Penile Cancer: Carcinoma in situ

Carcinoma in situ (CIS) of the penis refers to a squamous cell cancer limited to the most superficial layers of the penile skin. This cancer is also known as Erythroplasia of Queyrat if on the glans (head) of the penis or Bowen Disease if on the shaft of the penis and was covered in a previous blog. While CIS is technically a non-invasive cancer and believed to have low metastatic potential, it has features of high-grade (potentially aggressive) cancer that warrants careful management.

History

CIS was inititally described by Queyrat in 1911 as a red, velvety, well-marginated lesion of the glans penis or prepuce (of uncircumcised men). Bowen described a similar lesion of the penile skin in 1912. The original description of Bowen disease related to subsequent internal malignancy, however subsequent studies have demonstrated that this relationship was nothing more than coincidence.[1]

 

Presentation and Prognosis

CIS has a similar clinical presentation whether on the glans penis or shaft. As described above, CIS can appear as a red, velvety, well-marginated lesion on the penis. Alternatively the lesion can be scaly, crusted or ulcerated – similar in appearance to eczema or psoriasis. Development of metastasis for CIS is incredibly rare – however 10-33% of CIS on the glans and 5% of CIS on the shaft can progress to more invasive, dangerous disease.[2,3]

 

Management

As CIS rarely metastasizes, treatment is focused on (1) confirmation of a non-invasive lesion, (2) resection of lesions with an adequate microscopic margin and (3) penis-sparing techniques if the lesion is on the glans. Confirmation of non-invasive malignancy may require multiple biopsies or complete excision of the area of concern. A 5mm margin if often adequate for lesions on the shaft, while circumcision will cure most cases of CIS on the prepuce. Lymph node dissection is only performed in cases suspicious for invasion or enlarged lymph nodes.

Penis-sparing treatments

Lesions of the glans penis can be difficult to treat surgically without distorting normal penile anatomy or sensation. A number of topical treatments including 5-fluorouracil, 5% imiquimod, laser ablation (YAG or KTP lasers) and radiation therapy have all been used with success.[4-10] For patients with large tumors or lesions refractory to topical treatment, local skin excision can be performed with skin grafting as needed.

Penile lesion (CIS) completely excised (left) and with a skin graft using non-hair bearing skin of the groin (right).

For patients with CIS involving the glans, partial or complete excision with partial or complete resurfacing can be performed.[11,12]

A. CIS on the glans penis, B. Glanular skin removed, C. Skin graft placed on the glans, D. Final, cosmetically pleasant result.  From Palminteri etal. [12]

These penile surgeries often involve a multidisciplinary approach including a urologic oncologist, plastic (reconstructive) surgeon and excellent pathologists to ensure eradication of the disease.  Penile cancer is a rare disease and balancing the risks of cancer with penile reconstruction and function is best done at a center with experience treating this disease.

