, RNU still represents the ‘gold standard’ for the treatment of UUT‐UC.

     

Pathological characteristics and clinical course of bladder tumour developing after nephroureterectomy

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVES

To determine the pathological features and clinical course of intravesical recurrence after nephroureterectomy (NU) for upper urinary tract (UUT) cancer.

PATIENTS AND METHODS

Among 325 patients undergoing NU with bladder cuff excision for UUT cancer, in this retrospective multi‐institutional study we evaluated 113 who developed bladder tumour after NU. Excluding patients with (i) perioperative systemic chemotherapy or radiotherapy for UUT cancer; (ii) a history of previous or synchronous bladder cancer at the time of NU; (iii) distant metastasis at the time of NU; (iv) a follow‐up of <1 year after the initial bladder cancer recurrence; or (v) missing data, 74 patients were included in this study. We compared the pathology between UUT cancer and the first bladder cancer recurrence, using Fisher’s exact test. Further intravesical recurrence and bladder cancer progression was analysed using the Kaplan‐Meier method, with the log‐rank test used to assess significance. A Cox proportional hazard model was used for multivariate analysis.

RESULTS

The grade of the first bladder cancer recurrence strongly correlated with that of the UUT tumour (P < 0.001) and the carcinoma in situ (CIS) lesion with the first bladder cancer recurrence correlated with high grade (grade 3) UUT tumour (P < 0.001). In all, 56 of the assessable 70 patients further developed intravesical recurrence at a median interval of 7 months after the first bladder cancer recurrence. There were no clinicopathological factors that predicted the second recurrence. Progression occurred in 14 patients, at a median interval of 25 months. A CIS lesion with the first bladder cancer recurrence was a risk factor for progression on multivariate analysis.

CONCLUSIONS

A large proportion of the patients who developed bladder tumour after NU had further intravesical recurrence, which indicated its refractory nature. Especially when a CIS lesion is detected in the initial intravesical recurrence, a careful follow‐up is mandatory to detect bladder cancer progression.     

International validation of the prognostic value of lymphovascular invasion in patients treated with radical cystectomy

Study Type – Prognosis (retrospective cohort)
Level of Evidence 2b

OBJECTIVE

To externally validate the prognostic value of lymphovascular invasion (LVI) in a large international cohort of patients treated with radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB).

PATIENTS AND METHODS

We collected data from 4257 patients treated with RC and pelvic lymphadenectomy for UCB, without neoadjuvant chemotherapy, at 12 centres. LVI was defined as presence of nests of tumour cells within an endothelium‐lined space.

RESULTS

LVI was detected in 1407 patients (33.1%); the proportion of LVI increased with advancing stage, higher grade, soft‐tissue surgical margin involvement, and lymph node metastasis (P < 0.001 for all). In standard multivariate models, LVI was associated with both disease recurrence (hazard ratio 1.43, P < 0.001) and cancer‐specific mortality (1.45, P < 0.001). In the entire cohort, adding LVI to a base model that included standard features improved only minimally its predictive accuracy for both recurrence and cancer‐specific mortality (by 1.1% and 1.2%, respectively). In 3122 patients with negative lymph nodes, LVI remained independently associated with and improved the predictive accuracy of the standard predictors for recurrence (hazard ratio 1.68, P < 0.001; +2.3%) and cancer‐specific mortality (1.70, P < 0.001; +2.4%). By contrast, in 1071 node‐positive patients, LVI only marginally improved the prediction of cancer‐specific recurrence (hazard ratio 1.20, P < 0.001; +0.2%) and survival (1.23, P < 0.001; +0.5%).

CONCLUSIONS

LVI is strongly associated with clinical outcome in node‐negative patients treated with RC. The assessment of LVI might help to identify patients who could benefit from adjuvant therapy after RC. After confirmation in different populations, LVI should be included in the staging of UCB.     

