Journal Spotlight: How to Treat Non-Invasive Bladder Cancer

Approximately 60k new patients are diagnosed with bladder each year in the United States.[1]  Most of those cancers (upwards of 70-80%) are non-muscle invasive urothelial cancers of the bladder (NMIUC) - meaning these are cancers that arise from the lining of the bladder and grow outward into the lumen of the bladder.[2,3] Fortunately, most of these cancers are not inherently dangerous and can be safely managed with close surveillance and a variety of interventions.  However, NMIUC represent a wide variety of tumor types and has a wide range of prognoses and therapeutic options.  Most NMIUC are treated with a combination of surgical resection (or transurethral resection of bladder tumor, TURBT) and intravesical treatment (BCG is the most common).

The American Urological Association and other groups have attempted to stratify NMIUC patients based on their risk of recurrence, progression to muscle-invasive disease and effective treatment options.  Low- and high-risk groups are well agreed upon by a number of professional urologic and oncologic organizations. However, the risk of progression and treatment options are not well flushed out in the intermediate-risk group.  A recent publication by the International Bladder Cancer Group (IBCG), in the Journal of Urology, creates a framework for intermediate-risk patients.[4]

This blog will put this manuscript in a Journal Spotlight and review the suggested definitions and treatments for patients with low-, intermediate- and high-risk NMIUC.  For more details regarding the methodology and evidence behind these conclusions, you can access the manuscript by clicking on the subsequent link:

Kamat AM, Witjes JA, Brausi M, Soloway M, Lamm D, Persad R, Buckley R, Böhle A, Colombel M, Palou J.  Defining and Treating the Spectrum of Intermediate Risk Nonmuscle Invasive Bladder Cancer.  J Urol. 2014 Aug;192(2):305-315. Review.

Non-muscle Invasive Urothelial Cancers of the Bladder (NMIUC)

Low-Risk 

Definition: Solitary, primary low-grade papillary Ta tumor
Well-agreed upon definition
Treatment Options:
Transurethral Resection of Bladder Tumor (TURBT)
Single, immediate post-operative chemotherapy (mitomycin C) - [Evidence: 5,6]
Office Fulguration
Active surveillance with serial cystoscopy
Cancer Outcomes:
Recurrence: 50-70%
Progression:  5-10%
Deaths: 1-5%

Intermediate-Risk 

Definition: Multiple or recurrent low-grade Ta tumors***

The following risk factors stratify intermediate-risk patients:

• Multiple tumors
• Tumor size >3cm
• Early recurrence (<1 year)
• Frequent recurrences (>1 per year)

Those patients with no risk factors should be considered as Low-Risk NMIUC (see above).

Those patients with 1-2 risk factors should be considered as Intermediate-Risk NMIUC.

Those patients with 3 or more risk factors should be considered High-Risk NMIUC (see below).

***Not well-agreed upon definition (recently proposed by the IBCG)

Treatment Options:
Transurethral Resection of Bladder Tumor (TURBT)
Adjuvant intravesical treatment (BCG with maintenance for at least 1 year > chemotherapy)
     If recurrence while receiving chemotherapy, consider BCG induction and maintenance
     If recurrence while receiving BCG, consider maintenance therapy or alternative chemotherapy
Cancer Outcomes: [3,7]
Recurrence: 78%
Progression:  17%
Deaths: 10-25%

Evidence: A number of well-organized studies and meta-analyses demonstrate improvement in recurrence rates and other oncologic parameters for patients with intermediate-risk NMIUC receiving intravesical treatments.  BCG is superior to chemotherapeutic agents (epirubicin, mitomycin c) with regard to recurrence in nearly all studies, however progression and survival rates are often indeterminate.  Some of the important studies are highlighted:

• Meta-analysis: reduced recurrence rates for BCG maintenance > mitomycin C, no difference in progression or death between groups. [8]
• EORTC30911: Time to recurrence, time to distant metastases, disease-specific and overall survival improved with BCG > Epirubicin.[9]
• FinnBladder I: reduced recurrence rate with BCG maintenance > mitomycin C; trend toward decreased progression and death rates with BCG.[10]
• EORTC30962: full-dose BCG for 1 year associated with the best outcomes [11]

High-Risk 

Definition: Any T1 or high-grade tumor, and/or carcinoma in situ
Well-agreed upon definition
Treatment Options:
Transurethral Resection of Bladder Tumor (TURBT)
BCG maintenance
Consider early cystectomy
Cancer Outcomes:
Recurrence: >80%
Progression:  50% within 3 years
Deaths: 33%


While this journal article highlights a deficiency in our understanding of bladder cancer and offers a framework to better classify and treat patients, it should be clearly stated that this is not standard of care nor is it an endorsement from the Brady Urological Institute. This is merely a blog where we share important work from other contributors in the field.



[1] American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014.
[2] Heney NM, Ahmed S, Flanagan MJ, Frable W, Corder MP, Hafermann MD et al: Superficial bladder cancer: progression and recurrence. J Urol 1983; 130: 1083.
[3] Jones SJ and Larchian WA.  Non–Muscle-Invasive Bladder Cancer (Ta, T1, and CIS). In: Campbell-Walsh Urology, 10th ed. Edited by AJ Wein, LR Kavoussi, AC Novick, AW Partin, CA Peters. Philadelphia: W. B. Saunders 2012; chapt 81, pp 2335-54.
[4] Kamat AM, Witjes JA, Brausi M, Soloway M, Lamm D, Persad R, Buckley R, Böhle A, Colombel M, Palou J.  Defining and Treating the Spectrum of Intermediate Risk Nonmuscle Invasive Bladder Cancer.  J Urol. 2014 Aug;192(2):305-315. doi: 10.1016/j.juro.2014.02.2573. Epub 2014 Mar 25. Review.
[5] Gudjónsson, S., Adell, L., Merdasa, F. et al. Should all patients with non-muscle-invasive bladder cancer receive early intravesical chemotherapy after transurethral resection? The results of a prospective randomised multicentre study. Eur Urol. 2009; 55: 773
[6] Dobruch, J. and Herr, H. Should all patients receive single chemotherapeutic agent instillation after bladder tumour resection?. BJU Int. 2009; 104: 170
[7] Sylvester, R.J., van der Meijden, A.P., Oosterlinck, W. et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006; 49: 466
[8] Malmström, P.U., Sylvester, R.J., Crawford, D.E. et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guérin for non-muscle-invasive bladder cancer. Eur Urol. 2009; 56: 247
[9] Sylvester, R.J., Brausi, M.A., Kirkels, W.J. et al. Long-term efficacy results of EORTC Genito-Urinary Group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guérin and bacillus Calmette-Guérin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010; 57: 766
[10] Jӓrvinen, R., Kaasinen, E., Sankila, A. et al. Long-term efficacy of maintenance bacillus Calmette-Guérin versus maintenance mitomycin C instillation therapy in frequently recurrent TaT1 tumours without carcinoma in situ: a subgroup analysis of the prospective, randomised FinnBladder I study with a 20-year follow-up. Eur Urol. 2009; 56: 260
[11] Oddens, J., Brausi, M., Sylvester, R. et al. Final results of an EORTC-GU Cancer Group randomized study of maintenance bacillus Calmette-Guérin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol. 2013; 63: 462

Historical Contribution: 1940, Jewett, UPJ Obstruction

1940

H. J. Jewett.  Stenosis of the ureteropelvic juncture - Congenital and acquired.  Journal of Urology, 1940  44: 247-258.


Ureteropelvic junction (UPJ) obstruction is a partial or total blockage at the place where the kidney and the ureter are joined. UPJ obstruction is more common in children than in adults and often resulting from a congenital abnormality and is the most common cause of hydronephrosis (swelling of the renal pelvis, where urine collects from the kidney) detected on prenatal ultrasound or in newborns.  UPJ obstruction impedes the flow of urine, causing it to build up and resulting in hydronephrosis and has the potential complications of recurrent infection and kidney damage.

