Download What Is Kidney Cancer - Mediterranean School Of Oncology

Kidney cancer: prognostic factors
and new surgical approaches
Clinica Urologica ed Andrologica
Department of Medicine
and Aging Science
Chieti University
Università degli Studi di Chieti-Pescara
Scuola di Specializzazione in Urologia
Direttore. Prof. R.Tenaglia
Mediterranean School f Oncology ROMA 24 Novembre 2007
What Is Kidney Cancer (Renal Cell Carcinoma)?
Kidney cancer is a cancer that starts in the kidneys. In order to
understand kidney cancer, it helps to know about the normal
structure and function of the kidneys.
Renal Cell Carcinoma (RCC)
Renal cell carcinoma (also known as renal cell cancer or renal cell adenocarcinoma) is
by far the most common type of kidney cancer. It accounts for about 9 out of 10
kidney cancers.
Although RCC usually grows as a single mass within the kidney, sometimes tumors are
found in more than one part of the kidney or even in both kidneys at the same time.
Some renal cell carcinomas are noticed only after they have become quite large, but
most are found before they metastasize (spread) to distant organs in the body. Like
most cancers, RCC is hard to treat once it has metastasized.
There are five subtypes of RCC, based mainly on
how the cancer cells look under a microscope
This subtype accounts for about 5%
of RCCs. The cells of these cancers
are also pale, like the clear cells, but
are much larger and have certain
other features that can be
recognized.
This subtype is very rare. The major
feature is that the cancer cells can
form irregular tubes.
Clear Cell
Papillary
Chromophobe
Collecting Duct
Unclassified
In rare cases, renal cell cancers are
labeled as "unclassified" because their
appearance doesn't fit into any of the
other categories or because there is
more than one type of cell present.
This is the most common form of
renal cell carcinoma. About 8 out of
10 people with renal cell carcinoma
have this kind of cancer. When viewed
under a microscope, the cells that
make up clear cell RCC appear very
pale or clear.
The second most common subtype -about 10% to 15% of people have this
kind. These cancers form little fingerlike projections (called papillae) in
some, if not most, of the tumor. Some
doctors
call
these
cancers
chromophilic because the cells take
up certain dyes used in preparing the
tissue to be viewed under the
microscope, causing them to appear
pink.
Other Cancerous Kidney Tumors
Less common cancers
of the kidney include
Transitional cell carcinomas
Wilms tumors
And Renal Sarcomas
RCC - Epidemiology
Approximately 40,000 cases per year
~12,900 deaths per year
2% - 3% of all cancers
Average age at diagnosis 50-70
Nearly 40% of patients with RCC will eventually die
from the disease
Associated with inherited syndrome in 2%
RCC Age Distribution
800
Male
Female
Number of cases
700
600
500
400
300
200
100
0
<40
Source – BAUS 2001
40 to 49 50 to 59 60 to 69 70 to 79
>/= 80
It is important that VHL patients undergo a complete
screening and metabolic evaluation
PRIOR TO A SURGICAL PROCEDURE
to rule out such unsuspected manifestations as a CNS
hemangioblastoma orpheochromocytoma.
The VHL Gene Has Characteristics of a Tumor
suppressor Gene.
VHL: Surgical Management
Surgical management of the renal manifestations of VHL
patients involves nephron sparing surgery whenever possible.
Patients with small renal tumors, generally under 2.5 cm, are
often managed with expectant management.
When the tumors reach 3 cm, surgery is often recommended.
As it has been estimated that there can be up to 600 tumors per
kidney in VHL patients, surgical resection of renal lesions is not
considered “curative.” Rather, it is considered that surgical
management will hopefully “set back the clock”; i.e. help prevent
metastasis.
Historically 35 to 45% of VHL patients have died of
complications of metastatic renal cell carcinoma.
The decision to recommend surgery must balance the risk of
metastasis with the morbidity of surgery.
When surgery is performed, thorough evaluation of the kidney
with intraoperative ultrasound is considered a valuable adjunct
to the surgical procedure. This allows the surgeon to localize
renal tumors and cysts and to perform as thorough and safe a
procedure as possible.