Prognostic significance of lymphovascular invasion in radical prostatectomy specimens

Study Type – Prognosis (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? The reported incidence of lymphovascular invasion (LVI) in radical prostatectomy specimens ranges from 5% to 53%. Although LVI has a strong and significant association with adverse clinicopathologic features, it has almost uniformly not been found to be a predictor of biochemical recurrence (BR) on multivariate analysis. This study confirms that LVI is associated with features of aggressive disease and is an independent predictor of BCR. Given that LVI may play a role in the metastatic process, it may be useful in clinical decision‐making regarding adjuvant therapy for patients treated with RP.

OBJECTIVES

To determine whether lymphovascular invasion (LVI) in radical prostatectomy (RP) specimens has prognostic significance. The study examined whether LVI is associated with clinicopathological characteristics and biochemical recurrence (BCR).

PATIENTS AND METHODS

LVI was evaluated based on routine pathology reports on 1298 patients treated with RP for clinically localized prostate cancer between 2004 and 2007. LVI was defined as the unequivocal presence of tumour cells within an endothelium‐lined space. The association between LVI and clinicopathological features was assessed with univariate logistic regression. Cox regression was used to test the association between LVI and BCR.

RESULTS

LVI was identified in 10% (129/1298) of patients. The presence of LVI increased with advancing pathological stage: 2% (20/820) in pT2N0 patients, 16% (58/363) in pT3N0 patients and 17% (2/12) in pT4N0 patients; and was highest in patients with pN1 disease (52%; 49/94). Univariate analysis showed an association between LVI and higher preoperative prostate‐specific antigen levels and Gleason scores, and a greater likelihood of extraprostatic extension, seminal vesicle invasion, lymph node metastasis and positive surgical margins (all P < 0.001). With a median follow‐up of 27 months, LVI was significantly associated with an increased risk of BCR after RP on univariate (P < 0.001) and multivariate analysis (hazard ratio, 1.77; 95% confidence interval, 1.11–2.82; P= 0.017). As a result of the relatively short follow‐up, the predictive accuracy of the standard clinicopathological features was high (concordance index, 0.880), and inclusion of LVI only marginally improved the predictive accuracy (0.884).

CONCLUSIONS

Although associated with features of aggressive disease and BCR, LVI added minimally to established predictors on short follow‐up. Further study of cohorts with longer follow‐up is warranted to help determine its prognostic significance.     

High nuclear Livin expression is a favourable prognostic indicator in renal cell carcinoma

OBJECTIVES

To assess the protein expression of Livin, an apoptosis inhibitor, in renal cell carcinoma (RCC) and to determine its prognostic relevance.

PATIENTS AND METHODS

Immunohistochemical staining for Livin was performed in tissue microarrays (TMAs), including tumour tissue cores, from patients with RCC who had undergone renal surgery. In 682 TMAs cytoplasmatic staining intensity and nuclear staining quantity were evaluated, and the association of Livin expression with progression‐free survival (PFS) and cancer‐specific survival (CSS) was analysed with a multivariate Cox regression model.

RESULTS

Over a median (range) follow‐up of 5.2 (0–16.1) years, 204 patients (28%) had died from their disease. The CSS rates at 1 and 5 years for the entire cohort was 88% and 71%. Cytoplasmatic Livin staining was absent in 516 (76%) specimens; staining was positive in 166 (24%) specimens. Weak nuclear Livin staining (≤25%) was present in 571 (84%) specimens, strong nuclear staining (26–100%) in 111 (16%). In multivariate analysis, high (>25%) nuclear Livin expression was a favourable independent predictor of PFS and CSS even after adjusting for tumour stage, Fuhrman grade, age, sex and Karnofsky severity rating. Cytoplasmatic Livin expression did not offer additional prognostic information.

CONCLUSION

High nuclear Livin expression is a favourable independent predictor of PFS and CSS in patients with RCC.     

Relation of microvessel density with microvascular invasion, metastasis and prognosis in renal cell carcinoma

OBJECTIVE

To clarify the significance of microvessel density (MVD) in a retrospective investigation the relationship between the pattern of MVD (reflecting angiogenesis), and tumour stage, grade, size, and occurrence of microvessel invasion (MVI), metastasis, and cancer‐specific survival (CSS) in patients who had surgery for renal cell carcinoma (RCC).

