Micropapillary Bladder Cancer: I Have It, Now What Does it Mean?

More than 75k people in the United States are diagnosed with bladder cancer on an annual basis and its estimated that >500k people in the US are living with the disease.[1,2]  Greater than 90% of bladder cancers are urothelial cancer (UC; of the lining of the bladder); and 75% of UC are non-muscle invasive or growing out of the lining of bladder.  There are rare variants of UC including nested, microcystic, inverted, squamous and glandular differentiation, sarcomatoid, clear cell and micropapillary variants.

Micropapillary is currently the most well-studied, independent histology.  Although rare relative to the large number of patients with undifferentiated, conventional UC, micropapillary cancer still affects a significant proportion of patients.  Here we will review the definitions and implications of micropapillary bladder cancer for those patients with a new diagnosis.

Epidemiology and Statistics [3]

• 0.7-2.2% of all UC are micropapillary
• Average age at diagnosis: 65
• Male-to-female ratio  10:1

Histology and Pathology [4-8]

• Micropapillary tumors grow in delicate filiform processes in infiltrating clusters lacking vascular stalks (see images from WebPathology.com)
• Vascular and lymphatic invasion is common.
• 80% cases found with conventional UC

• The amount of micropapillary cancer does not have bearing on outcomes; outcomes are consistent if 10% or greater of the tumor contains micropapillary cancer
• Less than 9% have non-muscle invasive disease; 70% will progress to invasive disease.
• At cystectomy for non-muscle invasive disease:
• >50% can be upstaged
• >25% had occult lymph node metastases
• 50% present as muscle-invasive, node-positive or metastatic disease

Treatment and Outcomes

Retrospective studies show an overall worse prognosis for micropapillary cancer when compared to conventional UC of the bladder.[9-10]  However, micropapillary cancer often presents at and advanced stage and two case-matched series did not show a survival difference between micropapillary and conventional UC when matched stage-for-stage.[11,12]  

It is clear that micropapillary urothelial cancer is an aggressive variant of bladder cancer; it is unclear if it is independently worse than conventional urothelial cancer.

In general, surgical removal of the bladder (radical cystectomy) is the most effective treatment for micropapillary cancer.  Rare cures are achieved with transurethral resection if non-invasive cancer and complete resection is achieved; although BCG treatments are ineffective if tumors are incompletely resected.[8,13]   

In a few studies, neoadjuvant chemotherapy (NAC; chemotherapy before cystectomy) does not appear to be effective for micropapillary cancer.[8,14]  In the initial report of micropapillary cancer from MD Anderson Cancer Center demonstrated a 5-year survival of 71% for those undergoing immediate cystectomy and 63% for those receiving NAC before surgery.[8]  However, the data regarding the use of NAC is sparse and other centers have reported beneficial outcomes with NAC.  For instance, Meeks et al demonstrated 45% downstaging from transurethral resection to cystectomy and a significant survival advantage to patients downstaged to pT0 (no residual cancer in the bladder) with NAC.[15]  Ghonheim and colleagues argue for the use of NAC citing an 86% rate of micrometastatic lymph node metastases.

Therefore, the use of neoadjuvant chemotherapy remains controversial - with some centers advocating its use and some centers believing that neoadjuvant chemotherapy may actually worsen survival by delaying therapy.   

Survival Statistics for Micropapillary Cancer of the Bladder

All Patients [11,12,16]

• Overall Recurrence-Free Survival: 58% at 5 years
• Local Recurrence-Free Survival: 62% at 10 years
• Distant Metastases-Free Survival: 44% at 10 years
• Cancer-Specific Survival: 31% at 10 years
• Overall Survival: 40-67% at 5 years, 21% at 10 years

Non-Muscle Invasive Micropapillary Bladder Cancer

BCG failure: 67% progressed, of which 22% developed metastases

Immediate Cystectomy: 72% alive at 5-years

Cystectomy after Intravesical Treatment: 60% alive at 5-years

Muscle-Invasive Micropapillary Bladder Cancer

Immediate Cystectomy: 70% alive at 5-years

If pT0 (no cancer at found at cystectomy) or carcinoma-in-situ (CIS): no deaths at 38 months

If Locally Advanced Cancer: 22% alive at 4 years

If Non-Organ Confined Disease: 38.1 months median survival

If Non-Resectable Disease: 17 month median survival

1. American Cancer Society, Facts & Figures 2014; Accessed March 21, 2014.  http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf
2. Surveillance, Epidemiology, and End Results (SEER) Stat Fact Sheets: Bladder Cancer; Accessed March, 21, 2014.  http://seer.cancer.gov/statfacts/html/urinb.html  
3. Amin MB, Ro JY, el-Sharkawy T,et al: Micropapillary variant of transitional cell carcinoma of the urinary bladder. Histologic pattern resembling ovarian papillary serous carcinoma. Am J Surg Pathol 1994; 18: 1224-1232.
4. Johansson SL, Borghede G, Holmang S,et al: Micropapillary bladder carcinoma: a clinicopathological study of 20 cases. J Urol 1999; 161: 1798-1802.
5. Kamat AM, Dinney CP, Gee JR,et al: Micropapillary bladder cancer: a review of the University of Texas M.D. Anderson Cancer Center experience with 100 consecutive patients. Cancer 2007; 110: 62-67.
6. Lopez-Beltran A, Cheng L: Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications. Hum Pathol 2006; 37: 1371-1388.
7. Johansson SL, Borghede G, Holmang S,et al: Micropapillary bladder carcinoma: a clinicopathological study of 20 cases. J Urol 1999; 161: 1798-1802.
8. Kamat AM, Dinney CP, Gee JR,et al: Micropapillary bladder cancer: a review of the University of Texas M.D. Anderson Cancer Center experience with 100 consecutive patients. Cancer 2007; 110: 62-67.
9. Comperat E, Roupret M, Yaxley J, et al. Micropapillary urothelial carcinoma of the urinary bladder: a clinicopathological analysis of 72 cases. Pathology 2010; 42:650–654. 
10. Samaratunga H, Khoo K. Micropapillary variant of urothelial carcinoma of the urinary bladder; a clinicopathological and immunohistochemical study. Histopathology 2004; 45:55–64. 

11. Wang JK, Boorjian SA, Cheville JC, et al. Outcomes following radical cystectomy for micropapillary bladder cancer versus pure urothelial carcinoma: a matched cohort analysis. World J Urol 2012; 30:801–806.

12. Fairey AS, Daneshmand S, Wang L, et al. Impact of micropapillary urothelial carcinoma variant histology on survival after radical cystectomy. Urol Oncol 2013.

13. Gaya JM, Palou J, Algaba F, et al. The case for conservative management in the treatment of patients with nonmuscle-invasive micropapillary bladder carcinoma without carcinoma in situ. Can J Urol 2010; 17:5370–5376.

14. Bristow RE, Gossett DR, Shook DR,et al: Micropapillary serous ovarian carcinoma: surgical management and clinical outcome. Gynecol Oncol 2002; 86: 163-170.

15. Meeks JJ, Taylor JM, Matsushita K, et al. Pathological response to neoadjuvant chemotherapy for muscle-invasive micropapillary bladder cancer. BJU Int 2013; 111:E325–E330.
16. Ghoneim IA, Miocinovic R, Stephenson AJ, et al. Neoadjuvant systemic therapy or early cystectomy? Single-center analysis of outcomes after therapy for patients with clinically localized micropapillary urothelial carcinoma of the bladder. Urology 2011; 77:867–870.

Classic Manuscripts in Urology: Landmark Trials in BPH

Benign prostatic hyperplasia (BPH) is extremely common, affecting up to 25% of men throughout their lifetime.  Over the past 25 years, a number of important clinical trials were completed that define our current medical management of BPH.  These trials should be familiar to all urologists and urology residents; and patients with BPH should know these trials exist and may want to be familiar with their outcomes.

Here we review some of the landmark trials in the medical management of BPH. 

Tamsulosin Investigator Group

Alpha-Blocker Trial
Lepor H.  Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Tamsulosin Investigator Group.  Urology. 1998 Jun;51(6):892-900.

