Active Surveillance Proving Safe for Small Renal Masses

Although the incidence of kidney cancer has increased dramatically over the last few decades, Hopkins research is showing that the majority of patients can be safely followed without the need for surgery.  

For more than five years, Brady urologist Phillip Pierorazio, M.D., has run the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) Registry, following patients with small, localized kidney tumors (stage T1a, 4 cm or smaller), who choose either active surveillance or immediate surgery.  “The patients undergoing surveillance have done incredibly well,” he says.  “None have died of kidney cancer.”  About 500 patients at Hopkins, Columbia University, and Beth Israel Deaconess Medical Center are in the Registry; of those, nearly 200 have chosen surveillance.  The Columbia program in New York City is run by James M. McKiernan, MD and the Beth Israel Deaconess in Boston, Massachussets is run by Andrew A. Wagner, MD.  About 30 patients in the surveillance group later opted for surgery, either because their tumor grew or “they didn’t want to worry about it anymore, or because they had a medical issue that resolved.”

Phillip M. Pierorazio, MD recently received a Young Investigator's Award
from the National Comprehensive Cancer Network (NCCN) and will present
several abstracts at the upcoming American Urological Association
meeting in May.

In the 1970s, about 30,000 Americans were diagnosed yearly with kidney cancer; that number has jumped to about 60,000 today, in large part because of increasing use of CT scans.  But still, the number of annual deaths -- between 10,000 and 13,000 -- has remained unchanged, Pierorazio notes.

“So we’re operating on all these people, but we have not significantly changed the mortality of this disease.  Which begs the question, are all of these tumors of consequence?”  

Although several institutions have studied surveillance, the studies have been mainly retrospective.  Hopkins is one of three institutions worldwide with this kind of prospective protocol.

Once it escapes the kidney, cancer is fatal.  Surgical cure rates for kidney-confined tumors are excellent -- about 95 percent.  And yet:  “If you took everybody in this country with a small kidney tumor, anything 4 cm or less,” says Pierorazio, “upwards of 30 percent are benign lesions -- not even cancer.  Of the 70 percent left, half are low-grade, indolent tumors.  They’re not ever going to cause a problem.  That only leaves about a third that are potentially aggressive.”

Who can safely avoid surgery?  Pierorazio and colleagues have come up with a score based on some key clinical factors.  For example:  Tumors that are close to the renal hilum tend to be more aggressive.  Women are more likely to have benign tumors, and older people are more likely to have indolent tumors.  The risk of metastasis is extremely low in tumors under 2 centimeters.  Surveillance is better for people with heart problems, particularly congestive heart failure.  

With urologist Mohamad Allaf, M.D., Pierorazio runs a clinic for people with small kidney tumors.  All in one day, patients get an ultrasound and labwork, then meet with a physician.  “For patients who decide they want surgery, it’s very easy.  We offer basically every option there is,” including complex partial, open-incision and robotic procedures.  Patients who choose surveillance receive ultrasound every six months for the first two years, then annually.

Pierorazio, recently awarded a Young Investigator’s Award by the National Comprehensive Cancer Network (NCCN) for this work, will be presenting several abstracts summarizing data from DISSRM at the American Urological Association’s meeting in May.

If you or a loved one have a small renal mass, or you have a patient with a small renal mass who is interested in active surveillance or hearing all the options for the treatment of their tumor, 
call Drs. Allaf or Pierorazio at Johns Hopkins at (410) 955-6100; 
if in or around New York, call Dr. McKiernan at (212) 305-0114; 
if in or around Boston, call Dr. Wagner at (617) 667 2898.

This blog entry is extracted from the "Johns Hopkins Urology: News for Physicians from Johns Hopkins Medicine," Spring 2014.

Historical Contribution: 1920, Colston, Gun Shot Wounds to the Urethra

1920

Colston JAC.  Observations on Gun-Shot Wounds of the Urethra.  J of Urol.2;185-192.


John Archibald Campbell Colston, a John Hopkins urologist, served with the Allied Forces during WWI. Dr. Colston documented his entire experience in the "J.A.C. Colston WWI diaries," 1914-1915; and is considered a valuable first-hand look at the Great War from the prospective of a doctor who served.  In the above manuscript, published in the Journal of Urology after his return from the War, Dr. Colston describes his experience treating urethral injuries suffered during World War I.  He comments,

"Following an injury to the urethra there is usually obstruction to urination and often a rapid extravasation of urine.  On this account these cases urgently require immediate attention, but unfortunately, conditions on the field are such that is is rare for the wounded man to receive surgical intervention...  during which time the surrounding tissues, devitalized by the trauma of teh projectile and the increasing extravasation of urine, form a most favorable medium for the growth of microorganisms carried into the wound by the projectile." 

Therefore, very few of these wounds were seen in the hospital - as very few of these men made it off the battle field.  Of note, the three men presented in this report had soft tissue injuries to the lower extremities or scrotum, no intra-abdominal wounds.  From his experience and the experience of other genitourinary surgeons during the war, Colston draws the final recommendations for the management of urethral injury:

1. Divert the urine by suprapubic cystotomy and widely open the injured area.
2. Immediate suture should only be attempted after urinary diversion.
3. Transfer patients to hospitals specializing in urologic surgery once they are stabilized.

Read the entire manuscript using 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! 

Non-Cancerous Findings on Prostate Biopsy

Men with an elevated PSA often undergo prostate biopsy to look for prostate cancer.  Many times, the prostate biopsy does not demonstrate cancer but gives another diagnosis including:

• High-grade prostatic intraepithelial neoplasia (HGPIN)
• Proliferative Inflammatory Atrophy (PIA)
• Acute or Chronic Inflammation
• Atypia, or Atypical small acinar proliferation (ASAP)

None of these diagnoses are cancerous, however valuable information can be gained by each diagnosis, in some cases implications regarding the future risk of cancer.  Here we review the implications of benign diagnoses on prostate biopsy.

High-grade prostatic intraepithelial neoplasia (HGPIN)

HGPIN currently is the only recognized premalignant precursor to prostatic adenocarcinoma.  Under the microscope, HGPIN appears much like prostate cancer with atypical cells containing prominent nucleoli.  However, the main histologic difference between prostate cancer and HGPIN is that HGPIN has a preserved basal cell layer in the glandular architecture.  Morphologic and molecular data also support HGPIN as a precursor to prostatic carcinoma.[1,2]  Morphologically,  prostate cancer is observed budding off areas of HGPIN.[1,2]  Molecularly, HGPIN and prostate cancer share a number of molecular genetic and chromosomal abnormalities that support a common evolution.[3]

HGPIN appears in prostate biopsies in 5-8% of men and concomitantly with prostate cancer at radical prostatectomy in up to 80% of cases.[4,5]  HGPIN can be seen as early as the 3rd decade of life, preceding the age of prostate cancer diagnosis by at least 10 years.  However, the risk of detecting subsequent prostate cancer is the range of 22-24% - which is not clinically or statistically different from the risk of finding prostate cancer after a previous negative biopsy in men with an elevated PSA.[4,6]  The amount of HGPIN found may influence the detection of subsequent prostate cancer.  In men with 3 or greater cores of HGPIN, the risk of prostate cancer is significantly higher.[7-11]  Therefore, men with 1-2 cores of HGPIN should be followed with routine PSA and digital rectal examination with repeat biopsy within 3 years or as indicated sooner; and men with 3 or more cores of HGPIN undergo repeat biopsy within 12-18 months of the initial diagnosis.

