Wednesday, July 23, 2014

Renal Cell Carcinoma: Implications of Histology

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

  • Clear-cell RCC
  • Papillary RCC
  • Chromophobe RCC
  • Collecting duct carcinoma
  • Renal medullary carcinoma
  • Translocation tumors
  • Tubulocystic RCC
  • Clear Cell (Tubulo) Papillary RCC
  • Acquired Cystic Disease–associated RCC
  • Multilocular Cystic Renal Cell Neoplasm of Low Malignant Potential (Multilocular Cystic RCC)
  • Hybrid Oncocytic/Chromophobe Tumors
After a biopsy or surgery to remove a tumor, the pathology report will often define the tumor as one of these entities.  This blog will review the definitions and implications of some of the most common tumor histologies.

Clear-Cell Renal Cell Carcinoma

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

Prognosis

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


Papillary Renal Cell Carcinoma

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

  • commonly found in patients with end-stage renal disease
  • commonly found in patients with acquired cystic disease
  • often multifocal, upwards of 40% of papillary RCC are found in more than one site in the kidney
Papillary RCC (webpathology.com)
On imaging, they are often less intense than clear-cell or other "enhancing" tumors -- they can be mistaken for cysts.   While these are solid masses, like other forms of RCC, the cells grow in a papillary or tubular configuration, forming stalks of tumor cells rather than flat sheets.  There are two distinct patterns of growth under the microscope, in cytogenetics and molecular staining.

Papillary Type 1: 
  • more common form
  • dark cells with scant cytoplasm
  • associated with Hereditary Papillary RCC Syndrome 
Papillary Type 2: 
  • less common
  • eosinophilic (red) cells with abundant cytoplasm
  • sporadic forms of Papillary Type 2 are not necessarily dangerous
    • these tumors are potentially aggressive when associated with the hereditary Leiomyomatosis and RCC Syndrome -- these tumors are now given their own distinction and are no longer lumped with Type 2 tumors.

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

Prognosis

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

Chromophobe Renal Cell Carcinoma

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

Prognosis

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


Collecting Duct Carcinoma

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

Renal Medullary Carcinoma

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

Translocation Tumors

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

Prognosis

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



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

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

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


Tuesday, July 22, 2014

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

1938

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

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

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

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



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


The surface [of the kidney] showed great irregularity with numerous grooves and depressionswhich corresponded to its relationship with the renal artery and vein, the right iliac artery, and the surface of the sacrum...The renal artery was of small caliber and several cross sections showed at a point about 1cm. from the hilum of the kidney partial occlusion.
Interestingly, there was no evidence of inflammatory or infectious disease and the glomeruli were normal in appearance.

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

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

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





Monday, July 21, 2014

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

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

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

The idea of targeted therapy and theories of the immunoresponsive nature of clear cell RCC were combined to focus on specific parts of the immune interaction.   Among others, one important interaction is the Programmed Death Ligand 1 (PD-L1) interaction between the tumor cells and the immune cells.  T-cells are immune cells that target “foreign” cells in the body and trigger an immune response to kill those cells.  T-cells have receptors that have evolved (through genetic mutations and recombinations) to be specific for different surface proteins that may found in the cells of the body.  In a normal, healthy person, T-cells will even recognize normal, healthy cells.  However there are mechanisms to prevent the T-cell from killing good cells – a process called “anergy” which leads to T-cell death (or apoptosis).  One such signaling pathway is the PD-L1 on the healthy cell interacts with the receptor on the healthy cell (Figure 1).
Figure 1. T-Cell Recognizing Healthy Cell via PD-1-PD-L1 Interaction and Inducing Cell Death (Apoptosis).
If the T-cell identifies a tumor cell, it will not get the normal signal that it is a healthy cell, the T-cell can initiate processes to kill the tumor cell (Figure 2).
Figure 2. T-Cell Recognizing Tumor Cell without PD-1-PD-L1 Interaction.

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



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


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






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


Friday, July 18, 2014

The "Evolution" of Advanced Prostate Cancer Research

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

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

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

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



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

Wednesday, July 16, 2014

BCG Immunotherapy Alternatives

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

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

INTERFERON-ALPHA (IFN-α)

Interferons are glycoproteins with a number of anti-viral properties.  IFN-α (interferon-alpha) is known to stimulate NK (natural killer) cells, induce MHC (major histocompatibility complex) class I response, augments the ability of Th1 (T-helper cells) and increase antibody recognition -- all mechanisms that stimulate the immune response in the bladder [2,3]. 
See our prior blog on BCG For Bladder Cancer: Why it Works, How it Works for a better understanding of stimulating the immune system for the treatment of bladder cancer.
The ability of IFN-α to fight off cancers has been attributed to both an ability to stop cell growth and its immunomodulatory effects.  Because of its ability to augment the local immune response, IFN-α2b has been studied in conjunction with BCG.  There is only one published, randomized trial comparing BCG alone to BCG+IFN.  This group of patients did not receive any prior intravesical treatments, and there was no significant difference in recurrence-free survival at two years, although the IFN group did exhibit a higher incidence of constitutional symptoms and fever [4].

