Friday, November 21, 2014

Radiation Therapy after Prostate Surgery, Part III: Salvage Therapy


Some men prostate cancer are faced with the realization that treatment of their prostate cancer may require multimodal treatment including some combination of surgery, radiation therapy and/or hormone therapy. The combined ASTRO/AUA (American Society for Therapeutic Radiology and Oncology/American Urological Association) Guideline for "Adjuvant and Salvage Radiotherapy after Radical Prostatectomy" makes a number of statements regarding the use of radiation therapy after surgery that can be confusing to patients and practitioners. 

In the third part in this blog series, we review the statements from the ASTRO/AUA Guideline regarding salvage radiation therapy and the data supporting them.

To read Part I: Adjuvant Radiation following Surgery for Prostate Cancer click here.
To read Part II: Subgroup Analyses of Adjuvant Radiation for Prostate Cancer click here.
The Guideline Statements regarding adjuvant radiation therapy and three randomized studies (SWOG 8794, EORTC 22911, and ARO 96-02/AUO 09/95) that support their conclusions are detailed in Part I. To summarize, Part I: Adjuvant radiation therapy (ART), or radiation therapy given without evidence of cancer in men at high-risk for recurrence, is an option for men with advanced prostate cancer and adverse features after radical prostatectomy. Patients who undergo ART can expect an improvement in biochemical (PSA) and locoregional recurrence, although the benefits on distant metastases and overall survival is less clear. Part II reviews the subgroups of patients who may benefit from ART. Based on these subgroup analyses, ART appears to have the most benefit for patients with positive surgical margins and Gleason score 7-10. The benefit of ART in patients with Gleason 6, extraprostatic extension (in the absence of a positive surgical margin) and seminal vesicle invasion is less clear.

Salvage radiotherapy (RT) is defined as RT with clinical evidence of prostate cancer recurrence. Clinical evidence of prostate cancer recurrence can include any combination of:
  • Elevated PSA level
  • Recurrent mass or lymph node on imaging (CT scan usually)
  • Biopsy-proven cancer in a recurrent mass
The guideline statements regarding salvage RT are detailed below. There are no randomized studies regarding the use of salvage RT, however several well-designed retrospective studies provide evidence for the use of this treatment.


The Guideline Statements


Guideline Statement 4.

  • Patients should be informed that the development of a PSA recurrence after surgery is associated with a higher risk of development of metastatic prostate cancer or death from the disease. Congruent with this clinical principle, physicians should regularly monitor PSA after radical prostatectomy to enable early administration of salvage therapies if appropriate. (Clinical Principle)

Guideline Statement 5.

  • Clinicians should define biochemical recurrence as a detectable or rising PSA value after surgery that is ≥ 0.2 ng/ml with a second confirmatory level ≥ 0.2 ng/ml. (Recommendation; Evidence Strength: Grade C)

Guideline Statement 6.

  • A restaging evaluation in the patient with a PSA recurrence may be considered. (Option; Evidence Strength: Grade C)

Guideline Statement 7.

  • Physicians should offer salvage radiotherapy to patients with PSA or local recurrence after radical prostatectomy in whom there is no evidence of distant metastatic disease. (Recommendation; Evidence Strength: Grade C)

Guideline Statement 8.

  • Patients should be informed that the effectiveness of radiotherapy for PSA recurrence is greatest when given at lower levels of PSA. (Clinical Principle)

The Evidence

Based on a number of studies, including a study from Johns Hopkins, prostate cancer specific survival is significantly worse in men with a biochemical (PSA) recurrence after radical prostatectomy. In this study of over 600 men, the 5- and 10-year prostate-cancer survival for men receiving no salvage RT were 88% and 62%. For men receiving salvage RT, the prostate-cancer survival rates were 96% and 82-86% at 5- and 10-years respectively. This translates into a 3-fold increase in prostate-cancer survival for men receiving salvage RT.[1]

Importantly, these men only had a PSA recurrence and no evidence of distant metastatic disease. Men with distant metastatic disease are best treated by systemic therapy, either hormones and/or chemotherapy, and do not benefit from salvage radiation therapy. In addition, the benefit was only seen in men with a PSA doubling time of six months or less who underwent salvage RT within 2 years of biochemical recurrence. Another study of 500 men over 11 years demonstrated that salvage RT benefits men with both a PSA doubling time less than and greater to 6 months; however the benefit may be greater for men with PSA doubling time less than 6 months.[2]

