RENAL CELL CARCINOMARENAL CELL CARCINOMA

CLINICAL PROGRESS AND CURRENT CLINICAL PROGRESS AND CURRENT MANAGEMENTMANAGEMENT

DR KALYAN K SARKAR MS DR KALYAN K SARKAR MS FRCSEdFRCSEd

RCC : SURGICAL OR MEDICAL RCC : SURGICAL OR MEDICAL DISEASE ?DISEASE ?

Early initial diagnosis and Early initial diagnosis and advent of laparoscopic surgery advent of laparoscopic surgery has provided different has provided different treatment options.treatment options.

Molecular pathology of these Molecular pathology of these lesions is better understoodlesions is better understood

Advanced lesions remain Advanced lesions remain difficult to treat by conventional difficult to treat by conventional cytoreductive surgery or cytoreductive surgery or biological response modifier biological response modifier therapytherapy

INCIDENCEINCIDENCE

IncidenceIncidence – There are approximately 30,000 new cases per year There are approximately 30,000 new cases per year

and 12,000 cancer related deaths and 12,000 cancer related deaths – Incidence is rising 6.1 to 9.3 per 100,000 over 20 Incidence is rising 6.1 to 9.3 per 100,000 over 20

years years – Mortality rate has not decreased even with greater Mortality rate has not decreased even with greater

detection of small tumors detection of small tumors Lead time bias Lead time bias Short follow up Short follow up Less aggressive?Less aggressive?

– 25% of tumors present with advanced disease25% of tumors present with advanced disease

PREVALENCE IN INDIAPREVALENCE IN INDIA

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EPIDEMIOLOGYEPIDEMIOLOGY

Equal racial distribution Equal racial distribution 2:1 male to female distribution 2:1 male to female distribution Occurs in 5th to 7th decade of life Occurs in 5th to 7th decade of life Tobacco greatest risk factor Tobacco greatest risk factor Obesity may be a risk factor Obesity may be a risk factor Most cases sporadic, yet also occurs with Most cases sporadic, yet also occurs with Von Hippel-Lindau disease (VHL) [45%], Von Hippel-Lindau disease (VHL) [45%], and less commonly with tuberous and less commonly with tuberous sclerosis, and in rare familial distributions sclerosis, and in rare familial distributions

PATHOLOGYPATHOLOGY

RENAL CELL CARCINOMARENAL CELL CARCINOMA

– Clear cell renal cell carcinomaClear cell renal cell carcinoma– Papillary renal cell carcinomaPapillary renal cell carcinoma– OncocytomaOncocytoma– Chromophobe renal cell carcinomaChromophobe renal cell carcinoma– Collecting duct renal cell carcinomaCollecting duct renal cell carcinoma

Other parenchymal renal tumoursOther parenchymal renal tumours

PATHOLOGYPATHOLOGY

Clear cell carcinoma: comprises >70% of renal Clear cell carcinoma: comprises >70% of renal lesions lesions – VHL gene mutation principAL event. Recent VHL gene mutation principAL event. Recent

association between VHL protein and hypoxia association between VHL protein and hypoxia inducing factor [HIF] protein ties pathology into inducing factor [HIF] protein ties pathology into angiogenesis cascade pathway. angiogenesis cascade pathway.

Papillary renal cell carcinoma: comprises 10-Papillary renal cell carcinoma: comprises 10-15% of renal lesions 15% of renal lesions – Sporadic and hereditary forms Sporadic and hereditary forms – Associated with alterations in chromosomes 7, 17, Associated with alterations in chromosomes 7, 17,

and Y and Y – Generally better survival Generally better survival

PATHOLOGYPATHOLOGY

Chromophobe tumors: 5 % of cases Chromophobe tumors: 5 % of cases – Loss on chromosome 1 Loss on chromosome 1

Collecting duct carcinoma: one percent or less of cases Collecting duct carcinoma: one percent or less of cases – Can mimic transitional cell Ca Can mimic transitional cell Ca – Generally poor outcome Generally poor outcome