In this manuscript from 1940, Dr. Jewett reviews the cases of 71 patients with hydronephrosis and a UPJ obstruction.  Dr. Jewett found that 4 patients had stricture, 24 had a crossing vessel causing obstruction and the remaining 43 patients had an obstruction of unclear etiology.  In classifying these patients, in whom the etiology of the obstruction was unclear, Jewett found that a crossing vessel was the culprit in 10.

Drawing of a case of congenital stenosis of the ureteropelvic juncture associated with accessory renal vessel.

In the patients with a crossing vessel, Dr. Jewett made the following observations (that still hold true today):

• UPJ obstruction without a crossing vessel is 3x more common than with a crossing vessel
• The average age of onset in this cohort is younger (13 versus 24 years-old)
• A crossing vessel is not always associated with UPJ obstruction (24 cases)
• UPJ obstruction with a crossing vessel is characterized by a delicate and thin proximal ureter, as opposed to obstruction cases by trauma or inflammation.

In the remaining 33 patients, the UPJ obstruction was caused by a combination of inflammation and infection (16).  Under the microscope, these patients had a thickened, fibrous stricture at the UPJ.

Importantly, Jewett also identified 17 patients in which there was no crossing vessel or inflammatory reaction. Through careful pathologic and histologic analysis, Jewett concluded these patients had a congenital UPJ obstruction.  

Drawing of a case of congenital stenosis of the ureteropelvic juncture without associated vessels.

Therefore, Dr. Jewett embarked on an autopsy analysis of 11 embryos, 50 stillborn children and 200 consecutive urograms.  He was able to determine the relative frequencies of UPJ obstruction and its etiologies:

• Normal UPJ (85%)
• UPJ Obstruction (15%)
• Bands and kinks (5.6%)
• Crossing renal vessel (33.8%)
• Congenital Stenosis (60.5%)

In addition, from these studies he concluded: 

It is possible, therefore, that a ureteropelvic juncture represents a minimal narrowing which, when present in marked degree, becomes a congenital stenosis.     

In the group of cases comprising inflammatory strictures, it is impossible to determine with any degree of certainty whether the inflammatory reaction was primary or whether it was superimposed upon a simple congenital stenosis.

Finally, he theorized a model by which hydronephrosis would develop from stenosis and was accelerated by crossing vessels, infection, high ureteral insertion and, possibly, rapid growth during puberty.  This model, developed 70 years ago, has changed very little in our most contemporary understanding of the UPJ obstruction.

To read the entire manuscript: follow the link above, visit the Centennial Website 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! 

Dogs Detect Prostate Cancer: Give Hope for Better Diagnostic Test

German shepherds, Liu and Zoe, were trained to detect
prostate cancer in urine samples.

The diagnosis of prostate cancer is most often prompted by an elevated PSA (prostate specific antigen) level, or less commonly an abnormal digital rectal examination. An abnormality in PSA or digital rectal examination often prompts a prostate biopsy – almost X performed per year in the United States. However, PSA testing and digital rectal examination are far from perfect (See our prior blog on PSA Screening Controversies). Part of this stems from the fact that both normal and cancerous prostate cells make PSA. Distinguishing a normal PSA from a "cancerous" PSA can be very difficult. Therefore, the accuracy of detecting prostate cancer following an abnormal PSA test is only 30% - with a lot of room for improvement!!

An average dog nose has 200 million olfactory or smell-
sensing cells!  The average human has 5 million.

PSA is not the only molecule that prostate and prostate cancer cells release. For many years, researchers have been looking at the urine of men with and without prostate cancer in search of a better diagnostic test. Recently, researchers in Italy used two highly trained German shepherds to evaluate urine samples of men with and without prostate cancer – and the dogs were correct 98% of the time. Dogs have a dramatically stronger sense of smell than humans. The average human nose has approximately 5 million olfactory cells that detect volatile (airborne) compounds (our sense of smell) – dogs have 200 million. We have known this for years, making use of our canine friends in law enforcement, to detect drugs and bombs; and in medicine. In several studies, dogs have been able to detect the onset of epileptic seizures and to aid in the diagnosis of breast, lung and bladder cancers.

This study was completed in Italy with two German shepherds, a team of urologists, veterinarians, dog handlers, and over 900 urine samples from patients with and without prostate cancer. Three-hundred and sixty two men had prostate cancer in various stages, from very early, low-risk cancer to metastatic disease; the 540 men in the control group had neither benign prostatic hyperplasia nor prostate cancer. The dogs were exposed to half a dozen specimens at a time and were trained to sit down when they detected a cancer. The dogs were accurate in detecting either cancer or no cancer in 98% of cases. In fact, the sensitivity (or ability of the dogs to rule out cancer) was >99%; and if they identified cancer, they were right 97% of the time (specificity).

One of the biggest problems in using dogs in "sniffing" tests is that they can pick up on queues from their trainers. In this experiment, the trainers were completely blinded to the samples and the dogs were left to determine the status of the urine on their own. To ensure well-trained dogs, the process of teaching the dogs to smell cancer took over six months.

One of the biggest questions that remains is what were the dogs actually smelling? The dogs could be smelling a single molecule present in the cancer or a combination of chemicals produced by the cancer cells. In fact, it may not even be a cancer molecule, but a product of the microenvironment of that man's prostate that allowed the cancer to grow in the first place. Additional laboratory studies using complex gas chromatographers or "electronic noses" are needed to determine the exact molecule or chemicals present in the urine of men with prostate cancer. Whether dogs are in the future of prostate cancer detection remains to be seen, but this study proves that there is something detectable in the urine of men with prostate cancer that can be detected with incredible precision!

This study was presented by Dr. Gian Luigi Taverna, MD, at the American Urological Association (AUA) Annual Meeting in Orlando, Florida in May.  Read the abstract below:

PD19-01: Prostate Cancer Urine Detection Through Highly-Trained Dogs’ Olfactory System: A Real Clinical Opportunity 
Gianluigi Taverna*, Milan, Italy, Lorenzo Tidu, Grosseto, Italy, Fabio Grizzi, Guido Giusti, Mauro Seveso, Alessio Benetti, Rodolfo Hurle, Silvia Zandegiacomo, Luisa Pasini, Alberto Mandressi, Pierpaolo Graziotti, Milan, Italy
Abstract: PD19-01 
Introduction and Objectives: The analysis of volatile organic compounds (VOCs) in urines is a promising approach to cancer detection. Here, we establish the level of accuracy at which a rigorously trained canine olfactory system can recognize specific prostate cancer-VOCs in urine samples, thus reducing unnecessary prostate biopsies, and pinpointing patients at high-risk for prostate cancer. 
Methods: A total of 677 subjects were investigated. All the subjects included in the study were placed in one of two main Groups: Prostate Cancer Group (n = 320) and Control Group (n = 357). Prostate Cancer Group includes patients with PC ranging from those at very-low risk to metastatic PC. Control Group includes a large and heterogeneous cohort of healthy subjects or patients affected by non-neoplastic diseases or non-prostatic tumors. Each patient's clinical status and therapeutic regiment was known. We took into consideration all predictive values currently used in the clinical practice for prostate cancer management. Two dogs and a full-time, highly specialized, multidisciplinary team was dedicated. We have standardized a “work training” procedure and eliminated any possible olfactory interference. Each test was carried out blindfold. 
Results: The dogs achieved the following performances: Dog 1: sensitivity 100%, specificity 97.8%, accuracy 98.9%. Dog 2: sensitivity 98.6%, specificity 95.9%; accuracy 97.3%. When considered together, Dogs 1 + 2, we found an accuracy of 98.1% with a sensitivity of 99.2% and a specificity of 97.1%. Whether excluded the female control sub-groups we found that Dog 1 achieved a sensitivity of 100% and a specificity of 97.9%, while Dog 2 a sensitivity of 98.6% and a specificity of 94.5%. When evaluating the wrongly detected cases no differences were found between epidemiological, clinical or histopathological characteristics. 
Conclusions: The present study first demonstrates that a trained canine olfactory system detects specific PC-VOCs in urine samples from a large number of patients with PC at different stages and risks versus a heterogeneous control group, which is unthinkable in current clinical urological practice. Thanks to the early intuition, we have definitely turned what used to seem a myth into a real clinical opportunity.