Proliferative Inflammatory Atrophy (PIA) and Inflammation

Occasionally prostate biopsies will demonstrate inflammatory cells and PIA.  Atrophy occurs in the setting of inflammation and has been suggested relate to prostate cancer as early as the 1950's.[12,13]  PIA contains atrophic epithelial cells that appear to be regenerating in response to cellular damage.  The cellular damage is mediated by inflammatory cell infiltrates.[14]  PIA will occasionally merge directly with HGPIN and morphological transitions between PIA, HGPIN and prostate cancer have been described.[15,16]  However, other than its relationship to HGPIN and cancer, no association between PIA on biopsy on subsequent prostate cancer is noted.

Atypical small acinar proliferation (ASAP)

ASAP or atypia does not have specific histologic, morphologic or molecular features that align it with prostate cancer like HGPIN.  Rather, ASAP is a diagnosis of exclusion for glands within the prostate that do not meet criteria for prostate cancer but appear suspicious for the diagnosis.  The incidence of ASAP on initial prostate biopsy is 2-3%.  However, different from HGPIN, the risk of subsequent prostate cancer on repeat biopsy is as high as 60%.[17-21]  Therefore men with ASAP should undergo repeat biopsy within 6-12 months due to the high likelihood of harboring undetected prostate cancer.

Summary

• HGPIN is a premalignant prostate cancer lesion.  It is present in 5-8% of biopsies.
• If 1-2 cores of HGPIN, repeat PSA and DRE annually, consider repeat biopsy within 3 years or sooner if clinically indicated.
• If 3 or mores cores of HGPIN are found at biopsy, a repeat biopsy should be performed within 12-18 months.
• PIA is found with inflammation and in the spectrum of HGPIN and prostate cancer.  There is no evidence that inflammation or PIA on biopsy is indicative of prostate cancer on subsequent biopsy.
• ASAP or atypia is found in 2-3% of prostate biopsies and highly correlated with prostate cancer on subsequent biopsy; men with ASAP should be biopsied within 6-12 months of an initial diagnosis. 

[1] Bostwick DG, Qian J. High-grade prostatic intraepithelial neoplasia.  Mod Pathol. 2004;17(3):360-379.
[2] Joniau S, Goeman L, Pennings J, et al. Prostatic intraepithelial neoplasia  (PIN): importance and clinical management. Eur Urol. 2005;48(3): 379-385.
[3] Dickinson SI.  Premalignant and malignant prostate lesions: pathologic review.Cancer Control. 2010 Oct;17(4):214-22.
[4] Ayala AG, Ro JY. Prostatic intraepithelial neoplasia: recent advances. Arch Pathol Lab Med. 2007;131(8):1257-1266.
[5] Pierorazio PM, Lambert SM, Matsukhani M, Sprenkle PC, McCann TR, Katz AE, Olsson CA, Benson MC, McKiernan JM.High-grade prostatic intraepithelial neoplasia is an independent predictor of outcome after radical prostatectomy.BJU Int. 2007 Nov;100(5):1066-70. Epub 2007 Sep 3.
[6] McNeal JE. Origin and development of carcinoma in the prostate.  Cancer. 1969;23:24-34.
[7] Kronz JD, Allan CH, Shaikh AA, et al. Predicting cancer following a diagnosis of high-grade prostatic intraepithelial neoplasia on needle biopsy: data on men with more than one follow-up biopsy. Am J Surg Pathol. 2001; 25(8):1079-1085.
[8] Abdel-Khalek M, El-Baz M, Ibrahiem el-H. Predictors of prostate cancer on extended biopsy in patients with high-grade prostatic intraepithelial neoplasia: a multivariate analysis model. BJU Int. 2004;94(4):528-533.
[9] Netto GJ, Epstein JI. Widespread high-grade prostatic intraepithelial neoplasia on prostatic needle biopsy: a significant likelihood of subsequently diagnosed adenocarcinoma. Am J Surg Pathol. 2006;30(9):1184-1188.
[10] Akhavan A, Keith JD, Bastacky SI, et al. The proportion of cores with high-grade prostatic intraepithelial neoplasia on extended-pattern needle biopsy is significantly associated with prostate cancer on site-directed repeat biopsy. BJU Int. 2007;99(4):765-769.
[11] Godoy G, Taneja SS. Contemporary clinical management of isolated high-grade prostatic intraepithelial neoplasia. Prostate Cancer Prostatic Dis. 2008;11(1):20-31.
[12] De Marzo AM, Platz EA, Epstein JI et al. A working group classification of focal prostate atrophy lesions. Am.J. Surg. Pathol. 2006; 30: 1281–91.
[13] Liavåg I. Atrophy and regeneration in the pathogenesis of prostatic carcinoma. Acta Pathol. Microbiol. Scand. 1968;73: 338–50.
[14] De Marzo AM , Marchi VL , Epstein JI , Nelson WG . Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis . Am. J. Pathol. 1999 ; 155 ; 1985 – 1992 .
[15] Putzi MJ , De Marzo AM . Morphologic transitions between proliferative inflammatory atrophy and high-grade prostatic intraepithelial neoplasia . Urology 2000 ; 56 ; 828 – 832 .
[16] Wang W , Bergh A , Damber J-E . Morphological transition of proliferative inflammatory atrophy to high-grade intraepithelial neoplasia and cancer in human prostate . Prostate 2009 ; 69 ; 1378 – 1386 .
[17] Bostwick DG, Meiers I. Atypical small acinar proliferation in the prostate: clinical significance in 2006. Arch Pathol Lab Med. 2006;130(7): 952-957.
[18] Leite KR, Camara-Lopes LH, Cury J, et al. Prostate cancer detection at rebiopsy after an initial benign diagnosis: results using sextant extended prostate biopsy. Clinics (Sao Paulo). 2008;63(3):339-342.
[19] Montironi R, Scattoni V, Mazzucchelli R, et al. Atypical foci suspicious but not diagnostic of malignancy in prostate needle biopsies (also referred to as “atypical small acinar proliferation suspicious for but not diagnostic of malignancy”). Eur Urol. 2006;50(4):666-674.
[20] Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. J Urol. 2006;175(3 pt 1):820-834.
[21] Mallén E, Gil P, Sancho C, Jesús Gil M, et al. Atypical small acinar proliferation: review of a series of 64 patients. Scand J Urol Nephrol. 2006;40(4):272-275

BCG For Bladder Cancer: Why it Works, How it Works

Macrophage engulfing
Bacillus Calmette-Guérin

Nearly 60,000 patients are diagnosed with urothelial cancer (UC) of the bladder each year and 300-500,00 survivors are living 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.  

Despite its long-history of efficacy in the treatment of NMIUC, the mechanism of action of BCG is not well-defined.  Subsequently, it is not clear to many patients and practitioners why BCG works.  Here we review what is known about the mechanism of action of BCG for NMIUC.