765 men randomized to placebo, 0.4mg or 0.8mg of tamsulosin with the inclusion criteria: age >45, AUA symptom score >13, urinary flow rate (Qmax) 4-15mL/second and post-void residual (PVR) <300cc.  At the study endpoint, improvement in AUA-SS was 5.5, 8.3 and 9.6 points in the placebo, 0.4mg and 0.8mg groups respectively.  This correlated to a 25% AUA-SS improvement in 51%, 70% and 74% of patients.  Urinary flow rates (Qmax) improved by 0.5, 1.75 and 1.78; corresponding to a 30% Qmax improvement in 21%, 31% and 36% of men.

North American Finasteride Trial

5-Alpha Reductase Inhibitor Trial
Gormley GJ, Stoner E, Bruskewitz RC, et al: The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med 1992;327:1185-1191.

Over a 12 month period, Dr. Gormley and colleagues demonstrated that 5mg of finasteride demonstrated a consistent improvement in symptoms after week 2 through month 12, defining the few week lag period often observed in patients starting finasteride.  In addition, they demonstrated a maximum improvement of 2.7 points on the AUA-SS.  This correlated to an increase in Qmax of 3 mL/sec, a decrease in prostate volume of 19% and the 50% decrease in serum PSA (defining the adjustment in PSA needed for prostate cancer screening).

Proscar Long-term Efficacy and Safety Study (PLESS)

5-Alpha Reductase Inhibitor Trial

McConnell JD, Bruskewitz R, Walsh P, et al: The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338:557-563.

Dr. McConnell and colleagues evaluated 3,040 men in a multicenter, double-blind, placebo controlled study of finasteride (5mg) over 4 years.  The finasteride group had an average improvement in AUA-SS of 3.3 (compared to 1.8 in the placebo group) that only became evident after 1 year.  Importantly, there was a 57% reduction in acute urinary retention and 55% reduction in surgical intervention at 4 years.

Dutasteride ARIA Studies

5-Alpha Reductase Inhibitor Trial
Roehrborn CG, Boyle P, Nickel JC, et al: Efficacy and safety of a dual inhibitor of 5 alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002;60:434-441.
Roehrborn CG,Marks LS, Fenter T, et al: Efficacy and safety of dutasteride in the four-year treatment of men with benign prostatic hyperplasia. Urology 2004;63:709-715.

Dr. Roerhborn and colleagues published short- and long-term outcomes of men on the dual-5-ARI inhibitor dutasteride.  Men in this study had moderate-to-severe symptoms based on AUA symptoms score, peak flow <15mL/s and a prostate volume >30cc (average prostate volume 54cc).  AUA symptom scores improved a 6 months and reached a maximum at 24 months compared to placebo.  Similar to the PLESS trial, they found a 25% reduction in prostate volume, 2.2mL/s increase in Qmax, 57% risk reduction of urinary retention and 48% reduction in surgical intervention.

Veterans Affairs Cooperative Study 359

Combination Alpha-Blocker / 5ARI Trial

Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med. 1996;335:533–539.

This was the first trial directly comparing an alpha-blocker and 5ARI, and the first time combination therapy was explored.  1,229 men were randomized to terazosin, finasteride, combination or placebo for 1 year.  This study failed to demonstrate an improvement in finasteride when compared to placebo with respect to symptom scores or urinary flow rates. However, the average prostate size in this study was only 37cc and when subset analyses were performed, it was confirmed that the improvement due to terazosin was independent of prostate volume while finasteride was most effective in larger prostates.

Barry MJ1, Williford WO, Chang Y, Machi M, Jones KM, Walker-Corkery E, Lepor H.  Benign prostatic hyperplasia specific health status measures in clinical research: how much change in the American Urological Association symptom index and the benign prostatic hyperplasia impact index is perceptible to patients?  J Urol. 1995 Nov;154(5):1770-4.

In this analysis of the VA359 study, Dr. Barry and colleagues defined slight, moderate and marked improvement in AUA-SS as 3, 5 and 8 points respectively.

Medical Therapy of Prostate Symptoms (MTOPS)

Combination Alpha-Blocker / 5ARI Trial
McConnell JD1, Roehrborn CG, Bautista OM, Andriole GL Jr, Dixon CM, Kusek JW, Lepor H, McVary KT, Nyberg LM Jr, Clarke HS, Crawford ED, Diokno A, Foley JP, Foster HE, Jacobs SC, Kaplan SA, Kreder KJ, Lieber MM, Lucia MS, Miller GJ, Menon M, Milam DF, Ramsdell JW, Schenkman NS, Slawin KM, Smith JA; Medical Therapy of Prostatic Symptoms (MTOPS) Research Group.The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia.N Engl J Med. 2003 Dec 18;349(25):2387-98.


The MTOPS Trial was a prospective, multi-center, randomized, double-blind trial where 3047 patients randomized to doxazosin, finasteride or both versus placebo.  Mean prostate volume was 36cc, mean IPSS 16.7 and Qmax ranged from 4-15mL/s.  Over an average follow-up of 4.5 years, the risk reduction for progression (increase in IPSS of 4, acute urinary retention or surgery) was 39% for doxazosin, 34% for finasteride, and 67% for combination therapy compared with placebo.  The risk of acute urinary retention did not change for patients on doxazosin (although time to AUR was longer), but was reduced 68% for men on finasteride and 81% for patients on combination-therapy.  Similarly, there was no difference in surgical rates for patients on doxazosin, but a 64% and 67% reduction for men on finasteride or combination therapy respectively.  Importantly, the MTOPS trial also demonstrated a dramatic reduction in hematuria for patients on finasteride (63% hematuria recurrence on placebo, 14% recurrence in finasteride).

Combination of Avodart and Tamsulosin Trial (CombAT)

Combination Alpha-Blocker / 5ARI Trial

Roehrborn CG, Siami P, Barkin J, Damião R, Becher E, Miñana B, Mirone V, Castro R, Wilson T, Montorsi F; CombAT Study Group.  The influence of baseline parameters on changes in international prostate symptom score with dutasteride, tamsulosin, and combination therapy among men with symptomatic benign prostatic hyperplasia and an enlarged prostate: 2-year data from the CombAT study.  Eur Urol. 2009 Feb;55(2):461-71. doi: 10.1016/j.eururo.2008.10.037. Epub 2008 Nov 6.

Roehrborn CG, Siami P, Barkin J, Damião R, Major-Walker K, Nandy I, Morrill BB, Gagnier RP, Montorsi F; CombAT Study Group. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study.  Eur Urol. 2010 Jan;57(1):123-31. doi: 10.1016/j.eururo.2009.09.035. Epub 2009 Sep 19. Erratum in: Eur Urol. 2010 Nov;58(5):801.

In the multicenter, randomised, double-blind, parallel-group CombAT Trial, 4,844 men with age >50, IPSS>12, and prostate volume >30cc were randomized to tamsulosin, dutasteride or combination.  These researchers found improvements in acute urinary retention and surgical interventions in men who were taking dutasteride or combination therapy compared to those on tamsulosin alone.  These improvements were most evident in men with a prostate volume >42cc.  

In summary, we can draw the following conclusions from these studies:

• Significant improvements in AUA-SS are considered greater than 3 points.
• Alpha blockers can begin working as quickly as 8 hours.
• The effects of 5ARI may not be felt for 2 weeks to 2 months, and may take 6-12 months to reach their maximum benefit. 
• 5ARIs reduces the risk of acute urinary retention and surgical treatment associated with BPH.
• 5ARIs are effective only on men with larger prostates (>40g).

This blog was written by Mark W. Ball, MD, urology resident at the Brady Urological Institute at Johns Hopkins.

Stage 1 Testis Cancer: Recommendations from Hopkins

Testicular cancer is one of the true success stories in modern medicine.  With modern chemotherapy regimens, the overall cure rate for men with early stage (Clinical Stage I, CSI) testis cancer approaches 100%.  Given that these patients are often young men - each with a long life expectancy - consideration of side-effect profiles, specifically "late-effect" profiles (those occurring 10 or greater years after treatment), are of paramount consideration.

