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					Renal Cell Carcinoma
   : Update, 2003

      서울아산병원
  울산의대 비뇨기과학 교실
       김청수
          Incidence
Incidence : 30,800/yr in USA
           20,000/yr in European union
             1,853(2001년 수련병원통계)
Incidence has been rising
 Annual increase : 2.3-4.3%
 ↑ all age group
 ↑ all stages, including metastatic dis
 Greatest ↑ in localized tumor
 Mortality and metastasis
Death : 12,100 in US, 2002

5YSR
  34% in 1954
  62% in 1998

Matastasis
 At initial presentation, 30% has mets
 After Nx, 30% develop mets
         Subjects

1. Hereditary renal cell carcinoma

2. Nephron sparing surgery

3. Prognostic factors in RCC
        I. Hereditary RCC
             Genetic classification of RCC

    Tumor type        Tissue origin   Genetic Alteration

Clear cell         Proximal tubule    3p(VHL gene)

Papillary          Proximal tubule    +7(c-met
                                      oncogene), +17, -Y
Chromophobe        Collecting duct    -1, -2, -6, -10

Collecting duct    Medullary          -1, -6, -14, -11, LOH
                   collecting duct    8p and 13q
Oncocytoma         Distal tubule      -1. –Y, 11q

Papillary adenoma Proximal tubule     +7, +17, -Y
           Renal cell carcinoma
Sporadic RCC
Hereditary RCC : 4%,
   Multifocal, bilateral, young age
1. Von Hippel Lindau disease (VHL)
2. Hereditary type I papillary renal
     carcinoma (HPRC)
3. Familial renal carcinoma
     associated with
     Birt Hogg Dube syndrome (BHDS)
4. Hereditary type II papillary renal
     carcinoma (HLRCC)
5. Familial renal carcinoma
  Molecular genetic classification
   of hereditary renal carcinoma

Gene          Renal cell carcinoma

VHL       Clear cells/compact growth
Met       Type I papillary growth pattern
BHD      Chromophobe RCC,
            oncocytoma
FH (fumarate hydratase)
         Type II papillary growth pattern
            VHL disease
Autosomal dominant

Incidence - 1: 36,000/year

The most common familial syndrome in

  clear cell RCC

Frequency of cancer : 28-45%
VHL gene on chromosome 3
  Gene for clear cell renal carcinoma

  Knudson 'two-hit' hypothesis
    Loss of DNA or
    another mechanisms
    (mutation,
       transformation)

  Mutation in 57% of sporadic RCC
             VHL disease
Clinical features

 Multiple, bilateral RCC and cysts
 Cerebellar and spinal hemangioblastoma (MRI)
 Pheochromocytoma (abdomnal CT or US)
 Retinal angioma
 Epididymal cystadenoma (testicular US)
 Pancreatic cyst and islet tumor
 Tumor in inner ear, endolymphatic sac tumors
                 VHL disease
      Hypoxia and RCC tumorigenesis

                                    VHL

  HIF(hypoxia inducible factor)               HIF degradation

Hypoxia                            Normoxia


      Target gene induction
GULT-1      VEGF        IGF          CA
  ↓          ↓          ↓            ↓
Glucose     Angio-      Growth       Metabolism
Transport   genesis     Survival     pH regulation
   HPRC(hereditary papillary RCC)
AD, papillary type I RCC
HPRC gene : Met gene, 7q31.3
  Tyrosine kinase receptor superfamily
  Activation of mutation in
    tyrosine kinase domain of gene
Stomach CA, colon CA, breast CA, etc
Multiple RCC
  RCC ass with BHD(Birt-Hogg-Dube) syndrome

AD
BHD gene on chromosome 17
Skin fibrofolliculoma
  Benign, small, face, neck, ant. trunk
Lung cyst (70%) : spontaneous pneumothorax (25%)