Two additional studies provide evidence for the benefits of salvage RT in men with a rising PSA after surgery. A study of 500 patients from five centers demonstrated that more than two thirds of patients receiving salvage RT had a complete response (PSA became undetectable). In this study, patients with a PSA <0.6 had the best response to RT and patients with a PSA >2.0 had the highest risk of failure of salvage RT.[2] A follow-up study of over 1,500 patients confirmed the importance of pre-RT PSA value on prognosis. Patients treated with salvage RT alone at PSA levels of 0.5 ng/mL or lower had a 6-year progression-free survival rate of 48% compared with 26% for those treated at higher PSA levels.[3]

These data do not necessarily indicate that there is a causal relationship between PSA value and response to salvage RT. Likely, the PSA phenomenon reflect the biology of the recurrent prostate cancer and indicate groups of men most likely to have a meaningful benefit to RT.

 

Summary

Salvage RT should be offered to men with a biochemical (PSA) recurrence after radical prostatectomy. The benefits of RT are greatest in men with a low PSA level and low PSA doubling time.


This blog was written by Mark W. Ball, MD.  Mark is a 5th year urology resident at the Brady Urological Institute at Johns Hopkins and looking forward to a career in urologic oncology.


 






[1] Trock BJ, Han M, Freedland SJ, Humphreys EB, DeWeese TL, Partin AW, Walsh PC. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008 Jun 18;299(23):2760-9. doi: 10.1001/jama.299.23.2760.
[2] Cotter SE, Chen MH, Moul JW, Lee WR, Koontz BF, Anscher MS, Robertson CN, Walther PJ, Polascik TJ, D'Amico AV. Salvage radiation in men after prostate-specific antigen failure and the risk of death. Cancer. 2011 Sep 1;117(17):3925-32. doi: 10.1002/cncr.25993. Epub 2011 Mar 22.
[3] Stephenson AJ, Shariat SF, Zelefsky MJ, et al . Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA 2004;291:1325–1332.
[4] Stephenson AJ, Scardino PT, Kattan MW, et al . Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007;25:2035–2041. Erratum in: J Clin Oncol 2007;25:4153.

Tuesday, November 18, 2014

Historical Contribution: 1929, Young, Posterior Urethral Valves


1929
Posterior urethral valves: Congenital valve obstruction of the prostatic urethra. Young HH, McKay RW. Surg Gynecol Obstret 1929; 48:509.


 

Within this manuscript is the "classic" description of posterior urethral valves (PUV) and the first classification system taught to urologists to define the disease. PUV, or congenital valvular obstruction of the prostatic urethra, was described as a medical entity in the late-1700's and was first described in the medical literature by Dr. Conrad Johann Martin Langenbeck in 1802. In the first portion of this manuscript, Young and McKay detail the history of PUV from Langenbeck to their description including thoughtful descriptions of autopsy series, case reports and clinical outcomes from around the world. Common among all these reports was that all cases were found at autopsy or incidental discoveries during other genitourinary operations.


From Tolmatschew in 1870.

The etiology of PUV was unknown with a number of hypotheses put forward including: persistence of the urogenital membrane, or anomalous development of the Wolffian and Muellerian ducts. Young recognized that PUV was a clinical heterogeneous entity, with patients having a variety of clinical presentations and outcomes. Part of the objectives of this manuscript was to present a unifying theory of PUV – a challenging feat that Young recognized, "Apparently no single theory, as stated previously, will explain satisfactorily the formation of [PUV]."

 

The History of PUV at Johns Hopkins

The first cystoscopic diagnosis of PUV was at Johns Hopkins in 1912. The first curative, transurethral surgery was performed one year later, in 1913, by HH Young. By 1915, with a combination of cystoscopic evaluation and cystogram, Young and colleagues were able to demonstrate the clinical association between PUV and significant vesicoureteral reflux (VUR) often seen in the disease. In 1916, Young modified his famous "punch" operation for the prostate to the treatment of PUV in two patients. By 1919, Young, Frontz and Baldwin from Johns Hopkins reported 12 cases of PUV, of which 8 were treated transurethrally. The four patients who did not undergo treatment died of complications of urinary obstruction and renal failure.

Description of Cases and Clinical Outcomes from Hopkins

In this manuscript from 1929, Young added 21 cases from the Brady Urological Institute to the world's literature of 41 treated cases of PUV. This can be considered a very early, systematic review of PUV before that concept existed. In typical HH Young fashion, the clinical circumstances and outcomes of each case are recorded and reported with meticulous detail. Young reviews the "Symptomatology" or clinical presentation of patients, the diagnostic algorithm including differential diagnosis, treatment strategies including the prepatory treatment, and prognosis.
Importantly, incorporating all these concepts with careful attention to detail, Young was able to classify PUV into three main types (figure below):
  • Type I: valves of the distal verumontanum, classified into (a) two separate valves, (b) two fused valves, and (c) and unilateral single valve.
  • Type II: a bifurcated valve from the distal verumontanum to the more proximal prostatic urethra.
  • Type III: an "iris-like" valve above the verumontanum.