Oncocytoma: 5 % of renal tumors Oncocytoma: 5 % of renal tumors – Generally localized and encapsulated. 5% bilaterality Generally localized and encapsulated. 5% bilaterality – Mahogany brown color, acidophilic cells secondary to dense Mahogany brown color, acidophilic cells secondary to dense

mitochondrial hyperplasia mitochondrial hyperplasia – Distinction from renal cell cancer difficult on imaging or needle Distinction from renal cell cancer difficult on imaging or needle

biopsy. Best treated with surgical removal biopsy. Best treated with surgical removal

PATHOLOGYPATHOLOGY

Angiomyolipoma: Renal Hamartomas comprised Angiomyolipoma: Renal Hamartomas comprised of fat, muscle and blood vessels. Tissue of fat, muscle and blood vessels. Tissue signature on CT by demonstration of negative signature on CT by demonstration of negative Hounsfield units. Hounsfield units. – Sporadic, isolated lesions present age 35-50 with a Sporadic, isolated lesions present age 35-50 with a

4:1 female ratio 4:1 female ratio – Tuberous Sclerosis patients demonstrate multiple and Tuberous Sclerosis patients demonstrate multiple and

bilateral lesions. 80% of patients will develop AML. bilateral lesions. 80% of patients will develop AML. – Tumours <4 cm are observed, those >4cm undergo Tumours <4 cm are observed, those >4cm undergo

selective angioembolization or partial nephrectomy selective angioembolization or partial nephrectomy

PATHOLOGYPATHOLOGY

Renal Sarcoma Renal Sarcoma – Pure sarcoma is rare and usually lieomyosarcoma Pure sarcoma is rare and usually lieomyosarcoma – All tumor types can degenerate towards sarcoma All tumor types can degenerate towards sarcoma – Generally poorer outcome Generally poorer outcome

Rare Renal lesions Rare Renal lesions – Adult Wilms tumor Adult Wilms tumor – Lymphoma Lymphoma – Xanthogranulomatous Pyelonephritis [XPG] Xanthogranulomatous Pyelonephritis [XPG] – Haemangiopericytoma Haemangiopericytoma

GRADINGGRADING

Fuhrman grading system Fuhrman grading system – Grade is an important variable Grade is an important variable – Fuhrman system has issues with Fuhrman system has issues with

interobserver variability interobserver variability

STAGINGSTAGING

UICC-AJCC system is generally UICC-AJCC system is generally acceptedaccepted– Currently T1 lesion is 7 cm or less in size, Currently T1 lesion is 7 cm or less in size,

yet 4.0 cm associated with very low yet 4.0 cm associated with very low recurrence rate recurrence rate

– T1a category of <4.0 cm suggestedT1a category of <4.0 cm suggested

PROGNOSISPROGNOSIS

STAGESTAGE 5 YR5 YR 10 YR10 YR

II 90%90% 80%80%

IIII 80%80% 70%70%

IIIIII 50%50% 35%35%

IVIV 10%10% 3%3%

RECURRENCE PULMONARY, HEPATIC OR BONE

FEW ARE LOCAL

MSKCC NOMOGRAM

PARTIAL NEPH IN TUMOURS < 4 CM HAS SURVIVAL OF 100% AT 5 YRS

FOLLOW-UPFOLLOW-UP

– Traditionally, most patients with sporadic RCC are followed every 6 Traditionally, most patients with sporadic RCC are followed every 6 months or yearly with a history and physical examination (H&P), liver months or yearly with a history and physical examination (H&P), liver function studies, serum chemistry (including alkaline phosphatase), function studies, serum chemistry (including alkaline phosphatase), CXR, and abdominal cross-sectional imaging.CXR, and abdominal cross-sectional imaging.