Focusing on men with non-seminomatous germ cell tumors (NSGCT), the National Cancer Comprehensive Network (NCCN) outlines three management strategies for men with CSI NSGCT:

• Active Surveillance (AS)
• Primary Chemotherapy
• Nerve-Sparing Retroperitoneal Lymph Node Dissection (RPLND)

When choosing a management strategy for CSI NSGCT, the primary point of distinction is the presence of lymphovascular invasion (LVI) in the primary tumor in the testicle.  If no LVI is present, the risk of recurrence is low (15% or less) and these patients are classified as Clinical Stage Ia.  If LVI is present, the risk of recurrence is much higher (approaching 50%) and those patients are considered Clinical Stage Ib.  However, both CSIa and CSIb men have excellent cure rates with even those patients who recur being salvaged with chemotherapy and/or surgery.

Recently there has been a large impetus for active surveillance for men with CSI NSGCT.[1,2]  Here we review the management options, some of the literature and debate on this topic.

Active Surveillance for Clinical Stage I Disease

According to the NCCN Guidelines, AS is a relatively time- and radiology-intense follow-up that eases only after 5 years and continues indefinitely (see table).  AS has been demonstrated to be safe and effective treatment for CSI NSGCT.[3-7]  Protocols have been refined to be less intense, and continue to demonstrate excellent long-term survival rates.[8,9]  However, some of the issues with AS include: 

• Compliance - the testis cancer population, in general, is young and mobile; adherence to AS protocols can be difficult
• Radiation Exposure - repeat CT imaging over a life-time has a small, but not insignificant radiation exposure that should be addressed in young men
• Salvage - if recurrence while on AS, the most likely next treatment is chemotherapy, with the potential long-term side effects of chemotherapy (discussed in next section)

NCCN Guidelines for Surveillance of Patients with CSI NSGCT.

Primary Chemotherapy for Clinical Stage I Disease

The typical chemotherapy for patients with CSI NSGCT is BEP (a combination of bleomycin, etoposide and cisplatin) for one- or two-cycles.  Primary chemotherapy in this setting reduces the risk of recurrence to <1%, however will overtreat 50-85% of men.  The short-term side effects of chemotherapy are well-known (hair loss, nausea and vomiting, etc) and, in general, short-lived and well-tolerated in this young, healthy population.  Of important consideration, is that these men are subjected to the long-term side effects of chemotherapy without actually needing the drug.  

Late-effect side effects of chemotherapy:

• Secondary Malignancy: 
• Solid tumors: Relative Risk 1.8-2.1 [10,11] 
• Leukemia: 0.5-2% based on dose of etoposide [12], variably increased based on the dose of cisplatinum [13]
• Cardiovascular Toxicity: demonstrated increased risks of early-onset angina, myocardial infarcation (heart attack) with related hyperlipidemia, metabolic syndrome [14-16]
• Single-Organ Dysfunction:
• Neurotoxicity: approximately 20% have neurologic symptoms [17]
• Nephrotoxicity: 30% long-term reduction in glomerular filtration rate (kidney filtering) [18,19]
• Pulmonary Toxicity: 
• Increased risk of pulmonary disease and death from pulmonary disease [20]
• Most of this toxicity is related to bleomycin, as it can have long-term effects on pulmonary function by causing pulmonary fibrosis
• This was a major reason Lance Armstrong sought to avoid this chemotherapy.
• Hypogonadism (Decreased Testosterone)
• Infertility
• Unknown toxicities: cisplatinum chemotherapy can be found in the blood of patients 10 years after receiving a dose.  The long-term side effects of this medication are currently unknown. [21]

Other considerations before accepting chemotherapy include: (1) most recurrences after parimary chemotherapy are teratoma and occur in the retroperitoneum, necessitating serial abdominal imaging similar to an AS protocol, and (2) treatment for recurrence after chemotherapy is RPLND.  Post-chemotherapy RPLND can be a challenging and dangerous operation.  While complications are rare they can be serious, occasionally catastrophic and include:

• life-threatening bleeding requiring blood transfusion or reconstruction of vascular structures
• removal of adherent adjacent organs (small bowel, kidney, etc.)
• permanent anejaculation
• chylous ascites

Primary Retroperitoneal Lymph Node Dissection (RPLND) for Clinical Stage I Disease

The primary landing zone for metastases from testis cancer are the lymph nodes of the retroperitoneum, around and between the aorta and inferior vena cava at the level of the kidneys.  For many years, RPLND was a mainstay of therapy for CSI NSGCT as it better staged disease and offered a therapeutic benefit for many patients.  However, upwards of 70% of patients will never need an RPLND and are overtreated by surgery.  RPLND has fallen out of favor with many physicians and organization due to the morbidity of the procedure and high-risk of overtreatment.

Traditionally, RPLND is done through a large, midline incision (along the entire abdomen) and only performed at high-volume, centers of excellence due to the rarity of disease and technical challenges of the surgery.  More recently, minimally-invasive RPLND has become an option for men with testis cancer, dramatically reducing the convalescence of the operation and offering the benefits of avoiding chemotherapy and rigorous AS.[22]  Minimally-invasive RPLND changes the thought-process for CSI testis cancer, as it changes the ratio of risk to benefit as the morbidity associated with the procedure is dramatically reduced compared with the traditional, open surgery.  In addition, post-chemotherapy RPLND is a dramatically different operation (discussed above).  Avoiding a post-chemotherapy RPLND can prevent many undesirable side-effects in young men.

What do we recommend for men with CSI NSGCT?

One of the common sayings in testis cancer is, "All roads lead to Rome," and that patients need to choose the road that most suits their personality, lifestyle and concerns.  Basically, nearly 100% of men with CSI NSGCT will be cured.  Some (actually a minority) will require chemotherapy, some surgery and some a combination of both.  We often recommend that patients consider what treatment they would like to avoid most and prioritize the order of the treatments (if needed) from there.  

We often recommend that patients consider what treatment they would like to avoid most and prioritize the order of the treatments (if needed) from there. 

While every patient is an individual and individual health risks and preferences need to be considered, in general, we make the following recommendations at the Brady Urological Institute at Johns Hopkins for the treatment of CSI NSGCT.

Clinical Stage Ia (Tumor Confined to the Testicle, No Lymphovascular Invasion)

Men with CSIa have an incredibily low-risk of recurrence (5-15%).  Therefore we do not routinely recommend primary treatment (chemotherapy or RPLND) as most patients will be overtreated by these therapies.

• Active Surveillance is preferred
• Upwards of 90-95% of men are cured with orchiectomy alone
• AS involves tumor markers and CT scans every 3-4 months after surgery
• Primary Chemotherapy is an option
• for patients concerned about the risk of relapse 
• for patients with compliance or insurance issues
• Primary Minimally-Invasive RPLND is an option
• for patients concerned about the risk of relapse 
• patients with compliance or insurance issues
• patients who wish to avoid a post-chemotherapy RPLND

Clinical Stage Ib (Tumor Confined to the Testicle, Lymphovascular Invasion present)  

Men with CSIb NSGCT have upwards of a 50% chance of recurrence.  Therefore, we usually recommend primary chemotherapy or minimally-invasive RPLND as treatment for these men.  

• Minimally-Invasive RPLND
• most patients are discharge one day after surgery (although full recovery certainly can take weeks)
• nodal yields and ejaculatory function are excellent with a unilateral template surgery
• patients with one-positive lymph node (N1) can be monitored following surgery without necessitating chemotherapy
• we recommend adjuvant chemotherapy for all patients with greater than one positive lymph node (N2)
• Primary Chemotherapy
• will cure many patients with high-risk, CSIb disease
• patients must consider that they will require a post-chemotherapy RPLND
• patients must consider late-term side effects of chemotherapy (excellent treatment for older patients)
• Active Surveillance remains an option
• for patients desiring to avoid all additional treatments
• patients need to recognize that those who recur after a period of AS, will require full-dose chemotherapy (3-4 cycles of BEP) and potentially more side effects

Phillip M. Pierorazio, MD is the Director of the Division of Testicular Cancer at the Brady Urological Institute at Johns Hopkins.  If you or a loved one was recently diagnosed with testis cancer and would like a consultation please call the Urology Clinic at 410 955 6100.  If you or a loved one is a survivor of testis cancer, please take a look at our Facebook page for "Testis Cancer Survivors."  The page is designed to be a forum for patients to meet and discuss issues around Testis Cancer.  We will supply the page with updates and data regarding Testis Cancer.