Bilateral, multifocal RCC
 Chromophobe, oncocytoma,
   papillary, clear cell
HLRCC(hereditary leiomyomatosis RCC)
Reported a family from Finland
AD
Mutatinon in FH(fumarate hydratase) gene
 : urea producing Kreb’s cycle enzyme gene
Skin & uterine leiomyoma : hysterectomy
Type 2 papillary RCC : 20% of family
  Early onset, aggressive and
     early metastasis
    Other familial/hereditary RCC
Medullary carcinoma of the kidney
 Young patients with the sickle cell trait
 monosomy 11


Hereditary nonpolyposis colon cancer
 Lynch type 2 : associated kidney cancer
 2-9% of patients : urinary tract tumor


Familial papillary RCC with PTC(papillary thyroid carcinoma)
 Single clinical and genetic spectrum : ?
 no germline MET mutations


Familial renal cell carcinoma
 Iceland, 68% of sporadic RCC pts have 2nd drgree relative RCC pts
  Screening guidelines for
  hereditary renal cancer

No established guideline
Interval of follow-up study
 Aggressive phenotype : every 3-6 mos
 Mild phenotype : every 2-3 yrs
   II. Nephron sparing surgery

Open partial nephrectomy

Laparoscopic partial nephrectomy

Tissue ablation therapy

 Radiofrequency ablation

 Cryoablation

 High intensity focused USG
 Partial nephrectomy in sporadic RCC

Low dose heparin(50 u/kg) & IV mannitol(12.5g),
   5 min before occusion of renal artery
Surface cooling for 10 min : upto 3 hr safe ischemia
1cm margin

Extracorporeal partial nephrectomy
   with renal autotransplantation
: Jehovah's witness
   with multiple or complex tumors
87-90% 5YSR with a local recurrence in 4-6%
Partial nephrectomy in hereditary RCC

Nephron sparing surgery >= 3cm

Not curative but 'set back the clock’
  Prevention of metastasis
  Upto 600 tumors per kidney in VHL pts
  35-45% of VHL patients have died of
     complications of metastatic RCC

Intraoperative US : additional 20%
Laparoscopic partial nephrectomy
 TissueLink
 (RF)




RF : 0.5-1cm coagulation necrosis
              RFA (radiofrequency ablation)




Power : 50 – 250watt 10min Tx per tumor
10-70oC with cell death
5-6 cm with single needle insertion
Successful Tx. : HU < 10 with enhancement
       Cryoablation

Rapid freeze and slow thaw
Critical lethal temperature : -19.4℃
At least, 3.1mm beyond visible margin
          HIFU (High intensity focused USG)
Contactless thermal ablation

Above 65℃ within a pulse

 duration of less than 5 sec

Accessible to different organ

: liver, bladder, prostate,

 breast and brain
III. Prognostic factors of RCC
 Factors ass with tumor
 Traditional prognostic factor
   TNM stage
   Grade
   Histologic type
   ECOG performance status
 Biomolecular or genetic factor
   : promising
             TNM stage
The most important prognostic factor
2002 TNM : T1a (<4cm) : 98% 5YSR
             T1b (4-7cm) : 88% 5YSR
5YSR by TNM stage
                       %TNM stage
                 Ⅰ      Ⅱ      Ⅲ      Ⅳ
Javidan          95     88     59     20
Tsui et al       91     74     67     32
Kinouchi et al   96     95     70     24
Stein            95     85     60     23
Guinal et al     100    96     59     16
               FG1    2   3     4


Grade

: Second important prognostic factor

 Allan, 2001

 Grade   Ⅰ      Ⅱ    Ⅲ    Ⅳ
 5YSR    89%   65% 46.1% 0%
Histologic types


Mahul et al. 2002
           Chromophobe Papillary Clear Unclassified
5 YPFSR         100%               86%        76%   24%
5 YDFSR           94%              88%        70%   18%


