Historical Contribution: 1932, Colston & Lewis, Clinical Review of Prostate Cancer

1932

Carcinoma of the Prostate: A Clinical and Pathological Study J. Colston and L. Lewis Southern Medical Journal 1932  25: 696-703

Lloyd G. Lewis, MD

John Archibald Campbell (JAC) Colston was a John Hopkins urologist who worked closely with HH Young during the early 1900's.  Along with Young, he performed perineal prostatectomies and shaped the treatment and understanding of prostate cancer during this time period.  He served with the allied forces during World War I.

LLoyd G. Lewis graduated the Brady Residency in 1933.  He was remembered as a superb surgeon and co-author of The Physiology of Micturation, 1940 after undertaking a number of laboratory experiments involving the innervation of the feline bladder.  During World War II, Lewis served as Chief of Urology at Walter Reed General Hospital in Washington, DC and succeeded in having Walter Reed approved for residency training during his time there.

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In the early 1930's, the only means for detection of prostate cancer was a palpable lesion or symptomatic presentation, namely urinary obstruction.  As such, Colston and Lewis review the history of prostate cancer treated at the Brady since its founding in 1915 through 1932 and note that most prostate cancers "will be found to have progressed beyond the limits of the capsule or into the seminal vesicles so that a complete removal is impossible."  In fact, in 1,040 cases of prostate cancer over 17 years, only 36 cases were found to be eligible for radical prostatectomy.  When they reviewed the over 3,700 prostate operations, they found an additional 58 cancers that  were found during operations for presumed benign growth.

Through their thorough review, they were able to make a number of important observations that describe the understanding of prostate cancer at the time, but help shape our modern understanding of the disease today.  Some of the important observations are detailed below.

Colston and Lewis were able to classify prostate cancer patients into one of three categories:

1. cases suitable for radical prostatectomy
2. cases too extensive for radical surgery, but asymptomatic
3. cases too extensive for radical surgery, but with significant symptoms that require palliative treatment; either:
• radiation treatment
• intra-urethral treatment (or suprapubic diversion)
• palliative, perineal prostatectomy

Colston and Lewis were able to describe the anatomic location of prostate cancer within the gland by examining whole prostate glands removed during radical surgery.  They found the "posterior lamella involved in all cases;" and the lateral lobes involved in the majority.  

They described metastatic and local growth patterns.  Thirty percent of men presenting with prostate cancer had metastases at this time.  For the men with local extension, they reviewed infiltration patterns through the seminal vesicles and never into Denonvillier's fascia "explained by the lack of lymphatics in this thick fascial membrane."  In addition, they noted that, "The rapidity of growth depends on the particular type of tumor, and it may be said that the more cellular the tumor, the more rapid the extension," an early description of the grading of prostate cancer.

In addition, they review the available treatments for the symptoms associated with advanced prostate cancer: urinary obstruction, hematuria and pain.  These symptoms could be treated radiation, transurethral and/or perineal procedures.

Finally, they conclude that, "Every effort should be made by earlier diagnosis to increase the percentage of cases suitable for radical operation, which gives normal micturation with perfect control in most cases."

To read the entire manuscript click on the link above or click here.


HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

AUA Highlights: Infertility, by Dr. Rao

Male infertility was well represented at AUA (American Urological Association) Annual Meeting 2014 in Orlando, Florida. In the plenary session, the risks of increased paternal age were outlined. Notably, children of older fathers are at higher risk of autism, schizophrenia, and achondroplasia (dwarfism). Although the relative increase in incidence of these conditions is alarming, the overall incidence remains low, even in children of older fathers. (Click here to see the video of this Critical Discussion: Advanced Paternal Age - What Are the Real Risks?)

A topic that received continued attention is the increased use of testosterone. This is of particular importance for men with impaired fertility. Use of testosterone replacement therapy causes reversible infertility in most men, however some patients may not recover even after discontinuing the medication. It is critical that men with low testosterone and infertility should not be treated with testosterone replacement therapy, but other alternative medications should be considered instead.