Cryptorchidism: The Undescended Testicle

Cryptorchidism is the technical term for an undescended testicle.  Undescended testes are the most common congenital abnormality of the male genitals occurring in approximately 1 in 600 live births.  Most undescended testes will descend spontaneously, so the incidence is about 1% full-term infants at one year.  However, up to 1/3rd of premature boys will have one or more undescended testes.

This blog will review the proposed mechanisms of cryptorchidism and treatment options.

Embryology and Etiology

During development of the male embryo, the primitive testicles form near the developing kidneys.  As the embryo grows, the testicles remain relatively still while the embryo grows and lengthens.  Under the influence of testosterone and other hormones, the testicles exit the abdominal cavity and settle in the scrotum at about the 8th month of pregnancy - explaining why the incidence of cryptorchidism is much higher in premature infants.

There are a number of theories to explain why testicles fail to descend.  There are some known genetic causes and approximately 14% of boys with cryptorchidism have a positive family history.  Additional support for genetic causes of cryptorchidism include a number of mouse models with culprit genes and the observation that infants with severe congenital syndromes, like congenital adrenal hyperplasia, Klinefelter's disease, autosomal trisomy or disorders of sexual differentiation, will often have cryptorchidism. Maternal obesity is associated with an increased risk of cryptorchidism, as is low birth weight and cesarean section delivery.  Finally, environmental exposure to "endocrine disruptors" that elevate estrogens or decrease androgens may affect the ultimate descent of the testicle.

Locations of undescended testicles.

Undescended testicles are usually found along the path of normal descent.  The path of descent can be halted in the abdomen, inguinal canal or high in the scrotum.

Intra-abdominal testicle.

Less commonly, testicles can be found in ectopic locations - the most common ectopic location is in the superficial inguinal pouch of Denis Browne.

Retractile Testis

Retractile testes are occasionally misdiagnosed for cryptorchidism.  Retractile testes are normally descended testicles that ascend or retract into the inguinal region due to a strong cremasteric reflex.  The cremaster muscle is the muscle of the spermatic cord that can pull the testicle upward when the inner thigh is stroked. The management for retractile testis is observation as approximately 30% will descend, 40% will remain retractile (but not have any problems), and 30% will ascend and require intervention.

Management of Cryptorchidism

There are a number of goals in the management of undescended testicles:

1. Preserve fertility
2. Prevent and monitor for testis cancer
3. Repair inguinal hernia
4. Reduce the risk of testicular torsion

Sperm form from germ cells in testicle.  Germ cells function ideally at 2 degrees cooler than normal body temperature - which is why they settle outside of the body in the scrotum.  If the testicles fail to descend, the germ cells will deteriorate at about 18 months.  The rates of infertility for men with cryporchidism is 10-13%.  

Cryptorchidism is the number one risk factor for testicular cancer.  (See our prior blog on The Basics of Testis Cancer Diagnosis: Epidemiology & Presentation for more details)  Boys and men with cryptorchidism have a higher risk than the general population for developing testis cancer in both the undescended testicle and the normal, undescended testicle. In addition, surgically lowering a testicle reduces (but does not erase) the risk of testis cancer.  In addition, lowering the testicle facilitates surveillance.

Both inguinal hernia and testicular torsion are more common in boys with undescended testis.  Upwards of 90% of boys with undescended testicles and 50% of ectopic testicles will have an associated, congenital inguinal hernia.  In addition, acute testicular torsion is more common in these boys and the salvage rate is much lower (<10%) than the general population.

Non-Surgical Management

Human chorionic gonadotropin (HCG) increases testosterone production by the testis.  In approximately 25% of patients, the testicle will descend.  Success rates are higher for lower testicles and works best for patients with testicles in the high scrotum or low inguinal canal.  However, approximately 15% of the successfully treated testicles will "re-ascend."  HCG should not be given to newborns or post-pubertal males.  Side effects include temporary masculinization and premature closure of epiphyseal plates and growth arrest.

Surgical Management

Surgery is the gold standard for the treatment of cryptorchidism.  Surgery is typically deferred to 1 year of age, given that most undescended testicles will descend by one year of age.  For boys with ectopic or high undescended testicles (who have a low likelihood of spontaneous descent), surgery can be done at six months or later when the risks of anesthesia are improved.  

The most common surgery for a palpable, undescended testicle is called orchiopexy.  The goal of orchiopexy is to lengthen the spermatic cord so that the testicle can  be brought down to the scrotum without tension on the vascular blood supply to the testicle.  With good fixation techniques (using a subdartos pouch and stay suture or pledgit), the success rate for orchiopexy is 89%.

For patients with non-palpable testicles, the initial step in management is to locate the testicle.  This is usually achieved with diagnostic laparoscopy - placing a camera in the abdomen to look for an intra-abdominal testicle.  Most commonly, a viable intra-abdominal testis is found (37%), spermatic vessels are found entering the inguinal canal (40%) or a "peeping" testicle is found at the inguinal ring (11%).  If a testicle is found or supsected of being present, attempts should be made to place it in the scrotum.  If an intra-abdominal testis is found, a variety of procedures can be performed to lower the testicle.  The success rates for correcting an intra-abdominal testis are lower than an inguinal orchiopexy and vary from 67-77%.  If spermatic vessels are found but no testicle is seen, efforts should then be made to locate the testicle in the inguinal canal, perform an inguinal exploration and orchiopexy if possible.  Less commonly, blind-ending spermatic vessels are found (10%) indicating that the testicle never developed or lost its blood supply early in development.  

The major complication for orchiopexy is testicular atrophy, which is caused by damage to the testicular blood supply.  

For more information on cryptorchidism, visit Pediatric Urology at the Children's Center at Johns Hopkins.

   

Renal Cell Carcinoma: Implications of Histology

Renal cell carcinoma (RCC) is the most common kidney tumor worldwide.  In the United States, kidney cancer affects approximately 65k people and kills about 14k people per year.[1]  By definition, all RCC are adenocarcinomas -- meaning they derive from epithelium, or the lining, of the renal tubules that filter and conduct urine.  However, RCC represents several distinct entities including:

• Clear-cell RCC
• Papillary RCC
• Chromophobe RCC
• Collecting duct carcinoma
• Renal medullary carcinoma
• Translocation tumors
• Tubulocystic RCC
• Clear Cell (Tubulo) Papillary RCC
• Acquired Cystic Disease–associated RCC
• Multilocular Cystic Renal Cell Neoplasm of Low Malignant Potential (Multilocular Cystic RCC)
• Hybrid Oncocytic/Chromophobe Tumors

After a biopsy or surgery to remove a tumor, the pathology report will often define the tumor as one of these entities.  This blog will review the definitions and implications of some of the most common tumor histologies.