Renal Lesions in VHL Patient
Microscopic RCC Focus
in the Kidney of a VHL Patient
Clinical Applications of Cancer
Gene Mutation Detection
1) Molecular Genetic Classification of Kidney Cancer
The findings have lead to the introduction of a molecular genetic classification of
kidney cancer, papillary versus clear, with clear cell renal carcinoma being characterized
by mutation of the VHL gene.
Molecular Genetic Classification Of Renal Carcinoma Gene RCC
VHL Clear Cells/Compact Growth
Met Type I Papillary Growth Pattern
BHD Chromophobe renal cell carcinoma,
Oncocytoma
FH Type II Papillary Growth Pattern
Somatic VHL Gene Mutation Analysis:
Potential Clinical Applications
Detection of VHL gene abnormalities in:
- Formalin fixed tissues
-Tissue aspirates
Early Diagnosis
- Circulation Cells
- Urine
Renal Carcinoma Associated with
Birt Hogg Dube Syndrome (BHDS)
We have recently noted an associated of kidney cancer with an inherited
familial syndrome known as Birt Hogg Dube Syndrome (BHDS). BHDS is
an autosomal dominantly inherited syndrome in which affected individuals
are known to be at risk for a cutaneous manifestation, the presence of
fibrofolliculomas.
Familial Renal Carcinoma (FRC)
Recently scientists in Iceland have performed studies suggesting
that genetic susceptibility may be a major component in the
development of ordinary, “sporadic” renal carcinoma. In their
initial study, 68% of individuals in Iceland who had kidney cancer
had up to a second degree relative (a second cousin) with kidney
cancer. This work suggests that it is important to ask all patients
with renal carcinoma whether any other family member also was
affected with renal carcinoma. Urologic surgeons at the NCI are
currently studying families in which multiple members are affected
with kidney cancer (FRC) in order to identify the genetic basis of
this form of kidney cancer.
Risk Factors for RCC
•
•
•
•
•
•
Smoking
Occupational exposure to toxic compounds
Obesity
Acquired cystic kidney disease
Analgesic abuse nephropathy
Genetic predisposition
Risk Factors for RCC
• Smoking –
– Cigarette smoking doubles the risk
• Occupational exposure
–
–
–
–
cadmium
RR 2.0
asbestos
RR 1.4
gasoline
RR 1.6
increased exposure may be associated with gene
mutations such as vHL tumor suppressor gene
Diagnosis
•
•
•
•
•
CT scan
Ultrasonography
MRI
Renal arteriography
Percutaneous cyst puncture
RCC Genetics & Biology
• Pathogenesis
• VHL
• Autosomal dominant
• inheritance of one copy of a mutated allele followed by
a second somatic gene alteration in the remaining allele
leads to various cancers, including RCC
• genetic abnormality localized to 3p25 to 3p26
RCC Genetics & Biology
• Pathogenesis
• Sporadic Clear Cell RCC
• chromosomal losses often spanning 3p14 to 3p26
• VHL mutations found in up to 80% of sporadic clear
cell RCC
(Gnarra Nat Genet ’94; 7:85)
TNM Staging system
Primary Tumor (T)
T1 Tumor 7 cm or less in greatest dimension, limited to the
kidney
T2 Tumor more than 7 cm in greatest dimension limited to the
kidney
T3 Tumor extends into major veins or invades the adrenal
gland or perinephric tissues, but not beyond Gerota’s fascia
T3A Tumor invades adrenal gland or perinephric tissue but not
beyond Gerota’s fascia
T3B Tumor grossly extends into the renal vein (s) or vena cava
below the diaphragm
T3C Tumor grossly extends into the renal vein (s) or vena cava
above the diaphragm
T4 Tumor invades beyond Gerota’s fascia
Regional Lymph Nodes (N)
N0 No regional lymph node metastases
N1 Metastases in a single regional lymp h node
N2 Metastases in more than one regional lymph node
Distant Metastases (M)
M0 No distant metastases
M1 Distant Metastases
The prognostic value of size was further emphasized by
introducing an optional division of stage T1 into stage T1a
(4 cm or less) and stage T1b (4 to 7 cm). Five-year survival
for stage T1a and T1b was 98% and 88%, respectively.