BCG is a live attenuated strain of Mycobacterium bovis, a bacteria very similar to tuberculosis.  When in contact with the urothelium (lining of the urinary system), BCG elicits a variety of local immune responses which appear to correlate with its anti-tumor activity.  The role of the immune system in the action of BCG was clear even from the seminal work demonstrating the anti-cancer effects of BCG in 1959.[2]  Since then, additional studies demonstrate the importance of the immune system in the mechanism of BCG:

• A competent host immune system is required for BCG to work [3,4]
• Viable BCG is required for a response [5,6]
• More than 40% of patients receiving intravesical BCG instillation experience conversion of a previously negative tuberculin skin test.[7]
• BCG "priming" (exposing a patient to BCG prior to treatment) may improve response rates to intravesical BCG.[8]
• Mice immunized subcutaneously with BCG have improved survival, compared with BCG-naive mice, after intravesical BCG therapy. 
• Patients with a pre-existing positive tuberculin skin test have better recurrence-free-survival rates than those without, after intravesical BCG therapy.

MECHANISM OF bcg-mediated immune response IN TREATING BLADDER CANCER

The initial activating step for the inflammatory cascade is binding of BCG to fibronectin (a protein that helps the cell bind molecules) expressed on the urothelium [9]. The BCG is then internalized by both normal urothelial and cancer cells.  The host's immune system, through antigen presenting cells (APCs: specifically macrophages and dendritic cells), identifies components of BCG as foreign to the host.  Macrophages are the initial line of defense, allowing for cytokine production, BCG antigen presentation, and function in an anti-neoplastic manner against bladder cancer cells [10]. Along with its anti-BCG effects, macrophages also kill cancer cells through direct cell-to-cell contact as well as the release of the cytokines TNF-α and IFN-γ; and the molecule nitric oxide [11].

Once macrophages and dendritic cells identify components of BCG as foreign, these components are presented as BCG antigens (an antigen is any substance that provokes an immune response) via the MHC (major histocompatibility complex) II leading to a huge immune response.  The immune response is mediated through the T-helper (Th) 1 immune response, causing the release of cytokines (proteins used by cells to transmit signals to other cells) that attract more immune cells (neutrophils, lymphocytes, natural killer (NK) cells, macrophages, and dendritic cells) into the wall of the bladder.[12]  The Th1 cytokine profile (IFN-γ, IL-2, IL-12) has been demonstrated as necessary for a successful response to BCG; while the alternative Th2 pathway and related cytokines (IL10) are correlated with BCG failure.[13]

Neutrophils are another important cell in the BCG response pathway.  Neutrophils become activated and elicit production of tumor necrosis factor-related apoptosis-induced ligand (TRAIL) which specifically targets the malignant bladder cells. A significantly higher level of urinary TRAIL is seen in patients responding to BCG therapy than in non-responders [14]. A systemic immune response is also seen in the form of elevated serum cytokines, cellular and humoral BCG reactivity with in vivo evidence pointing to involvement of CD4+ and CD8+ lymphocytes, NK cells, and granulocytes.[15,16]

From Luo Y et al. [10]

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] Old, L. J., Clarke, D. A. & Benacerraf, B. Effect of Bacillus Calmette-Guerin infection on transplanted tumours in the mouse. Nature 184 (Suppl. 5), 291–292 (1959).
[3] Zbar, B. & Rapp, H. J. Immunotherapy of guinea pig cancer with BCG. Cancer 34 (Suppl.), 1532–1540 (1974).
[4] Morton, D., Eilber, F. R., Malmgren, R. A. & Wood, W. C. Immunological factors which influence response to immunotherapy in malignant melanoma. Surgery 68, 158–163 (1970).
[5] Zbar, B. & Tanaka, T. Immunotherapy of cancer: regression of tumors after intralesional injection of living Mycobacterium bovis. Science 172, 271–273 (1971).
[6] Kelley, D. R. et al. Intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: effect of bacillus Calmette-Guerin viability on treatment results. J. Urol. 134, 48–53 (1985).
[7] Kelley, D. R. et al. Prognostic value of purified protein derivative skin test and granuloma formation in patients treated with intravesical bacillus Calmette-Guerin. J. Urol. 135, 268–271 (1986).
[8] Biot, C. et al. Preexisting BCG-specific T cells improve intravesical immunotherapy for bladder cancer. Sci. Transl. Med. 4, 137ra72 (2012).
[9] Kavoussi LR, Brown EJ, Ritchey JK, and Ratliff TL. Fibronectin-mediated Calmette-Guerin bacillus attachment to murine bladder mucosa. Requirement for the expression of an antitumor response. Journal of Clinical Investigation 1990; 85 (1): 62-67.
[10] Luo Y, Askeland EJ, Newton MR, et al. Immunotherapy of Urinary Bladder Carcinoma: BCG and Beyond, Cancer Treatment - Conventional and Innovative Approaches, Prof. Letícia Rangel (Ed.), ISBN: 978-953-51-1098-9, InTech, DOI: 10.5772/55283.
[11] Luo Y, Yamada H, Chen X, et al. Recombinant Mycobacterium bovis bacillus Calmette- Guérin (BCG) expressing mouse IL-18 augments Th1 immunity and macrophage cytotoxity. Clin Exp Immunol 2004; 137: 24-34.
[12] Askeland EJ, Newton MR, O’Donnell MA, Luo Y. Bladder cancer immunotherapy: BCG and beyond. Adv Urol 2012; article ID 181987.
[13] Saint F, Patard JJ, Maille P, et al. Prognostic value of a T helper 1 urinary cytokine response after intravesical bacillus Calmette-Guerin treatment for superficial bladder cancer. J Urol 2002; 167 (1): 364-7.
[14] Ludwig AT, Moore JM, Luo Y, et al. Tumor necrosis factor-related apoptosis-inducing ligand: A novel mechanism for bacillus Calmette-Guerin-induced antitumor activity. Cancer Res 2004; 64 (10): 3386-90.
[15] Lamm DL, Thor DE, Winters WD, et al. BCG immunotherapy of bladder cancer: inhibition of tumor recurrence and associated immune responses. Cancer 1981; 48 (1):82-88.
[16] Gil Redelman-Sidi,  Michael S. Glickman, and Bernard H. Bochner.  The mechanism of action of BCG therapy for bladder cancer—a current perspective.  Nature Reviews Urology 11, 153–162 (2014) doi:10.1038/nrurol.2014.15

Upper Tract Urothelial Cancer Chemotherapy: When? For Whom?

Urothelial cancer refers to cancer of the lining of the urinary tract and was previously known as transitional cell carcinoma.  Urothelial cancers can occur in the bladder or the upper tract of the urinary system which includes the lining of the kidney (otherwise known as the renal pelvis) and the ureter.  Biologically, upper tract urothelial cancers (UTUC) are similar to urothelial cancers of bladder.  However, they have several important distinctions:

• UTUC is rare, accounting for only 5% of all urothelial cancers. [1]
• UTUC are more difficult to visualize and treat endoscopically.
• UTUC are morphologically similar to bladder cancers but have different embryologic origins and genetic characteristics.  
• Like urothelial cancer of the bladder, stage (i.e. depth of invasion) is the most important predictor of prognosis.  However, unlike the bladder, grade is highly correlated to stage:
• 91% of high-grade tumors in the renal pelvis are invasive
• 64% of high-grade tumors in the ureter are invasive [2] 
• Prognosis is different for UTUC compared to urothelial cancer of the bladder.
• Upwards of 19% of patients with UTUC present with metastases.[3]
• However, in matched cohorts with less aggressive disease, progression and death occurred with equal frequency among patients with UTUC and bladder cancers.[4] 
• The role of neoadjuvant and adjuvant chemotherapy is not well-established in UTUC (see below).