Clear-Cell Renal Cell Carcinoma

Clear-cell RCC under the microscope.

Clear-cell RCC is the most common RCC, accounting for 70-80% of all tumors.  Clear-cell RCC was formerly known as "conventional" RCC.  In general, they are well-cricumscribed, yellow and lobulated tumors.  They can have necrosis, hemorrhage or invade vascular structures around the kidney.  The cells of clear-cell RCC are full of glycogen, cholesterol and phospholipids which are washed out during the specimen processing - giving these cells their characteristics clear appearance.  Upwards of 75% of clear-cell tumors have a defect in the von Hippel-Lindau (VHL) gene on chromosome 3.  

Prognosis

Patients with clear-cell RCC have a worse prognosis, in general, when compared to patients with papillary or chromophobe RCC.  However, most systemic therapies are designed to target clear-cell RCC and therefore, most responses for immuno- and other systemic therapies have been in clear-cell RCC patients.  

Papillary Renal Cell Carcinoma

Papillary RCC accounts for 10-15% of RCC tumors, making it the second most common tumor subtype. Papillary RCC was previously known as "chromophilic" RCC.  Papillary RCC have a few important clinical correlations:

• commonly found in patients with end-stage renal disease
• commonly found in patients with acquired cystic disease
• often multifocal, upwards of 40% of papillary RCC are found in more than one site in the kidney

Papillary RCC (webpathology.com)

On imaging, they are often less intense than clear-cell or other "enhancing" tumors -- they can be mistaken for cysts.   While these are solid masses, like other forms of RCC, the cells grow in a papillary or tubular configuration, forming stalks of tumor cells rather than flat sheets.  There are two distinct patterns of growth under the microscope, in cytogenetics and molecular staining.

Papillary Type 1: 

• more common form
• dark cells with scant cytoplasm
• associated with Hereditary Papillary RCC Syndrome 

Papillary Type 2: 

• less common
• eosinophilic (red) cells with abundant cytoplasm
• sporadic forms of Papillary Type 2 are not necessarily dangerous
• these tumors are potentially aggressive when associated with the hereditary Leiomyomatosis and RCC Syndrome -- these tumors are now given their own distinction and are no longer lumped with Type 2 tumors.

Common cytogenetic abnormalities in papillary RCC are trisomy 7 and 17, and loss of the Y chromosome.

Prognosis

Most papillary RCC are low-grade and upwards of 80% are confined to the kidney.  While papillary RCC can still present with advanced and dangerous cancers, when compared to clear-cell RCC by stage and grade, papillary RCC is believed to have a better prognosis.  However, papillary RCC is generally not responsive to systemic and immuntherapies for advanced cancer.

Chromophobe Renal Cell Carcinoma

Chromophobe RCC represents only 3-5% of RCC.  Unlike clear-cell and papillary RCC, which derive from the proximal tubule of the nephron, chromophobe RCC derives from the collecting duct.  Under the microscope, chromophobe RCC cells are recognized by a perinuclear "halo" or clear cytoplasm around the nucleus; and microvesicles which can be seen with electron microscopy or with Hale's colloidal iron stain. The most common cytogenetic abnormality is loss of a whole chromosome (usually 1, 2, 6, 10, 13, 17, and 21).

Prognosis

In general, chromophobe RCC has a better prognosis than clear-cell RCC when localized and are most patients are diagnosed with a small, early-stage, low-grade tumor.  However, chromophobe cancers have a worse prognosis when present with advanced disease (sarcomatoid features or metastases) and are resistant to all current forms of immunotherapy.

Collecting Duct Carcinoma

As the name suggests, collecting duct carcinoma derives from the collecting duct (or Bellini's duct) of the nephron and are also known as Bellini tumors.  They account for less than 1% of RCC.  Collecting duct carcinoma often presents in younger patients with advanced disease and is unresponsive to most therapies, leading to a poor prognosis.

Renal Medullary Carcinoma

Also a rare and aggressive form of cancer, renal medullary carcinoma often presents in young, African-Americans with sickle-cell trait with a locally advanced tumor and metastatic disease.  The prognosis is poor.

Translocation Tumors

Translocation tumors are a relatively new diagnostic entity and describes a relatively common form of RCC in children.  While RCC is less than 5% of renal tumors in children (Wilms and neuroblastoma are much more common), >50% of the RCC are translocation tumors.  These tumors are rare in adults, but may be more common in patients exposed to chemotherapy for a prior malignancy.  Under the microscope, these tumors represent a combination of both clear-cell and papillary RCC.  The term "translocation" defines these tumors as they uniformly demonstrate chromosomal translocations involving the TFE3 transcription factor gene (maps to Xp11.2 locus).

Prognosis

As these tumors are a relatively new entity, data regarding outcomes is still premature.  Children have a relatively good prognosis, even with nodal (but not distant) metastases with >90% alive at about 5 years. Data suggests that adults have a worse prognosis, more often presenting with advanced disease and with an average survival of 1-2 years.  Interestingly, these tumors can metastasize 20 to 30 years after an initial diagnosis - so long-term follow-up is required.



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

Other Resources:
Campbell SC, Lane BR. "Malignant Renal Tumors" in Campbell-Walsh Urology, 10th Edition.  Wein, Kavoussi, Novick, Partin and Peters (Eds.).  Philadelphia: Elsevier, 2012. chapter 49, page 1413-1474.

Srigley JR, Delahunt B, Eble JN, Egevad L, Epstein JI, Grignon D, Hes O, Moch H, Montironi R, Tickoo SK, Zhou M, Argani P; ISUP Renal Tumor Panel.The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia.  Am J Surg Pathol. 2013 Oct;37(10):1469-89. doi: 10.1097/PAS.0b013e318299f2d1.

Historical Contribution: 1938, Leadbetter & Burkland, Hypertension in Unilateral Renal Disease

1938

WF Leadbetter, CE Burkland. Hypertension in unilateral renal disease.  - The Journal of Urology, 1938; 39:5, 611-26.

In the 1930's, it was well-established that bilateral renal disease - either obstructive or vascular - could lead to hypertension.  These findings were understood both in laboratory models and corroborated with clinical findings in patients with obstruction due to benign prostatic hyperplasia, vascular nephritis, polycystic kidney disease and polyarteritis nodosa.  In laboratory experiments, scientists were able to induce hypertension with unilateral renal injuries due to a variety of mechanisms: direct surgical destruction of a kidney, ligation of unilateral renal vessels, radiation damage to a kidney and ligation of the ureter to name a few.  However, a consistent clinical correlation was lacking.

Therefore, Drs. Leadbetter and Burkland present a case in which unilateral renal disease resulted in hypertension, and the hypertension resolved with removal of the diseased kidney.  The patient was 5 year-old boy with an ectopic, pelvic kidney and hypertension (consistently 150-170 systolic and 70 diastolic) for a number of years.  Following nephrectomy, the patients blood pressure decreased to normal and persisted there throughout follow-up.

This manuscript is:
1) a wonderful anatomic description of a pelvic kidney

At this point the ectopic kidney could be readily palpated lying over the promontory of the sacrum between the iliac vessels just below the bifurcation of the aorta.  It was necessary to bluntly incise a connective tissue layer, which corresponded to Gerota's fascia, before the anterior surface of the kidney could be exposed...Study of the kidney in situ showed that the artery and vein came from above to enter the hilum of the kidney just above the pelvis, lay in a deep grove on the anterior surface of the kidney, and were under considerable tension.  The renal artery appeared unusually small.