Staging - Prognoses
Predictors of Response
• Historically, clinical factors alone were used as prognostic
markers for RCC:
– 1999 MSKCC (Motzer et al, J Clin Oncol)*
• PS
• LDH
• Hgb
• Corrected serum Ca++
• Nephrectomy status
(*0 favorable risk, 1-2 intermediate risk, >3 poor risk)
- Median Survival
- favorable
- intermediate
- poor
20 months
10 months
5 months
Staging - Prognoses
Predictors of Response
International Kidney Cancer Working Group – currently creating a
comprehensive data base of >4,000 patients with metastatic RCC to
provide and
validate a single model that can be used to predict survival.
• Biomarkers being evaluated for their potential as
prognostic factors:
• tumor proliferation
• tumor growth
• angiogenesis
• loss of cell adhesion
• CA-IX is highly expressed in RCC, may be a useful
prognostic and predictive marker.
Promising Therapies
Target Specific
Antibody Therapy
VEGF +/– EGFR TKI
EGFR
CAIX
Vaccine

mTOR, VEGF, EGFR,
PDGF, RAF, KIT,
proteosome
Renal CA cell
Dendritic
cell
gp 96 HSP
CAIX/GM-CSF
T cell
Systemic cytokines (IL-2, IFN)
Allogeneic stem cell transplant
T Cell
Treatment
• Surgery is the standard treatment for contained kidney
cancer.
• Various surgical options may be available to you, depending
on tumor size and location within the kidney capsule. Such
surgery is performed by a urologic surgeon.
• Radiation and chemotherapy are not very effective in
treating kidney cancer. Biologic therapies are used more
frequently.
Treatment Options
Surgery is best option
Radical nephrectomy is the established therapy
for localized renal carcinoma
Surgical Treatment
Radical nephrectomy
has been the standard of care for localized renal cell carcinoma
since the description by Robson.
Partial nephrectomy
has been used to avoid dialysis in patients with a solitary kidney, compromised renal func tion,
or bilateral multifocal (hereditary) tumors. However, performed in patients with small renal
tumors (less than 4 cm) has been associated with survival similar to that found
after radical nephrectomy.
Treatment Options
Other treatments include:
– Radiation therapy for renal cell carcinoma
– Chemotherapy – not effective
– Treatment with interleukin II and interferon can be
used and at times renal cell carcinoma will respond
– Interleukin II has resulted in 14% remission rate, 5%
complete response and 9% partial response –
approved by FDA
Five- year survival for localized renal
cancers is related to size
100% (< 2.5 cm)
83% (2.5- 4.9cm)
61% (5.0- 7.4 cm)
51% (7.5- 10.0 cm)
27 % (greater than 10.0 cm)
These and other observations led to a change in the TMN classification of stage
T1 renal tumors from 2.5 cm in diameter to 7.0 cm in diameter.
Partial Nephrectomy
Sporadic renal cancer
A solitary small renal tumor is ideally suited for partial nephrectomy with an adequate
margin. Surface cooling for 10 minutes with ice slush will then provide up to 3 hours safe
ischemia. Excision of the renal tumor with a 1 cm margin is performed by the appropriate
technique, including wedge resection, transverse or amputation, or segmental renal artery
occlusion with resection of the appropriate renal segment. Small polar tumors may be exc
ised with local pressure in the absence of renal artery occlusion. Extracorporeal partial
nephrectomy with renal autotransplantation is seldom performed now except in the setting
of the Jehovah’s witness with multiple or complex tumors. Five- year cancer specific survival
after partial nephrectomy has been reported to be 87 to 90%, with a local recurrence in 4 to
6%.
Hereditary renal cancer
Hereditary renal cancer syndromes are characterized by the presence of bilateral,
multiple renal tumors, often presenting in the third and fourth decade of life.
Examples of hereditary renal cancer syndromes include
Von Hippel-Lindau disease (VHL)
Hereditary Papillary Renal Cancer (HPRC)
Hereditary Renal Oncocytoma (HRO)
Burt-Hogg-Dubé.
Examination of normal renal tissue from patients with renal cancer and VHL has shown
microscopic renal tumors are frequently present. Extrapolations based on these studies
predict as many as 600 clear cell renal cancers and 1100 clear cell cysts per kidney. These
cysts are found only in VHL patients, and are microscopically and genetically similar to
clear cell renal cancer.
.