The last important distinction is that chemotherapy is almost considered "standard-of-care" either before or after removal of the bladder in certain circumstances.  Adjuvant chemotherapy (AC or chemotherapy immediately after surgery without any evidence of metastases) has an established niche for patients with adverse pathological features at the time of radical cystectomy for urothelial cancer of the bladder.
Similarly, neoadjuvant chemotherapy (NAC or chemotherapy before surgery) has a growing role in the treatment of muscle-invasive urothelial cancer of the bladder (please see prior blog entry Neoadjuvant Chemotherapy for Bladder Cancer: What Does It All Mean?). 

The role of NAC prior to nephroureterectomy (NU or removal of the kidney and ureter) or AC following surgery is less well-understood.  The lack of data supporting the use of either NAC or AC is based mostly on the poor overall survival rate for patients with high-grade and high-stage UTUC regardless of treatment and the subsequent lack of overall response rate to chemotherapy.  

However, there are a number of reasons that chemotherapy surrounding surgery makes sense.  First, patients with locally advanced disease experience a 50% or greater risk of progression and less than a 2-year median survival duration.[5-8]  Therefore surgery alone is not curative and the addition of a systemic therapy may improve cancer outcomes.   

Here we review the limited data regarding AC and NAC in the treatment of UTUC.

Adjuvant Chemotherapy (AC) Following Nephroureterectomy (NU)

A recent, systematic review of AC following NU examined one prospective study and nine retrospective studies (no randomized trials were available) comparing 482 patients receiving AC after NU and 1300 patients undergoing NU alone.  This analysis demonstrated a 50% reduction in disease recurrence and 60% reduction in overall death in favor of those patients receiving AC.[9]  Importantly, this was a heterogeneous group of patients with pT2-4, node-negative and node-positive disease; and all patients receiving AC had adequate renal function.         

Neoadjuvant Chemotherapy (NAC) Prior to Nephroureterectomy (NU)

There are a number of specific reasons why NAC before NU makes sense:

• NAC works for the bladder.
• Survival is improved 5-10% with chemotherapy before surgical removal of the bladder.
• UTUC is biologically similar to urothelial cancer of the bladder.
• NAC effectively down-stages urothelial cancer (discussed below)
• Many patients who undergo NU are not eligible for chemotherapy after surgery because they are older and/or have baseline chronic kidney disease.
• The best chemotherapies for urothelial cancer are filtered by the kidneys.
• Reduced filtering ability of the kidneys can cause:
• decreased efficacy of chemotherapy
• increased toxicities including worsening renal function

In two retrospective series of patients receiving NAC compared to historical patients undergoing NU alone, there was a significant proportion of down staging in the NAC group with a 14% complete response rate.[10]  The follow-up study demonstrated a 90% cancer-specific survival rate at 5-years compared to 57% in the NU alone group.[11]  A meta-analysis of NAC data demonstrated a disease-specific survival improvement of nearly 60% for NAC in retrospective studies; and favorable pathologic downstaging rates and survival rates upwards of 90% in two, prospective phase 2 NAC trials.[9]

Summary

Chemotherapy should play a role in the treatment of UTUC, should be considered in the time period surrounding NU and should be discussed as an option with patients.

  

Adjuvant Chemotherapy (AC) can improve cancer-recurrence rates and overall survival.  AC should be considered following NU in patients with:

• adequate renal function
• high-risk pathological features (pT3 or pT4, N1 or positive surgical margins)

Neoadjuvant Chemotherapy (NAC) effectively downstages tumors and may improve survival in limited studies.  NAC should be considered prior to NU in patients:

• invasive high-grade UTUC
• high-volume, high-grade UTUC with clinical suspicion of invasive disease
• baseline renal dysfunction that may preclude chemotherapy following surgery

More data and well-designed prospective studies are needed to define the exact role and benefits of AC and NAC in UTUC.

This entry was written by Phillip M. Pierorazio, MD, Assistant Professor of Urology and Oncology at the Brady Urological Institute at Johns Hopkins.

[1] Melamed MR, Reuter VE: Pathology and staging of urothelial tumors of the kidney and ureter. Urol Clin North Am 1993; 20: 333

[2] McCarron JP Jr, Mills C, Vaughn ED Jr. Tumors of the renal pelvis and ureter: current concepts and management. Semin Urol 1983;1:75–81.

[3] Akaza H, Koiso K, Niijima T,et al: Clinical evaluation of urothelial tumors of the renal pelvis and ureter based on a new classification system. Cancer 1970; 26: 58

[4] Catto JW, Yates DR, Rehman AR,et al: Behavior of urothelial carcinoma with respect to anatomic location. J Urol 2007; 177: 1715-1720

[5] Brown GA, Busby JE, Wood CG, et al. Nephroureterectomy for treating upper urinary tract transitional cell carcinoma: time to change the treatment paradigm? BJU Int. 2006; 98: 1176-1180.

[6] Hall MC, Womack S, Sagalowsky AI, Carmody T, Erickstad MD, Roehrborn CG. Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. Urology. 1998; 52: 594-601.

[7] Lehmann J, Suttmann H, Kovac I, et al. Transitional cell carcinoma of the ureter: prognostic factors influencing progression and survival. Eur Urol. 2007; 51: 1281-1288.

[8] Ozsahin M, Zouhair A, Villa S, et al. Prognostic factors in urothelial renal pelvis and ureter tumours: a multicentre Rare Cancer Network study. Eur J Cancer. 1999; 35: 738-743.

[9] Jeffrey J. Leow, William Martin-Doyle, André P. Fay, Toni K. Choueiri, Steven L. Chang, Joaquim Bellmunt, A Systematic Review and Meta-analysis of Adjuvant and Neoadjuvant Chemotherapy for Upper Tract Urothelial Carcinoma, European Urology, Available online 16 March 2014, ISSN 0302-2838, http://dx.doi.org/10.1016/j.eururo.2014.03.003.

[10] S.F. Matin, V. Margulis, A. Kamat et al.  Incidence of downstaging and complete remission after neoadjuvant chemotherapy for high-risk upper tract transitional cell carcinoma.  Cancer, 116 (2010), pp. 3127–3134

[11] S. Porten, A. Siefker-Radtke, A. Kamat, C. Dinney, S. Matin.  Survival outcomes in patients undergoing neoadjuvant chemotherapy for upper tract urothelial cell carcinoma [abstract].  J Clin Oncol (Suppl 6) (2013), p. 311

Historical Contribution: 1919, HH Young, Mercurochrome

1919

Young HH, White EC, Swartz EO. A New Germicide for the Use in the Genitourinary Tract: "Mercurochrome-220". JAMA. 1919;73:20:1483-91.


At the turn of the 20th Century, one of the urologists biggest tasks was the treatment of urinary tract  and sexually transmitted infections; and their sequelae (including abscess, strictures, etc.).  Hugh Hampton Young and other urologists were in search of a sufficient urinary antiseptic, especially after World War I where venereal disease accounted for an estimated 7 million person-days lost and 10,000 discharges in the US army; and 416,891 hospital admissions among British troops accounting nearly 5% of the entire British force.[1]

mercurochrome-220

In 1919, HH Young reported results from Johns Hopkins in the Journal of the American Medical Association (JAMA), where mercurochrome-220 was used to sterilize the bladder.  Dr. Young wrote:

"The speed with which some old infections of the bladder and kidney pelvis have disappeared after its use is striking, and the absence of irritating and toxic qualities, together with the ability of the patient to retain a 1 per cent, solution for hours without discomfort, are sufficiently proved to establish the possibilities of the drug in these conditions." 