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

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

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

INTERLEUKIN-2 (IL-2)

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

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

INTERLEUKIN-12 (IL-12)

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

INTERLEUKIN-10 (IL-10)

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

SUMMARY


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


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

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



[1] Kemp TJ, Ludwig AT, Earel JK, et al. Neutrophil stimulation with Mycobacterium bovis bacillus Calmette-Guérin (BCG) results in the release of functional soluble TRAIL/Apo-2L. Blood 2005; 106: 3474-82.
[2] Kamat AM, Lamm DL. Immunotherapy for bladder cancer. Curr Urol Rep 2001; 2: 62-9.
[3] Luo Y, Chen X, O’Donnell MA. Role of Th1 and Th2 cytokines in BCG-induced IFN-γ production: cytokine promotion and stimulation of BCG effect. Cytokine 2003; 21: 17-26.
[4] Nepple KG, Lightfoot AJ, Rosevear HM, et al; Bladder Cancer Genitourinary Oncology Study Group.  Bacillus Calmette-Guérin with or without interferon α-2b and megadose versus recommended daily allowance vitamins during induction and maintenance intravesical treatment of nonmuscle invasive bladder cancer. J Urol 2010; 184: 1915-9.
[5] O’Donnell MA, Krohn J, DeWolf WC. Salvage intravesical therapy with interferon-alpha-2b plus low dose bacillus Calmette-Guérin is effective in patients with superficial bladder cancerin whom bacillus Calmette-Guérin alone previously failed. J Urol 2001; 166: 1300-4.
[6] Joudi FN, Smith BJ, O’Donnell MA. National BCG-Interferon Phase II Investigator Group Final results from a national multi-center phase II trial of combination bacillus Calmette-Guérin plus interferon α-2b for reducing recurrence of superficial bladder cancer. Urol Oncol 2006; 24: 344-8.
[7] Gallagher BL, Joudi FN, Maymí JL, et al. Impact of previous bacillus Calmette-Guérin failure pattern on subsequent response to bacillus Calmette-Guérin plus interferon intravesical therapy. Urology 2008; 71: 297-301.
[8] Yron I, Wood TA, Spiess PJ, et al. In vitro growth of murine T cells v. the isolation and growth of lymphoid cells infiltrating syngeneic solid tumors. J Immunol 1980; 125: 238-45.
[9] Lotze MT, Grimm EA, Mazunder A. Lysis of fresh and cultured autologous tumor by human lymphocytes cultures in T-cell growth factor. Cancer Res 1981; 41: 4420-5.
[10] Henney CS, Kuribayashi K, Kern DE, et al. Interleukin-2 augments natural killer cell activity. Nature 1981; 291: 335-8.
[11] Malkovsky M, Loveland B, North M. Recombinant interleukin-2 directly augments the cytotoxicity of human monocytes. Nature 1987; 325: 262-5.
[12] Tubaro A, Velotti F, Stoppacciaro A, et al. Continuous intra-arterial administration of recombinant interleukin-2 in low stage bladder cancer: a phase 1B study. Cancer 1991; 68: 56-61.
[13] Gomella LG, McGinnis DE, Lattime EC, et al. Treatment of transitional cell carcinoma of the bladder with intravesical interleukin-2: a pilot study. Cancer Biother 1993; 8: 223-7.
[14] Den Otter W, Dobrowolski  Z, Bugajski A, et al. Intravesical interleukin-2 in T1 papillary bladder carcinoma: regression of marker lesion in 8 of 10 patients. J Urol 1998; 159: 1183-6.
[15] O’Donnell MA, Aldovini A, Duda RB et al. Recombinant Mycobacterium bovis BCG secreting functional interleukin-2 enhances gamma interferon production by splenocytes.  Infect Immun 1994; 62: 2508-14.
[16] Yamada H, Matsumoto S, Matsumoto T, et al. Murine IL-2 secreting recombinant bacillus Calmette-Guérin augments macrophage-mediated cytotoxicity against murine bladder cancer MBT-2. J Urol 2000; 164: 526-31.
[17] Gately MK, Desai BB, Wolitzky AG, et al. Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor). J Immunol 1991; 147: 874-82.
[18] Nastala CL, Edington HD, McKinney TG, et al. Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production. J Immunol 1994; 153: 1697-706.
[19] Teicher BA, Ara G, Buxton D,et al. Optimal scheduling of interleukin-12 and chemotherapy in the murine MB-49 bladder carcinoma and B16 melanoma. Clin Cancer Res 1997; 3: 1661-7.
[20] O’Donnell MA, Luo Y, Hunter SE, et al. Interleukin-12 immunotherapy of murine transitional cell carcinoma of the bladder: dose dependent tumor eradication and generation of protective immunity. J Urol 2004; 171: 1330-5.
[21] O’Donnell MA, Luo Y, Hunter SE, et al. The essential role of interferon-gamma during interleukin-12 therapy for murine transitional cell carcinoma of the bladder. J Urol 2004; 171: 1336-42.
[22] O’Donnell MA, Luo Y, Chen X, et al. Role of IL-12 in the induction and potentiation of IFN-gamma in response to bacillus Calmette-Guérin. J Immunol 1999; 163: 4246-52.
[23] Weiss GR, O’Donnell MA, Loughlin, K, et al. Phase I study of the intravesical administration of recombinant human interleukin-12 in patients with recurrent superficial transitional cell carcinoma of the bladder. J Immunother 2003; 26: 343-8.
[24] Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 1989; 170: 2081-95.
[25] Nadler R, Luo Y, Zhao W, et al. Interleukin-10 induced augmentation of delayed-type hypersensitivity (DTH) enhances Mycobacterium bovis bacillus Calmette-Guérin (BCG) mediated antitumor activity. Clin Exp Immunol 2003; 131: 206-16.
[26] Ferguson TA, Dube P, Griffith TS. Regulation of contact hypersensitivity by interleukin-10. J Exp Med 1994; 179: 1597-1604.
[27] Bockholt NA, Knudson MJ, Henning J, et al. Anti-IL-10R1 monoclonal antibody enhances BCG-induced Th1 immune responses and antitumor immunity in a mouse orthotopic model of bladder cancer. J Urol 2012; 187: 2228-35.