Treatment options
Bilateral nephrectomy
Included observation, or renal parenchymal sparing surgery to remove renal
tumors while sparing normal tissue. Before the widespread use of
computerized tomography, VHL renal tumors were not well imaged, and 35
to 45% of VHL patients died of metastatic renal cancer. Median age at
death was 44 years and the youngest reported patient died at age 23 years.
These data represent the best available estimate of the natural history of
untreated VHL. HP RC is a recently described hereditary cancer syndrome
inherited in an autosomal dominant fashion.
The treatment strategy
of bilateral nephrectomy and renal replacement removes all
tissue at risk of developing renal cancer and metastases.
The one-year survival in 30 to 40 year old, white,nondiabetic renal failure
patients (characteristics similar to those of VHL patients detected by
screening) is 78% with dialysis. Two- year survival with a living related or
cadaver transplant is 96% and 78%, respectively. Similarly, a 65% 5-year
survival of VHL patients has been reported after bilateral nephrectomy and
renal replacement.
The treatment strategy
In order to delay surgeries and improve quality of life, a strategy
consisting of observing patients with hereditary renal cancer
until the largest tumor was 3 cm in diameter before
recommending surgery, regardless of the recurrence pattern or
number of tumors was implemented. Fifty-two VHL patients
had renal tumors less than 3 cm in diameter (group 1), and were
followed a median of 5 years. No metastases were observed in
these patients
1. The renal capsule is first incised sharply.
2. The tumor is gradually dissected out.
3. The defect is packed with thrombin
soaked gelfoam.
Nephrectomy in Metastatic
RCC
Nephrectomy in pts with metastatic RCC
– palliation of symptoms
– therapeutic
• Metastatic disease: Resection of solitary mets – 5-yr.
survival of 35-50%
(Kavolius J Clin Oncol ’99; 16:2261)
Nephrectomy in Metastatic
RCC
• α-IFN +/- Nephrectomy in Metastatic Dz
SWOG 8949 (246 pts)
Survival (months)
All Pts
PS
0
1
No
Nephrectomy
8.1
Nephrectomy
12.5
12.8
4.8
17.4
6.9
Radiofrequency Ablation
Tissue radiofrequency ablation (RFA) takes advantage of the same technology present in
the surgical Bovie we use every day, when tissue is cauterized or cut. Fourteen to eighteen
gauge needles, some with deployable arrays, are inserted in the tumor using ultrasound or
CT guidance. Power output has increased from 50 watts in early models to 250 watt
generators that will soon be available, allowing increases heat delivery to tissues. The
ablation process is monitored using temperature feedback from thermocouples located in
the tips of the catheter prongs or by changes in impedance during treatment. At least two
10-minute treatments per tumor are performed. The needle tract is cauterized to avoid
bleeding and prevent tumor seeding. Energy delivered to tissues resulting in heating tissues
to 60- 70o C, causing cell death. Currently, tumors up to 5- 6 cm in diameter may be treated
with a single needle insertion. Three companies have commercially available radiofrequency
ablation generators and needles; Radionics, Radiotherapeutics, and RITA Medical Systems.
The greatest experience with RFA has been in the treatment of normal and
malignant liver tissue. RITA was the first device available for soft tissue treatment.
The lesions induced by RITA are well demarcated and well seen as early as one day
after treatment. Gross examination of treated porcine liver tissue has shown a
central firm core of cooked tissue, with a surrounding 1-2 mm hemorrhagic, well
demarcated perimeter. Microscopic examination demonstrates microvascular
thrombosis and coagulative necrosis. In the porcine model, 3.5 to 4 cm lesions
could be reproducibly generated, and larger lesions in humans have undergone
treatment. The greatest human experience with this system is in the treatment
of liver metastases. Few complications have been reported in treating liver tumors,
except for mild discomfort at the skin site, when percutaneous RITA is performed.
A similar, although limited, experience has been observed in radiofrequency ablation
of renal cancers.
Histologic exam of treated tumors is very
limited. We have recently excised tumors
from previously treated patients that
responded or did not respond to RFA.
Tumors with a “halo” sign consisted of a
fibrous capsule containing necrotic fluid and
tumor. Enhancing tumors had focal areas of
residual tumor.