Resources:

NCCN website: http://www.nccn.org/professionals/physician_gls/pdf/testicular.pdf

[1] Nichols CR1, Roth B, Albers P, Einhorn LH, Foster R, Daneshmand S, Jewett M, Warde P, Sweeney CJ, Beard C, Powles T, Tyldesley S, So A, Porter C, Olgac S, Fizazi K, Hayes-Lattin B, Grimison P, Toner G, Cathomas R, Bokemeyer C, Kollmannsberger C.  Active surveillance is the preferred approach to clinical stage I testicular cancer.  J Clin Oncol. 2013 Oct 1;31(28):3490-3. doi: 10.1200/JCO.2012.47.6010. Epub 2013 Sep 3.

[2] Schmidt C. Debates emerge over active surveillance in testicular cancer.  J Natl Cancer Inst. 2014 Feb;106(2):dju040. doi: 10.1093/jnci/dju040.

[3] Duran I, Sturgeon JF, Jewett MA, et al: Initial versus recent outcomes with a non-risk adapted surveillance policy in stage I non-seminomatous germ cell tumors (NSGCT). J Clin Oncol 25:240s, 2007 (suppl; abstr 5021) 

[4] Kollmannsberger C, Moore C, Chi KN, et al: Non-risk-adapted surveillance for patients with stage I nonseminomatous testicular germ-cell tumors: Diminishing treatment-related morbidity while maintaining efficacy. Ann Oncol 21: 1296-1301, 2010

[5] Kollmannsberger C, Tyldesley S, Moore C, et al: Evolution in management of testicular seminoma: Population-based outcomes with selective utilization of active therapies. Ann Oncol 22:808-814, 2011

[6] Tandstad T, Smaaland R, Solberg A, et al: Management of seminomatous testicular cancer: A binational prospective population-based study from the Swedish Norwegian Testicular Cancer Study Group. J Clin Oncol 29:719-725, 2011.

[7] Tandstad T, Dahl O, Cohn-Cedermark G, et al: Risk-adapted treatment in clinical stage I nonseminomatous germ cell testicular cancer: The SWENOTECA management program. J Clin Oncol 27:2122-2128, 2009.

[8]  Rustin GJ, Mead GM, Stenning SP, et al. (2007) Randomized trial of two or five computed tomography scans in the surveillance of patients with stage I nonseminomatous germ cell tumors of the testis: Medical Research Council Trial TE08, ISRCTN56475197–the National Cancer Res Institute Testis Cancer Clinical Studies Group. J Clin Oncol 25:1310–1315.

[9] Cathomas R, Helbling D, Stenner F, et al. (2010) Interdisciplinary evidence-based recommendations for the follow-up of testicular cancer patients: A joint effort. Swiss Med Wkly 140:356–369.

[10] Travis LB, Fossa SD, Schonfeld SJ, et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst 2005;97(18):1354-1365.

[11] van den Belt-Dusebout AW, de Wit R, Gietema JA, et al. Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 2007;25(28):4370-4378.

[12] Kollmannsberger C, Hartmann JT, Kanz L, et al. Therapy-related malignancies following treatment of germ cell cancer. Int J Cancer 1999;83(6):860-863.

[13] Travis LB, Andersson M, Gospodarowicz M, et al. Treatment-associated leukemia following testicular cancer. J Natl Cancer Inst 2000;92(14):1165-1171.

[14] Meinardi MT, Gietema JA, van der Graaf WT, et al. Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 2000;18(8):1725-1732.

[15] van den Belt-Dusebout AW, Nuver J, de Wit R, et al. Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 2006;24(3):467-475.

[16] Haugnes HS, Aass N, Fossa SD, et al. Components of the metabolic syndrome in long-term survivors of testicular cancer. Ann Oncol 2007;18(2):241-248.

[17] Mykletun A, Dahl AA, Haaland CF, et al. Side effects and cancer-related stress determine quality of life in long-term survivors of testicular cancer. J Clin Oncol 2005;23(13):3061-3068.

[18] Hansen SW, Groth S, Daugaard G, et al. Long-term effects on renal function and blood pressure of treatment with cisplatin, vinblastine, and bleomycin in patients with germ cell cancer. J Clin Oncol 1988;6(11):1728-1731.

[19] Fossa SD, Aass N, Winderen M, et al. Long-term renal function after treatment for malignant germ-cell tumours. Ann Oncol 2002;13(2):222-228.

[20] Fossa SD, Gilbert E, Dores GM, et al. Noncancer causes of death in survivors of testicular cancer. J Natl Cancer Inst 2007;99(7):533-544.

[21] Travis LB, Beard C, Allan JM, Dahl AA, Feldman DR, Oldenburg J, Daugaard G, Kelly JL, Dolan ME, Hannigan R, Constine LS, Oeffinger KC, Okunieff P, Armstrong G, Wiljer D, Miller RC, Gietema JA, van Leeuwen FE, Williams JP, Nichols CR, Einhorn LH, Fossa SD.Testicular cancer survivorship: research strategies and recommendations. J Natl Cancer Inst. 2010 Aug 4;102(15):1114-30. doi: 10.1093/jnci/djq216. Epub 2010 Jun 28.

[22] Hyams ES1, Pierorazio P, Proteek O, Sroka M, Kavoussi LR, Allaf ME.Laparoscopic retroperitoneal lymph node dissection for clinical stage I nonseminomatous germ cell tumor: a large single institution experience. J Urol. 2012 Feb;187(2):487-92. doi: 10.1016/j.juro.2011.10.035. Epub 2011 Dec 16.

Historical Contribution: HH Young, Perineal Prostatectomy for Benign and Malignant Disease, 1905

1905

Simple perineal prostatectomy for benign disease.  Conservative Perineal Prostatectomy: The Results of Two Years' Experience and Report of Seventy Five Cases.  Young H.H. VIII. Ann Surg. 1905;41:549-57.     

Radical Prostatectomy for the cure of cancer: The early diagnosis and radical cure of carcinoma of the prostate.  Being a study of 40 cases and presentation of a radical operation which was carried out in 4 cases.  Young H.H. Bull. Johns Hopkins Hosp. 1905:16:315

In these two manuscripts, the father of modern urology, Hugh Hampton Young, describes his outcomes with perineal prostatectomy for both benign disease and cancer.  He originally described the operation in 1904 and presents his outcomes in 1905.

In the first manuscript, HH Young describes his technique for treating benign prostatic disease in 75 patients.  Dr. Young created many instruments for the manipulation of the urinary system and demontrates a tractor to be inserted into the urethra and manipulate the prostate for enucleation.  He discusses management of large median lobes, bladder stones and the difficult median bar (or high-riding bladder neck as commonly discussed in current times).  More importantly, Dr. Young clearly detailed his outcomes for urinary continence, erectile dysfunction and mortality.  The vast majority of patients had volitional voiding restored with low post-void residuals.  Many of the men suffered erectile dysfunction; however, HH Young clearly demonstrated that younger men fared better than older.  Finally, four men died of causes unrelated to surgery during short follow-up.

In the second manuscript, HH Young describes
the radical perineal prostatectomy as the proposed, routine operation for cases of cancer of the prostate.  As background he details cases of early carcinoma and partial resection was performed erroneously.  He then reviews clinical and pathological study of 40 cases of prostate cancer, compares early cases in the literature in which
operations for carcinoma of the prostate were performed and finally draws conclusions from his work and the work of others regarding the practicability of early diagnosis and the radical cure of the disease.