Much research was presented on the outcomes after varicocele. Notably, a meta-analysis of previous studies showed an improvement in pregnancy and life birth rates after varicocele repair in couples using assisted reproductive techniques such as IVF and ICSI. In addition, successful sperm retrieval rates were higher in men who underwent extraction procedures after varicocele repair compared to men with untreated varicoceles. (PD24-01; see below)

In addition, many studies were presented that investigated various genes and DNA modifications that may play a role in infertility. However, none of these will cause immediate change in the treatment of infertile men. Currently, here at the Brady, we are collaborating with many Hopkins scientists to investigate molecular causes for infertility. These studies include finding unidentified genes causing infertility, investigating whether transposons are interrupting critical DNA sequences of sperm production, and identifying other molecules that may play roles and in male infertility treatment for male contraception.

This blog was written by Pravin Rao, M.D., Assistant Professor and Director of Reproductive Medicine and Surgery at the Brady Urological Institute at Johns Hopkins.

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PD24-01: The role of varicocele repair prior to assisted reproductive technology 

Saneal Rajanahally*, Houston, TX, Edgar Kirby, Karen Crowell, Robert Coward, Chapel Hill, NC

Abstract: PD24-01 

Introduction and Objectives 

While it has been established that varicoceles can contribute to infertility, and that varicocele repair (VR) can improve semen parameters such that fertility can be achieved, the relationship between VR and subsequent success with assisted reproductive technologies (ART) has yet to be definitively elucidated. This study is a systematic review the available literature describing the impact of VR on ART outcomes. 

Methods 

A PubMed search from 1/1982-9/2013 was performed to identify prospective, prospective-controlled, and retrospective studies addressing the relationship between VR and ART outcomes in couples with male factor infertility. Studies were excluded if they did not include fertilization, pregnancy, and/or live birth rates. Statistical analysis was performed using Fisher’s exact test. 

Results 

Seven studies were identified (1 prospective, 4 prospective controlled, 2 retrospective). Five of 7 studies utilized intracytoplasmic sperm injection (ICSI), 1 reported in vitro fertilization (IVF) outcomes, and 1 used intrauterine insemination (IUI). There was no difference in fertilization rate between surgical and non-surgical groups (67.8% vs 66.1%). However, 245 of 505 patients (48.5%) who underwent VR achieved pregnancy compared with 199 of 475 (41.9%) with untreated varicocele (p<0.05). Live birth rate was significantly higher after VR (n=314, 46.5%) in comparison to the uncorrected varicocele cohort (n=374, 32.1%, p<0.001). Pregnancy (11.8% vs. 6.3%, p<0.05) and live birth rate (11.8% vs. 2.1%, p<0.05) per IUI cycle were both significantly higher in patients after VR in comparison to those untreated. Individuals with non-obstructive azoospermia (NOA) had a significantly higher sperm retrieval rate after VR (n=140, 57.1%) than those with NOA and untreated varicocele (n=218, 38.9%, p<0.005). 

Conclusions 

Available data in this systematic review demonstrate a higher pregnancy and live birth rate in men after VR compared with those with uncorrected varicoceles, along with increased sperm retrieval rates in men with NOA. The positive impact that VR may have on ART outcomes should be discussed with couples with male factor infertility due to varicocele. 

Date & Time: May 19, 2014 3:30 PM-5:30 PM 

Session Title: Infertility: Therapy 

Sources of Funding: None 

Bladder Cancer Institute to Open at Hopkins

Approximately 75,000 people are diagnosed with urothelial cancer of the bladder each year.[1]  It is estimated that nearly 300,000 people are walking around right now with bladder cancer in a variety of stages and that the annual costs of bladder cancer care approach $4 billion in the United States.  However, bladder cancer receives very little media coverage, public attention and subsequently, little funding exists for bladder cancer research relative to other malignancies.  There is therefore a definite need for a focused, comprehensive research program to improve our understanding and treatment of bladder cancer.

To meet this need, Baltimore-area commercial real estate developer Erwin L. Greenberg and his wife Stephanie Cooper Greenberg have pledged a $15 million gift through the Erwin and Stephanie Greenberg Foundation to create the Johns Hopkins Greenberg Bladder Cancer Institute. Their gift is the largest bladder cancer research gift ever given to Johns Hopkins and is part of a $45 million co-investment with Johns Hopkins University that will support a multidisciplinary team from the Johns Hopkins Kimmel Cancer Center.  Beneficiaries of the gift include faculty and researchers from the Brady Urological Institute, Departments of Radiation Oncology and Molecular Radiation Sciences, and Departments of Oncology, Pathology and Surgery.  Leaders of this team include:

Alan W. Partin, Director of the Brady
and Theodore DeWeese, Chair of
Radiation Oncology

BRADY UROLOGICAL INSTITUTE

• Trinity J. Bivalacqua, MD, PhD, Director of Urologic Oncology 

• Alan W. Partin, MD, PhD, Chairman, Professor and Director of Urology

RADIATION ONCOLOGY

• Theodore DeWeese, MD, PhD, Chair of the Department of Radiation Oncology and Molecular Radiation Sciences

MEDICAL ONCOLOGY

• Charles G. Drake, MD, PhD 

• Noah Hahn, MD  

According to Johns Hopkins officials, no other institution in the world houses a collaborative program with this expansive scope and intensive focus on bladder cancer. The Institute will begin formal operations in 2014.

William Nelson, MD, PhD

“We are so very grateful to the Greenbergs for this transformational gift, which supports our shared vision of saving lives with an institute dedicated to developing innovative research and treatments for bladder cancer patients,” says William Nelson, M.D., Ph.D., Director of the Kimmel Cancer Center.

“Bladder cancer is not as well-known among the general public as other cancers,” says Theodore R. DeWeese, M.D. “This new institute will provide needed resources to increase awareness, education, and new research and treatments related to this disease.”

Trinity J. Bivalacqua, MD, PhD, shares, "We have an incredible history and clinical experience at Hopkins treating many, many patients with bladder cancer.  We also participate in world-class research to improve our understanding and treatment of the disease.  With the start of the Greenberg Institute, we have the ability to be true world leaders in the treatment, research and delivery of care to the many patients with bladder cancer."

“Stephanie and I have been committed to cancer programs for many years. We recognize that there are many ways we could focus our resources but wanted to concentrate on one of the least supported cancers. We’re excited to be part of creating a comprehensive bladder cancer initiative that will bring new resources for patients and could ultimately save thousands of lives,” says Erwin Greenberg.

Portions of this blog, specifically quotes, were extracted from "$45 Million Co-Investment to Fund Johns Hopkins Greenberg Bladder Cancer Institute" from Johns Hopkins Medicine. http://www.hopkinsmedicine.org/news/media/releases/45_million_co_investment_to_fund_johns_hopkins_greenberg_bladder_cancer_institute

May is national bladder cancer awareness month. Learn more about bladder cancer signs, symptoms and current treatment options at the Brady Urological Institute Website and from prior blog entries.

[1] American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014.

Historical Contribution: 1930, Andres, Medical Aspects of... BPH

1930

Andres EC.  Medical Aspects of the Treatment of Benign Prostatic Hypertrophy.  Amer J of Surgery. 1930;9;3:502-6.

By the 1930's it was well established that benign prostatic hypertrophy (BPH, now known as benign prostatic hyperplasia) was the leading cause of urinary obstruction in elderly men, requiring intervention in nearly 85% of these men.  The progression of BPH was well-established, from changes in the bladder leading to retrograde changes in the ureter, kidney and eventually the nephrons.  Andrus astutely noted that progressive renal deterioration was due to the back pressure of urine, recurrent infections and underlying renal disease in this elderly population.

Interestingly, Andres made the observation that patients with progressive urinary obstruction due to BPH also had dramatic effects on their cardiovascular system.  He noted that patients were often clinically fluid overloaded and their hearts suffered through this with compensatory left ventricular hypertrophy and fibrotic changes in the aorta.

To combat these cardiovascular changes, Andres recommended that patients rest, make changes to the diet, and keep hydrated to prevent the effects of azotemia.  If unable to tolerate oral hydration, "A siIver cannula is inserted into a superficial vein, usually on the foot,and is tied in pIace. Through this normal saIt soIution is injected continuously, reguIated by a drop device quite simiIar  to the Murphy drip so that the patient receives not more than IOO to 200 C.C. per hour. In this fashion Iarge amounts of fluid may be given over a period of days and so sIowIy that the circulation is not embarrassed thereby."

In addition, Andres recommended digitalis to stabilize the myocardium and an operation if the obstruction was refractory to the conservative, medical treatments described above.

In summation, Andres depicted the comorbid conditions (specifically cardiovascular) common in the elderly man presenting with obstruction from BPH.  He defined a management algorithm that progressed from acute stabilization, laboratory evaluation, medical treatment and finally surgery if needed.