This work earned Young and colleagues a grant from the Interdepartmental Social Hygiene Board.

Young detailed the important properties needed for a new "urinary germicide":

1. ready penetration of the tissues in which the infection exists
2. lack of irritation of the drug to tissues
3. high germicidal activity
4. ready solubility in water and stability of the solution
5. freedom from precipitation in urine
6. sufficiently low toxicity to avoid systemic effects from the small amount of the drug that may be absorbed. 

Young and colleagues then demonstrated the ability of mercurochrome to kill a variety of bacteria including Balantidium Coli and Staphylococcus aureus; and compared its efficacy to other, known antimicrobial compounds.

In Dr. Young's typical meticulous fashion, the authors report the outcomes of 10 patients treated for cystitis, 14 treated topically for chancroid and comment on the outcomes of 51 patients treated for gonorrheal urethritis - all of which responded to treatment.

Read the entire manuscript using 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! 

[1] Mitchell, T.J, & Smith, G.M. (1931) Medical Services: Casualties and Medical Statistics of the Great War, History of the Great War, Based on Official Documents (London: HMSO).

Stone Disease: Minimizing Recurrence Through a Comprehensive Approach

The lifetime prevalence of kidney stones is estimated to be 10-15% in the United States.[1-2]  While kidney stones are more common in men, caucasians, and in warmer climates; the most common risk factor for a kidney stone is a prior stone.  After one episode, the risk of recurrence is 50% in the next 5-10 years.[3-5]

Brian Matlaga, MD, is the Director of Stone Disease at the Brady Urological Institute at Johns Hopkins,

"If you have one stone, you have a 50% lifetime recurrence risk, which is pretty high.  Patients with a stone have two problems: [the first is treating the stone, then] we need to figure out why the stone formed and how to lower those risk factors." 

For the majority of first-time stone formers, dietary and behavioral modifications are enough to reduce the risk of a second stone.  It is estimated that of patients with a first-time stone, 60% or greater are idiopathic stone formers (or stone formers without a particular cause).[6]  Therefore, making simple dietary modifications can help most people who form a stone, without subjecting them to a plethora of diagnostic tests.
These modifications include:

1. hydration
2. minimizing salt intake
3. normal calcium in the diet
4. low animal protein

     See the blog entry: Classic Manuscripts in Urology: Borghi, NEJM 2002 to learn more about dietary modifications in stone disease. 

However, other studies demonstrate that 50% of stone formers will have hypercalciuria or hyperuricosuria (elevated amounts of common components of kidney stones in the urine) and 20% of patients will have a systemic disease that contributes to stone formation.[7,8]  Therefore the decision to undergo a complete metabolic stone work-up should be based on an assessment and discussion of patient risk factors and evaluation of the obstructing kidney stone when it has been removed.

In general, a complete metabolic stone evaluation includes:

• a thorough history and physical
• medication review
• blood work (basic metabolic panel, calcium , parathyroid hormone, uric acid)
• stone analysis
• 24-hour urinalysis (a patient may be required to do one or several repeat tests)

Patients at high-risk of stone recurrence (and therefore those that should undergo complete metabolic evaluation at the time of their first stone) include:

• family history of stones
• those with intestinal disease (particularly when causing chronic diarrheal states)
• pathologic skeletal fractures/osteoporosis
• urinary tract infection
• gout
• stones composed of: 
• cystine
• uric acid
• struvite 
• all children (children have a much higher risk of underlying systemic disease or metabolic derangement leading to recurrent stones)[9-13]

At the Brady Urological Institute, Dr. Matlaga helps coordinate a Comprehensive Stone Clinic, in which a patient can be seen, evaluated and managed by a urologist, nephrologist and nutritionist.  This "team approach" often helps determine who needs a complete metabolic evaluation and how often do patients need to be seen.  Using 24-hour urine tests, Dr. Matlaga and colleagues can "back-calculate" a patient's metabolic risk factors to see whether "it's too much calcium, too much oxalate or not enough inhibitors of stone formation, and then we can say,

"Your recurrence risk is now 50 percent; let's try and get it down to about 10% (the general population's risk)."

This works particularly well in the pediatric population where "[urologists] are used to taking care of complex surgical problems, we have a pediatric nephrologist who is used to taking care of complex medical problems, and the nutritionist manages the dietary issues."

If you, a loved one, or a patient has stone disease and would like to be evaluated by Dr. Matlaga and colleagues at Johns Hopkins, please call 410 955 6100 (adults) or 410-955-6108 (children).

Part of this blog was extracted from "A Comprehensive Approach to Stone Disease" in Johns Hopkins Urology News for Physicians, Spring 2014.

[1] Johnson CM, Wilson DM, O’Fallon WM,et al: Renal stone epidemiology: a 25-year study in Rochester, Minnesota. Kidney Int 1979; 16: 624-631
[2] Sierakowski R, Finlayson B, Landes R,et al: The frequency of urolithiasis in hospital discharge diagnoses in the United States. Invest Urol 1978; 15: 438-441
[3] Uribarri J, Oh MS, Carroll HJ,et al: The first kidney stone. Ann Intern Med 1989; 111: 1006-1009
[4] Ljunghall S, Danielson BG: A prospective study of renal stone recurrences. Br J Urol 1984; 56: 122-124
[5] Ljunghall S, Backman U: Calcium and magnesium metabolism during long-term treatment with thiazides. Scand J Urol Nephrol 1981; 15: 257-262
[6] Hosking DH, Erickson SB: The stone clinic effect in patients with idiopathic calcium urolithiasis. J Urol 1983; 130: 1115-1118
[7] Pak CY: Should patients with single renal stone occurrence undergo diagnostic evaluation?. J Urol 1982; 127: 855-858
[8] Strauss AL, Coe FL: Factors that predict relapse of calcium nephrolithiasis during treatment: a prospective study. Am J Med 1982; 72: 17-24
[9] Bartosh SM: Medical management of pediatric stone disease. Urol Clin North Am 2004; 31: 575-587x–xi
[10] Coward RJ, Peters CJ: Epidemiology of paediatric renal stone disease in the UK. Arch Dis Child 2003; 88: 962-965
[11] Pietrow PK, Pope JC: Clinical outcome of pediatric stone disease. J Urol 2002; 167: 670-673
[12] Polito C, Manna ALa: Clinical presentation and natural course of idiopathic hypercalciuria in children. Pediatr Nephrol 2000; 15: 211-214
[13] Tekin A, Tekgul S: Ureteropelvic junction obstruction and coexisting renal calculi in children: role of metabolic abnormalities. Urology 2001; 57: 542-545discussion 545–6

Is a DMSA Scan Necessary for UTI in Children?

The classic teaching in the evaluation of children with febrile, culture-proven urinary tract infections (UTI) is to order a DMSA (dimercaptosuccinic acid) Scan to look for scarring of the kidney.  If the kidney is scarred, it indicates a serious infection that warrants treatment to prevent long-term damage to the kidney.

DMSA is injected intravenously, taken up by the kidney over the next two to four hours during which repeat imaging is taken.  It requires that child get an IV, stay in the hospital for a few hours, are often given general anesthesia, and has a small, but not negligible, radiation exposure.  Areas of decreased uptake on a DMSA Scan represent pyelonephritis or scarring. In a systematic review of 33 studies, approximately 60 percent of children with initial UTI had DMSA scans consistent with acute pyelonephritis in the acute phase of illness, but only 15 percent had renal scarring at follow-up [1].  Many children are given one or more repeat DMSA Scans as follow-up to monitor their infections.