T1: H&P, serum chemistry, and CXR yearly for 5 years T1: H&P, serum chemistry, and CXR yearly for 5 years

T2: H&P, serum chemistry, and CXR every 6 months; T2: H&P, serum chemistry, and CXR every 6 months; abdominal CT scan at 2 and 5 years for 5 years abdominal CT scan at 2 and 5 years for 5 years

T3: H&P, serum chemistry, and CXR at 3 months, then every T3: H&P, serum chemistry, and CXR at 3 months, then every 6 months; abdominal CT scan at 2 and 5 years 6 months; abdominal CT scan at 2 and 5 years

CLINICAL PRESENTATIONCLINICAL PRESENTATION

A QUARTER PRESENT WITH ADVANCED A QUARTER PRESENT WITH ADVANCED DISEASE, LOCALLY ADVANCED OR DISEASE, LOCALLY ADVANCED OR METASTATICMETASTATIC

A THIRD OF PATIENTS POST SURGERY FOR A THIRD OF PATIENTS POST SURGERY FOR LOCALISED DISEASE WILL RELAPSELOCALISED DISEASE WILL RELAPSE

WITH METASTATIC DISEASE THE MEDIAN WITH METASTATIC DISEASE THE MEDIAN SURVIVAL IS 13 MONTHSSURVIVAL IS 13 MONTHS

CLINICAL PRESENTATIONCLINICAL PRESENTATION

THE CLASSIC TRIAD THE CLASSIC TRIAD <10 %<10 %

INCIDENTAL DETECTION INCIDENTAL DETECTION ALMOST 50%ALMOST 50%

SYSTEMIC SYNDROMESSYSTEMIC SYNDROMES– ANAEMIA, FATIGUE, CACHEXIA, WEIGHT LOSS, ANAEMIA, FATIGUE, CACHEXIA, WEIGHT LOSS,

HYPERCALCEMIA, HEPATIC DYSFUNCTIONHYPERCALCEMIA, HEPATIC DYSFUNCTION

RARE SYNDROMESRARE SYNDROMES– ERYTHROCYTOSIS, ENtEROPATHY, NEUROPATHY, ERYTHROCYTOSIS, ENtEROPATHY, NEUROPATHY,

AMYLOIDOSISAMYLOIDOSIS

ImagingImaging

Increased use of imaging has increased the Increased use of imaging has increased the detection of renal lesions most of which are detection of renal lesions most of which are simple cysts. Also a greater percentage of small simple cysts. Also a greater percentage of small renal lesions have been noted which has renal lesions have been noted which has changed the therapeutic strategy towards renal changed the therapeutic strategy towards renal lesions. CT and MRI findings are fairly classical lesions. CT and MRI findings are fairly classical for renal tumors. Initial diagnosis with IV for renal tumors. Initial diagnosis with IV urography or ultrasound may require further urography or ultrasound may require further confirmatory testing.confirmatory testing.

ImagingImaging

Ultrasonagraphy Ultrasonagraphy – Excellent in distinguishing cystic from solid Excellent in distinguishing cystic from solid

masses. masses. – 30-50% of patients >50 years will have renal 30-50% of patients >50 years will have renal

cysts cysts – Bosniak classification provides guidelines. Bosniak classification provides guidelines.

I [Simple cyst] 0% cancer riskI [Simple cyst] 0% cancer riskII [Minimally complicated] 2-10% cancer risk II [Minimally complicated] 2-10% cancer risk III [Indeterminate cyst] up to 50% cancer risk III [Indeterminate cyst] up to 50% cancer risk IV [Cystic renal cell] up to 90% cancer riskIV [Cystic renal cell] up to 90% cancer risk

ImagingImaging

Intravenous Urography Intravenous Urography – Starting point for hematuria evaluations Starting point for hematuria evaluations – Abnormal findings require other imaging for Abnormal findings require other imaging for

conformation conformation – Calcification pattern suggestive Calcification pattern suggestive

Speckled or mottled, 90% cancer Speckled or mottled, 90% cancer

Rim calcification 10-20% cancer Rim calcification 10-20% cancer

ImagingImaging

Computed tomography Computed tomography – Provides an excellent assessment of the Provides an excellent assessment of the

parenchyma and nodal status. Thin slice parenchyma and nodal status. Thin slice images provide superior definition of smaller images provide superior definition of smaller lesions. Good assessment of nodal status is lesions. Good assessment of nodal status is provided. Tissue signature of fat allows provided. Tissue signature of fat allows diagnosis of AML. 3-D reconstruction now diagnosis of AML. 3-D reconstruction now availableavailable