Finally, Andres, a medical doctor at Johns Hopkins offered the following acknowledgement:

The author desired to express his appreciation to Dr. Hugh H. Young for permission to follow these cases on his service, and to acknowledge with thanks the assistance of the staff of the Brady Urological Institute.

To read the entire manuscript click on the title above or click here.


HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

AUA 2014 Outstanding Posters

The American Urological Association (AUA) Annual Meeting, 2014 has been a tremendous success for the Brady Urological Institute.  With greater than 60 faculty and research presentations over a five day period, members of the Brady team have been extremely busy sharing our discoveries with the world.  On Saturday, May 18, 2014, 36 presentations were awarded "Outstanding Poster" designations for the entire meeting in three categories: benign disease, oncology and research.  Brady researchers were awarded two Outstanding Poster Awards, which we share below:

OUTSTANDING POSTER #1

OP1-04: Identification and Validation of Protein Biomarkers of Response to Neoadjuvant Chemotherapy in Muscle Invasive Urothelial Carcinoma 

Alexander Baras*, Nilay Gandhi, Enrico Munari, Sheila Faraj, Mohammad Hoque, Mark Schoenberg, Trinity Bivalacqua, George Netto, Baltimore, MD

Summary: Neoadjuvant chemotherapy improves survival for patients undergoing radical cystectomy for muscle-invasive urothelial cancers of the bladder.  The greatest survival benefit is seen in those patients in whom all cancer is eradicated from the bladder (pT0).  However, the prognosis for patients who fail to respond to chemotherapy or progress while on chemotherapy is poor.  Predicting who will and will not respond to chemotherapy has huge importance in this area.  Researchers from Hopkins identified two genetic markers that could be identified from tissue obtained prior to chemotherapy, to assess the potential response to the medication.  Further studies are needed, however these data may help identify patients best served by chemotherapy and those who should forego chemotherapy for a rapid cystectomy.

Introduction and Objectives Neoadjuvant chemotherapy (NAC) results in 5-10% increase in 5-year survival rate in muscle invasive bladder cancer (MIBC) patients. More importantly, those who achieve a complete response (ypT0) have a 5 year survival rate of 80% as opposed to 40% for those who do not. However, NAC is not widely utilized due to concerns related to delay of cystectomy, potential side-effects, and inability to predict effectiveness. Recently suggested molecular signatures of chemoresponsiveness, which could prove useful in this setting, are yet to be translated into clinical practice. 
Methods mRNA expression data from a prior report on a NAC-treated MIBC cohort (Kato et. al) were analyzed in combination with the antibody database of the Human Protein Atlas (HPA). We identified classifier candidate biomarkers that can be detected by immunohistochemistry (IHC) in TURB biopsy material prior to NAC. The candidate biomarkers were subsequently validated in an independent cohort of 52 MIBC specimens. Response to NAC was defined as the lack of residual MIBC at cystectomy. 
Results By filtering based on large amplitude mRNA changes and the area under the receiver operator curve (AUROC), we identified 21 genes whose mRNA expression profiles differentiate response to NAC (n=33), Figure 1A. Using the HPA, we found that commercially available antibiodies to the protein products of 8 of these genes exhibited differential staining across a set of urothelial carcinomas cataloged in the HPA. In addition, 12 normal tissues were identified from the HPA that can serve as positive and negative controls for the 8 proteins. Our initial studies with 2 of these markers in a multivariate logistic regression model have yielded strong performance (80% accuracy) in identifying patients in our independent validation cohort that are not likely to benefit from NAC due to chemoresistance (Fischer’s exact test p-value 0.02), Figure 1B & 1C. 
Conclusions We illustrate the feasibility of translating gene expression signature data on NAC response into an IHC classifier applicable to TURB specimens. The performance achieved by the initial two markers in our study is being further characterized and the other putative protein markers are being assessed in our TMA cohort. 

OUTSTANDING POSTER #2

OP1-10: Rho-kinase inhibition prevents nNOS uncoupling in the MPG, erectile dysfunction and increases neuronal outgrowth following cavernous nerve injury 

Johanna Hannan*, Xiaopu Liu, Ahmet Hoke, Arthur Burnett, Trinity Bivalacqua, Baltimore, MD
Funding: NIH K08DK090370 and Urology Care Foundation.