PATIENTS AND METHODS

Vessels were labelled in sections of formalin‐fixed, paraffin‐embedded tissues from 54 RCCs by CD34 immunohistochemistry. The mean MVD, expressed as the number of vessels per 10 high‐power fields (HPF, ×400) were measured for each case. In addition, all pathological slides were reviewed for the presence and absence of MVI. The prognostic value of MVD and MVI was then evaluated, and correlated with the usual prognostic variables, tumour metastasis and CSS.

RESULTS

In a univariate analysis of CSS, the MDV tended to be lower as stage increased from pT1 to pT3, and as grade increased from G1 to G4, although it was statistically significant only for stage (P < 0.001 and 0.050, respectively). The mean MVD was higher in 42 nonmetastatic than in 12 metastatic tumours, and in 33 tumours associated with MVI than in 21 with no MVI (P < 0.001). The mean MVD was also lower and significantly different for 28 large than 26 small tumours (P = 0.005). The survival rate of patients with tumours that were small, low‐stage, of higher MVD, with no MVI and metastasis was significantly higher than that of patients with large, high‐stage, low MVD, with MVI and metastatic tumours (all P < 0.001). MVI was significantly more common with a decreasing trend in MVD and the presence of metastasis (Spearman rank correlation r_s = ?0.68, P = 0.01, and r_s = 0.39, P = 0.01, respectively). Independent prognostic factors in a multivariate analysis were: in all patients with RCC, tumour stage (P = 0.013) and metastasis (P = 0.028); in those with low MVD, MVI (P = 0.004) and metastases (P = 0.016); in those with no MVI, stage (P = 0.020); in those with MVI, MVD (P = 0.001); in those with no metastases, stage (P = 0.045); and in those with metastases, MVD (P < 0.001). No independent predictor was identified in patients with high MVD. In patients with no metastases there was a significantly shorter median CSS time in RCCs with low MVD and with MVI (P = 0.004 for both). Similarly, patients who had grade 3–4 tumours, vs those with lower MVD and with MVI, had a significantly shorter median CSS (P = 0.020 for MVD, and 0.01 for MVI).

CONCLUSIONS

This study suggested that MVD in RCC was inversely associated with MVI, tumour metastasis, patient survival and tumour diameter and stage, from the usual prognostic variables, but MVD was not an independent prognostic factor in multivariate analysis for all patients with RCC. Low MVD and the presence of MVI appears to be a marker for identifying patients with an adverse prognosis.     

Tumour architecture is an independent predictor of outcomes after nephroureterectomy: a multi-institutional analysis of 1363 patients

OBJECTIVE

To assess whether tumour architecture can help to refine the prognosis of patients treated with nephroureterectomy (NU) for urothelial carcinoma (UC) of the upper urinary tract (UT), as the prognostic value of tumour architecture (papillary vs sessile) in UTUC remains elusive.

PATIENTS AND METHODS

The study included 1363 patients with UTUC and treated with radical NU at 12 centres worldwide. All slides were re‐reviewed according to strict criteria by genitourinary pathologists who were unaware of the findings of the original pathology slides and clinical outcomes. Gross tumour architecture was categorized as sessile vs papillary.

RESULTS

Papillary growth was identified in 983 patients (72.2%) and sessile growth in 380 (27.8%). The sessile growth pattern was associated with higher tumour grade, more advanced stage, lymphovascular invasion, and metastasis to lymph nodes (all P < 0.001). In multivariable Cox regression analyses that adjusted for the effects of pathological stage, grade and lymph node status, tumour architecture (sessile or papillary) was an independent predictor of cancer recurrence (hazard ratio 1.5, P = 0.002) and cancer‐specific mortality (1.6, P = 0.001). Adding tumour architecture increased the predictive accuracy of a model that comprised pathological stage, grade and lymph node status for predicting cancer recurrence and cancer‐specific death by a minimal but statistically significant margin (gain in predictive accuracy 1% and 0.5%, both P < 0.001).