Major insights from this manuscript include:

• prostate cancer occurs in approximately 10% of cases of benign prostatic enlargement
• marked induration in any man greater than 50 years of age should be considered suspicious for cancer
• advocating frozen analysis of prostatic tissue if the diagnosis of cancer is uncertain
• the definition of pathways of local (along the ejaculatory ducts, between the prostate and seminal vesicles) and metastatic spread (out through the lymphatics near the trigone of the bladder to the pelvic lymph nodes and osseous sites)
• radical prostatectomy (removal of the prostate, vasa and seminal vesicles) as the only means of cure for men with prostate cancer

Follow the links above to read these manuscripts in their entirety.

History of the Brady Urological Institute: Scientific Contributions

Dear Brady Alum and Social media followers,

We are on the verge of the 100th Anniversary of the Brady Urological Institute.  To understand how the Brady and the field of Urology has evolved over the last 100 years we have assembled a list of the most significant articles published in each of the last 99 years.  Mark Ball and Nate Readal, two of our current lab residents,  along with mentorship from Ted Schaeffer developed an algorithm to identify the most highly referenced article from each year of the Brady.  

Over the next 99 weeks we will be posting summaries, links and pdfs of these articles for you viewing.  

Its an amazing snapshot into the many contributions we have made.  I hope you enjoy.

Alan W. Partin, MD, PhD

Chairman, Department of Urology

David Hall McConnell, Professor and Director

Urologist-in-Chief

Professor, Department of Oncology

Professor, Department of pathology

Johns Hopkins Medical Institutions

Urinary Tract Infection Prophylaxis without Antibiotics: What Really Works

Urinary tract infections (UTIs) are a significant burden on the health care system responsible for 8.1 million office visits, over 100,000 hospitalizations, and $1.6 billion in direct and indirect cost. [1] The vast majority of infections are caused by Escherichia coli (E. coli), which is a colonizer of our gastrointestinal tracts that can infect our normally sterile urinary tracts. Modifiable and nonmodifiable factors have been identified that predispose individuals to having a UTI (see below).

Risk factors for UTI: [2,3]

• female sex (simply due to shorter urethral length)
• being sexually active
• poor hygiene
• altered urinary anatomy
• infected urinary stones
• catheterization
• advanced age
• hormonal changes (such as menopause)
• chronic illness
• immune suppression

Many individuals will have recurrent UTIs, which is generally defined as having more than 2 urinary tract infections in a year. [4] Unfortunately, many of these individuals will require antibiotic prophylaxis to help prevent these infections putting them at risk for developing infections with antibiotic resistant organisms and altering their beneficial natural microbial flora. [5] Therefore, there is great interest in finding non-antibiotic treatments that can be used to prevent UTIs.

Here, we review the two most commonly encountered non-antimicrobial prophylaxis treatments and whether they really work. 

Cranberry Juice - an Age Old Remedy or Placebo?

For hundreds of years, cranberry juice has been used to treat and prevent urinary tract infections. [6] Rigorous research into its mechanism began in the early 20th century.[6]  Initial research suggested that the benzoic acid in cranberry juice, which is excreted as hippuric acid, makes urine more acidic and inhibits bacterial growth.[7]   Research towards the end of the 20th century suggested that fructose and proanthocyanidins found in cranberry juice help coat the bladder and prevent the bacterial attachment and growth.[8]  However their exact role and whether additional unidentified compounds are at play have not been definitively concluded. This uncertainty raises into question what is the true “active ingredient” in cranberry juice. This also makes it difficult to accurately compare the various concentrates and extracts available on the market.

The first small randomized placebo-control trial with post-menopausal women published 1994 demonstrated that chronic cranberry juice consumption decreased yearly UTIs sparking a flurry of additional studies to evaluate cranberry juice’s effectiveness in other populations.[9]  However, many of these additional studies, including 2 larger randomized placebo-controlled studies, did not show the same effect. These studies also examined juice concentrates and concentrated tablets which advertise their increased strength over off the shelf cocktail juice and found questionable to no benefit. Finally, in 2012 the Cochrane Collaboration, a well respected group that assimilates and analyzes previously performed studies in order to reach a consensus, reviewed 24 studies and concluded that “cranberry juice does not appear to have a significant benefit in preventing UTIs.”[10]

Probiotics - A New Hope? 

Probiotics, which are a preparation of live bacteria administered to restore beneficial bacteria, are a rapidly growing area of interest. Many of us are aware of probiotic laden yogurt to help improve bowel regularity - which has become a billion dollar industry. A different organism than those found in yogurt, lactobacillus, has been found to colonize the areas around the urethral orifice (where urine leaves the body) and that their levels may be disrupted in individuals suffering from recurrent UTIs . Two small studies demonstrated that lactobacillus vaginal suppositories decreased recurrent UTIs.[11] There are currently no FDA approved lactobacillus vaginal suppositories.  However there are over the counter products currently being sold in Europe (most are not available in the U.S., however there are trials underway).[12]

Given these promising results and looking for an easier application, a randomized double-blinded non-inferiority trial comparing lactobacillus tablets and the antibiotic sulfamethoxazole/trimethoprim (bactrim) was published in 2012.[5]  Although they found the lactobacillus tablets inferior in reducing the time to the first infection and had more bacterial proven UTIs within the year of treatment, the two treatments were equivocal in several other important parameters. Additionally, whereas 80+% of bacteria from individuals taking the antibiotic had developed antimicrobial resistance, the lactobacillus group did not. These findings have been seen overall as positive for lactobacillus prophylaxis and that although perhaps not as effective as antibiotics, lactobacillus can confer some UTI prevention without promoting antibiotic resistances. Lactobacillus tablets are as of now not readily available, however one hopes this research will promote its development.

Summary

• UTIs affect many individuals and have a large impact on the health system.
• Despite their age old use, cranberry juice has not been shown to be effective in preventing UTIs.
• Lactobacillus, although not as effective as antibiotics, may provide some prevention in developing UTIs, however more research is needed. 

This blog was written by Nikolai Sopko, MD, PhD and 1st Year Urology Resident at the Brady Urological Institute and Department of Urology at Johns Hopkins.  








1. Foxman B, Barlow R, D’Arcy H, Gillespie B, Sobel JD. Urinary Tract Infection. Ann Epidemiol. 2000;10(8):509–515. doi:10.1016/S1047-2797(00)00072-7.
2. Remis RS, Gurwith MJ, Gurwith D, Hargrett-Bean NT, Layde PM. Risk factors for urinary tract infection. Am J Epidemiol. 1987;126(4):685–94. Available at: http://www.ncbi.nlm.nih.gov/pubmed/3631058. Accessed March 21, 2014.
3. Pabich WL, Fihn SD, Stamm WE, Scholes D, Boyko EJ, Gupta K. Prevalence and determinants of vaginal flora alterations in postmenopausal women. J Infect Dis. 2003;188(7):1054–8. doi:10.1086/378203.
4. Commentary SI. Lactobacilli vs Antibiotics to Prevent Urinary Tract Infections. 2014;172(9):704–712.
5. Beerepoot MAJ, ter Riet G, Nys S, et al. Lactobacilli vs antibiotics to prevent urinary tract infections: a randomized, double-blind, noninferiority trial in postmenopausal women. Arch Intern Med. 2012;172(9):704–12. doi:10.1001/archinternmed.2012.777.
6. Raz R, Chazan B, Dan M. Cranberry juice and urinary tract infection. Clin Infect Dis. 2004;38(10):1413–9. doi:10.1086/386328.
7. Sobota AE. Inhibition of bacterial adherence by cranberry juice: potential use for the treatment of urinary tract infections. J Urol. 1984;131(5):1013–6. Available at: http://www.ncbi.nlm.nih.gov/pubmed/6368872. Accessed March 21, 2014.
8. Howell AB, Vorsa N, Der Marderosian A, Foo LY. Inhibition of the adherence of P-fimbriated Escherichia coli to uroepithelial-cell surfaces by proanthocyanidin extracts from cranberries. N Engl J Med. 1998;339(15):1085–6. doi:10.1056/NEJM199810083391516.
9. Avorn J, Monane M, Gurwitz JH, Glynn RJ, Choodnovskiy I, Lipsitz L a. Reduction of bacteriuria and pyuria after ingestion of cranberry juice. JAMA. 1994;271(10):751–4. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8093138.
10. Rg J, Williams G, Jc C, Jepson RG, Williams G, Craig JC. Cranberries for preventing urinary tract infections ( Review ) Cranberries for preventing urinary tract infections. 2013;(10):2012–2014. doi:10.1002/14651858.CD001321.pub5.Copyright.
11. Reid G, Bruce AW, Taylor M. Influence of three-day antimicrobial therapy and lactobacillus vaginal suppositories on recurrence of urinary tract infections. Clin Ther. 14(1):11–6. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1576619. Accessed March 21, 2014.
12. Czaja CA, Stapleton AE, Yarova-Yarovaya Y, Stamm WE. Phase I trial of a Lactobacillus crispatus vaginal suppository for prevention of recurrent urinary tract infection in women. Infect Dis Obstet Gynecol. 2007;2007:35387. doi:10.1155/2007/35387. 