 

When describing the clinical outcomes the first nine patients treated with the modified "punch procedure," HH Young demonstrated: six curative treatments, one curative treatment with resulting incontinence and two deaths (one due to sepsis following treatment, one death due to sepsis prior to treatment). Young was extremely selective in choosing patients for an operation, as he recognized many patients had end-stage renal disease – a terminal condition at the time. According to Young, "These results show conclusively that the punch operation was the method of choice but should always be preceded by thorough prepatory drainage until functional tests show sufficient improvement in renal function to warrant an operation."


The "punch procedure" modified for posterior urethral valves (PUV).


 

In summation, Young stressed the following points in the work-up and treatment of PUV – much of which are still relevant today!
  • Initial evaluation should involve:
    • Anatomic investigation of the upper tracts
    • Investigation of renal function
  • Initial management can involve insertion of small catheters to gain adequate drainage of the bladder and evaluate subsequent renal function.
  • Cystoscopic evaluation and possible treatment (punch procedure) is the second step in management of these children and can be very effective in carefully selected patients.

 

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! 

Monday, November 17, 2014

A Social Media Experiment in Childrens’ Urinary Tract Infections


It has been reported that the incidence of urinary tract infections (UTI) in children younger than 6 years is 3-7% for girls and 1- 2% for boys.

Studies on UTIs are important because the disease not only causes acute illness, but can also result in long-term complications such as hypertension and reduced renal function. One of the many challenges in the treatment and prevention of UTIs is the rising rate of antibiotic-resistant bacteria due to the widespread use of antibiotics.

Dr. Ming-Hsien Wang
Dr. Ming-Hsien Wang is an Assistant Professor of Pediatric Urology at Johns Hopkins, whose research focus is on children with urinary tract infections, a common infection in infants and young children.  Dr. Wang is collaborating with other Johns Hopkins faculty to study how infections develop in the urinary tract and establish safer protocols for the evaluation of children with UTIs. Read more about Dr. Wang's research and previous studies by reading the blog, "Is a DMSA Scan Necessary for UTI in Children?" 

With the reduction in national funding for medical research, especially in pediatric medical research, Dr. Wang is working through gofundme.com – a "crowdfunding" resource, to further her work on pediatric UTI. Crowdfunding was made most popular by websites like kickstarter.com. However, kickstarter.com is designed for entry-level venture capitalism and for-profit companies. Sites like gofundme.com are designed strictly for non-profit organizations like Johns Hopkins and researchers like Dr. Wang. 

To complete this important work, Dr. Wang is relying on the support of men and women who deeply care about the health and well-being of all children. If you have interest in funding Dr. Wang's research, please click here: http://www.gofundme.com/h45avw.


Friday, November 14, 2014

Radiation Therapy after Prostate Surgery, Part II: Subgroups Who May Benefit From Adjuvant Therapy


Some men prostate cancer are faced with the realization that treatment of their prostate cancer may require multimodal treatment including some combination of surgery, radiation therapy and/or hormone therapy. The combined ASTRO/AUA (American Society for Therapeutic Radiology and Oncology/American Urological Association) Guideline for "Adjuvant and Salvage Radiotherapy after Radical Prostatectomy" makes a number of statements regarding the use of radiation therapy after surgery that can be confusing to patients and practitioners. 

In the second part of this blog series, we review the statements from the ASTRO/AUA Guideline regarding subgroups who may benefit from adjuvant radiation therapy and the data supporting them.


To read Part I: Adjuvant Radiation following Surgery for Prostate Cancer click here.

The Guideline Statements and three randomized studies (SWOG 8794, EORTC 22911, and ARO 96-02/AUO 09/95) that support their conclusions are detailed in Part I. To summarize, Part I:
Adjuvant radiation therapy (ART) is an option for men with advanced prostate cancer and adverse features after radical prostatectomy. Patients who undergo ART can expect an improvement in biochemical (PSA) and locoregional recurrence, although the benefits on distant metastases and overall survival is less clear.

Looking closely at the data regarding ART, some patients – or subgroups – may be more likely to benefit from immediate treatment than others. It is important to mention before delving into the data from these studies, that these trials were not designed to investigate sub-groups and conclusions need to be drawn with care.