1. Anderson SL, Nielson A, and Reymann F: Relationship between Bowen disease and internal malignant tumors. Arch Dermatol 1973; 108: pp. 367.
2. Buechner SA: Common skin disorders of the penis. BJU Int 2002; 90: pp. 498-506.
3. Bleeker MCG, Heideman DAM, Snijders PJF, et al: Penile cancer: epidemiology, pathogenesis, and prevention. World J Urol 2009; 27: pp. 141-150.
4. Harrington KJ, Price PM, Fry L, Witherow RO. Erythroplasia of Queyrat treated with isotretinoin. Lancet. Oct 16 1993;342(8877):994-5. 
5. Micali G, Nasca MR, De Pasquale R. Erythroplasia of Queyrat treated with imiquimod 5% cream. J Am Acad Dermatol. Nov 2006;55(5):901-3. 
6. Conejo-Mir JS, Munoz MA, Linares M, Rodriguez L, Serrano A. Carbon dioxide laser treatment of erythroplasia of Queyrat: a revisited treatment to this condition. J Eur Acad Dermatol Venereol. Sep 2005;19(5):643-4. 
7. Arlette JP. Treatment of Bowen's disease and erythroplasia of Queyrat. Br J Dermatol. Nov 2003;149 Suppl 66:43-9. 
8. Orengo I, Rosen T, Guill CK. Treatment of squamous cell carcinoma in situ of the penis with 5% imiquimod cream: a case report. J Am Acad Dermatol. Oct 2002;47(4 Suppl):S225-8. 
9. Micali G, Lacarrubba F, Dinotta F, Massimino D, Nasca MR. Treating skin cancer with topical cream. Expert Opin Pharmacother. Jun 2010;11(9):1515-27. 
10. Grabstald H, and Kelley CD: Radiation therapy of penile cancer. Urology 1980; 15: pp. 575-576.
11. Pompeo AC, Zequi Sde C, Pompeo AS. Penile cancer: organ-sparing surgery. Curr Opin Urol. 2015 Mar;25(2):121-8. doi: 10.1097/MOU.0000000000000149.
12. Palminteri E, Berdondini E, Lazzeri M, Mirri F, Barbagli G. Resurfacing and reconstruction of the glans penis. Eur Urol. 2007 Sep;52(3):893-8. Epub 2007 Jan 22.

Historical Contribution: 1964, Schirmer & Walton, Hypothermia and Kidney Function

1964
Schirmer HKA, Walton K. The Effet of Hypothermia upon Respiration and Anerobic Glycolysis of Dog Kidney. Invest Urol. 1964. 1;6:604-9.

 
The first deliberate partial nephrectomy for the excision of a tumor was credited to Vincenz Czerny in 1887. Numerous studies over the next decades defined the surgical anatomy and feasibility of partial nephrectomy for a variety of localized kidney processes (including cancer). Lack of early diagnostics and technical challenges prevented the operation from being widely utilized in the early 1900's. While these early researchers investigated repair mechanisms of the kidney, advances in the understanding of segmental blood supply and renal hypothermia to prevent ischemic damage were not introduced until the 1950's and 1960's.[1] 

Horst Schirmer, MD

In 1964, Horst Schirmer and Kenneth Walton of the Brady Urological Institute investigated the effects of hypothermia on the kidney. Prior work demonstrated that, with local cooling, renal function would only be temporarily depressed and irreversible damage (under normothermic conditions) could be limited. They investigated ox'ygen consumption and glycolysis in the kidneys of dogs. They found:

• With decreasing temperature, the reduction in glycolysis associated with ischemia was tempered (33% at 27C, 17% at 17C and near zero at 7C).
• After achieving hypothermia of 7C, normal function returned after 1 hour.
• Interruption of blood flow for 4 hours resulted in:
  • 75% reduction in function in the normothermic kidney
  • Unchanged function in the cooled (7C) kidney
• By examining both tissue from the cortex and medulla of the kidney, the cortex is nearly 7x more active than the medulla – providing evidence that cortical cooling is sufficient to provide effective hypothermia.

 
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! 

[1] Herr HW.A history of partial nephrectomy for renal tumors.J Urol. 2005 Mar;173(3):705-8.

Getting closer to an “quantitative” diagnosis of prostate cancer

Histomorphometry is the study of the microscopic organization and structure of tissue in a quantitative manner under the microscope. This process was briefly described in a prior blog, and often involves computer-assisted technology to provide objective measures cellular architecture to aide in diagnosis – a process that is often based on subjective classification of microscopic features.

Most cancers, prostate cancer included, are diagnosed by a pathologist – who examines tissue under a microscope to determine the presence and aggressiveness of a cancer. The future of digital pathology will likely use prostate cancer quantitative histomorphometry using computer-assisted scanned image features and may serve as a new and innovative predictive tool to improve determination of aggressive phenotypes of cancer. In prior work, Dr. Robert Veltri, PhD, of the Brady Urological Institute, demonstrated that a special "spectrophotometer" microscope was accurate and capable of predicting stage, recurrence and progression of prostate cancer when examining portions of prostate cancer slides.[1] 

An original, high-powered image of prostate cancer (a) is segmented into areas of individual nuclei (b), classified into individual sets (c) and segmented by the computer-alogorithm.  From Ali etal [2].