Summary: Post-radical prostatectomy erectile dysfunction is a major issue faced by many patients and urologists today.  In order to potentially improve ED, inhibition of molecules that potentiate nerve injury, RhoA and RhoKinase (ROCK), an experimental medication was given to rats with a nerve injury.  This experiemental medication, U-27632, a ROCK inhibitor, improved post-nerve injury erectile function by preventing nitric oxide degeneration and promoting nerve regrowth and regeneration.  This may be a medication suitable to prevent post-prostaetectomy ED in the future.

Introduction and Objectives RhoA and Rho-kinase (ROCK) are implicated in the inhibition axonal growth/neurite sprouting, and neurodegeneration via regulation of inflammation and apoptosis following peripheral nerve injury. We hypothesize that degeneration of the cavernous nerve (CN) after injury is due to increased RhoA/ROCK signaling in the major pelvic ganglion (MPG) leading to neuronal nitric oxide synthase (nNOS) uncoupling and nerve degeneration. This study aimed to characterize the role of ROCK inhibition in preserving erectile responses, penile contractions, nNOS uncoupling and neurite outgrowth following bilateral cavernous nerve injury (BCNI). 
Methods Male Sprague-Dawleys rats (12 wks) were separated into sham, BCNI and BCNI treated with Y-27632 (ROCK inhibitor, 5 mg/kg twice daily; n=8/group). 14 days after BCNI, groups underwent CN stimulation to determine erectile function. Penes were dissected and contractile responses to phenylephrine (PE) and electrical field stimulation (EFS) were assessed. MPGs were excised and protein (Western blots) and gene expression (q-PCR) of nNOS and growth associated protein 43 (GAP43) were assessed. Additional MPGs (n=3/group) were cultured in reduced growth factor matrigel for 48h and neurite growth was measured. 
Results While erectile function was severely decreased in BCNI rats, daily administration of Y-27632 improved erections 2-fold (p<0.05). nNOS MPG gene expression was decreased by 50% after BCNI and recovered to sham levels with Y-27632 (p<0.05). nNOS uncoupling was increased in BCNI MPGs and completely prevented in y-27632 treated rats (p<0.05). Cavernous contractile responses to PE were unchanged. EFS-mediated penile contractions were significantly lower following BCNI and treatment with Y-27632 increased EFS-mediated contractions 2-fold compared to sham and BCNI penes (p<0.05). MPG neurite outgrowth was unchanged in sham and BCNI; however, BCNI+Y MPGs had significantly increased growth (S:328±9μm; BCNI:349±14μm; BCNI+Y:405±11μm, p<0.05). GAP43, a growth protein highly expressed during axonal regeneration, was increased 25% following BCNI and 30% with Y-27632 treatment indicating treatment increased axonal growth. 
Conclusions Inhibition of ROCK preserved erections, prevented nNOS uncoupling, mediated increased neurite growth and increased nerve-mediated penile contractions in BCNI rats. Preventing the activation of RhoA/ROCK signaling in the MPG and CN after injury may inhibit neurodegeneration and post-radical prostatectomy erectile dysfunction. 


For more Brady Urological Presentations, visit the AUA2014 Website or stay tuned.

2014 American Urological Association (AUA) Annual Meeting: Kickoff

Today marks the start of the Annual American Urological Association (AUA) Annual Meeting in Orlando, Florida.  This annual meeting hosts approximately 20,000 urologists from around the world and offers an exciting forum in which new guidelines are released for a variety of disease states, new research and breakthroughs in urology are showcased, and advances in technology are displayed for everyone to see.

The Brady Urological Institute is once again represented very strongly at this year's meeting.  Below you can find links to calendars showing (1) the faculty appearances and presentations throughout the meeting and (2) each poster, podium and video session where urology research from Johns Hopkins is being presented.

In total, there are 17 faculty presentations and 45 research presentations over the 5 day meeting.  Some of the highlights include:

FACULTY PRESENTATIONS

• Dr. H Ballentine Carter will be addressing the Early Detection of Prostate Cancer and discussing last year's AUA Prostate-Specific Antigen Best Practice Statement at:
• Plenary II: Crossfires in Urology on Friday, May 16th at 1pm in the Chapin Theater.
• American Society for Men's Health (ASMH) Meeting on Monday, May 19th at 230pm in the Orange County Convention Center (OCCC), Room W224G.
• Society Presidential Addresses:
• Dr. Arthur L. Burnett, Sexual Medicine Society of North America (SMSNA), Saturday, May 17, 730am Hyatt Regency BR R&S
• Dr. Jennifer Dodson, Society of Women in Urology (SWIU), Sunday, May 18th, 630am in the Hyatt Regency Orlando BR M
• Dr. Brian Matlaga will be discussing the management of kidney stones at:
• Confederacion Americana de Urologia (CAU), "Overview of Renal Calculi," Saturday, May 17th at 130pm in the Valencia Board Room of the OCCC.
• Plenary I, "Point Counterpoint: Sterile Urine Before PCNL, One Week of Antibiotic Therapy," Monday, May 19th at 933am in the OCCC Valencia Ballroom.
• ROCK Society (Research on Calculus Kinetics), "What is the Preferred Management of Proximal Ureteral Stones: Medical Expulsive Therapy, Surgical Therapy," on Monday, May 19th at 420pm in the OCCC, W314.
• Dr. Ken Pienta will be giving the Coffey Lecture at the joint SBUR (Society for Basic Urologic Research)/ SUO (Society of Urologic Oncology) Meeting on "Cancer and Metastases: What Ecology Can Teach Us."
• Dr. Alan Partin will be discussing "Prostate Cancer Tissue Methylation as a Marker for Repeat Biopsy: Update from the MATLOC and DOCUMENT Trials" at the joing BAUS/BJUI/USANZ Meeting, Sunday, May 18th, at 220pm in the Hyatt Regency BR P.

RESEARCH PRESENTATIONS

• Dr. Trinity Bivalacqua's group will be presenting over 13 posters and podiums on a variety of topics incuding urothelial cancer, penile cancer, erectile dysfunction and return of sexual function after pelvic surgery.  Two of those posters were selected as Outstanding Posters and will be presented on Saturday, May 17th at 1pm in the OCCC W303.
• Baras, Gandhi, Munari, Faraj, Hoque, Schoenberg, Bivalacqua and Netto.  "Identification and Validation of Protein Biomarkers of Response to Neoadjuvant Chemotherapy in Muscle Invasive Urothelial Carcinoma."
• Hannan, Liu, Hoke, Burnett and Bivalacqua. "Rho-kinase inhibition prevents nNOS uncoupling in the MPG, erectile dysfunction and increases neuronal outgrowth following cavernous nerve injury."
• The Kidney Cancer Research Team, led by Dr. Mohamad Allaf will be presenting 11 posters and podiums.  Highlights include:
• Results from the Multi-Institutional Consortium of Robotic Partial Nephrectomy.
• Assessment of complications following Radical and Partial Nephrectomy in NSQIP.
• Robotic Retroperitoneal Lymph Node Dissection for Stage 1 Testis Cancer.
• Dr. Phillip Pierorazio will be championing the six presentations from the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) Registry looking at comparative oncologic outcomes, selection criteria, growth kinetics and quality of life for patients undergoing active surveillance or surgery for small kidney tumors.

Click here to download the full calendar of Faculty Presentations.

 Click here to download the full calendar of Research Presentations.

Aristolochic Acid, Balkan Nephropathy, Chinese Herbal Nephropathy: A Saga of Upper Tract Urothelial Cancer

Urothelial cancer refers to cancer of the lining of the urinary tract.  Urothelial cancers can occur in the bladder or the upper tract of the urinary system which includes the lining of the kidney (otherwise known as the renal pelvis) and the ureter.

There are a number of risk factors for the development of upper tract urothelial cancer (UTUC).  Most of these risk factors are related to chronic exposure to carcinogens.  This blog will focus on one of the more rare, but interesting dietary risk factors for UTUC, Aristolochic Acid.  The other known risk factors for UTUC are:

• smoking - the most important modifiable risk factor
• coffee - higher risk of UTUC if >7 cups of coffee per day [1]
• not as big an impact if cigarette smoking is considered
• analgesics - phenacetin, caffeine, codeine, acetaminophen, and aspirin or other salicylates have all been implicated
• arsenic - discovered in Taiwan, where drinking wells are contaminated by arsenic; natives have a higher risk of Blackfoot Disease and UTUC, both believed to be caused by arsenic [2] 
• occupation - chronic exposure to chemicals, dyes, asphalt, tar, petroleum and plastics

Aristocholic Acid - For many years, it was observed that rates of UTUC were higher in the Balkans of Southeastern Europe (Bosnia, Bulgaria, Croatia, Romania, and Serbia) and many Asian countries including China and Taiwan.  The incidence of UTUC in the US is approximately 0.7-1.0 per 100,000 person-years.[3]  In these affected Asian countries and Balkan families, the risk of UTUC rises dramatically, reaching as high as 100-200x the risk of the general population.[4,5]  

The The Balkan Peninsula, popularly referred to as the Balkans,
is a geographical region of Southeast Europe. The region takes
its name from the Balkan Mountains that stretch from
the east of Bulgaria to the very east of Serbia.