Necrotic tumor 1 year after ablation
Foci of viable tumor 1 year after RFA
Laparoscopic Radical Nephrectomy
Localized Renal Cancer
Laparoscopic radical nephrectomy was first performed by
Clayman in 1990, and a growing worldwide experience has shown
laparoscopic surgery is safe and associated with similar survival as
open
surgery.
Patients
eligible
for
laparoscopic
radical
nephrectomy have similar characteristics as those undergoing open
nephrectomy, with the exception of a vena caval thrombus. While
local invasion of tumor, large tumors, metastatic disease, and
extensive retroperitoneal lymphadenopathy add significantly to the
degree of difficulty, they are not absolute contraindications to
laparoscopic radical nephrectomy. Hand assisted laparoscopic
surgery and retroperitoneal or transperitoneal approaches can be
used at the surgeons preference. Small localized tumors are best
suited to gain experience with this approach.
Laparoscopic Radical Nephrectomy
Several hundred laparoscopic nephrectomies have been reported for cancer. Laparoscopic
radical nephrectomy has been associated with a decrease in blood loss, postoperative
analgesic requirements, hospital stay, and time to return to normal activities, compared to
open radical nephrectomy. Two-year follow-up has shown an over 95% cure rate, similar to
open nephrectomy.
The nephrectomy specimen may be removed through a small incision, or fragmented and
removed in pieces through a 10 mm port. Placement of the kidney in an impermeable sac
prior to morcellation is performed to prevent tumor spillage. Tumor morcellation has been
performed with ring forceps or a high-speed electrical tissue morcellator. Pathologic
evaluation of morcellated tissue can be performed, although very small tumors may not be
identified. Staging information is lost during morcellation.
Metastatic Renal Cancer 1
Tumor bleeding and pain can often adversely affect the ability to treat patients with
metastatic renal cancer. At the NIH, over 200 patients with metastatic renal cancer
underwent cytoreductive nephrectomy as preparation for systemic treatment with
Interleukin-2, chemotherapy based regimens, or anti-angiogenic based regimens. These were
bulky tumors usually required a chevron incision. 23% of patients required an additional
resection, most commonly a regional lymph node dissectio n or vena caval thrombus
extraction. While there was similar morbidity to surgery performed in patients with localized
renal cancer, 38% were not eligible for high dose Interleukin-2, usually because of
progression of disease during the 6-week recovery time prior to treatment.
We looked at laparoscopic surgery as a way to decrease morbidity and shorten time to
treatment. The benefit of laparoscopic nephrectomy in terms of time to recovery and
completeness of resection has been demonstrated in patients with small renal tumors and no
local invasion or metastases, but has not been reported in patients with metastatic disease.
Tumor morcellation further reduces surgical trauma, since tumor dissemination is not a
primary concern in patients with metastatic cancer. Laparoscopic techniques thus offer the
possibility of lower morbidity, faster recovery, and more rapid patient availability for systemic
treatment
Others strategy
From January, 1995 to November, 1997, 44 patients with metastatic renal cell
carcinoma and renal primary in place underwent cytoreductive surgery prior
to systemic treatment with Interleukin-2. Patients undergoing open
cytoreductive nephrectomy served as historical controls.
•Schmidt, L et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in
papillary renal carcinomas. Nat.Gen., 16: 68-73,1997.
•Schmidt, L. et al .Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene, 18: 23432350, 1999.
•Latif, F et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science, 260: 1317-1320,
1993.
Large renal tumors
Could not be lifted and placed into the 8 by 10 inch "lapsac" surgical tissue pouch used for
morcellation. Instead, with the patient in the Trendelenburg position, one or two additional
ports were used to facilitate opening the morcellation sac, allowing the specimen to slide in.
The mouth of the sac was draped with towels and an occlusive adhesive barrier. A COOK
Tissue MorcellatorTM (COOK, Spencer, IN) was used to extract the tumor from the
"lapsac". The use of twelve- inch tissue forceps alternating with the morcellator greatly
facilitated tissue removal. Contaminated drapes, gloves, gowns and instruments were
removed after tumor morcellation. Patients undergoing laparoscopic surgery had their
tumor removed without an incision using morcellation, or through a small incision.
Patients undergoing radical nephrectomy by an open, laparoscopic, or laparoscopic assisted
technique had similar gender, age, performance status, tumor size, and number of
metastatic sites.