ImagingImaging

Magnetic Resonance Imaging Magnetic Resonance Imaging – Non ionizing radiation modality provides Non ionizing radiation modality provides

excellent demonstration of solid renal masses excellent demonstration of solid renal masses and is image test of choice to demonstrate and is image test of choice to demonstrate extent of vena caval involvement with tumor. extent of vena caval involvement with tumor. Useful in patients with renal insufficiency Useful in patients with renal insufficiency

ImagingImaging

Angiography Angiography – Generally supplanted by MRI angiography Generally supplanted by MRI angiography – Used for embolization of large lesions preoperatively Used for embolization of large lesions preoperatively

Radionuclide Imaging Radionuclide Imaging – Most useful in detecting pseudo-masses Most useful in detecting pseudo-masses – Tumors and cysts are photo-deficient areas Tumors and cysts are photo-deficient areas

Percutaneous biopsy Percutaneous biopsy – Generally not useful due to the high [30-50 percent] Generally not useful due to the high [30-50 percent]

false positive rate false positive rate – Some value in ruling out metastatic disease or Some value in ruling out metastatic disease or

lymphomalymphoma

CLINICAL STAGINGCLINICAL STAGING

Chest X-ray or Chest CT Chest X-ray or Chest CT

CT/MRI scan of abdomen or pelvis CT/MRI scan of abdomen or pelvis

Bone scan with plan films (for elevated Bone scan with plan films (for elevated alkaline phosphatase or bone pain). alkaline phosphatase or bone pain).

Laboratory: CBC, LFT's, alkaline Laboratory: CBC, LFT's, alkaline phosphotase, BUN, creatinine.phosphotase, BUN, creatinine.

SURGICAL TREATMENT SURGICAL TREATMENT OPTIONS IN RCCOPTIONS IN RCC

CLASSICAL RADICAL NEPHRECTOMYCLASSICAL RADICAL NEPHRECTOMY

OPEN PARTIAL NEPHRECTOMYOPEN PARTIAL NEPHRECTOMY

LAPAROSCOPIC PARTIAL LAPAROSCOPIC PARTIAL NEPHRECTOMYNEPHRECTOMY

ENERGY APPLICATIONS ENERGY APPLICATIONS PERCUTANEOUS, EXTRACORPOREAL, PERCUTANEOUS, EXTRACORPOREAL, LAPAROSCOPICLAPAROSCOPIC

EXPECTANT TREATMENTEXPECTANT TREATMENT

TREATMENTTREATMENT

Classic Radical Nephrectomy Classic Radical Nephrectomy – Gold standard of comparison. Performed Gold standard of comparison. Performed

through several different flank or subcostal through several different flank or subcostal approaches. Well tolerated. approaches. Well tolerated.

– Minimal role for aggressive Minimal role for aggressive lymphadenectomy. Nodes generally removed lymphadenectomy. Nodes generally removed from ipsilateral great vessel. from ipsilateral great vessel.

– Adrenalectomy not required if preoperative Adrenalectomy not required if preoperative imaging is normal or if the renal tumor is in the imaging is normal or if the renal tumor is in the mid or lower pole of the kidney. mid or lower pole of the kidney.

TREATMENTTREATMENT

Inferior vena cava Inferior vena cava extension extension – Sub classification based on Sub classification based on

cranial extent of lesion cranial extent of lesion figure 1 figure 1

– Patient prognoses based Patient prognoses based on stage of lesion and not on stage of lesion and not extent of thrombus extent of thrombus

– Complexity of surgery Complexity of surgery ranges from partial ranges from partial clamping of the vena cava clamping of the vena cava to cardiopulmonary bypass to cardiopulmonary bypass with hypothermia and with hypothermia and circulatory arrest. Mortality circulatory arrest. Mortality 2-14 %.2-14 %.