2) correlation between meticulous clinical measurements,observation and anatomy/pathology to arrive at a hypothesis of pathophysiology

The surface [of the kidney] showed great irregularity with numerous grooves and depressionswhich corresponded to its relationship with the renal artery and vein, the right iliac artery, and the surface of the sacrum...The renal artery was of small caliber and several cross sections showed at a point about 1cm. from the hilum of the kidney partial occlusion.

Interestingly, there was no evidence of inflammatory or infectious disease and the glomeruli were normal in appearance.

3) important evidence and hypothesis for unilateral disease causing hypertension.  

The authors hypothesized that "renal ischemia" produces nervous impulses that reflexly cause a rise in blood pressure.  Part of this was believed to be a compensatory phenomenon to preserve renal blood flow in a condition of compromised flow.  Possibly, the kidney secretes a hormone or substance in response to impaired local circulation that exercises a pressor action.  Today we know that all three of these mechanisms exist in renovascular hypertension.

To read the entire manuscript click on the link above or 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! 

Systemic Treatment of Renal Cell Carcinoma: Programmed Death Ligand 1 Inhibitors

Greater than 80% of renal tumors are renal cell carcinoma (RCC), of which about 70% is of clear-cell pathology.[1]   There are about 64,000 new RCC cases and 14,000 deaths from RCC each year, but due to increased imaging it is thought that we are catching these cancers at an earlier stage, when they are still resectable.  Unfortunately, mortality rates have not decreased and the burden of metastatic disease persists.[2]  Twenty to thirty percent of patients present with metastatic cancer and 20-30% of patients who have resectable disease later return with systemic disease following surgical management, whether it be partial or radical nephrectomy.[3,4] This underscores the necessity of management options outside of surgery.

RCC has largely been termed “chemoresistant,” meaning response to existing cytotoxic chemotherapeutic agents has been limited.  Therefore, cancer doctors and researchers continue to search for different forms of systemic treatments.[5]  In the early 1990s, immunotherapy was successfully used as systemic treatment for RCC.  The idea for this treatment came from the wide range in prognoses among patients with seemingly similar disease burden -- for example, among patients with similarly sized tumors (whether small or large), some were cured with surgery alone while patients with very similar tumors developed metastatic cancer and died.  In addition, a significant proportion of patients would have spontaneous regression of metastatic disease once the primary tumor was surgically removed.  Both of these observations suggest an interaction between the immune system and disease.[6,7] Ultimately, immunotherapies (like IFN-alpha and IL-2) were found to be more effective than previously attempted chemotherapies.  More recently, targeted therapies were developed to interrupt specific portions of the cell-cycle and endothelial attachment processes in clear-cell RCC.[8]

The idea of targeted therapy and theories of the immunoresponsive nature of clear cell RCC were combined to focus on specific parts of the immune interaction.   Among others, one important interaction is the Programmed Death Ligand 1 (PD-L1) interaction between the tumor cells and the immune cells.  T-cells are immune cells that target “foreign” cells in the body and trigger an immune response to kill those cells.  T-cells have receptors that have evolved (through genetic mutations and recombinations) to be specific for different surface proteins that may found in the cells of the body.  In a normal, healthy person, T-cells will even recognize normal, healthy cells.  However there are mechanisms to prevent the T-cell from killing good cells – a process called “anergy” which leads to T-cell death (or apoptosis).  One such signaling pathway is the PD-L1 on the healthy cell interacts with the receptor on the healthy cell (Figure 1).

Figure 1. T-Cell Recognizing Healthy Cell via PD-1-PD-L1 Interaction and Inducing Cell Death (Apoptosis).

If the T-cell identifies a tumor cell, it will not get the normal signal that it is a healthy cell, the T-cell can initiate processes to kill the tumor cell (Figure 2).

Figure 2. T-Cell Recognizing Tumor Cell without PD-1-PD-L1 Interaction.

However, some cancers like kidney cancer, can “trick” the T-cell into thinking the tumor cell is a normal, healthy cell.  One mechanism these cancers use is to express PD-L1, allowing tumor cell to escape the immune system and proliferate (Figure 3).[9]

Figure 3. Tumor Cell Expressing PD-L1 and Avoiding Detection by Immune System.

It has been noted that patients with tumors that have high expression of PD-L1 have a worse prognosis, which further suggests its involvement in the lifecycle of the disease -- although there is significant heterogeneity in expression of PD-L1 within individuals.[10]    Drugs have been developed that target both the PD-L1 on the tumor cells and the PD-1 receptor on the T-cells.  Nivolumab is the drug furthest along in the drug approval process that targets PD-1 on the T-cell.  There have been significant responses to this agent among about 30% patients who had failed treatment with the targeted therapies and enrolled in the trials. Interestingly, responses were only seen in patients who had clear-cell RCC that expressed PD-L1.[11] This response in patients who had failed the first-line targeted therapy shows promise for these novel agents. The heterogeneity of expression suggests it could play a future role in multimodal therapy.

This blog was written by Jason Cohen, Medical Student at Johns Hopkins Medical School.  Jason recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "Programmed Death Ligand 1 Inhibitors: Systemic Treatment of Renal Cell Carcinoma" from which this blog is inspired. Jason is looking forward to a career in urology.






[1]  Siegel R et al. CA Cancer J Clin 2014; 64:9.
[2]  Hollingsworth et al. J Natl Cancer Inst. 2006; 98:1331
[3]  Curti B et al. J Am Med Assoc 2004; 292: 97
[4]  Levi D et al. J Urol 1998; 159: 1163
[5]  Chung EK et al. Am J Clin Oncol 2011; 34: 150
[6]  Oliver RT et al. Br J Urol 1989; 63: 128
[7]  Vogelzang NJ et al. J Urol 1992; 148: 1247
[8]  Rini BI et al. Lancet 2009; 373: 1119
[9]  Dong H et al. Nat Med 2002; 8: 793
[10]  Thompson RH et al. PNAS 2004; 101: 17174
[11]  Topalian SL et al. N Engl J Med 2012; 366: 2443

The "Evolution" of Advanced Prostate Cancer Research

Ken Pienta, MD and Director of Research
at the Brady Urological Institute

Prostate cancer affects approximately 230k men per year in the US.  Fortunately, over 90% of men present with localized, treatable prostate cancer.  Unfortunately, approximately 30k men still die of the disease each year in the United States.[1]  Advanced prostate cancer is treated with hormonal therapy, chemotherapy or radiation treatment in combination or alone.  As prostate cancer is a male cancer and driven by testosterone, hormone therapies can shrink and limit the growth of cancer cells.  Chemotherapy and radiation kill rapidly dividing cancer cells -- and have some effect on prostate cancer cells.  In them men who die of prostate cancer, the cancer cells learn or "evolve" to escape these treatments.  

In this blog entry, Ken Pienta, MD and Director of Research at the Brady Urological Institute, discusses how our understanding of advanced prostate cancer has "Evolved" to meet this challenge.  Dr. Pienta was recently awarded a $1.5 million Challenge Award from Prostate Cancer Research Foundation and Movember organizations to investigate circulating tumor cells and disseminated tumor cells in men with metastatic prostate cancer.