Six patients had laparoscopic ports placed and the tumor specimen removed with
morcellation.
Five additional patients did not undergo morcellation and had their tumors removed intact.
Laparoscopic Radical Nephrectomy
The year 1990 ushered in the minimally invasive management of renal malignancy. Clayman
and colleagues reported the first laparoscopic radical nephrectomy for suspected renal cell
carcinoma. Over the last decade, we have seen a rapid movement toward minimally invasive
surgery of the kidney. The decreased perioperative morbidity, less pain, and shorter
hospitalization and convalescence have primarily been responsible for this movement. As
surgeons seek to expand their surgical armamentarium, we have seen the development of
Hand Assisted Laparoscopic techniques. Indications for miminally invasive surgery have
also expanded to other indications such as nephron sparing surgery. The mo st recent
direction of the minimally invasive movement has been toward incorporating ablative
technologies such as cryoablation and Radiafrequency thermal ablation into laparoscopic
and even percutaneous treatment of small renal lesions.
Laparoscopic Radical Nephrectomy
The gold standard for surgical management of T1 –T3N0M0 RCC is the
removal of the kidney and surrounding tissues as originally described by Robson
in the 1960’s.
Clayman and collegues applied laparoscopic techniques to perform a
laparoscopic radical nephrectomy for suspected RCC in 1990. The initial reports
were met with some skepticism, but now multiple institutions have adopted the
minimally invasive approach for the treatment of RCC. There is a growing body
of evidence that demonstrates the safety and efficacy of laparoscopic radical
nephrectomy.
In 2001, Chan et al reported on 67 laparoscopic nephrectomies performed for renal cell
carcinoma. The authors reported a 5 year disease free survival of 95% for this series, despite
at least some degree of understaging in the laparoscopic cases done with specimen
morcellization. This was consistent with earlier results from Ono (1999) and Cadeddu (1998)
demonstrating 97.5% and 91% 5 year disease free survival rates. Portis et al reported a
multicenter experience with 64 patients undergoing laparoscopic radical nephrectomy,
comparing these cases to a series of 69 comparable open radical nephrectomy patients. The
authors noted excellent oncologic results noting no positive margins in the laparoscopic
group, no port site or local recurrence. The disease free survival overall was 92% in the
laparoscopic group (91% in the open cohort) and cancer specific survival was 98%
(laparoscopic) vs. 92% (open). The laparoscopic group has slightly smaller tumors but
analysis of survival by tumor size (> or < 7cm) demonstrated comparable results in the open
and laparoscopic cohorts.
All of these series continue to demonstrate the acceptable morbidity, shorter hospitalization,
faster convalescence and less pain associated with the laparoscopic vs. open radical
nephrectomy. With the emergence of 5 year data demonstating excellent oncologic results,
the move toward minimally invasive surgery of the kidney as first line therapy for T1 – T2
renal cell carcinoma appears justified.
Partial Nephrectomy
Nephron sparing surgery (NSS) is an accepted method of treatment for selected renal masses.
Long term results for properly selected masses reveal oncologic control comparable to the golden
standard, radical nephrectomy. Laparoscopic partial nephrectomy (LPN), has been shown to be
technically feasible by several authors including Janetschek, McDougall, Gill, Rassweiler, and others.
The goal of LPN is to maintain the principles of open NSS in order to maintain the excellent
oncologic control associated with NSS. The challenge with LPN is attainment of suitable
hemostasis.
The indications for LPN are fairly straightforward. The patient must be able to tolerate a
laparoscopic procedure. The properly selected renal lesion should be less than 4cm in size and
peripheral in nature. Polar lesions are preferable, especially early in the laparoscopic surgeon’s
experience with this technique. Renal masses abutting the hilar vessels and central collecting system
can be safely resected by the experienced surgeon. Patients with prior renal surgery or history of
anyinflammatory conditions of the operative kidney should be avoided.
Survival with renal cell carcinoma
• Factors affecting survival
– Stage
– Performance status
– Pathology
– Treatment given
Conclusions
• Good prognostic models available
• Assessment of prognosis important in
choosing treatment
– Palliative nephrectomy
– Immunotherapy
– Other palliative surgery
• Previous therapy may influence anticipated
survival