Classic Manuscripts in Urology: Borghi, NEJM 2002

Idiopathic hypercalciuria is one of the most common risk factors for the formation of kidney stones.  It is a modifiable risk factor that can be altered with medications (like thiazide diuretics) or changes in diet.  Prior to this landmark trial it was common practice to recommend a low-calcium diet to patients with kidney stones and hypercalciuria.  However, some short-term and retrospective trials indicated that low calcium diets could adversely affect urinary stone parameters, high calcium diets improved rates of stone formation and protein and salt restriction influenced calcium excretion.  With this background, Loris Borghi and colleagues from the University of Parma initiated a study comparing the effects of a low-calcium diet compared to normal-calcium diet with low animal protein and salt intake.  The results are discussed below and serve as the best evidence for the "stone former" diet recommended by most urologists.

Loris Borghi, M.D., Tania Schianchi, M.D., Tiziana Meschi, M.D., Angela Guerra, Ph.D., Franca Allegri, M.D., Umberto Maggiore, M.D., and Almerico Novarini, M.D.  Comparison of Two Diets for the Prevention of Recurrent Stones in Idiopathic Hypercalciuria.  N Engl J Med 2002; 346:77-84January 10, 2002DOI: 10.1056/NEJMoa010369

NEJM.

Summary

In this manuscript, 120 men with recurrent calcium oxalate stones and hypercalciuria were randomized to one of two diets:

NORMAL CALCIUM, REDUCED ANIMAL PROTEIN SALT DIET (DIET 1)

normal calcium (30 mmol per day)
reduced animal protein (52 grams per day)
reduced salt intake (50 mmol sodium chloride daily)

LOW CALCIUM DIET (DIET 2)

low calcium intake (10 mmol per day)


After 5 years of follow-up, only 12 of 60 men on Diet 1 had recurrent stones while 23 on Diet 2 had stones.  The relative risk of stones in Diet 2 was therefore 0.49 (p=0.04).  The increased rate of stone recurrence while on Diet 2 was most pronounced after 3 years.  This "delayed effect" was due to the fact that most of the early recurrences occurred in patients at high-risk for stone formation (5 or more colic episodes in the year prior to randomization and/or 10 or more stones prior to randomization) regardless of the diet to which they were randomized.

Borghi et al. NEJM, 2002.

In addition, urinary calcium levels dropped in both groups.  However, urinary oxalate levels increased dramatically in patients on Diet 2 - confirming the probable mechanism that a low-calcium diet promotes hyperoxaluria and increased stone formation.

Take home: Low-calcium diets do not prevent, and in fact increase, the risk of urinary calcium stone formation.  A normal calcium diet with restricted animal protein and salt intake is the best diet to prevent recurrent stones in patients with hypercalciuria.  Along with increased hydration, the diet validated by Borghi and colleagues is the basis for the dietary modifications most widely suggested to recurrent stone formers worldwide.

Classic Manuscripts in Urology will be posted on this blog on regular basis.  These articles are meant to highlight the achievements of our predecessors, recognize the work from which we build our careers and stimulate new conversations and discussion on a variety of urological topics.  Please feel free to comment on this manuscript, help point out its strengths and weaknesses, or suggest a new manuscript and topic. 

Is Gleason 6 Prostate Cancer Really a "Cancer?"

Dr. Alan W. Partin, MD, PhD, Chairman and Urologist-in-Chief, of the Brady Urological Institute at Johns Hopkins and David Hall McConnell Professor of Urology, Oncology and Pathology, was invited to discuss the malignant potential of low-grade, Gleason 6 prostate cancer at the Urology Society of Australia and New Zealand (USANZ) 2014 Annual Meeting in Brisbane, Australia.

The controversy regarding Gleason 6 cancer stems from:

• the surge in prostate cancer diagnoses due to widespread PSA screening
• the almost universal "cure" for men with Gleason 6 (low-risk) disease 
• the question of over-treatment and/or needlessly subjecting men to the side effects of the treatments of prostate cancer (surgery or radiation) without benefit

Here we review the salient points of Dr. Partin's lecture on Why Gleason 6 is Really "Cancer"

First, there are a number of Pathological Considerations:

Morphologically it is cancer

• Cytologically (indistinguishable from higher grade cancer)
• Architecturally (ie. infiltrative)
• Perineural invasion can occur with GS6
• Extra-prostatic extension can occur with GS6
• Merges in with higher grade cancer frequently

Gleason 3+3=6 can be Infiltrative Cancer

Men with Gleason 6 make up:

• 26% of men with perineural invasion 
• 8% of men with extraprostatic extension (pT3a)
• 1% of men with seminal vesicle invasion (pT3b)

What about undergrading?
20% of Gleason 6 on biopsy are Gleason 7 or higher due to sampling error.

Second, how do we classify Gleason 6 if it's not a cancer?

What are alternative names?

• Pre-cancer
• Tumor of low malignant potential
• Tumor of borderline malignancy
• Prostatic Epithelial Neoplasia of Indeterminate Significance (PENIS)

Many of these terms are oxymorons, juxtaposing contadictory elements.

How do we rectify the risk of cancer with other clinical parameters (i.e. PSA, digital rectal examination)?

• Even though a patient may have a "Tumor of Low Malignant Potential," if their PSA is high (>10 or >20), or they have a palpable abnormality on digital rectal examination, they have significant risk of having a serious prostate cancer.  
• Other biopsy parameters like number of cores, percentage of core positivity also augment the risk of having serious cancer.
• Molecular and genetic markers (PTEN, TMPRSS2:ERG, Ki67, GPS, Prolaris, Decipher, etc.)  have demonstrated the ability to risk-stratify patients and further complicates the issue.

How do we rectify patients with Gleason 6 and Gleason 7 or higher disease?

• Patients with multiple cores of both Gleason 6 and Gleason 7 would therefore have two diagnoses: cancer and pre-cancer.
• It makes the Gleason system inconsistent as patients with Gleason 3+4, 4+3, 3+5, 5+3 have cancer, but those with Gleason 3+3 do not.

Third, it opens up a variety of medicolegal problems.

• Currently in USA am unaware of any lawsuits where 1 pathologist called Gleason 6 which on review was changed to a Gleason 7.
• Could foresee many lawsuits for cases where “non cancerous term for Gleason 6” called Gleason 7 on review (ie. missed a cancer) even though semantics. 

Fourth, how do we follow patients with "pre-cancerous" lesions?

• If  GS6 not called cancer, will a significant number of men with Gleason score 6 cancer not be followed as closely and potentially progress to un-curable cancer?
• In our Active Surveillance program where we biopsy every year (all have GS6) nearly 25% eventually progress to GS7 and require treatment.