CONCLUSION

The tumour architecture of UTUC is associated with established features of biologically aggressive disease, and more importantly, with prognosis after radical NU. Including tumour architecture in predictive models for disease progression should be considered, aiming to identify patients who might benefit from early systemic therapeutic intervention.     

Histopathological characteristics of lymph node metastases predict cancer-specific survival in node-positive prostate cancer

OBJECTIVE

To correlate the histopathological characteristics of lymph node metastases in prostate cancer with cancer‐specific survival (CSS).

PATIENTS AND METHODS

The histopathological slides from 142 patients who had had a pelvic lymph node dissection for node‐positive prostate cancer were reviewed. For each patient we recorded the number of lymph nodes removed, the number of positive nodes, the diameter of the largest metastasis and extranodal extension (ENE). The lymph node metastases were graded according to the Gleason system. These variables were correlated with CSS.

RESULTS

The mean age of the patients was 62.4 years and the mean preoperative prostate‐specific antigen level was 40.2 ng/mL. The median follow‐up was 77.5 months, and the median overall and CSS were 91 and 112 months, respectively. On univariable analysis the following variables correlated with poor CSS: a nodal Gleason score of >7 (hazard ratio 2.4, P < 0.001), a diameter of the largest metastasis of >3 mm (2.2, P = 0.025), more than two lymph node metastases (2.0, P = 0.003), and ENE in more than one lymph node (1.9, P = 0.014). Multivariable analysis showed only the nodal Gleason score and the diameter of the largest metastasis to be independent predictors of CSS (1.8, P = 0.021, and 2.2, P = 0.046, respectively).

CONCLUSION

The histopathological characteristics of lymph node metastases in prostate cancer have predictive value for the clinical outcome. The nodal Gleason score and the diameter of the largest metastasis are independent predictors of survival.     

Evaluation of fluorodeoxyglucose positron‐emission tomography with computed tomography for staging of urothelial carcinoma

Study Type – Diagnostic (case series)
Level of Evidence 4

OBJECTIVE

To investigate the role of ¹⁸F‐fluorodeoxyglusose positron‐emission tomography (FDG‐PET), combined with computed tomography (CT) and forced diuresis, in the staging and follow‐up of urothelial carcinoma (UC).

PATIENTS AND METHODS

We recruited 44 patients with muscle‐invasive urothelial bladder cancer (UBC) before radical cystectomy (RC), 19 under follow‐up after RC and seven after systemic chemotherapy. For those who had RC, histopathology was used as the reference standard to compare the sensitivity and specificity of FDG‐PET/CT and standard CT in detecting UBC and pelvic lymph node metastasis. Furthermore, 36 patients with ≥6 months of follow‐up imaging were considered to describe the progression of UC and extrapelvic positive FDG‐PET/CT images.

RESULTS

For the detection of primary UBC, FDG‐PET/CT was slightly more sensitive than CT (85% vs 77%) but less specific (25% vs 50%). For the detection of pelvic node metastasis FDG‐PET/CT was more sensitive than CT (57% vs 33%) with a specificity of 100% for both imaging techniques. In 20 patients, extrapelvic FDG‐PET/CT images showed suspected disease at the first evaluation. UC progressed in nine of the 10 patients who had synchronous multiple PET‐positive retroperitoneal or mediastinal lymph nodes, and in only two of the nine with unique hyperactive lesions in the lung. FDG‐PET/CT also detected a pT1G3 UC of the renal pelvis and all bone metastases detected by bone scintigraphy.

CONCLUSIONS

FDG‐PET/CT could replace standard CT and bone scintigraphy in the presurgical staging and monitoring of patients with UC after surgery or chemotherapy.     