China and Taiwan.

Both regions share a common plant genus, Aristolochia (which includes over 500 plant species), that is commonly incorporated into the diet.  In the Balkans, Aristolochia plants grow as weeds alongside wheat and are incorporated into locally produced breads and bread-products.  In Asia, Aristolochia plants are incorporated into many herbal and natural remedies.  While the higher rate of UTUC runs in families, studies demonstrate that the increased risk of UTUC is related to diet and not genetics.   These studies include examination of both molecular markers that implicate diet, and epidemiologic studies that demonstrate that family members who leave home early in life are less likely to develop UTUC.[6,7]

Aristolochia Plant Species, of which over 500 individual species exist.
These plants are known for their strong scent and are often nicknamed
"Birtwort," referring to the birth canal-like shape of the plants.   

A number of studies validate Aristolochic Acid (AA) as a strong carcinogen, demonstrating higher rates of somatic DNA mutations in patients exposed to long-term AA.[8,9]  AA creates DNA mutations by entering the cell nucleus, binds to DNA where it can cause replication errors.[10]  

Patients with AA-related UTUC often present with multiple and/or bilateral, low-grade tumors.[7]  Women, patients with large tumors (>3cm) and invasive tumors (T3 or T4) have worse outcomes.[11]

SUMMARY

• Aristolochic Acid is a risk factor for the development of UTUC through chronic dietary exposure.
• Laboratory studies demonstrate mechanisms by which AA exposure can cause cancer.
• Epidemiologic studies demonstrate increased risk of UTUC related to dietary exposure and not familial genetics.
• Countries of the Balkans and Eastern Asia are two areas in the world where AA ingestion can be considered an endemic cause of UTUC.

[1] Ross RK, Paganini-Hill A, Landolph J,et al: Analgesics, cigarette smoking, and other risk factors for cancer of the renal pelvis and ureter. Cancer Res 1989; 49: 1045.

[2] Tan LB, Chen KT, Guo HR,et al: Clinical and epidemiological features of patients with genitourinary tract tumour in a blackfoot disease endemic area of Taiwan. BJU Int 2008; 102: 48-54.

[3] Munoz JJ, Ellison LM: Upper tract urothelial neoplasms: incidence and survival the last 2 decades. J Urol 2000; 164: 1523-1525.

[4] Petkovic SD: Epidemiology and treatment of renal pelvic and ureteral tumors. J Urol 1975; 114: 858-865.

[5] Yang MH, Chen KK, Yen CC, et al. Unusually high incidence of upper tract urothelial carcinoma in Taiwan. Urology, 2002.  59: 681.

[6] Grollman AP, Shibutani S, Monya M,et al: Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci U S A 2007; 104: 12129-12134.

[7] Radovanovic Z, Krajinovic S, Jankovic S,et al: Family history of cancer among cases of upper urothelial tumours in the Balkan nephropathy area. J Cancer Res Clin Oncol 1985; 110: 181.

[8] SL Poon, ST Pang, JR McPherson, et al. Genome-Wide Mutational Signatures of Aristolochic Acid and Its Application as a Screening Tool.Sci. Transl. Med. 5, 197ra101 (2013)

[9] M. L. Hoang, C.-H. Chen, V. S. Sidorenko, et al.  Mutational Signature of Aristolochic Acid Exposure as Revealed by Whole-Exome Sequencing. Sci. Transl. Med. 5, 197ra102 (2013)

[10]  Chen, C., et al. (2012) Aristolochic acid-associated urothelial cancer in Taiwan. Proceedings of the National Academy of Sciences 109(21) 8241-46.

[11] Dragicevic D, Djokic M, Pekmezovic T,et al: Survival of patients with transitional cell carcinoma of the ureter and renal pelvis in Balkan endemic nephropathy and non-endemic areas of Serbia. BJU Int 2007; 99: 1357-1362.