With collaborator, Anant Madabhushi, PhD, and his team at Case Western Reserve University, Dr. Veltri is working to develop new techniques to examine the entire slide image in a high-throughput process. These novel tools could form the basis of future software tools to conduct, in cooperation with the pathologist, automated, rapid and reproducible identification and quantification of tissue histology morphologic and molecular events – enabling machine-based predictions of tumor aggressiveness and outcomes such as recurrence, metastasis and survival.

 
In a recent experiment, Drs. Veltri and Madabhushi examined 80 prostate cancers looking at a variety of cellular features. Through a complex computer algorithm termed adaptive active contour scheme (AdACM), they were able to distinguish features of nuclei, gland architecture, and texture and then identify the best features to discriminate Gleason grade patterns. Using these features, AdACM was able to distinguish Gleason score patterns with an accuracy of 86%.[2]

Different computer-generated features to model architecture of prostate cancer in a core of tissue from a prostate biopsy. From Ali etal [2].

This is just some of the exciting research ongoing at the Brady Urological Institute at Johns Hopkins that will improve the way we diagnose and treat prostate cancer.

 
[1] Ali S, Veltri R, Epstein JI, Christudass C, Madabhushi A.Adaptive energy selective active contour with shape priors for nuclear segmentation and gleason grading of prostate cancer.Med Image Comput Comput Assist Interv. 2011;14(Pt 1):661-9.

[2] Ali S, Veltri R, Epstein JI, Christhunesa Christudass CS, Madabhushi A. Selective Invocation of Shape Priors for Deformable Segmentation and Morphologic Classification of Prostate Cancer Tissue Microarrays. CMIG, December, 2014. dx.doi.org/10.1016/j.compmedimag.2014.11.001

A new trial down the “Hedgehog” pathway for men with high-risk prostate cancer

Nearly ten years ago, Johns Hopkins researchers David Berman and Philip Beachy discovered the hedgehog pathway in mice with prostate cancer.[1] This molecular pathway is turned on in the embryologic development of lung, pancreas, prostate, brain and other organs during normal development. In prostate cancer, this pathway is abnormally turned "on" as prostate cancer grows and spreads. Patrick C. Walsh, MD, describes the pathway, "It's like soil and seeds. The soil is the stroma of the prostate — the connective tissue that serves as its framework — and the cancer cells are the seeds." And the Hedgehog protein is compost, sunlight and water — everything the seeds need to grow. "If these cells spread but try to grow in poor soil, they can't survive. But if they can manufacture the Hedgehog signal, they can make the soil that they need — they can pack their lunch and take it with them."

In their original study, published in Nature,[1] Drs. Berman and Beachy demonstrated that giving drugs that could block the Hedgehog pathway, could shrink human prostate cancer tumors in animals. That model is now ready for prime-time testing in humans. Dr. Ashley Ross, MD, PhD, Assistant Professor in Urology, Oncology, and Pathology, is partnering with Emmanuel Antonarakis, MD, medical oncologist, are opening a randomized, placebo-controlled clinical trial of a highly selective Hedgehog pathway inhibitor, called LDE225 and made by Novartis. Dr. Ross explains the hypothesis of the trial:

Ashley E. Ross, MD, PhD

"By looking at gene expression patterns, we and others have found that the Hedgehog pathway appears up-regulated in men with disease that metastasizes after local therapy. Also, in men with advanced prostate cancer, Itraconazole, which inhibits the Hedgehog pathway, appears to slow the disease by a mechanism independent of the androgen receptor. Itraconazole is an antifungal drug. Recently, new, Hedgehog pathway specific drugs with much more favorable toxicity profiles are available."