Tuesday, July 15, 2014

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

Electron micrograph of gonococcus. (from gov.uk)
1937

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

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

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

They concluded that sulfanilamide was of "great value" and:
This preliminary report is therefore presented for the purpose of stimulating the careful use of this drug in clinics where large numbers of gonococcic infections can be closely followed, so that an accurate evaluation of sulfanilamide in the treatment of gonococcic infections can be determined and the optimum dosage and possible deleterious effects further studied.
This manuscript serves as the first example of sulfa-medications in the treatment of urinary tract infections.

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

Friday, July 11, 2014

Lymph Node Dissection for Renal Cancer

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

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

Certain or Uncertain Lymphatic Drainage of Renal Cell Carcinoma?

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

Retroperitoneal lymph node locations.  From Crispen et al.
European Urology, 2011. [3]
However, looking at the epidemiologic data, upwards of 30% of patients with RCC will present with metastatic disease; however, only 3-10% will have lymph node involvement only.  Of the patients with metastatic disease, upwards of 40% will have no lymph node involvement - indicating that RCC, unlike other cancer, can spread without first involving the regional lymph nodes.  

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

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

Improved Staging, Improved Survival?

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

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

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

  • In a study of over 2,500 patients, for those with positive lymph nodes, 22% were disease-free at 44 months [9]
    • Of the recurrences, the majority were detected within 4 months of nephrectomy and 51% were at multiple organ sites
  • In a study of over 500 patients, CSS was significantly better for patients who underwent a systematic, extended lymph node dissection (66%) when compared to those who had only clinically abnormal lymph nodes removed (58%, p<0.01).[10]  
  • In a study on 800 patients, 5% with positive lymph nodes and 9% with positive lymph nodes and metastatic disease:
    • For patients without clinically evident nodal disease, survival was not impacted by LND.
    • For patients with distinct clinical nodal disease, survival was positively impacted by cytoreductive nephrectomy, LND and postoperative immunotherapy.
    • LND was predictive of survival in multivariable analysis of lymph node positive patients.[11]
  • In a study of 10,000 patients in the National SEER (Surveillance, Epidemiology, and End Results) Database:
    • For patients with negative lymph nodes, there was no effect on CSS with increasing extent of LND. 
    • An absolute survival increase of 10 % (39–49 %) at 5 years was seen in patients with one positive lymph node in whom ten lymph nodes were removed indicating that the number of lymph nodes removed correlates to an improvement in CSS.[12]
However, a number of studies fail to find a survival benefit in patients with positive lymph nodes who underwent LND.[13,14]

How about Level 1 Evidence?

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

Who Should Undergo Lymphadenectomy (LND)?