For instance, the SWOG trial demonstrated a benefit for all patients receiving ART. However, when looking at subgroups, patients with high Gleason score (7-10) had the largest significant effect.

From Thompson et al. Journal of Urology, 2009.
In the ARO/AUO trial, benefit was seen for patients with positive surgical margins, high PSA, extraprostatic extension only and all Gleason scores – rather confusing.

From Wiegel et al. JCO 2009; 27: 2898.
To gain a better perspective, we will analyze each adverse feature individually.

 

POSITIVE SURGICAL MARGINS

For patients without a positive surgical margin, there was no benefit to ART for biochemical recurrence, metastasis-free survival (MFS) or overall survival (OS) in the EORTC or ARO studies (SWOG did not report data for patients without positive margins).
For patients with a positive surgical margin, all three studies demonstrated a benefit to ART with regard to biochemical recurrence. SWOG and the EORTC study demonstrated improved recurrence-free survival (or MFS) – ARO did not report this data. OS was not improved in the EORTC study – the only trial that demonstrated this data.

 

GLEASON SCORE

For patients with Gleason Score 2-6:

  • Both the EORTC and ARO study demonstrated an improvement in biochemical recurrence.
  • SWOG did not show a benefit in MFS.
For patients with Gleason Score 7-10:
  • ARO demonstated a benefit to biochemical-free survival
  • SWOG demonstrated an improvement in MFS
  • EORTC did not demonstrate a benefit in biochemical recurrence for either patients with Gleason 7 or patients with Gleason 8-10.
    • The effect for patients with Gleason 7 was apparent, but not statistically significant (Hazard Ratio: 0.63, 95% Confidence Interval: 0.38-1.0).

 

EXTRAPROSTATIC EXTENSION

For patients with extraprostatic extension (pT3a),
  • EORTC and ARO demonstrated a benefit with regard to biochemical recurrence.
  • EORTC did not demonstrate a benefit for recurrence-free survival or OS.
  • SWOG did not report on patients with extraprostatic extension.

 

SEMINAL VESICLE INVASION

For patients with seminal vesicle invasion (pT3b),
  • SWOG and EORTC demonstrated a benefit with regard to biochemical recurrence, ARO did not.
  • Neither SWOG nor EORTC demonstrated a benefit to recurrence-free survival or MFS.
  • EORTC did not demonstrate an OS benefit to ART.

CONCLUSIONS

Based on the subgroup analyses, adjuvant ART appears to have the most benefit for patients with positive surgical margins and Gleason score 7-10. The benefit of ART in patients with Gleason 6, extraprostatic extension (in the absence of a positive surgical margin) and seminal vesicle invasion is less clear.


This is most likely explained by the fact that patients with a high Gleason score and positive surgical margin are at risk for residual, local disease and benefit from additional local therapy (in the form of radiation). Patients with Gleason 6 are unlikely to benefit as Gleason 6 is believed to be indolent disease and extra therapy to the pelvis is unlikely to affect an already slow-growing, benign-behaving disease process. Patients with seminal vesicle invasion have the opposite problem – they are at extremely high-risk for systemic disease, or disease that has spread from the prostate. Therefore, treating the pelvis is unlikely to benefit patients who are likely to have disease in their lymph nodes or bones – and catching the prostate cancer in the pelvis with additional radiation therapy is unlikely.
Stay tuned for this continued series on Radiation Therapy after Surgery for Prostate Cancer.

 

This blog was written by Mark W. Ball, MD. Mark is a 5th year urology resident at the Brady Urological Institute at Johns Hopkins and looking forward to a career in urologic oncology.


 

Tuesday, November 11, 2014

Historical Contribution: 1923, Young & Hill,Mercurochrome & Gentian Violet

1923
HH Young, Hill JA. The Treatment of Septicemia and Local Infections By Intravenous Injection of Mercurochrome 220 Soluble and of Gentian Violet. JAMA. 1924;82:669-75.


 

In 1919, Hugh Hampton Young published the first report of mercurochrome-220 to sterilize the bladder in the Journal of the American Medical Association (JAMA) (click here for link to Historical Contribution: 1919). Four years later, he writes the follow-up manuscript demonstrating the effectiveness of mercurochrome in the treatment of a variety of bacterial infections. In addition, he describes the use of gentian violet, a potent antimicrobial for gram-positive staphylococci. After proving intravenous instillation of gentian violet in rabbits is safe – Young endeavors on human treatment with the medication.

In total, Young presents 12 cases treated and cured with mercurochrome – the first one in 1922. In patients 1-7, Young meticulously details the tenuous clinical course of patients afflicted with septicemia, retroperitoneal and abdominal abscesses, kidney and bladder infections treated by intravenous mercurochrome.