Ureteroscopic and extirpative treatment of upper urinary tract urothelial carcinoma: a 15‐year comprehensive review of 160 consecutive patients

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Upper urinary tract urothelial carcinomas (UTUC) have historically been treated with radical, extirpative surgery, primarily nephroureterectomy with bladder‐cuff excision. In general, there has been growing interest in renal preservation, as evidenced by the broadening application of nephron‐sparing surgery for renal parenchymal tumours. Beyond imperative reasons such as tumour in a solitary kidney, bilateral disease, or comorbidities preventing radical surgery, there is a growing role for endoscopic management of upper tract tumours. The aim has been to obtain similar oncological results to those of extirpative surgery, while preserving long‐term renal function. Properly selecting patients for these therapies, designing specific treatments based on a complex presentation, and general information with regard to outcomes and risks for patient counselling have been based historically on results from relatively small series without long‐term follow‐up. This study reflects all patients with UTUC treated by a single tertiary referral surgeon, accrued prospectively over 15 years using the same surgical techniques and treatment algorithms throughout the entire study period, with 10‐year survival data. The consecutively accrued nature and size of the study groups, uniformity in treatments, statistical review and long‐term follow‐up provide baseline oncological data that could help frame future study.

OBJECTIVE

• ? To present long‐term oncological outcomes of all patients treated surgically for upper urinary tract urothelial carcinoma (UTUC) over a 15‐year period.

PATIENTS AND METHODS

• ? All patients (N= 160) treated from January 1996 to August 2011 were prospectively studied and placed into three distinct groups after initial diagnostic ureteroscopy (URS): Group 1: low grade lesions treated with URS (n= 66); Group 2: high grade lesions palliatively treated with URS (n= 16); and Group 3: extirpative surgery (nephroureterectomy [NU]; n= 80).
• ? Statistical analysis was performed using Kaplan–Meier methodology to calculate overall (OS), cancer‐specific (CSS) and metastasis‐free survival (MFS).

RESULTS

• ? The median patient age at presentation was 73 years, and the mean (range) follow‐up time was 38.2 (1–185) months. At initial diagnostic URS, 71 (44.4%) patients presented with high grade and 89 (55.6%) patients presented with low grade disease.
• ? The 2‐, 5‐ and 10‐year CSS rates were 98, 87 and 81% for patients with low grade disease, and 97, 87 and 78% for patients treated with URS (Group 1), not significantly different from those patients with low grade disease treated with NU (Group 3), (P= 0.54).
• ? Of the patients treated with URS for low grade disease, 10 (15.2%) progressed to high grade disease at a mean time of 38.5 months.
• ? Patients with high grade disease treated with NU had a 2‐, 5‐, and 10‐year CSS of 70, 53 and 38%, with a MFS of 55, 45 and 35%.
• ? Median survival of patients with high grade disease treated with palliative URS was 29.2 months with a 2‐year OS of 54%.
• ? On multivariate analysis only high grade lesion on initial presentation was found to be a significant factor (P < 0.001; hazard ratio = 7.27).

CONCLUSIONS

• ? Grade is the most significant predictor of OS and CSS in those with UTUC, regardless of treatment method.
• ? Ureteroscopic and extirpative therapy are acceptable options for those with low grade disease showing excellent long‐term CSS.
• ? Extirpative therapy was found to result in relatively poor long‐term CSS in patients with high grade disease, underscoring the need for adjuvant or neoadjuvant therapies.

     

Ureteral tumours showing a worse prognosis than renal pelvis tumours may be attributed to ureteral tumours more likely to have hydronephrosis and less likely to have haematuria

Purpose

To demonstrate the relationships among tumour location, hydronephrosis, and tumour stage in patients with Upper Urinary Tract Urothelial Carcinoma (UUT-UC). Moreover, we want to determine whether primary tumour location is an independent predictor of prognosis in those patients.