Ming-Hsien Wang, MD, Assistant Professor of Pediatric Urology at the Brady Urological Institute at Johns Hopkins challenges the use of DMSA as a first-line study of children with UTI,

"A baseline ultrasound can tell you whether there's significant scar, and it can do so without exposing children to the side effects of a test that has minimal clinical benefit."

Dr. Wang and colleagues investigated 126 Johns Hopkins Children's Center patients (age 1 month to 5 years) and found that DMSA did not improve the diagnosis when ultrasound was used as the initial test to evaluate for renal scarring and infection.  This research will be presented at the upcoming American Urological Association (AUA) Annual Meeting in Orlando, Florida; and the European Society for Pediatric Urology (ESPU) Annual Meeting in Innsbruck, Austria.

Dr. Wang and colleagues see approximately 200 children each year with fever and culture-proven UTI.  "Our protocol for these children is baseline ultrasound, and we do not order a DMSA unless the ultrasound shows evidence of scar."  Dr. Wang is a co-principle investigator for an ongoing NIH study of UTI in children and is working to develop evidence-based clinical decision rules to improve diagnosis and avoid unnecessary tests in children.


Portions of this blog entry are extracted from "Rethinking the DMSA Scan" in the Johns Hopkins Urology Newsletter for Physicians.


[1] Shaikh N, Ewing AL, Bhatnagar S, Hoberman A.  Risk of renal scarring in children with a first urinary tract infection: a systematic review.  Pediatrics. 2010 Dec;126(6):1084-91. doi: 10.1542/peds.2010-0685. Epub 2010 Nov 8.

Historical Contribution: 1918, HH Young, High Frequency Current for Extraction of Calculi

Hugh Hampton Young

1918

Young HH.  The Employment of the High Frequency Current for the Extraction of Calculi Incarcerated in the Lower End of the Ureter.  Journal of Urology. 1918;2:35-38

At the turn of the century, the management options for ureteral stones were limited and most were treated with open surgery.  In this 1918 manuscript, HH Young describes an "exhaustive study," in which one distal stone was able to be freed from the distal ureter by manipulating it with a ureteral catheter, but most stones were removed by suprpubic cystotomy with use of "dilating instruments, forceps or scissors."

Known for his innovation, HH Young developed an instrument and "[t]he technique which is presented herewith consists in the employment of high frequency spark to incise the mucous membrane covering the incarcerated calculus, thus enlarging the ureteral orifice to a degree sufficient to permit its passage into the bladder."

Using a device similar to our modern day bugbee electrocautery, HH Young incised the distal ureter in three patients, described their clinical presentation, treatment and outcomes.  He describes one of the first endoscopic operations on the upper tract that involved more than a catheter, wire or simple dilation.  This opened the possibilities of the wide variety of endoscopic operations urologists perform on a daily basis.  In HH Young's words, "this operation is simple, can be carried out without anesthetia, and does not produce more than a slight hemorrhage."

Read the entire manuscript using 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! 

Classic Manuscript in Urology: Schoor et al, Testicular Biopsy & Infertility, 2002

Azoospermia is the condition in which there are no sperm in the semen (ejaculate fluid).
In the past, almost all men with azoospermia underwent a diagnostic testicular biopsy to distinguish obstructive (blockage) from non-obstructive (sperm production) causes; normal sperm production found in the tissue suggests obstructive causes. Previously, most men with non-obstructive azoospermia had no options to father biologically related children. However, with the emergence of assisted reproductive techniques (ART) such as in-vitro fertilization  (IVF) and intracytoplasmic sperm injection (ICSI), a pregnancy could be initiated using very low numbers of sperm.

For men with non-obstructive azoospermia, we typically offer microsurgical-dissection testicular sperm extraction (microTESE), which gives the best chance of finding sperm within the testis that can be used with ART. In contrast, men with obstructive azoospermia can seek reconstruction to relieve the obstruction and attempt natural conception, or they can use surgically retrieved sperm with similar assisted reproductive techniques. To plan for the most appropriate treatment, it is highly valuable to be able to characterize the cause of azoospermia without a diagnostic biopsy.

Schoor RA, Elhanbly S, Niederberger CS, Ross LS.  The Role of Testicular Biopsy in the Modern Management of Male Infertility.  J Urol 2002; 167(1):197-200.

PubMed.
Journal of Urology.

In this study, Dr. Schoor and colleagues retrospectively reviewed the records of 153 azoospermic men.  The authors recognized that classic texts of infertility described men with obstructive azoospermia having “normal” endocrine profiles, testicular volumes and long axis length, while men with nonobstructive azoospermia will have an abnormality in 1 or more of these parameters.  However, the importance of these abnormalities had not been defined in the modern era of infertility.

They investigated a number of parameters including follicle stimulating hormone (FSH), leutenizing hormone (LH), prolactin, and testicular size, were analyzed as predictors for obstructive vs. non-obstructive azoospermia.  FSH and testicular long axis were found to be the best individual diagnostic predictors:

• 96% of men with obstructive azoospermia had:
• FSH <7.6 mIU/mL
• Testicular Long Axis > 4.6cm
• 89% of men with nonobstructive azoospermia had: 
• FSH >7.6 mIU/mL
• Testicular Long Axis < 4.6cm 

Take Home: Not only did this study define clinical parameters to distinguish obstructive and nonobstructive azoospermia, but is also implies that testicular biopsy is generally unnecessary in the initial evaluation of azoospermia.  Avoiding testicular biopsy reduced the cost and risk associated with evaluation of azoospermia for many men.

For the majority of patients with findings suggesting non-obstructive azoospermia, we now proceed directly to microTESE. Diagnostic biopsy is still performed for a small subset of patients whose findings suggest obstructive azoospermia, as a significant fraction of them may still have a sperm production problem within the testis. For more information, see: http://malefertility.jhu.edu/fertility_evaluation.php

This blog entry was written by Pravin Rao, MD, Director of Reproductive Medicine and Surgery at the Brady Urological Institute at Johns Hopkins.

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

Renal Cysts: Cause for Concern?

A cyst is a thin-walled, cell-lined collection of fluid.  They can occur in nearly every tissue type and many places in the body including the brain, lung, nerve tissue and skin. Renal cysts are incredibly common, affecting up to 50% of 50-year olds in the United States and increasing in prevalence with age.[1]  Renal cysts represent upwards of 70% of the asymptomatic, benign renal masses discovered incidentally.[2]  Risk factors for cyst formation include:

• increasing age
• male gender
• hypertension
• chronic kidney disease (renal insufficiency) [3]

The main concern of patients and physicians is that renal cysts are cancerous or will develop into a cancer.  In an excellent study of the natural history of renal cysts, with increasing time cysts are demonstrated to grow slowly (average 1.9mm/year), increase in number and only rarely develop into cancers.[4]  Predicting which cysts are potentially malignant is a tough task.

The Bosniak Classification System

Bosniak I

In 1986, Dr. Bosniak, radiologist at New York University in New York City, defined the characteristics of simple and complex renal cysts to reduce unnecessary surgery on benign lesions.  Thus the Bosniak System was created, categorizing each renal cyst into four (and then five in 1993) categories that predict malignant behavior.[5] The single-most important imaging characteristic that predicts malignancy is enhancement (brightening) on contrast-based CT imaging.