In patients 8-12, Young describes the use of intravenous gentian violet. The first intravenous dose of gentian violet was given July 12, 1923 to a patient with staphylococcus aureus urinary tract infection related to a ureteral calculus. The remaining cases demonstrated cure of systemic staphylococcal infections including those stemming from complications of diabetes, osteomyelitis, urinary system infections. Importantly, gentian violet cleared the source of infection, improved systemic infection, and cleared sequealae of the systemic infection (i.e. abscesses).
In his typical fashion, Young took meticulous notes regarding the clinical course and laboratory values associated with each patient. Not only was the defervescence and normalization of vital signs in septic patients impressive, but the hourly documentation of blood and urine cultures demonstrating true sterilization of the infection.

 

To summarize, in the early 1900's, septicemia was almost universally fatal and mercurochrome ushered in a new era of antimicrobial treatment and hope for the treatment of infectious disease. Patients in this series were described as "desperate cases" – in which experimental antimicrobial treatments were justified. Young was extremely pleased with the results; he describes the sure and sterilization of the blood by intravenous mercurochrome "miraculous" and goes on to say,
"In these cases we have the first demonstration that gentian violet may be used intravenously to combat general septicemia or local infections, and with remarkable success in the case of gram-positive staphylococci. Coupled with the equally amazing results obtained by mercurochrome, these cases represent a splendid therapeutic achievement, and one is tempted to soar into realms of fancy and see a great variety of infectious processes treated and cured intravenously;"
Read more about mercurochrome in publications by Hugh Hampton Young by clicking on the following links:
Historical Contribution, 1919
Historical Contribution, 1925

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! 

Monday, November 10, 2014

Oncocytoma: A Benign Kidney Tumor Often Confused for Cancer

Upwards of 15-20% of kidney tumors may be benign lesions. While physicians and surgeons can use patient information, radiographic imaging and biopsy to provide information, the definitive diagnosis of cancer or benign tumor is established only after the tumor has been removed. For instance, smaller tumors, female sex and age are associated with benign tumors - younger women are nearly twice as likely as age-matched men to have benign masses.[1-5] While certain characteristics are indicative of benign tumors (i.e. fat always indicates an angiomyolipoma), many other benign tumors – like oncocytoma – can appear similar to renal cell carcinoma (RCC) on CT scan and biopsy.

This blog will review oncocytoma, one of the most common benign tumors of the kidney.


Epidemiology and Etiology

Renal oncocytoma is one of the most common of benign renal masses, accounting for 3-7% of kidney tumors.[6] Oncocytomas appear as enhancing renal masses and are often indistinguishable from clear-cell RCC on CT scans (see Diagnosis below). Both oncocytomas and clear-cell RCC pick up contrast material and enhance brightly. However, oncocytoma is a distinct entity from RCC with unique cell of origin and cytogenetic abnormalities.[7-8]

Oncocytomas are more common in older patients with small, incidentally discovered renal masses. [4,9] Generally, they are more common in men than women (2:1 ratio), present in the 4th to 6th decade of life and can present bilaterally, multifocally or recur in 6-13% of cases.[10] Patients with the rare, Birt-Hogg-DubĂ©, genetic syndrome can present with oncocytomatosis – the presence of multiple oncocytomas in both kidneys. [11] Oncocytomas are benign tumors and rare case reports of metastatic oncocytoma represent either malignant degeneration, coexistence of RCC or pseudometastases (not really metastatic disease).[12]


Diagnosis

In general, oncocytoma appear similar to RCC on imaging. However, a number of characteristic radiographic findings are common in oncocytoma:
  • On CT scan, bright, rapidly-enhancing pattern and a central stellate scar [13]
  • On angiography, a spoke wheel pattern of feeding arteries may be present
  • On MRI, a well-defined capsule, central stellate scar, and distinctive pattern on T1 and T2 images may indicate oncocytoma.[14,15]
The similar appearance of clear-cell RCC and oncocytoma on contrast-enhanced CT scan.
The Houndsfield Unit (HU) -based enhancement patterns for clear-cell RCC and oncocytoma are overlapping on CT scan. [13]




Renal biopsy has a limited role in the diagnosis of oncocytoma, particularly because it can be difficult to distinguish from chromophobe RCC (see our blog entry on Renal Cell Carcinoma: Implications of Histology for more information about chromophobe RCC), the eosinophilic-variant of clear-cell RCC (a rare and potentially aggressive form of kidney cancer) and may be co-exist with RCC in 7-32% of cases. However, surgical series indicate that if oncocytoma is present with RCC in the same tumor, the tumor is often low-grade and indolent (benign-behaving).[16]