YPFSR : year progression-free survival rate
YDFSR : year disease-free survival rate
      Histologic types
Sarcomatoid change
 No more histologic type
 < 5% in all histologic type of RCC
 Early metastasis, locally invasive
   : 35% 5YSR
 Correlation with overexpression of p53
   Tumor thrombus
4-10%
Skinner et al.
 Location of thrombus Subheptic Intrahepatic   Atrial
      5YSR               35%          18%      0%

Paulson and Libertino
 5YSR : 40-65%
 No correlation with location of thrombus

If no vein wall invasion and complete remove of
 thrombus, venous thrombus does not dictate prognosis
Survival of thrombus(+), 72%
 is similar to that of thrombus(-), 81%
 if no perinephric fat invasion,
   hepatic vein invasion,
   renal pelvic invasion

Microscopic vein invasion
 correlated with disease progression
 not an independent prognostic factor

Into the veins of the renal sinus
 ↑ risk for metastasis, even confined to kidney
           Thrombectomy at AMC
Thrombectomy with nephrectomy
  : 47 pts
Period : 1990-2003.1
M/F : 39/8
Average age : 58.9 ( 33-77)

With symptom at initial presentation : 29 (61.7%)
Gross hematuria : 19 abdominal mass : 2 flank pain : 4 weight loss : 4
Average tumor size : 10.2cm(2-24)
Location of thrombus
  I (renal vein)         23 (48.9%)
  II (infrahepatic)      16 (34.1%)
  III (infradiaphragm)    6 (12.8%)
  IV (supradiaphragm) 2 (4.2%)
         Thrombectomy at AMC
Distant metastasis, initially : 8 (17%)
 Lung :5 bone :1 liver :1 lung & brain :1

Lymph node invasion : 12 (25.5%)
Histologic type
        Conventional 38
        Papillary     3
        Chromophobic 2
        Mixed         4
Recurrence
       III 14/29 (48.2%)
       IV 8/18 (44.4%)
Lymph node involvement
Giberti, 1997

 Extensive dissection of
  retrocaval, interaortocaval or
  paraaortic lymph node
  in the absence of distant mets
   improvement of prognosis
                   Metastasis
Sites and frequency
      Site            %      Good prognosis
      Lung           50-60
                             1. single metastatic site
  Lymph node         30-40
                             2. time without mets :
      Liver          30-40
                                > 1 or 2 year
      Bone           30-40
                             3. lung metastasis
    Adrenal           20
                             4. curative surgical excision
 Opposite kidney      10
      Brain           5
             Metastasis

Motzer, 1999 (Poor prognostic factors)

Low Karnofsky performance < 80%
High LDH > 1.5 times of upper limit of normal
Low Hb < normal limit of Hb
High corrected s-calcium > 10mg/dl
No nephrectomy
         Metastasis
Motzer et al. 1999 (3   Risk Groups)


 Favorable risk (no risk factor, 25%)
   20mo median survival
 Intermediate risk group(1-2 risk factor, 53%)
   10mo median survival
 Poor risk (>=3 risk factor, 22%)
   4mo median survival
    Proliferation marker

AgNOR : silver-staining nucleolar organizing regions
Transcriptional activity of ribosomal RNA
Cellular mitotic activity
Score : number of intranucleolar dot-like
        AgNOR
Independent predictors of survival
    Proliferation marker
PCNA : Proliferating cell nuclear antigen
Protein synthesized during late G1and S phase
PCNA index ≤ 10% :
 significant for disease free period
 no stastistically difference of survival


Ki-67
Detectable during G1 phase
 ↑ during S phase, ↓ during mitosis
More accurate cell proliferation than PCNA
Chemoresistance
MDR1 : Multidrug resistance 1,
          Poor survival with low expression

GST-π : glutathione-S-transferase-pi

MRP : multidrug resistance associated
         protein genes
Topoisomerase-Ⅱα

Apoptosis
p53 : poor prognosis
      but no related to survival
  CA Ⅸ (carbonic anhydrase Ⅸ)
Regulation of cell proliferation in hypoxia
Oncogenesis and tumor progression