"Our understanding of how advanced prostate cancer changes over time is rapidly evolving. Prostate cancer changes over time because it mutates as part of its innate instability of its DNA as well as mutations that develop as the cancer adapts to the therapy to which we subject it (therapeutic pressure). As our understanding of prostate cancer evolution during progression grows, the challenge is to effectively sequence and combine our growing armamentarium of therapeutic agents for maximal patient benefit -- the right drugs, in the right combinations, given at the right time.  

It is especially important to anticipatie the need for therapy before it is clinically apparent; i.e. to move beyond anatomically-based clinical decisions and prognostication to biologically (marker)-driven therapy prediction. Treatment with androgen deprivation therapy (castration therapy, hormonal therapy) inevitably leads to the development of castrate resistant prostate cancer. The second generation anti-androgen (supra-castration) therapies, while effective, are leading to the emergence of new types of prostate cancer. Three phenotypes/genotypes of CRPC after treatment with second-generation agents appear to be increasing in prevalence and remain resistant to treatment: NeuroEndocrine Prostate Cancer (NEPC), Persistent AR – Dependent Prostate Cancer (PADPC), and Androgen Receptor Pathway Independent Prostate Cancer (APIPC). 

It is clear that new treatment paradigms, taking into account cancer cell genetic and epigenetic pathways, contributing factors within the microenvironment, and the macroenvironment of the host / patient need to be developed for this diverse group of diseases."

BCG Immunotherapy Alternatives

Nearly 300,000 patients are diagnosed with urothelial cancer (UC) of the bladder each year in the United States.  The majority of these cancers (>70%) are non-muscle invasive disease, however 40-80% of these tumors will recur within the first year and 10-25% will develop muscle-invasive disease [1]. Intravesical treatments after transurethral resection (TUR) are the mainstay of treatment for non-muscle invasive urothelial cancer (NMIUC), and Bacillus Calmette-Guerin (BCG) immunotherapy is the standard, most commonly used intravesical treatment.

When and if BCG fails, patients are left with the difficult choice of proceeding to radical surgery or, often unproven, additional intravesical therapies.  Here we present some of the data on additional immunotherapies for the treatment of bladder cancer.

INTERFERON-ALPHA (IFN-α)

Interferons are glycoproteins with a number of anti-viral properties.  IFN-α (interferon-alpha) is known to stimulate NK (natural killer) cells, induce MHC (major histocompatibility complex) class I response, augments the ability of Th1 (T-helper cells) and increase antibody recognition -- all mechanisms that stimulate the immune response in the bladder [2,3]. 

See our prior blog on BCG For Bladder Cancer: Why it Works, How it Works for a better understanding of stimulating the immune system for the treatment of bladder cancer.

The ability of IFN-α to fight off cancers has been attributed to both an ability to stop cell growth and its immunomodulatory effects.  Because of its ability to augment the local immune response, IFN-α2b has been studied in conjunction with BCG.  There is only one published, randomized trial comparing BCG alone to BCG+IFN.  This group of patients did not receive any prior intravesical treatments, and there was no significant difference in recurrence-free survival at two years, although the IFN group did exhibit a higher incidence of constitutional symptoms and fever [4].

IFN-α may play a role in patients who have failed an initial course of intravesical BCG therapy.  A study of 40 patients failing one or more courses of BCG showed a disease-free rate of 53% at 24 months when they went on to receive 6-8 weekly instillations of low-dose BCG plus IFN-α [5].  A multicenter trial including 467 patients with previous BCG failure demonstrated a disease-free rate of 45% after being treated with reduced-dose BCG and IFN-α [6].  Risk factors for recurrence were stage T1, tumor size >5 cm, multifocality, more than one prior BCG failure and age >80.

Timing of recurrence predicts effectiveness of BCG, IFN-α combination therapy.  Patients with recurrence >12 months after initial BCG treatment who were treated with low-dose BCG plus IFN-α had a disease-free rate of 53-66% at 24 months.  However, patients with recurrence within one year did poorly, with a disease-free rate of 34-43% at two years.[7]

Therefore, combination therapy with both BCG and IFN-α may have a salvage role in patients with single course BCG failure or late relapse, while those who recur quickly after initial BCG treatment may be destined to failure and better served by radical cystectomy.

INTERLEUKIN-2 (IL-2)

Interleukin (IL)-2 is a cytokine that enhances the production of cytotoxic lymphocytes capable of lysing tumor cells while leaving benign cells unharmed -- IL-2 activated lymphocytes are known as “lymphocyte-activated killer” or LAK cells [8,9].  Additionally, IL-2 augments the immune system through a variety of interactions with NK cells, monocytes and Th1 cells [9,10].

IL-2 is poorly tolerated when given systemically, however intravesical administration has a much improved side effect profile [11,12]. In a small cohort, intravesical IL-2 administered after incomplete TUR of low grade T1 papillary UC demonstrated regression of the “marker lesion” in 8 of 10 patients [13].  Animal models with recombinant IL-2-secreting strains of BCG have shown an enhanced antitumor cytotoxicity and local immune response when compared with BCG alone [14-16].

INTERLEUKIN-12 (IL-12)

Interleukin-12 (IL-12) is known to be synergistic with IL-2 since the 1980's, and has therefore been the subject of considerable cancer research.  Multiple animal studies have shown tumor responsiveness to IL-12, including bladder cancer models [17-19].  In mice, bladder cancers responded to intravesical treatments of IL-12 and BCG, the levels of urinary IFN-α were noted to be significantly increased after therapy, and immune reaction dampened when IL-12 was neutralized. [20-22].  However, a recent Phase I monotherapy trial of intravesical IL-12 in humans, failed to show any clinical effectiveness [23].

INTERLEUKIN-10 (IL-10)

Interleukin-10 (IL-10) is an inhibitor of immune response, decreasing the production of several cytokines produced by Th1, including IFN-γ [24].  Several initial studies demonstrated an improved BCG and local immune response in IL-10 knockout mice after being inoculated with bladder cancer with greater antitumor activity and prolonged survival [10, 25, 26].  Therefore, more recent research has attempted to block the IL-10 receptor.  Mice treated with BCG and an anti-IL-10 receptor antibody show improved overall and tumor-free survival when compared to BCG controls -- although not all of these differences reached statistical significance [27]. Further testing showing more confirmatory results is necessary but these initial results are promising.

SUMMARY

• Interferon-alpha may be effective for patients who have failed an initial course of BCG.
• IFN-α is not more effective than BCG alone for initial treatment.
• Patients who recur quickly after the first dose of BCG are less likely to benefit from IFN-α.
• Interleukin-2 and -12 have immunostimulatory effects and have demonstrate some efficacy for treating bladder cancer in animal models.
• Interleukin-10 is an inhibitor of immune response and animal studies blocking this cytokine have promising early results. 

This entry was written by Nilay M. Gandhi, MD, senior assistant resident at the Brady Urological Institute at Johns Hopkins.  

Some of the data is extracted from the chapter Intravesical Immunotherapy - Bladder Cancer: Diagnosis and Clinical Management by Nilay M. Gandhi, Laura A. Bertrand, Donald L. Lamm, and Michael A. O’Donnell which will appear in newest edition of The Textbook of Bladder Cancer.