Methods

Retrospective analysis of 251 UUT-UC patients from our centre treated with radical nephroureterectomy between 2000 and 2010. Patients who had previous radical cystectomy, preoperative chemotherapy, previous contralateral UUT-UC, multifocal tumours, or metastatic disease at presentation were excluded. Overall, 217 patients were then available for evaluation. The relationships among tumour location, hydronephrosis, and tumour stage were analysed. Tumour location was categorized as renal pelvis or ureter. Progression-free survival (PFS) and cancer-specific survival (CSS) probabilities were estimated using Kaplan–Meier and Cox regression analyses.

Results

Tumour location was renal pelvis in 146 cases (67 %), ureter in 71 cases (33 %). Median follow-up was 52 months. Compared with renal pelvic tumours, ureteral tumours were more likely to have hydronephrosis and to be associated with advanced stages (p < 0.001), but less likely to have haematuria. The 5-year CSS estimate was 79.3 % for renal pelvic tumours and 64.7 % for ureteral tumours (p = 0.03). The 5-year PFS probability was 68.7 % for renal pelvic tumours and 54.2 % for ureteral tumours (p = 0.02). On univariable and multivariable analysis, tumour location was an independent prognostic factor for CSS (p < 0.05).

Conclusions

Ureteral tumours were associated with a worse prognosis than renal pelvis tumours. The possible hypothesis may be due partially to that ureteral tumours are more likely to have hydronephrosis and less likely to have haematuria.     

Development of a new outcome prediction model in carcinoma invading the bladder based on preoperative serum C-reactive protein and standard pathological risk factors: the TNR-C score

Study Type – Prognosis (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? There is increasing evidence for a prognostic significance of pretherapeutically elevated serum C‐reactive protein levels in various cancers. However, little is known about its significance in patients with invasive bladder cancer. This study shows that serum CRP is an independent predictor for cancer‐specific survival in bladder cancer, and its incorporation into a new outcome model (TNR‐C Score) encompassing major pathological determinants for survival, increases significantly its predictive accuracy.

OBJECTIVE

? To assess the predictive value of preoperative C‐reactive protein (CRP) in patients undergoing radical cystectomy (RC) for carcinoma invading the bladder in light of recent data showing it to be an independent indicator of adverse oncological outcome in other malignancies.

PATIENTS AND METHODS

? A contemporary, consecutive series of 246 patients undergoing RC and bilateral pelvic lymphadenectomy for bladder cancer between 1999 and 2009. ? Elevated CRP was defined as >0.5 mg/dL and was consistent during the study period. The median (range) follow‐up was 30 (6–116) months. ? Kaplan–Meier analysis was used to estimate cancer‐specific survival (CSS) using a log‐rank test and Cox regression analysis for multivariate analysis of risk factors. ? Based on regression estimates of significant parameters in multivariate analysis, a new CRP‐based scoring model was developed to predict cancer‐specific outcomes. The predictive accuracy of the model was evaluated using the concordance index.

RESULTS

? The 3‐year CSS was 74.0% in patients with normal and 44.0% with elevated CRP (P < 0.001). ? In multivariate analysis, CRP (P < 0.001; used as a continuous variable), tumour stage (P= 0.001), lymph‐node density ≥0.09 (P= 0.02) and resection margin status (P < 0.001) were independent predictors of CSS. ? The 3‐year CSS in patients with a score in the ranges 0–2, 3–6 and 7–10 was 80.5%, 44.9% and 7.1%, respectively (P < 0.001). Consideration of CRP in the final model increased its predictive accuracy by 4.9% with a concordance index of 0.788 (P= 0.01).

CONCLUSIONS

? This is the largest, contemporary series to date indicating that preoperative serum CRP is an independent risk factor for CSS. ? CRP may be a useful parameter to include in predictive bladder cancer nomograms.     