Men with high-risk prostate cancer are badly in need of a drug that could potentially prevent cancer growth and metastasis. In these patients, there is always the possibility that, even after surgery or radiation therapy, some cancer cells have already escaped the prostate, are hiding somewhere in the body, and will repopulate. Use of a systemic Hedgehog inhibitor may help wipe out these "micrometastatic" cells. Dr. Ross explains,

"We need to start thinking of high-risk disease as a different type of cancer, a systemic disease, and we have to start treating them like we treat other cancers, with a systemic approach in addition to surgery and/or radiation."

The trial is open to radical prostatectomy patients at Johns Hopkins with high-risk prostate cancer: men with a Gleason score of 8 to 10, a PSA of 20 or greater, or clinical stage T3 disease. The men who receive the drug will take the pill for four weeks before radical prostatectomy. All of the men will undergo a repeat biopsy and will have a molecular profile done on their cancer cells before surgery, and then will have the radical prostatectomy specimens examined afterward. Dr. Ross explains, "It's a pharmacodynamic trial, to see if this new drug actually gets into the prostate and inhibits the Hedgehog pathway as we expect it should. Of course, men will be followed closely following prostatectomy and we will also monitor whether superior cancer control results are achieved in those who received LDE225."

 

 
This blog and quotations are extracted from:
Target: Hedgehog Pathway, New Trial Opens for Men with High-Risk Prostate Cancer in Discovery, Volume XI, Winter 2015.

Hedgehog Blockers:Can They Stop Advanced Prostate Cancer? Scientists One Step Closer To Finding Out in Prostate Cancer Discovery, Volume II, Autumn 2005.

 
[1] Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A, Isaacs JT, Berman DM, Beachy PA. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature. 2004 Oct 7;431(7009):707-12. Epub 2004 Sep 12.

 

Historical Contribution: 1963, King et al, The Bladder Neck in Childhood

1963
King LR, Mellins HZ, Scott WW. Radiographic Evaluation of the Bladder Neck in Childhood. Trans of Amer Assoc of Genito-urinary Sugeons. 1963. 55:7-12.


 
In the Transcripts of the American Association of Genitourinary Surgeons, Lowell King, Harry Mellins and William Wallace Scott detail the anatomy of voiding in 121 pediatric patients. Children ranged from one day to 17 years old. They found a number of interesting observations they describe in the manuscript:

• Approximately 40% of normal girls will have a narrowed proximal urethra – this has no bearing on incidence of vesicoureteral reflux or clinical outcomes and can therefore be considered normal.
• Of boys with outlet obstruction, about half of the patients had meatal stenosis and the other half had posterior urethral valves (PUV).
• Of boys with recurrent urinary tract infections (UTI), approximately half had a congenital abnormality of the outlet – either PUV or an ureterocele. The rest had normal anatomy but functional deficits that led to residual urine and UTI.

In conclusion, King, Mellins and Scott found that there was a characteristic appearance of the bladder neck in pediatric patients with obstruction. However, "A narrow bladder neck relative to the proximal urethra as seen in the AP view is a common finding, and is certainly not a specific sign of bladder neck contracture."

 
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! 

The Brady Centennial: “Diamond Jim” Brady

James "Diamond Jim" Buchanan Brady

One hundred years ago, the Brady Urological Institute opened its doors to patients. The funding for the institute came to Hugh Hampton Young as a gift from James "Diamond Jim" Buchanan Brady. Brady was a wealthy railroad tycoon who sought treatment for prostatic disease at Johns Hopkins.  His story is told in this blog.

Diamond Jim was born in New York City in 1856 to a modest household. Through a number of employment opportunities he worked himself into the railroad industry, starting first with the New York Central Railroad and gaining prominence with Manning, Maxwell and Moore (a railroad supply company), the Pressed Steel Car Company, and Vice President of the Standard Steel Company.