[1] Kemp TJ, Ludwig AT, Earel JK, et al. Neutrophil stimulation with Mycobacterium bovis bacillus Calmette-Guérin (BCG) results in the release of functional soluble TRAIL/Apo-2L. Blood 2005; 106: 3474-82.
[2] Kamat AM, Lamm DL. Immunotherapy for bladder cancer. Curr Urol Rep 2001; 2: 62-9.
[3] Luo Y, Chen X, O’Donnell MA. Role of Th1 and Th2 cytokines in BCG-induced IFN-γ production: cytokine promotion and stimulation of BCG effect. Cytokine 2003; 21: 17-26.
[4] Nepple KG, Lightfoot AJ, Rosevear HM, et al; Bladder Cancer Genitourinary Oncology Study Group.  Bacillus Calmette-Guérin with or without interferon α-2b and megadose versus recommended daily allowance vitamins during induction and maintenance intravesical treatment of nonmuscle invasive bladder cancer. J Urol 2010; 184: 1915-9.
[5] O’Donnell MA, Krohn J, DeWolf WC. Salvage intravesical therapy with interferon-alpha-2b plus low dose bacillus Calmette-Guérin is effective in patients with superficial bladder cancerin whom bacillus Calmette-Guérin alone previously failed. J Urol 2001; 166: 1300-4.
[6] Joudi FN, Smith BJ, O’Donnell MA. National BCG-Interferon Phase II Investigator Group Final results from a national multi-center phase II trial of combination bacillus Calmette-Guérin plus interferon α-2b for reducing recurrence of superficial bladder cancer. Urol Oncol 2006; 24: 344-8.
[7] Gallagher BL, Joudi FN, Maymí JL, et al. Impact of previous bacillus Calmette-Guérin failure pattern on subsequent response to bacillus Calmette-Guérin plus interferon intravesical therapy. Urology 2008; 71: 297-301.
[8] Yron I, Wood TA, Spiess PJ, et al. In vitro growth of murine T cells v. the isolation and growth of lymphoid cells infiltrating syngeneic solid tumors. J Immunol 1980; 125: 238-45.
[9] Lotze MT, Grimm EA, Mazunder A. Lysis of fresh and cultured autologous tumor by human lymphocytes cultures in T-cell growth factor. Cancer Res 1981; 41: 4420-5.
[10] Henney CS, Kuribayashi K, Kern DE, et al. Interleukin-2 augments natural killer cell activity. Nature 1981; 291: 335-8.

[11] Malkovsky M, Loveland B, North M. Recombinant interleukin-2 directly augments the cytotoxicity of human monocytes. Nature 1987; 325: 262-5.

[12] Tubaro A, Velotti F, Stoppacciaro A, et al. Continuous intra-arterial administration of recombinant interleukin-2 in low stage bladder cancer: a phase 1B study. Cancer 1991; 68: 56-61.

[13] Gomella LG, McGinnis DE, Lattime EC, et al. Treatment of transitional cell carcinoma of the bladder with intravesical interleukin-2: a pilot study. Cancer Biother 1993; 8: 223-7.

[14] Den Otter W, Dobrowolski  Z, Bugajski A, et al. Intravesical interleukin-2 in T1 papillary bladder carcinoma: regression of marker lesion in 8 of 10 patients. J Urol 1998; 159: 1183-6.

[15] O’Donnell MA, Aldovini A, Duda RB et al. Recombinant Mycobacterium bovis BCG secreting functional interleukin-2 enhances gamma interferon production by splenocytes.  Infect Immun 1994; 62: 2508-14.

[16] Yamada H, Matsumoto S, Matsumoto T, et al. Murine IL-2 secreting recombinant bacillus Calmette-Guérin augments macrophage-mediated cytotoxicity against murine bladder cancer MBT-2. J Urol 2000; 164: 526-31.

[17] Gately MK, Desai BB, Wolitzky AG, et al. Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor). J Immunol 1991; 147: 874-82.

[18] Nastala CL, Edington HD, McKinney TG, et al. Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production. J Immunol 1994; 153: 1697-706.

[19] Teicher BA, Ara G, Buxton D,et al. Optimal scheduling of interleukin-12 and chemotherapy in the murine MB-49 bladder carcinoma and B16 melanoma. Clin Cancer Res 1997; 3: 1661-7.

[20] O’Donnell MA, Luo Y, Hunter SE, et al. Interleukin-12 immunotherapy of murine transitional cell carcinoma of the bladder: dose dependent tumor eradication and generation of protective immunity. J Urol 2004; 171: 1330-5.

[21] O’Donnell MA, Luo Y, Hunter SE, et al. The essential role of interferon-gamma during interleukin-12 therapy for murine transitional cell carcinoma of the bladder. J Urol 2004; 171: 1336-42.

[22] O’Donnell MA, Luo Y, Chen X, et al. Role of IL-12 in the induction and potentiation of IFN-gamma in response to bacillus Calmette-Guérin. J Immunol 1999; 163: 4246-52.

[23] Weiss GR, O’Donnell MA, Loughlin, K, et al. Phase I study of the intravesical administration of recombinant human interleukin-12 in patients with recurrent superficial transitional cell carcinoma of the bladder. J Immunother 2003; 26: 343-8.

[24] Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 1989; 170: 2081-95.

[25] Nadler R, Luo Y, Zhao W, et al. Interleukin-10 induced augmentation of delayed-type hypersensitivity (DTH) enhances Mycobacterium bovis bacillus Calmette-Guérin (BCG) mediated antitumor activity. Clin Exp Immunol 2003; 131: 206-16.

[26] Ferguson TA, Dube P, Griffith TS. Regulation of contact hypersensitivity by interleukin-10. J Exp Med 1994; 179: 1597-1604.

[27] Bockholt NA, Knudson MJ, Henning J, et al. Anti-IL-10R1 monoclonal antibody enhances BCG-induced Th1 immune responses and antitumor immunity in a mouse orthotopic model of bladder cancer. J Urol 2012; 187: 2228-35.

Historical Contribution: 1937, Dees and Colston, Sulfanilamide in Gonococcal Infections

Electron micrograph of gonococcus. (from gov.uk)

1937

The use of sulfanilamide in gonococcal infections. Dees JE, Colston,  JAC.   JAMA 1937; 108: 1855.

In 1935, para-aminobenzenesulfonamide (sulfanilamide) emerged as an effective treatment for streptococcal infections.  Subsequent experiments in mice and humans proved that sulfanilamide was an effective treatment for menignococcic infections.  Given that sulfanilamide was proven to be non-toxic at high doses in humans and its clinical efficacy against meningococcus, allowed Drs. Dees and Colston to embark on a clinical trial of sulfanilamide in gonoccocal infections.

In 19 patients, the diagnosis of gonococcal urethritis was confirmed with visualization of cellular diplococci in urethral discharge or centrifuge of collected urine.  In all patients, active urethral discharge disappeared in 1-7 days, with most patients improved within 3 days.  Gonococci were eliminated from the urethral discharge in 2-5 days for the majority of patients -- as did the majority of symptoms.  Some patients did have a slower response to the treatment, and the authors hypothesized this could be due to non-compliance or an abnormality of metabolism of the medication.

They concluded that sulfanilamide was of "great value" and:

This preliminary report is therefore presented for the purpose of stimulating the careful use of this drug in clinics where large numbers of gonococcic infections can be closely followed, so that an accurate evaluation of sulfanilamide in the treatment of gonococcic infections can be determined and the optimum dosage and possible deleterious effects further studied.

This manuscript serves as the first example of sulfa-medications in the treatment of urinary tract infections.

To read the entire manuscript click on the link above or 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! 

Lymph Node Dissection for Renal Cancer

CT Scan showing a large right renal mass and enlarged
lymph node between the kidney and inferior vena cava.