Bosniak II: hyperdense cyst (right)

Bosniak I

Risk of Malignancy: 0-1.7%

Non-enhancing
Benign simple cyst
Water density
Hairline thin cyst wall
No septa, calcifications, or solid components

Bosniak II

Bosniak IIF

Risk of Malignancy: 0-18.5%

Non-enhancing

Benign cyst
May have a few thin septa
May have fine calcification in wall or septa
May be hyperdense (uniformly high attenutation lesions) if <3cm
Perceived enhancement may be present

Bosniak IIF

Bosniak III

Bosniak IV

Risk of Malignancy: 5-18.5%

Non-enhancing

May have a few thin septa
May have minimal wall thickening in wall or septa
May have thin or nodular calcifications
Perceived enhancement may be present
May be hyperdense (uniformly high attenutation lesions) if ≥3cm
Require follow-up studies to prove benignity

Bosniak III

Risk of Malignancy: 33-82%

Indeterminate cystic mass
Thickened and/or irregular walls/septa
Measurable enhancement
Surgical lesion

Bosniak IV

Risk of Malignancy: 92-93%

Clearly malignant cystic masses

Enhancing soft tissue components

Surgical lesion

Management of Renal Cysts

Most Bosniak I and II cysts do not require follow-up or treatment due to the low rate of documented progression to malignancy.  There is an association between renal cysts, chronic kidney disease and renal cell carcinoma; therefore it is reasonable to follow patients with Bosniak I and II lesions with serial ultrasounds and labs for renal function (creatinine, urinalysis) on an annual or biannual basis.  

Bosniak IIF cysts, however, should have repeat imaging on a regular basis to ensure they do not progress to malignant disease.  Progression of a cyst is defined by an increase in the Bosniak Classification Score.  In studies of Bosniak IIF cysts, 13-15% progress to Bosniak III lesions while under observation and 50-100% of the resected cysts were renal cancers.[6-8]

Bosniak III and IV cysts warrant consideration of surgical treatment.  Treatments may include partial nephrectomy (removal of the cyst only), radical nephrectomy (removal of the entire kidney) or ablative therapies.  While it is generally believed that most complex renal cysts are low-grade renal cell carcinomas, there is a significant proportion that are high-grade tumors.  

Summary

• Renal cysts are the most common benign lesion in the kidney.  
• The risk of malignancy increases with increasing complexity of the cyst.
• Bosniak I, II and IIF cysts have low-risk of malignancy and should be observed.
• Bosniak III and IV cysts have a higher risk of malignancy and therefore warrant surgical treatment.

  

This blog entry was written by Debasish Sundi, MD, Senior Assistant Resident at the Brady Urological Institute at Johns Hopkins University.  Dr. Sundi is pursuing a career in urological oncology.








[1] Torres VE, Grantham JJ. Cystic diseases of the kidney. In: Brenner BM, ed. Brenner & Rector’s The Kidney. Vol. 2. 8th ed. Philadelphia: Saunders Elsevier; 2008: 1451–1453.
[2] Terada N, Ichioka K: The natural history of simple renal cysts. J Urol 2002; 167: 21-2
[3] Terada N, Arai Y: Risk factors for renal cysts. BJU Int 2004; 93: 1300-1302
[4] Terada N, Arai Y: The 10-year natural history of simple renal cysts. Urology 2008; 71: 7-11discussion 11–12
[5] Israel GM, Bosniak MA: An update of the Bosniak renal cyst classification system. Urology 2005; 66: 484-488
[6] O'Malley RL, Godoy G, Hecht EM, Stifelman MD, Taneja SS.Bosniak category IIF designation and surgery for complex renal cysts.  J Urol. 2009 Sep;182(3):1091-5. doi: 0.1016/j.juro.2009.05.046. Epub 2009 Jul 18.
[7] Smith AD, Remer EM, Cox KL, Lieber ML, Allen BC, Shah SN, Herts BR.Bosniak category IIF and III cystic renal lesions: outcomes and associations.  Radiology. 2012 Jan;262(1):152-60. doi: 10.1148/radiol.11110888. Epub 2011 Nov 21.
[8] El-Mokadem I, Budak M, Pillai S, Lang S, Doull R, Goodman C, Nabi G.  Progression, interobserver agreement, and malignancy rate in complex renal cysts ( ≥ Bosniak category IIF).  Urol Oncol. 2014 Jan;32(1):24.e21-7. doi: 10.1016/j.urolonc.2012.08.018. Epub 2013 Feb 6.

Adrenal Tumors: Minimally-Invasive Considerations

The paired adrenal glands sit above the kidneys bilaterally.

Adrenal tumors are common entities, with incidental adrenal masses found in 3.4-7% of patients on imaging studies[1].  After appropriate imaging and endocrine workup, the majority of functional adrenal masses, masses over 4 cm, and masses with concerning radiographic features are candidates for surgical resection. Once the decision is made to undergo surgery, an adrenal tumors can be removed via a traditional “open” approach or through a minimally-invasive approach -- either laparoscopic or robotic.

Many patients with adrenal masses wonder if there are minimally-invasive options for adrenal surgery and if minimally-invasive surgery is a good idea?  

The following blog reviews the data and outcomes for minimally-invasive adrenal surgery.

Laparoscopic adrenalectomy was initially described by Gagner et al in 1992.[2]  Since its introduction, it has become the gold standard for the surgical treatment of benign adrenal neoplasms and is increasingly used for malignant tumors [3-6].  Multiple study have demonstrated decreased pain, lower blood loss, faster convalescence, less ileus, and shorter hospital stays.[4, 7-14]  Regardless of underlying pathology, the best outcomes for adrenal resection have been associated with high volume surgeons.[15]  While the majority of studies have focused on outcomes in adults, emerging literature also supports safety and feasibility of a laparoscopic approach in children also. [16, 17]

Laparoscopy for Specific Adrenal Tumors

Primary Hyperaldosteronoma

In patients with symptomatic primary hyperaldosteronism, laparoscopic adrenalectomy was associated with few postoperative complications, shorter hospital stay and equivalent improvement of hypertension and hypokalemia compared to patients treated with an open approach. [7, 18]

Pheochromocytoma

Similarly, the resection of pheochromocytomas, though to be more difficult both to catecholamine release during manipulation as well as increased vascularity, is aided by a laparoscopic approach. Compared to open surgery, laparoscopy was associated with lower blood loss [19-22] and shorter length of stay. [11, 19, 20, 23-25] Additionally, episodes of intraoperative hypertension or hypotension were either less [20, 25] or similar during laparoscopic procedures.

Adrenocortical Carcinoma (ACC)

The use of laparoscopy for adrenocortical carcinoma (ACC) is debated.  While no prospective, comparative series have been reported, retrospective series have reported increased recurrence, peritoneal carcinomatosis, positive margins and local recurrence rates for laparoscopic cases compared to open. [26-30] Conversely, in a matched-comparison of laparoscopic and open adrenalectomy for ACC less than 10 cm, no difference in cancer-specific survival, tumor capsule violation of carcinomatosis was noted. [31] Taken together, while a laparoscopic approach may be feasible for select cases of ACC without adjacent organ invasion, an open surgical approach remains the gold standard.