 
Diamond Jim had a passion for fine clothes, expensive jewelry, women and food. A NY Times article in 2008 detailed the enormity of a typical Brady diet (see picture). He is rumored to have been the first owner of an automobile in New York City (1895). His long time girlfriend was Lillian Russell, a well-known actress and singer of the times. He garnished himself and Lillian in an extensive jewelry collection – conservatively estimated to be worth $2 million at that time!

Diamond Jim also suffered from obstructive uropathy. As Diamond Jim was obese, diabetic and in poor general health, a number of hospitals in Boston, New York, and Philadelphia turned him away from open prostate surgery (the treatment of choice at the time for benign prostatic hyperplasia, BPH). Hugh Hampton Young had developed his "punch" procedure, a transurethral surgery for BPH and precursor to the modern TURP (transurethral resection of the prostate), and successfully treated Diamond Jim. Diamond Jim was so grateful he contributed $200k "for a building in which the laboratory and experimental side should play a very important role, and in which clinical material, public and private, outpatient and inpatient could be used for study, research and advancement in the field of urology."

The legacy of Diamond Jim lives on in the Brady Urological Institute which turns 100 years old this month.









Read more about Diamond Jim at:

The Brady Centennial Website:
http://urology.jhu.edu/centennial/

Diamond Jim Brady, The New York Times.

Diamond Jim Brady, Wikipedia.

James "Diamond Jim" Brady: Honored Gourmandizer

"Whether True or False, a Real Stretch," by DAVID KAMP. New York Times, Published: December 30, 2008

Centralizing Care for Testicular Cancer

A number of studies and a growing body of evidence indicates that high hospital and surgeon volume can be associated with improved outcomes for a number of surgical diseases. Research involving the Institute of Medicine[1] and a number of large, national databases including SEER (Surveillance, Epidemiology, and End Results) Cancer Program,[2] National Inpatient Sample [3] and others [4,5] indicate associations between hospital volume and outcome for a variety of cardiovascular and oncologic surgeries. While not specifically focused on urologic oncology, these studies demonstrate modest but significant improvements in mortality for radical cystectomy and nephrectomy.[3,5]
In the urologic literature, significant improvements have been demonstrated for the treatment of prostate,[6-11] bladder,[3,5,12-16] and kidney cancer[3,17-18] at high-volume centers and by high-volume surgeons. There is less, well-established literature in the treatment of testicular cancer (TC) and this blog will focus on the relationship between hospital volume and outcomes for TC.

 
A study of the Irish Testicular Tumor Registry (1980-1985) evaluated 246 patients over 41 hospitals. Inferior survival outcomes were associated with patients who received incomplete orchiectomy, were not staged by tumor markers, did not receive appropriate chemotherapy, had less frequent imaging or marker surveillance and did not have a urologist and/or oncologist involved in their care.[19] In an early study from the SWENOTECA (Swedish Norweigan Testicular Cancer) Project (1981-1986), high-volume cancer centers were associated with improved care – especially in patients with large volume, advanced disease.[20] Of 440 men treated in Scotland, 87% of 235 men treated at the highest volume center were alive at 5 years. Of the 194 treated at other, smaller centers, only 73% were alive at 5 years – much of this difference was attributed to various treatment protocols independent of other prognostic variables.[21]

In the United States, 172 men with advanced testicular cancer in the national, SEER database were matched to 133 men from MSKCC (Memorial Sloan Kettering Cancer Center) in New York (1978-1984). Survival rates were higher at MSKCC despite similar treatment regimens. The benefit at MSKCC was highest in men with minimal to moderate disease and therefore attributed to the combination of surgery and chemotherapy at this tertiary care center.[22] This relationship was validated in 380 patients with metastatic TC enrolled in an EORTC (European Organization for Research and Treatment of Cancer) Trial. The trial was conducted over 49 sites, and patients treated at the 26 sites with the fewest patients (five or fewer) had inferior survival outcomes.[23]