Lymph node dissection (LND) is an integral portion of many cancer surgeries including those of the colon, breast and prostate. However, the role of lymphadenectomy (or lymph node dissection) in the management of renal cell carcinoma (RCC) remains controversial mainly because of the poor overall survival for patients with metastatic RCC in their lymph nodes or beyond.  The cancer-specific survival (CSS) for these patients is in the range of 5-35% at 5 years.[1]

In this blog we will highlight some of the important data regarding LND and RCC.

Certain or Uncertain Lymphatic Drainage of Renal Cell Carcinoma?

Early anatomic studies demonstrate a system of predictable lymphatic drainage from the kidneys; with the right kidney draining through the precaval, retrocaval, and interaortocaval nodal groups from right to left, and the left kidney draining to left-sided only regions including para-aortic, preaortic, and retroaortic nodal groups.[2]  Surgical series confirmed this drainage pattern with primary landing zones (paracaval for right, paraaortic for left) being involved prior to involvement of additional nodes.  However, they also note that perihilar lymph nodes (lymph nodes closest to the kidney) are rarely involved and often skipped, with 45% of hilar nodes negative despite other ipsilateral lymph nodes involved.[3]

Retroperitoneal lymph node locations.  From Crispen et al.
European Urology, 2011. [3]

However, looking at the epidemiologic data, upwards of 30% of patients with RCC will present with metastatic disease; however, only 3-10% will have lymph node involvement only.  Of the patients with metastatic disease, upwards of 40% will have no lymph node involvement - indicating that RCC, unlike other cancer, can spread without first involving the regional lymph nodes.  

Correlation of Clinically-Positive Lymph Nodes to Pathologically-Positive Lymph Nodes

Radical nephrectomy specimen
with tumor and lymph node that
correlate to the CT Scan above.

The subsequent consideration is: how well do we predict lymph node positive disease?  The answer is pretty poorly.  Many patients with large and/or bulky kidney tumors will have enlarged lymph nodes on imaging. However, the correlation with enlarged lymph nodes on imaging and cancer in those nodes is poor.  In fact, enlarged lymph nodes on CT scan correlate to metastatic RCC in only 32-43% of patients and a false-positive rate of 58%.[4-6]  In addition, The false-negative rate is estimated to be 4%, meaning many patients without lymph nodes on imaging will ultimately have positive lymph nodes at the time of surgery.[6]

Improved Staging, Improved Survival?

LND has been demonstrated to improve staging in a number of studies.  Rates of lymph node positive disease have been demonstrated to be higher in patients who had more lymph nodes removed.[7]

While it is generally accepted that LND improves staging, it is not clear if this translates into a tangible survival benefit.  Some studies demonstrate an improvement in cancer-specific survival (CSS) with lymphadenectomy.  This is rooted in the belief that LND may remove metastatic disease and be curative in some patients with lymph node positive disease.[8]

In studies where systematic LND was routinely performed and a benefit was observed:

• In a study of over 2,500 patients, for those with positive lymph nodes, 22% were disease-free at 44 months [9]
• Of the recurrences, the majority were detected within 4 months of nephrectomy and 51% were at multiple organ sites
• In a study of over 500 patients, CSS was significantly better for patients who underwent a systematic, extended lymph node dissection (66%) when compared to those who had only clinically abnormal lymph nodes removed (58%, p<0.01).[10]  
• In a study on 800 patients, 5% with positive lymph nodes and 9% with positive lymph nodes and metastatic disease:
• For patients without clinically evident nodal disease, survival was not impacted by LND.
• For patients with distinct clinical nodal disease, survival was positively impacted by cytoreductive nephrectomy, LND and postoperative immunotherapy.
• LND was predictive of survival in multivariable analysis of lymph node positive patients.[11]
• In a study of 10,000 patients in the National SEER (Surveillance, Epidemiology, and End Results) Database:
• For patients with negative lymph nodes, there was no effect on CSS with increasing extent of LND. 
• An absolute survival increase of 10 % (39–49 %) at 5 years was seen in patients with one positive lymph node in whom ten lymph nodes were removed indicating that the number of lymph nodes removed correlates to an improvement in CSS.[12]

However, a number of studies fail to find a survival benefit in patients with positive lymph nodes who underwent LND.[13,14]

How about Level 1 Evidence?

The biggest argument against LND is a prospective, randomized trial of LND versus standard radical nephrectomy run by the EORTC (European Organization for Research and Treatment of Cancer) Genitourinary Group.[15]  Nearly 800 patients were randomized to radical nephrectomy alone (n = 389) or nephrectomy plus LND (n = 383). Only 4% of patients had positive lymph nodes and there was no improvement in survival in patients undergoing LND.  However, >70% of the patients had clinically localized and organ-confined (pT1-2) or low-grade RCC, allowing critics to argue that LND would have been unlikely to benefit these patients.  Importantly, there were no differences in complication rates between the two groups - definitively demonstrating that LND does not increase the morbidity of the operation.

Who Should Undergo Lymphadenectomy (LND)?

There are a number of predictive models that identify patients most at risk of having positive lymph nodes at the time of surgery.  Many of these models use criteria like tumor and lymph node size to predict positive lymph nodes; however these models also include pathological features like grade, stage and sarcomatoid features.[16]  Other studies have used pre-operative variables only (clinical tumor stage, clinical nodal status, presence of metastases, and tumor size), however are limited by small number of patients with positive lymph nodes and non-standardized lymph node dissection.[17]

Summary

In general, the evidence is clear that patients with low-risk RCC do not benefit from lymphadenectomy.  These include patients with clinically-localized (T1, 7cm or less) or biopsy-proven, low-grade (Grade 1 or 2) disease.  

LND should be strongly considered in patients with high-risk RCC who have the potential to have positive lymph nodes and therefore benefit from their removal.  These include patients with:

• Large, clinically-localized tumors: upwards of 40% of cT2 (>7cm) tumors will have pathological T3 disease
• Locally-invasive tumors: cT3 or cT4 disease
• Clinically enlarged lymph nodes
• Limited metastatic disease, especially if an isolated site can be resected
• Biopsy-proven, high-grade RCC (Grade 3 or 4)

Other considerations:

• Many radical nephrectomy surgeries can be performed laparoscopically, however LND can be challenging with standard laparoscopy.  Robot-assisted laparoscopy may facilitate lymph node dissection by affording the surgeon more control near the great vessels in the body.
• There is no, well-agreed upon consensus regarding LND.  While the risks of LND are relatively low, not all patients will benefit from a LND and careful thought should go into the decision to perform a LND.

Phillip M. Pierorazio, MD is an Assistant Professor of Urology & Oncology, Director of the DISSRM Registry for Kidney Cancer and Director of the Division of Testicular Cancer at the Brady Urological Institute at Johns Hopkins.  








[1] Pantuck AJ, Zisman A, Dorey F, Chao DH, Han KR, Said J, Gitlitz B, Belldegrun AS, Figlin RA. Renal cell carcinoma with retroperitoneal lymph nodes. Impact on survival and benefits of immunotherapy. Cancer. 2003 Jun 15;97(12):2995-3002.
[2] Parker AE (1935) Studies on the main posterior lymph channels of the abdomen and their connections with the lymphatics of the genito-urinary system. Am J Anat 56:409–443
[3] Crispen PL, Breau RH, Allmer C et al (2011) Lymph node dissection at the time of radical nephrectomy for high-risk clear cell renal cell carcinoma: indications and recommendations for surgical templates. Eur Urol 59:18–23
[4] Blute ML, Leibovich BC, Cheville JC et al (2004) A protocol for performing extended lymph node dissection using primary tumor pathological features for patients treated with radical nephrectomy for clear cell renal cell carcinoma. J Urol 172:465–469
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