High expression : upper GI mucosa, pancreas, GB, liver

No expression : normal human heart, lung, kidney, prostate,
           brain, peripheral blood, placenta, and skeletal muscle
             CA Ⅸ
Overexpressed in RCC
e.g) cervical squamous, ovarian, colorectal,
    esophageal, bladder, NSCLC, breast CA

   Benign                       Malignant
  (% CA9 positive)            (% CA9 positive)
Normal       0              All RCC      86
Oncocytoma 0                Clear cell    93
                            Papillary     5
                            Chromophobe 0
                            Collecting duct 25
              CA Ⅸ
Matthew, Clin Cancer Res 2003

Low CA Ⅸ(85%)staining :
 1. Independent prognostic factor
     in survival with mets
 2. Even nonmets, worse outcome similar to mets
 3. Lower CA Ⅸ levels in metastatic lesion
     relative to matched primary lesion
       the most significant molecular marker
          : need for adjuvant immunotherapy and
              CA Ⅸ-targeted therapy
                 CA Ⅸ
Jose, Clin Cancer Res 2003

GMCA-9 : Fusion protein of CA Ⅸ and GM-CSF
         Maturation of dendritic cell and CA-9 specific
          cytotoxic lymphocyte in vitro
         Inhibition of growth of tumor cell in mice


  generating an immune response both in vitro and in vivo
  ex vivo GMCA-9-transduced DCs as kidney cancer vaccine
            Angiogenesis

Density of intratumoral microvessel
  Controversial
VEGF (Vascular endothelial growth factor)
  Not independent prognostic factor
  Ass with histologic grade and stage
         Cytogenetics

Aneuploid DNA
  Controversial


Numerous chromosomal anomalies &
  overexpression of mYC(I-MYC, c-MYC) gene
  Associated with histologic grade and stage
   No independent prognostic factor
     Factors ass with patient

Weight loss > 10% of body weight before diagnosis
  : independent prognostic factor


ECOG PS (Eastern Cooperative Oncology Group
         Performance status) ≥ 2
  : independent factor for low survival
   little effect on immunotherapy


Elevated ESR, Decreased Hb, IL-6, β2-microglobulin,
serum albumin, calcium, LDH, alkaline phosphatase
Factors ass with Tx
     Surgery
Combining prognostic factors
 UCLA integrated staging system (UISS)
    (Zisman, J Clin oncol 2001)
  TNM stage + ECOG PS + tumor grade
  UISS   Stage   PS    Grade   2Yr(%)   5Yr(%)
   Ⅰ      Ⅰ       0     1,2     96       94
          Ⅰ       0     3,4
          Ⅱ      any    any
   Ⅱ      Ⅱ       0     any     89       67
          Ⅲ      ≥1      1
   Ⅲ      Ⅲ      ≥1     2-4     66       39
          Ⅲ       0     1,2
   Ⅳ      Ⅳ       0     3,4     42       23
          Ⅳ      ≥1     1-3
   Ⅴ      Ⅳ      ≥1      4        9       0
UISS
                      UISS
           (Zisman, J Clin Oncol 2002)
Risk group for metastasis vs nonmetastasis


 Risk group for nonmetastatic RCC

 T stage          1               2            3            4
 Grade     1-2        3-4             1        >1
 ECOG PS    0    ≥1    0     ≥1       0   ≥1       0   ≥1
 Risk      Low             Intermediate                High
                     UISS
   Risk groups for metastatic RCC

 Stage       N1M0             N2 or M1
 Grade               1 or 2     3        4
 ECOG PS             0   ≥1    any   0       ≥1
 Risk          Low        Intermediate       High


NM-high risk group ≈ M-low risk group
   in disease progression rate &
        effectiveness of IMT
UISS
      Kattan’s nomogram
        (Kattan, J Urol 2001)
Symptom, histology, TNM stage, tumor size
 5 year recurrence free survival rate

				
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posted:6/25/2012
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