Considering Laparoscopic or Open Adrenal Surgery

Laparoscopic resection of “large” adrenal masses is not well studied, due to both inconsistency of what size constitutes a large mass and a dearth of studies addressing this question. It is well established, however, that size is correlated with the risk of ACC. Using a size cutoff of 4 cm, the sensitivity for ACC is 93%, though the specificity is only 42%.[32] As previously described, tumors with preoperative concern for ACC are most safely resected by an open approach. For benign tumors, however, most series describe similar outcomes across size ranges, with similar morbidity [24, 33, 34]. However, resection of adrenal masses greater than 8 cm are associated with longer operative, increased blood loss and longer hospital stay.[34] Moreover, larger tumors may be associated with a higher risk of open conversion.[35]  For larger tumors found to be locally invasive or otherwise concerning for ACC during laparoscopy, most authors recommend an open conversion [36, 37]

Robotic Adrenalectomy

Robotic surgery is increasingly utilized as an alternative to laparoscopic surgery. Multiple feasibility studies have demonstrated the safety and feasibility of robotic adrenalectomy. [38-44] The perceived advantage of robotics over traditional laparoscopy includes stereoscopic vision, improved magnification, and greater range of motion.[45]  A recent systematic review and meta-analysis, including 1 randomized clinical trial and 8 observational studies demonstrated lower blood loss and hospital stay in robotic cases, and similar operative times, conversion rates, and complication rates.

This blog was written by Mark W. Ball, MD, urology resident at the Brady Urological Institute at Johns Hopkins.  It is extracted from a publication written with Mohamad E. Allaf, MD, Associate Professor and Director of Robotic Surgery at the Brady, for the ICUD-EAU Consultation on Minimally Invasive Surgery in Urology, 2014 Guidelines.











[1] Nieman LK. Approach to the patient with an adrenal incidentaloma. Journal of Clinical Endocrinology & Metabolism. 2010;95(9):4106-13.
[2] Gagner M, Lacroix A, Bolte E. Laparoscopic adrenalectomy in Cushing’s syndrome and pheochromocytoma. N Engl j Med. 1992;327(14):1033.
[3] Nehs MA, Ruan DT. Minimally invasive adrenal surgery: an update. Current opinion in endocrinology, diabetes, and obesity. 2011;18(3):193-7.
[4] Wang HS, Li CC, Chou YH, Wang CJ, Wu WJ, Huang CH. Comparison of laparoscopic adrenalectomy with open surgery for adrenal tumors. The Kaohsiung journal of medical sciences. 2009;25(8):438-44.
[5] Ariyan C, Strong VE. The current status of laparoscopic adrenalectomy. Advances in surgery. 2007;41:133-53.
[6] Hall DW, Raman JD. Has laparoscopy impacted the indications for adrenalectomy? Curr Urol Rep. 2010;11(2):132-7.
[7] Shen WT, Lim RC, Siperstein AE, Clark OH, Schecter WP, Hunt TK, et al. Laparoscopic vs open adrenalectomy for the treatment of primary hyperaldosteronism. Archives of surgery (Chicago, Ill : 1960). 1999;134(6):628-31; discussion 31-2.
[8] Hallfeldt KK, Mussack T, Trupka A, Hohenbleicher F, Schmidbauer S. Laparoscopic lateral adrenalectomy versus open posterior adrenalectomy for the treatment of benign adrenal tumors. Surg Endosc. 2003;17(2):264-7.
[9] Kim HH, Kim GH, Sung GT. Laparoscopic adrenalectomy for pheochromocytoma: comparison with conventional open adrenalectomy. J Endourol. 2004;18(3):251-5.
[10] Ramachandran MS, Reid JA, Dolan SJ, Farling PA, Russell CF. Laparoscopic adrenalectomy versus open adrenalectomy: results from a retrospective comparative study. The Ulster medical journal. 2006;75(2):126-8.
[11] Humphrey R, Gray D, Pautler S, Davies W. Laparoscopic compared with open adrenalectomy for resection of pheochromocytoma: a review of 47 cases. Canadian journal of surgery Journal canadien de chirurgie. 2008;51(4):276-80.
[12] Kirshtein B, Yelle JD, Moloo H, Poulin E. Laparoscopic adrenalectomy for adrenal malignancy: a preliminary report comparing the short-term outcomes with open adrenalectomy. Journal of laparoendoscopic & advanced surgical techniques Part A. 2008;18(1):42-6.
[13] Lubikowski J, Uminski M, Andrysiak-Mamos E, Pynka S, Fuchs H, Wojcicki M, et al. From open to laparoscopic adrenalectomy: thirty years' experience of one medical centre. Endokrynologia Polska. 2010;61(1):94-101.
[14] Mir MC, Klink JC, Guillotreau J, Long JA, Miocinovic R, Kaouk JH, et al. Comparative outcomes of laparoscopic and open adrenalectomy for adrenocortical carcinoma: single, high-volume center experience. Ann Surg Oncol. 2013;20(5):1456-61.
[15] Park HS, Roman SA, Sosa JA. Outcomes from 3144 adrenalectomies in the United States: which matters more, surgeon volume or specialty? Archives of surgery. 2009;144(11):1060-7.
[16] Lopes RI, Denes FT, Bissoli J, Mendonca BB, Srougi M. Laparoscopic adrenalectomy in children. Journal of pediatric urology. 2012;8(4):379-85.
[17] Yankovic F, Undre S, Mushtaq I. Surgical technique: Retroperitoneoscopic approach for adrenal masses in children. Journal of pediatric urology. 2013.
[18] Duncan JL, 3rd, Fuhrman GM, Bolton JS, Bowen JD, Richardson WS. Laparoscopic adrenalectomy is superior to an open approach to treat primary hyperaldosteronism. The American surgeon. 2000;66(10):932-5; discussion 5-6.
[19] Tiberio GA, Baiocchi GL, Arru L, Agabiti Rosei C, De Ponti S, Matheis A, et al. Prospective randomized comparison of laparoscopic versus open adrenalectomy for sporadic pheochromocytoma. Surg Endosc. 2008;22(6):1435-9.
[20] Lang B, Fu B, OuYang JZ, Wang BJ, Zhang GX, Xu K, et al. Retrospective comparison of retroperitoneoscopic versus open adrenalectomy for pheochromocytoma. J Urol. 2008;179(1):57-60; discussion
[21] Ichikawa T, Mikami K, Komiya A, Suzuki H, Shimizu A, Akakura K, et al. Laparoscopic adrenalectomy for functioning adrenal tumors: clinical experiences with 38 cases and comparison with open adrenalectomy. Biomed Pharmacother. 2000;54 Suppl 1:178s-82s.
[22] Hemal AK, Kumar R, Misra MC, Gupta NP, Chumber S. Retroperitoneoscopic adrenalectomy for pheochromocytoma: comparison with open surgery. Jsls. 2003;7(4):341-5.
[23] Davies MJ, McGlade DP, Banting SW. A comparison of open and laparoscopic approaches to adrenalectomy in patients with phaeochromocytoma. Anaesthesia and intensive care. 2004;32(2):224-9.
[24] Hemal AK, Singh A, Gupta NP. Whether adrenal mass more than 5 cm can pose problem in laparoscopic adrenalectomy? An evaluation of 22 patients. World J Urol. 2008;26(5):505-8.
[25] Edwin B, Kazaryan AM, Mala T, Pfeffer PF, Tønnessen TI, Fosse E. Laparoscopic and open surgery for pheochromocytoma. BMC surgery. 2001;1(1):2.
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