Histology and Pathology

Oncocytomas appear grossly as tan, homogenous tumors with a distinct border (composed of a well-formed pseudocapsule) and typically have a central stellate scar. Microscopically, cells are derived from distal tubules, are rounded and highly-eosinophlic (pink) due to an abundance of mitochondria (the energy producing portion of the cell). As stated above, it can extremely difficult to distinguish oncocytoma from chromophobe RCC or the eosinophilic-variant of clear-cell RCC under the microscope. Cells are typically arranged in a nested pattern and can demonstrate perinephric extension, pleomorphism (variability in size and shape), prominent nucleoli and atypia, making the distinction between RCC difficult.[17,18] On a percutaneous renal biopsy, where only a portion of tumor is present and cellular architecture is incomplete, distinguishing oncocytoma from RCC can be extremely challenging.


From pathologyatlas.com

To distinguish ococytoma from RCC, a number of features can be examined. Chromosomal abnormalities associated with RCC are not present in oncocytoma, and oncocytoma will commonly present with loss of chromosome 1p, loss of Y- or 14q- and rearrangements of 11q13. [7,8] Hale's colloidal iron stain has traditionally been used to identify oncoctyoma, however can have nonspecific staining patterns leading to difficult interpretation.[19] One of the distinguishing cellular features of oncocytoma is uniform, round mitochondria with lamellar cristae – in chromphobe RCC, mitochondria are variable in size and shape with tubulocystic cristae; and in eosinophilic-variant of clear-cell RCC, mitochondria are pleomorphic and have attenuated cristae.[20] Researchers at Johns Hopkins are taking advantage of differences in mitochondria among oncocytoma and RCC to come up with a better, preoperative diagnostic test to distinguish oncocytoma before a sending a patient to surgery.


Electron micropscopy of oncocytoma with uniform, round mitochondria (left) and chromophobe RCC with the pale area around the nucleus is predominantly occupied by microvesicles and irregular mitochondria (right).[20]

Management

Most often oncocytoma are clinically assumed to be RCC and have the same management strategies available including active surveillance, radical nephrectomy (for large tumors of uncertain etiology) and nephron-sparing surgeries including partial nephrectomy and thermal ablation. Oncocytomas under active surveillance can demonstrate rapid growth and are often the fastest growing tumors in active surveillance studies! Therefore, growth rate is not able to distinguish oncocytoma from RCC during periods of AS.[21,22] When the diagnosis of oncocytoma is known or highly-suspected, nephron-sparing approaches should be employed due to the benign nature of these lesions. At Johns Hopkins, partial nephrectomy is preferred to thermal ablation as a definitive diagnosis can be made from analysis of the tumor rather than biopsy specimens.



This blog is adapted from the Handbook of Urology, Chapter 24: Angiomyolipoma, Oncocytoma and Retroperitoneal Fibrosis, by Phillip M. Pierorazio, MD; Edited by John Kellogg Parsons, John B. Eifler, and Misop Han available from Wiley.


 