Dr. Partin offered the following as possible solutions to this dilemma:

Improve Patient & Public Education

In squamous and basal cell cancers of the skin, patients have been educated that these are not, in general, lethal cancers and are therefore dealt with in a rational manner.  Similarly, we, as urologists, are the first physicians to see patients following their biopsy/diagnosis and its imperative that we educate our patients and the public that:

• most Gleason score 6 cancers can be followed with AS.
• “You have a very good type of cancer that in general does not cause harm if observation is organized and effective”
• “However, there is a risk that there may be more aggressive cancer in you that the biopsy missed or that the cancer could change over time so that we need to make sure we continue to closely follow you.”

Change or Include within the Gleason System a Prognostic Grade Group

• Gleason patterns 1 and 2 or scores 2-4 in the classic system are not diagnosed on needle biopsies because of poor correlation with RP grade and poor reproducibility among expert pathologists. 
• Many patients, when told they have a Gleason score 6 cancer, have read that Gleason scores range from 2-10 and worry that their tumor is in the middle.  
• Therefore, Gleason scores can be grouped and range from Prognostic Grade Group I (most favorable) to Prognostic Grade Group V (least favorable).

Gleason score <6:   Prognostic Grade Group I

Gleason score 3+4=7:   Prognostic Grade Group II

Gleason score 4+3=7:   Prognostic Grade Group III

Gleason score 8:   Prognostic Grade Group IV

Gleason score 9-10:   Prognostic Grade Group V

Pierorazio PM, Walsh PC, Partin AW, Epstein JI.  Prognostic Gleason grade grouping: data based on the modified Gleason scoring system. BJU Int. 2013 May;111(5):753-60

In summary:

• No need to change calling Gleason score 6 “ a cancer”
• Rather there is a need to change what patients think when they hear they have Gleason score 6 cancer. 
• Urologists need to reassure and educate patients. 
• Modify how we report Gleason scores to more accurately reflect their behavior. 

This Blog Entry was abstracted from the Opening Plenary & BJUI Lecture: Is Gleason 6 Prostate cancer a real cancer? at the USANZ 2014 Annual Meeting.

PSA Screening for Men in their 40's: Message from the Brady

PSA screening for prostate cancer has been one of the most controversial issues in medicine, medical literature and the lay press over the past few years.  Arguably the most controversial aspects of the recent AUA (American Urological Association) Guideline on "Early Detection of Prostate Cancer" is

Guideline Statement 2:  The Panel does not recommend routine screening in men between ages 40 to 54 years at average risk. (Recommendation; Evidence Strength Grade C).

Here we review review the data regarding PSA screening in men aged 40-54.  Drs. H. Ballentine Carter, Bruce Trock, and Ashley E. Ross provide their expert interpretation of these data and comment on the AUA Guidelines.

Data Regarding PSA Screening in Men Aged 40-55

• There are no randomized, controlled studies (Level 1 Evidence) of PSA screening of men in their 40's.
• Baseline testing at 40-years of age can identify men at increased risk of developing prostate cancer.[1]   
• 44% of prostate cancer deaths occur in men age 45-55 years with a PSA in the top 10th percentile.[2]
• In the Malmo study, a single baseline PSA level in 21,277 men (age 27-52 between 1974-1984) was correlated to metastatic disease and prostate-cancer death over 25 year follow-up.[2]
• In over 4,500 men followed for 20 years at Duke Medical Center, 0.6% of men with a PSA <4ng/mL died of prostate cancer whereas 5.9% of men with a PSA >4ng/mL died of prostate cancer.[3]
• 98% of all prostate cancer deaths occur after age 54, 91% after age 70 years.
• PSA Velocity (PSAV) from age 40-55 can identify men at high-risk for aggressive prostate cancer.
• If PSAV exceeds 0.4ng/mL/year in two or more consecutive years, men had a 50% increased risk of aggressive prostate cancer.[4]
• In a screening study, a PSAV "risk count" (the number of times PSAV exceeded 0.4ng/mL/year) >2 corresponded to a five-fold risk of Gleason 8-10 disease.[5]
• PSAV is associated with prostate-cancer specific mortality after surgery.[6,7]
• Randomized trials and epidemiological evidence indicate that early diagnosis and treatment of aggressive prostate cancer improves prostate cancer survival.[8-10]
• Younger men are more likely than older men to have low-grade cancer with a longer lead time.[11]

Professional Organization in Favor of Baseline PSA Screening of Men in their 40's

• The National Comprehensive Cancer Network (NCCN)
• European Association of Urology 2013 Guidelines
• Melbourne Consensus Statement on Prostate Cancer Testing

Professional Organizations Against or Not in Favor of Routine Baseline PSA Screening of Men in their 40's

• The United States Preventive Services Task Force (USPTF) 
• American Urological Association (AUA)

Expert Commentary:

H. Ballentine Carter

H. Ballentine Carter, MD

Professor of Urology and Oncology

Director, Division of Adult Urology

Chair, AUA Early Detection of Prostate Cancer Panel

"Screening for prostate cancer using prostate specific antigen (PSA) is a form of prevention among asymptomatic men. PSA based screening has been shown to reduce prostate cancer deaths among men age 55-69 years, but not among men outside this age range that were part of a randomized screening trial. The American Urological Association panel that developed a Prostate Cancer Detection Guideline concluded that as a routine, screening was not recommended in average risk, asymptomatic men age 40-54 years. To do so would be to assume that benefits would outweigh harms and there is no data to support this assumption. The Malmo study demonstrates that to detect 70% of those cancers that become lethal would require PSA testing of half of the men below age 50 years. There is no evidence that this would reduce prostate cancer mortality, but plenty of evidence to suggest that over diagnosis and over treatment would occur with the associated side effects of treatment. Younger men are more likely, when compared to older men, to harbor the low-grade cancers for which treatment has been shown to provide the least benefit, and would live with any side effects of treatment for a longer period."

"There is no evidence that this would reduce prostate cancer mortality, but plenty of evidence to suggest that over diagnosis and over treatment would occur with the associated side effects of treatment."

Bruce J. Trock

Bruce J. Trock, Ph.D.

Professor of Urology, Epidemiology, Oncology, Environmental Health

Director, Division of Epidemiology

"Routine screening in men aged 40-54:  is the glass half-full or just twice as big as it needs to be?

Lets start by considering a few things that, hopefully, are beyond dispute:

1.  Men with PSA above the median at a baseline screen below age 55 have increased lifetime risk of prostate cancer and prostate cancer mortality compared to men with PSA below the median.
2.  PSA screening explains a portion of the decrease in U.S. prostate cancer mortality since the early 1990’s.
3.  PSA screening leads to over-diagnosis and over-treatment.

That was easy.

Now let’s consider the choice between engaging in some form of screening at ages 40-54 vs. beginning screening around age 55.  Who would be screened and how often if beginning at ages 40-54?  We often hear of “baseline” screening to segregate men into those with PSA below vs. above the age-specific median, with the latter being at significantly increased risk.  But what happens after baseline?

For men below age 55 most data relevant to PSA screening comes from large prospective cohorts where PSA was measured at baseline and men were followed for cancer outcomes.  Given the attention focused on the age to start screening it is surprising that there is so little data with detailed distributions of PSA by age group and associated prostate cancer outcomes from these cohorts.  Some of the most informative data come from the group that has evaluated PSA and prostate cancer outcomes in the cohort of men from the Malmo Preventive Project.  21,277 men aged 33-50 provided baseline blood samples for a study of cardiovascular disease; the samples were subsequently tested retrospectively for PSA and correlated to cancer outcomes.  Because this cohort represented 74% of the men in this age group in Malmo, the study is essentially a population study.  Active PSA screening was minimal in this population.

A case-control study nested in the Malmo cohort suggests that men with baseline PSA <1.0 ng/ml (median PSA at age 60) may require only 3 lifetime PSA tests – at age mid-to-late 40’s, early 50’s, and age 60, while those >1 ng/ml should repeat testing at intervals of 2-4 years, based on the literature.[2]  This sounds reasonable at first, after all, data from the same case-control study show that only 0.2% of men with PSA<1.0 at age 60 will die from prostate cancer by age 85.[12]

But how much is gained by beginning PSA testing in the 40’s vs. waiting until age 55?  In the same case-control study, the highest quartile of PSA in men 45-49 is >1.06 ng/ml, virtually identical to the cut-point above.  So the scheme proposed above would mean that 25% of men would undergo biennial or quadrennial screening beginning in their mid 40s, while 75% of men would not need to be screened until early 50s.  What happens if the 25% of men with PSA above the cut-point at age 45-49 wait until the early 50s to be screened?