More recent studies from Japan have investigated the volume-outcome relationship, demonstrating increasing volume of treatment to be associated with improved survival.[24] However the rates did not achieve the survival rates demonstrated in western countries like the US or countries of Europe. Based on these data, efforts have been made to centralize TC care in a risk-adapted algorithm – as severity of disease increases, patients are referred to more centralized, specialized referral centers. One study evaluating this "centralization" demonstrated markedly improved and excellent survival in patients receiving induction chemotherapy, with the majority of patients receiving care at one, large center.[25]

While much of the data regarding hospital volume and outcome for TC patients is dated, the argument for centralization of care is poignant. As outcomes for a variety of urologic malignancies including prostate, bladder and kidney cancer are established to be improved in high-volume centers, it is rational that TC care could also be better served by centralized care – TC is a rare disease that often requires multi-disciplinary care and a thorough understanding of management options and outcomes (especially for men with advanced disease). A risk-adapted centralization, where following a diagnosis of TC patients are referred to an increasingly experienced center for the stage of their disease, may help improve outcomes for patients.  For instance, a man with early stage disease who is a candidate for active surveillance can be followed by his local urologic oncologist, and the man with high-volume metastatic disease should be referred to a large, tertiary care center with extensive experience treating men in the region.  In addition, while this blog does not discuss the costs associated with the treatment of advanced TC, centralization may provide improved population-based outcomes in a cost-effective manner and this is a disease where reimbursements may reinforce quality care.

This blog was written by Phillip M. Pierorazio, MD, Assistant Professor of Urology and Oncology and Director of the Division of Testicular Cancer.

 