  1. Kutikov A, Fossett LK, Ramchandani P, et al.: Incidence of benign pathologic findings at partial nephrectomy for solitary renal mass presumed to be renal cell carcinoma on preoperative imaging. Urology 2006; 68(4): 737-40.
  2. Kouba E, Smith A, McRackan D, Wallen EM, Pruthi RS: Watchful waiting for solid renal masses: insight into the natural history and results of delayed intervention. J Urol 2007; 177(2): 466-70; discussion 470.
  3. Pierorazio PM, Murphy AM, Benson MC, McKiernan JM: Gender discrepancies in the diagnosis of renal cortical tumors. World J Urol 2007; 25(1): 81-5.
  4. Cao Y, Paner GP, Perry KT, Flanigan RC, Campbell SC, Picken MM: Renal neoplasms in younger adults: analysis of 112 tumors from a single institution according to the new 2004 World Health Organization classification and 2002 American Joint Committee on Cancer Staging System. Arch Pathol Lab Med 2005; 129(4): 487-91.
  5. Snyder ME, Bach A, Kattan MW, Raj GV, Reuter VE, Russo P: Incidence of benign lesions for clinically localized renal masses smaller than 7 cm in radiological diameter: influence of sex. J Urol 2006; 176(6 Pt 1): 2391-5; discussion 2395-6.
  6. Morra MN, Das S: Renal oncocytoma: a review of histogenesis, histopathology, diagnosis and treatment. J Urol 1993; 150(2 Pt 1): 295-302.
  7. Lindgren V, Paner GP, Omeroglu A, et al.: Cytogenetic analysis of a series of 13 renal oncocytomas. J Urol 2004; 171(2 Pt 1): 602-4.
  8. Paner GP, Lindgren V, Jacobson K, et al.: High incidence of chromosome 1 abnormalities in a series of 27 renal oncocytomas: cytogenetic and fluorescence in situ hybridization studies. Arch Pathol Lab Med 2007; 131(1): 81-5.
  9. Skolarus TA, Serrano MF, Berger DA, et al.: The distribution of histological subtypes of renal tumors by decade of life using the 2004 WHO classification. J Urol 2008; 179(2): 439-43; discussion 443-4.
  10. Minor LD, Picken MM, Campbell SC: Benign renal tumors. AUA Update 2003; 22: 170-175.
  11. Al-Saleem T, Cairns P, Dulaimi EA, Feder M, Testa JR, Uzzo RG: The genetics of renal oncocytosis: a possible model for neoplastic progression. Cancer Genet Cytogenet 2004; 152(1): 23-8.
  12. Oxley JD, Sullivan J, Mitchelmore A, Gillatt DA: Metastatic renal oncocytoma. J Clin Pathol 2007; 60(6): 720-2.
  13. Pierorazio PM1, Hyams ES, Tsai S, Feng Z, Trock BJ, Mullins JK, Johnson PT, Fishman EK, Allaf ME. Multiphasic enhancement patterns of small renal masses (≤4 cm) on preoperative computed tomography: utility for distinguishing subtypes of renal cell carcinoma, angiomyolipoma, and oncocytoma. Urology. 2013 Jun;81(6):1265-71. doi: 10.1016/j.urology.2012.12.049. Epub 2013 Apr 17.
  14. Licht MR: Renal adenoma and oncocytoma. Semin Urol Oncol 1995; 13(4): 262-6.
  15. Harmon WJ, King BF, Lieber MM: Renal oncocytoma: magnetic resonance imaging characteristics. J Urol 1996; 155(3): 863-7.
  16. Ginzburg S, Uzzo R, Al-Saleem T, Dulaimi E, Walton J, Corcoran A, Plimack E, Mehrazin R, Tomaszewski J, Viterbo R, Chen DY, Greenberg R, Smaldone M, Kutikov A. Coexisting hybrid malignancy in a solitary sporadic solid benign renal mass: implications for treating patients following renal biopsy. J Urol. 2014 Feb;191(2):296-300. doi: 10.1016/j.juro.2013.07.059. Epub 2013 Jul 27.
  17. Amin MB, Crotty TB, Tickoo SK, Farrow GM: Renal oncocytoma: a reappraisal of morphologic features with clinicopathologic findings in 80 cases. Am J Surg Pathol 1997; 21(1): 1-12.
  18. Perez-Ordonez B, Hamed G, Campbell S, et al.: Renal oncocytoma: a clinicopathologic study of 70 cases. Am J Surg Pathol 1997; 21(8): 871-83.
  19. Leroy X, Moukassa D, Copin MC, Saint F, Mazeman E, Gosselin B: Utility of cytokeratin 7 for distinguishing chromophobe renal cell carcinoma from renal oncocytoma. Eur Urol 2000; 37(4): 484-7.
  20. Tickoo SK, Lee MW, Eble JN, Amin M, Christopherson T, Zarbo RJ, Amin MB. Ultrastructural observations on mitochondria and microvesicles in renal oncocytoma, chromophobe renal cell carcinoma, and eosinophilic variant of conventional (clear cell) renal cell carcinoma. Am J Surg Pathol. 2000 Sep;24(9):1247-56.
  21. Kawaguchi S, Fernandes KA, Finelli A, Robinette M, Fleshner N, Jewett MA: Most renal oncocytomas appear to grow: observations of tumor kinetics with active surveillance. J Urol 2011; 186(4): 1218-22.
  22. Siu W, Hafez KS, Johnston WK, 3rd, Wolf JS, Jr.: Growth rates of renal cell carcinoma and oncocytoma under surveillance are similar. Urol Oncol 2007; 25(2): 115-9.