Based on the data from the same Malmo cohort, [2] men in the upper PSA quartile at age 45-49 had a 2.7% risk of prostate cancer death within 25 years, that is by the early 70s.  If we assume that most of the men in the upper quartile at age 45-49 will also be in the upper quartile of PSA (>1.40 ng/ml) at ages 51-55*, their risk of prostate cancer death was 3.0% by the early 70s (within 20 years).  Thus, waiting to begin screening until the early 50s results in an increase in the risk of death of only 0.3% by the early 70s.  This is actually an upper limit on the increase in deaths because it is based on death rates in an unscreened population; if active screening were occurring some of the men in the upper quartile would be treated while still curable and death prevented.  It is likely that few men would progress from curable to incurable cancer by age 51-55, since the median time from baseline blood draw to cancer diagnosis was 18 years,[13] and 94% of advanced cancer cases were diagnosed after age 60.[14]  Another way to look at the deaths avoided is by analogy to number needed to treat, in this case number of men needed to evaluate at ages 45-49 to avoid one prostate cancer death that would occur if waiting until 51-55 = 100/0.3 = 333.

From this it seems clear that proposals to conduct a baseline screen in the early 40s, followed by targeted screening of those men with PSA above a cut-point will result in only a small decrease in the absolute risk of prostate cancer death, compared to beginning screening for all men in the early 50s.

Finally, we need to consider that interpretation of the guidelines depends on whether we are addressing the perspective of an individual man aged 40-54 facing the decision to screen, the physician who is talking to that man, or the public health scientist who is considering the impact of population screening for men 40-54.  From the perspective of the individual man the absolute probabilities may have little impact.  Individuals tend to think that outcomes will be either good or bad, which is closer to reality, i.e. an individual will either not die of prostate cancer (0% probability) or he will (100% probability).  So other factors may have greater weight (friends or relatives with prostate cancer, perceived harms of treatment).  In this regard the guidelines state “we are not explicitly stating that screening should be actively discouraged in this group of men.”[15]  The physician’s perspective (this is a personal view since the author is not a physician) is to balance risk of prostate cancer morbidity or death vs. harms of over diagnosis and over treatment.  So the physician tries to find common ground between the probabilistic risk information and the patient’s wishes and concerns.  This perspective is included in the guidelines:  “recommendation against routine screening in men aged 40-54 years is not a recommendation against screening per se, but a benefit to harm assessment of beginning screening before the age of 55 years vs initiating at the age of 55 years for those who wish to be screened.” [16]  Finally, the public health scientist, perhaps an epidemiologist, will focus primarily on the population probabilities of benefit vs. harm, which favor beginning screening in the early 50s, in accord with the guidelines statement:  “Routine screening in men aged 40-54 years at average risk is not recommended.”[15]"

_________________________________________________

* This seems reasonable since the highest quartile and highest 10% of PSA at age 45-49 capture 54% and 44%, respectively, of prostate cancer deaths, while the highest quartile and highest 10% of PSA at age 51-55 capture 59% and 44%, respectively.[2]
 

"Thus, waiting to begin screening until the early 50s results in an increase in the risk of death of only 0.3% by the early 70s. Another way to look at the deaths avoided is by analogy to number needed to treat, in this case number of men needed to evaluate at ages 45-49 to avoid one prostate cancer death that would occur if waiting until 51-55 = 100/0.3 = 333."

Ashley E. Ross

Ashley E. Ross, MD, PhD
Assistant Professor, Departments of Urology, Oncology and Pathology

"The new AUA guidelines aim to maximize the benefits of screening while reducing harms by targeting a select population of men where the incidence of clinically significant prostate cancer is relatively high and for whom level one clinical data exists.  As pointed out, perhaps the most controversial part of the guidelines was the somewhat radical change from recommendations to begin shared decision making regarding routine screening at 40 to now beginning this at 55 for those who are not at increased risk.

The AUA identifies African Americans and those with family history of prostate cancer as being of increased risk and as men in whom individualized decision making regarding screening during the ages of 40 and 55 can be considered, but what of the men who do not meet these criteria?  As a population yes, the majority of them who will develop clinically significant prostate cancer may be identified at curable stages of disease after age 55, That said, while the practice of medicine should be evidence based we should also treat our patients as individuals and it may not be sound to only use race and family history as the determinants of risk.  The guideline authors are correct, it is hard as a urologist to separate yourself from anecdotal experiences, particularly as we are not on the front lines of PSA screening and suffer from "denominator neglect."  Not to feed into that, but in defense of my bias for not lumping all the "average risk" men together and not screening them, there are a lot of anecdotes.     For instance, I looked back at our radical prostatectomy dataset of over 20,0000 men diagnosed in the PSA screening era which contained over 5,500 men who were under 55 years old at diagnosis of which about 3,800 were of "average risk" men.  For these average risk men men 37% were diagnosed with NCCN intermediate or high risk disease and at prostatectomy over 30% had Gleason 7 or above prostate cancer and about 30% had non-organ confined disease (all characteristics of cancer very likely to harm these young men in their lifetime).  Of note, among the NCCN intermediate or high risk men, only 7.3% and 4.6% respectively had PSA of less than 3 at diagnosis.  I find it hard to not want to diagnose these men.
This brings up the concept of a baseline prostate cancer risk assessment among those of "average risk" to then guide screening.  I think that over the next several years, structured on discoveries like those of Dr. Isaacs and others of genetic influences of prostate cancer (such as HoxB13 mutations) and as we find superior molecular markers for the disease (or propensity to develop it) we will see the increased availability of "Prostate Cancer Risk Tests" and these tests might help inform us on who may need screening.  Certainly if there was a test that told a young "average risk" man that he was at as high risk or more of having significant prostate cancer as say an African American man, and we think screening in African Americans makes sense then we logically would consider screening that previously average risk man, right?  In that regard, while we wait for the better tests on the horizon would it be helpful to use PSA to determine risk?  What was brought up in our discussion is that the data on using PSA for baseline risk assessment are flawed and hazy in both pro and con directions.  In addition, after 5 years a previous baseline PSA may not be meaningful and a new baseline may be needed.  Suddenly PSA based "risk assessment" seems very much like PSA screening.  And perhaps, until a better risk assessment tool is developed that is what we should do for younger men.  PSA screening but at wide intervals (every 4-5 years) with strict thresholds for action (i.e. PSA >3 for discussion of biopsy).  The argument can be made that we don't have enough self control to do this kind of long interval screening, but I think that perspectives towards cancer screening have evolved substantially among providers and patients alike in a very short time frame and will evolve more as health care and the structure of compensation changes.  I also believe we will become more comfortable screening younger men as better screening tests are developed (even incrementally better ones)."

"For these average risk men men 37% were diagnosed with NCCN intermediate or high risk disease and at prostatectomy over 30% had Gleason 7 or above prostate cancer and about 30% had non-organ confined disease (all characteristics of cancer very likely to harm these young men in their lifetime)...  I find it hard to not want to diagnose these men."

Additional reading on the PSA Screening Controversy for Men Aged 40-55

Judd W. Moul et al.  Re: Early Detection of Prostate Cancer: AUA guideline: H. B. Carter, et al.  J Urol 2013; 190: 419–426, The Journal of Urology, Volume 190, Issue 3, September 2013, Pages 1134-1139, ISSN 0022-5347, http://dx.doi.org/10.1016/j.juro.2013.07.002.

(http://www.sciencedirect.com/science/article/pii/S002253471304857X)

Catalona WJ and Carter HB.   Pro/ Con: Baseline PSA Testing for Men in Their 40s: Currently Available Evidence Strongly Supports Baseline PSA Measurements in This Age Group.  ONCOLOGY ( Feb 2014), pp 82-84.  http://www.cancernetwork.com/prostate-cancer

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