1. E.A. Halm, C. Lee, M.R. Chassin. Is volume related to outcome in health care? A systematic review and methodologic critique of the literature. Ann Intern Med, 137 (2002), p. 511
2. C.B. Begg, L.D. Cramer, W.J. Hoskins, M.F. Brennan. Impact of hospital volume on operative mortality for major cancer surgery. JAMA, 280 (1998), p. 1747
3. J.D. Birkmeyer, A.E. Siewers, E.V. Finlayson, T.A. Stukel, F.L. Lucas, I. Batista,et al. Hospital volume and surgical mortality in the United States. N Engl J Med, 346 (2002), p. 1128
4. R.A. Dudley, K.L. Johansen, R. Brand, D.J. Rennie, A. Milstein. Selective referral to high-volume hospitals: estimating potentially avoidable deaths. JAMA, 283 (2000), p. 1159
5. J.D. Birkmeyer, T.A. Stukel, A.E. Siewers, P.P. Goodney, D.E. Wennberg, F.L. Lucas. Surgeon volume and operative mortality in the United States. N Engl J Med, 349 (2003), p. 2117
6. F.J. Bianco Jr, P.T. Scardino, M.W. Kattan, A.C. Rhee, J.A. Eastham. Surgeon volume is predictor of improved outcomes in radical prostatectomy patients. J Urol, 171 (suppl.) (2004), p. 211 abstract 796
7. C.B. Begg, E.R. Riedel, P.B. Bach, M.W. Kattan, D. Schrag, J.L. Warren, et al. Variations in morbidity after radical prostatectomy. N Engl J Med, 346 (2002), p. 1138
8. J.A. Eastham, M.W. Kattan, E. Riedel, C.B. Begg, T.M. Wheeler, C. Gerigk, et al. Variations among individual surgeons in the rate of positive surgical margins in radical prostatectomy specimens. J Urol, 170 (2003), p. 2292
9. L.M. Ellison, J.A. Heaney, J.D. Birkmeyer. The effect of hospital volume on mortality and resource use after radical prostatectomy. J Urol, 163 (2000), p. 867
10. J.C. Hu, K.F. Gold, C.L. Pashos, S.S. Mehta, M.S. Litwin. Role of surgeon volume in radical prostatectomy outcomes. J Clin Oncol, 21 (2003), p. 401
11. S.L. Yao, G. Lu-Yao. Population-based study of relationships between hospital volume of prostatectomies, patient outcomes, and length of hospital stay. J Natl Cancer Inst, 91 (1999), p. 1950
12. L.S. Elting, C.A. Pettaway, H.B. Grossman, B.N. Bekele, K.R. Saldin, C.P.N. Dinney. Relationship between postoperative in-hospital mortality and annual hospital volume of cystectomies: the effect of centres of experience. J Urol, 169 (suppl.) (2003), p. 336 abstract 1301
13. H.W. Herr, J.R. Faulkner, H.B. Grossman, R.B. Natale, R. DeVere White, M.F. Sarosdy, et al. Surgical factors influence bladder cancer outcomes: a cooperative group report. J Clin Oncol, 22 (2004), p. 2781
14. H.W. Herr, J.A. Smith, J.E. Montie. Standardization of radical cystectomy: time to count and be counted. BJU Int, 94 (2004), p. 481
15. B.R. Konety, V. Dhawan, V. Allareddy, S.A. Josyln. Impact of hospital and surgeon volume on in-hospital mortality from radical cystectomy: data from the Health Care Utilization Project. J Urol, 173 (2005), p. 1695
16. B.R. Konety, V. Dhawan, V. Allareddy, M.A. O'Donnell. Association between volume and charges for most frequently performed ambulatory and nonambulatory surgery for bladder cancer is more cheaper? J Urol, 172 (2004), p. 1056
17. E.V. Finlayson, P.P. Goodney, J.D. Birkmeyer. Hospital volume and operative mortality in cancer surgery: a national study. Arch Surg, 138 (2003), p. 721
18. D.A. Taub, D.C. Miller, J.A. Cowan, J.B. Dimick, J.E. Montie, J.T. Wei. Impact of surgical volume on mortality and length of stay after nephrectomy. Urology, 63 (2004), p. 862
19. J.A. Thornhill, A. Walsh, R.M. Conroy, J.J. Fennelly, D.G. Kelly, J.M. Fitzpatrick. Physician-dependent prognostic variables in the management of testicular cancer. Br J Urol, 61 (1988), p. 244
20. N. Aass, O. Klepp, E. Cavallin-Stahl, O. Dahl, H. Wicklund, B. Unsgaard, et al. Prognostic factors in unselected patients with nonseminomatous metastatic testicular cancer: a multicenter experience. J Clin Oncol, 9 (1991), p. 818
21. M.J. Harding, J. Paul, C.R. Gillis, S.B. Kaye. Management of malignant teratoma: does referral to a specialist unit matter? Lancet, 341 (1993), p. 999
22. E.J. Feuer, C.M. Frey, O.W. Brawley, S.G. Nayfield, J.B. Cunningham, N.L. Geller, et al. After a treatment breakthrough: a comparison of trial and population-based data for advanced testicular cancer. J Clin Oncol, 12 (1994), p. 368
23. L. Collette, R.J. Sylvester, S.P. Stenning, S.D. Fossa, G.M. Mead, R. de Wit, et al. Impact of the treating institution on survival of patients with "poor-prognosis" metastatic nonseminoma. European Organization for Research and Treatment of Cancer Genito-Urinary Tract Cancer Collaborative Group and the Medical Research Council Testicular Cancer Working Party. J Natl Cancer Inst, 91 (1999), p. 839
24. Suzumura S, Ioka A, Nakayama T, Tsukuma H, Oshima A, Ishikawa O. Hospital procedure volume and prognosis with respect to testicular cancer patients: a population-based study in Osaka, Japan. Cancer Sci. 2008 Nov;99(11):2260-3. doi: 10.1111/j.1349-7006.2008.00920.x.
25. Inai H, Kawai K, Kojima T, Joraku A, Shimazui T, Yamauchi A, Miyagawa T, Endo T, Fukuhara Y, Miyazaki J, Uchida K, Nishiyama H. Oncological outcomes of metastatic testicular cancers under centralized management through regional medical network. Jpn J Clin Oncol. 2013 Dec;43(12):1249-54. doi: 10.1093/jjco/hyt152. Epub 2013 Oct 6.