Friday, November 7, 2014

Bladder Preservation Strategies in the Treatment of Muscle-Invasive Bladder Cancer

It is estimated that in 2014, there will be 74,690 new cases bladder cancer and 15,580 deaths secondary to bladder cancer.1 Approximately 20-30% of patients with bladder cancer present with muscle-invasive bladder cancer (MIBC). The standard of care for MIBC is a radical cystectomy with removal of the pelvic lymph nodes, with some patients undergoing chemotherapy prior to surgery (neoadjuvant chemotherapy). While radical cystectomy is the preferred treatment option, it has significant morbidity and implications on quality of life.2,3 Therefore, bladder preservation therapies for MIBC have been developed, and may be an option for a select group of patients.4

Bladder preservation strategies include combination therapies as well as single modality therapies. Trimodal therapy, consisting of an aggressive transurethral resection of bladder tumor followed by concurrent chemotherapy and radiation therapy, is the most strongly supported and accepted bladder preservation option. In a recent systematic review, the 5-year cancer specific survival in medically operable patients undergoing trimodal therapy was 50-82%.5 These numbers are comparable to large radical cystectomy series. While there are no randomized trials comparing trimodal therapy to radical cystectomy, there is a growing body of accumulated data suggesting that trimodal therapy is a reasonable treatment option in well-selected patients.

While trimodal therapy is the most accepted option for bladder preservation, for the remainder of this post, we will discuss the role of each individual modality (transurethral resection, chemotherapy, and radiotherapy) in trimodal therapy, and outline some non-traditional approaches to bladder preservation.

Transurethral resection of bladder tumor

Transurethral monotherapy involves excising all visible tumor with deep resection. In highly selected patients, Dr. Harry Herr presented a series of 151 patients with MIBC that underwent an aggressive transurethral resection of bladder tumor with 10 years of follow-up.6 Of these patients, 99 underwent transurethral resection alone and 52 underwent radical cystectomy. There was no significant difference in survival between these groups, and overall, 57% of patients in this study survived more than 10 years with a functioning bladder. While these results are noteworthy, limited data overall supporting radical transurethral resection as monotherapy. Furthermore, there is a lifelong risk of developing recurrent invasive tumor in retained bladder: 42% of patients in this study underwent salvage radical cystectomy. The general consensus is that transurethral resection alone provides inadequate cancer control with high rate of recurrence and progression.

Chemotherapy

While the primary role for chemotherapy in the treatment of MIBC is neoadjuvant chemotherapy, there are circumstances where a patient will have no evidence of tumor following chemotherapy, and will subsequently refuse a cystectomy. Small series have described this scenario with good outcomes. In a recent retrospective review of 32 patients with muscle-invasive bladder cancer that had a clinical complete response to neoadjuvant chemotherapy, 25 patients refused to undergo an immediate cystectomy.7 Of the 25 patients that refused immediate cystectomy, 7 patients underwent delayed cystectomy for relapse and 18 patients successfully maintained their bladders. There was no difference in the cancer specific survival between patients that underwent immediate cystectomy and patients that opted for a bladder preservation strategy. We see that in select patients that achieve a complete response to neoadjuvant chemotherapy, bladder preservation may be achieved. However, at this point, it is difficult to determine who will have a response to neoadjuvant chemotherapy, and of those, who will be able to durably maintain their bladders.

Radiation Therapy

A multicentered randomized phase 3 trial examined the role of radiation alone versus radiation with chemotherapy in the treatment of MIBC.8 The authors found that the locoregional and invasive disease free survival was significantly better in the patients that underwent chemoradiation therapy as opposed to radiation alone. Furthermore, there was no increased toxicity with the addition of chemotherapy. The authors did not compare these modalities to patients undergoing cystectomy. Overall, when examining bladder preservation options, there is no role for radiation therapy alone, as concurrent chemoradiation is more effective.

SUMMARY

In conclusion, there are multiple options for bladder preservation. There are large trials reporting outcomes for trimodal therapy and small series for single modality treatments. From these experiences, we see that bladder preservation strategies can lead to acceptable outcomes, and may be considered a reasonable treatment option in select patients. Bladder preservation is not an option for all patients with MIBC, and patient selection is of paramount importance. Furthermore, it is essential to recognize that in these studies, only select patients were included. Bladder preservation is a treatment approach under investigation, and prospective trials comparing trimodal therapy and single modality bladder preservation options to radical cystectomy are needed to better define their role in the treatment of MIBC.



This blog was written by Alexa Meyer, Medical Student at Columbia University College of Physicians & Surgeons in New York, New York.  Alexa recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "Trimodal Therapy for Bladder Cancer" from which this blog is inspired. Alexa is looking forward to a career in urology.






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5. Ploussard G, Daneshmand S, Efstathiou JA, et al. Critical analysis of bladder sparing with trimodal therapy in muscle-invasive bladder cancer: a systematic review. Eur Urol 2014;66:120-37.
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