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

Summary

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

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

  • Large, clinically-localized tumors: upwards of 40% of cT2 (>7cm) tumors will have pathological T3 disease
  • Locally-invasive tumors: cT3 or cT4 disease
  • Clinically enlarged lymph nodes
  • Limited metastatic disease, especially if an isolated site can be resected
  • Biopsy-proven, high-grade RCC (Grade 3 or 4)
Other considerations:
  • Many radical nephrectomy surgeries can be performed laparoscopically, however LND can be challenging with standard laparoscopy.  Robot-assisted laparoscopy may facilitate lymph node dissection by affording the surgeon more control near the great vessels in the body.
  • There is no, well-agreed upon consensus regarding LND.  While the risks of LND are relatively low, not all patients will benefit from a LND and careful thought should go into the decision to perform a LND.

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








[1] Pantuck AJ, Zisman A, Dorey F, Chao DH, Han KR, Said J, Gitlitz B, Belldegrun AS, Figlin RA. Renal cell carcinoma with retroperitoneal lymph nodes. Impact on survival and benefits of immunotherapy. Cancer. 2003 Jun 15;97(12):2995-3002.
[2] Parker AE (1935) Studies on the main posterior lymph channels of the abdomen and their connections with the lymphatics of the genito-urinary system. Am J Anat 56:409–443
[3] Crispen PL, Breau RH, Allmer C et al (2011) Lymph node dissection at the time of radical nephrectomy for high-risk clear cell renal cell carcinoma: indications and recommendations for surgical templates. Eur Urol 59:18–23
[4] Blute ML, Leibovich BC, Cheville JC et al (2004) A protocol for performing extended lymph node dissection using primary tumor pathological features for patients treated with radical nephrectomy for clear cell renal cell carcinoma. J Urol 172:465–469
[5] Hutterer GC, Patard JJ, Perrotte P, Ionescu C, de La Taille A, Salomon L, Verhoest G, Tostain J, Cindolo L, Ficarra V, Artibani W, Schips L, Zigeuner R, Mulders PF, Valeri A, Chautard D, Descotes JL, Rambeaud JJ, Mejean A, Karakiewicz PI. Patients with renal cell carcinoma nodal metastases can be accurately identified: external validation of a new nomogram.  Int J Cancer. 2007 Dec 1;121(11):2556-61.
[6] Studer UE, Scherz S, Scheidegger J et al (1990) Enlargement of regional lymph nodes in renal cell carcinoma is often not due to metastases. J Urol 144:243–245.
[7] Terrone C, Guercio S, De Luca S, Poggio M, Castelli E, Scoffone C, Tarabuzzi R, Scarpa RM, Fontana D, Rocca Rossetti S. The number of lymph nodes examined and staging accuracy in renal cell carcinoma. BJU Int. 2003 Jan;91(1):37-40.
[8] Freedland SJ, Dekernion JB. Role of lymphadenectomy for patients undergoing radical nephrectomy for renal cell carcinoma. Rev Urol. 2003 Summer;5(3):191-5.
[9]  Delacroix SE Jr, Chapin BF, Chen JJ et al (2011) Can a durable disease-free survival be achieved with surgical resection in patients with pathological node positive renal cell carcinoma? J Urol 186:1236–1241
[10] Herrlinger A, Schrott KM, Schott G, Sigel A.  What are the benefits of extended dissection of the regional renal lymph nodes in the therapy of renal cell carcinoma.J Urol. 1991 Nov;146(5):1224-7.
[11] Pantuck AJ, Zisman A, Dorey F et al (2003) Renal cell carcinoma with retroperitoneal lymph nodes: role of lymph node dissection. J Urol 169:2076–2083
[12] Whitson JM, Harris CR, Reese AC et al (2011) Lymphadenectomy improves survival of patients with renal cell carcinoma and nodal metastases. J Urol 185:1615–1620.
[13]  Terrone C, Cracco C, Porpiglia F et al (2006) Reassessing the current TNM lymph node staging for renal cell carcinoma. Eur Urol 49:324–331
[14] Feuerstein MA, Kent M, Bazzi WM, Bernstein M, Russo P. Analysis of lymph node dissection in patients with ≥7-cm renal tumors. World J Urol. 2014 Jan 9.
[15] Blom JH, van Poppel H, Marechal JM et al (2009) Radical nephrectomy with and without lymph-node dissection: final results of European Organization for Research and Treatment of Cancer (EORTC) randomized phase 3 trial 30881. Eur Urol 55:28–34
[16] Blute ML, Leibovich BC, Cheville JC et al (2004) A protocol for performing extended lymph node dissection using primary tumor pathological features for patients treated with radical nephrectomy for clear cell renal cell carcinoma. J Urol 172:465–469
[17] Capitanio U, Abdollah F, Matloob R et al (2013) When to perform lymph node dissection in patients with renal cell carcinoma: a novel approach to the preoperative assessment of risk of lymph node invasion at surgery and of lymph node progression during follow-up. BJU Int 112:E59–E66