TREATMENTTREATMENT

Expectant management Expectant management – Small lesions [<3.0 cm] have a minimal risk of Small lesions [<3.0 cm] have a minimal risk of

metastasis and increase in size approximately metastasis and increase in size approximately 6 mm per year. In elderly and very ill patients 6 mm per year. In elderly and very ill patients minimal intervention may be warrantedminimal intervention may be warranted

TREATMENTTREATMENT

Percutaneous or laparoscopic ablation Percutaneous or laparoscopic ablation – CT guided radiofrequency ablation - potential CT guided radiofrequency ablation - potential

minimally invasive therapy requiring further minimally invasive therapy requiring further follow-up follow-up

– Laparoscopic cryosurgical ablation - less Laparoscopic cryosurgical ablation - less invasive ablation technique will require further invasive ablation technique will require further follow-up follow-up

– These and similar technologies promising and These and similar technologies promising and suited to the higher incidence of smaller suited to the higher incidence of smaller lesions detected incidentally. lesions detected incidentally.

TREATMENTTREATMENT

Nephron-sparing surgery Nephron-sparing surgery – Local recurrence rate 1-2% Local recurrence rate 1-2% – 15% of small lesions may not be renal cell Ca 15% of small lesions may not be renal cell Ca – Preservation of renal function is laudable Preservation of renal function is laudable – Indicated in small lesions [<4cm], patients with poor Indicated in small lesions [<4cm], patients with poor

renal function, bilateral disease, and solitary kidney renal function, bilateral disease, and solitary kidney – Renal cooling and intraoperative ultrasound required Renal cooling and intraoperative ultrasound required

in more difficult cases. in more difficult cases. – Open vs. laparoscopic approach based on tumor Open vs. laparoscopic approach based on tumor

location, size, and operator experience. location, size, and operator experience.

TREATMENTTREATMENT

Laparoscopic nephrectomy Laparoscopic nephrectomy – Pure laparoscopic and "hand-assisted" Pure laparoscopic and "hand-assisted"

techniques available. Hand- assisted techniques available. Hand- assisted approach has promulgated the technique, approach has promulgated the technique, feasible for most tumors <8-10 cm depending feasible for most tumors <8-10 cm depending on location. on location.

– Operative time longer, hospital stay and pain Operative time longer, hospital stay and pain requirement less, time to normal function requirement less, time to normal function shorter than flank incision. shorter than flank incision.

– Learning curve associated with this approach. Learning curve associated with this approach.

TREATMENTTREATMENT

Metastatic disease - Surgery Metastatic disease - Surgery – Outcome with metastatic disease depends on Outcome with metastatic disease depends on

performance status performance status – Low volume metastasis, especially pulmonary Low volume metastasis, especially pulmonary

involvement tend to respond best. involvement tend to respond best. – Recent data to suggest a slight but Recent data to suggest a slight but

statistically significant survival benefit if statistically significant survival benefit if nephrectomy performed in conjunction with nephrectomy performed in conjunction with immunotherapy. Patients with significant immunotherapy. Patients with significant disease burden and poor performance status disease burden and poor performance status less likely to benefitless likely to benefit

TREATMENTTREATMENT

Metastatic disease - Medical therapy Metastatic disease - Medical therapy – Few cytoreductive agents have any significant Few cytoreductive agents have any significant

impact on renal cell carcinoma impact on renal cell carcinoma – Radiation therapy has little proven effect on Radiation therapy has little proven effect on

renal cell carcinoma renal cell carcinoma – Cytokine therapy [IL-2] demonstrates a Cytokine therapy [IL-2] demonstrates a

complete response in 4% of patients and a complete response in 4% of patients and a partial response in 12-20% of patients partial response in 12-20% of patients

– Antiangiogenesis agents have theoretical Antiangiogenesis agents have theoretical promise for this diseasepromise for this disease

THANK YOUTHANK YOU