Histological variants and lymphovascular invasion in upper tract urothelial carcinoma can stratify prognosis after radical nephroureterectomy

ObjectivesPatients with histological variants (HV) of bladder cancer have more advanced disease and poorer survival rates than those with pure urothelial carcinoma (UC). Moreover, lymphovascular invasion (LVI) is an important biomarker after RNU in systematic reviews and meta-analyses. Thus, here we investigated the clinical and prognostic impact of HV and LVI in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU).MethodsData from 223 UTUC patients treated with RNU without neoadjuvant chemotherapy were retrospectively evaluated. We analyzed differences in clinicopathological features and survival rates between patients with pure UC and those with HV. Conditional survival (CS) analysis was performed to obtain prognostic information over time.ResultsA total of 32 patients (14.3%) had HV, with the most common variant being squamous differentiation, followed by glandular differentiation. UTUC with HV was significantly associated with advanced pathological T stage (pT ≥ 3), higher tumor grade (G3), and LVI, compared to pure UC (all P < 0.01). Progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS), were all significantly worse in the HV group compared to the pure UC group (all, P < 0.001). In multivariable analysis, HV and LVI were independent predictors of CSS and OS. We classified the patients into three groups using these two predictors: low-risk (neither HV nor LVI), intermediate-risk (either HV or LVI), and high-risk (both HV and LVI). Significant differences in PFS, CSS, and OS rates were found among the 3 groups. In CS analysis, the conditional PFS, CSS, and OS rates at 1, 2, 3, 4, and 5 years improved with increased duration of event-free survival. CS analysis revealed that most progression events occurred within 2 years after RNU, and patients with risk factors had worse PFS at all time points.ConclusionsA risk model using HV and LVI can stratify PFS, CSS, and OS of patients treated with RNU. In addition, CS analysis revealed that HV and LVI were poor prognostic factors over time after RNU.     

Longitudinal evaluation of the concordance and prognostic value of lymphovascular invasion in transurethral resection and radical cystectomy specimens

THIS IS A COMMENT MODERATED PAPER
available at http://www.bjui.org/commentary Study Type – Therapy (case series)
Level of Evidence 4 What’s known on the subject? and What does the study add? Lymphovascular invasion (LVI) is a prognostic marker for biologically aggressive disease in numerous tumour types. Indeed, numerous studies have documented the negative prognostic value of LVI in bladder cancer patients who have undergone radical cystectomy, however few studies have evaluated the prognostic value of LVI at TURBT. The current study examines both the concordance between the presence of LVI at TURBT and radical cystectomy specimens and furthermore examines the survival implications of the presence of LVI at both TURBT and radical cystectomy.

OBJECTIVE

To evaluate the concordance transurethral resection of bladder tumour (TURBT) and radical cystectomy (RC) specimens with regard to the presence of lymphovascular invasion (LVI). Additionally, to evaluate the prognostic value of LVI in the prediction of lymph node metastases, overall survival, disease‐specific survival and recurrence‐free survival following RC.

PATIENTS AND METHODS

The records of 487 patients who underwent RC at our institution between 1987 and 2008 were retrospectively reviewed and evaluated for the presence or absence of LVI as determined by pathological evaluation. The presence or absence of LVI was then evaluated on previous transrectal resection specimens of this cohort of patients undergoing RC. Cox regression and Kaplan–Meier analysis were undertaken to evaluate the contribution of LVI to various outcomes.

RESULTS

Of 474 patients with complete LVI data, 60 (12.3%) were found to have LVI at TURBT compared to 161 (33.1%) at RC. Although the presence of LVI at TURBT was more significantly associated with the presence of LVI at RC, only 42.9% of patients in whom LVI was documented at TURBT were found to harbour LVI at RC. The risk of nodal disease was higher in those patients with LVI at TURBT than in those with no evidence of LVI at TURBT (48.3% vs 25.0%, P < 0.001). Additionally, LVI at TURBT was associated with an increasing risk of pathological upstaging and the receipt of adjuvant chemotherapy. Survival analysis showed a significant decrement in overall and recurrence‐free survival among those with LVI at TURBT compared to those with no evidence of LVI.

CONCLUSIONS

Lymphovascular invasion at TURBT provides useful prognostic information that should be incorporated into clinical decision‐making, particularly with regard to cystectomy for nonmuscle‐invasive carcinoma and the administration of neoadjuvant chemotherapy.