renal cell carcinoma and its management

1. RENAL CELL CARCINOMA
MODERATOR : DR VIKAS KUMAR
Mch( urology & renal transplant)
presentor : DR SHIV KISHOR
DNB SURGERY

2. • 2% to 3% of all adult malignant neoplasms
• Most lethal of the common urologic cancers.
• 12 new cases per 100000 population
• male-to-female predominance of 3 : 2
• sixth and seventh decades of life

3. • Majority sporadic- 2%to 3 % familial
• Incidence is increasing 3-4% per year
• Mortality rates are also increasing
• RCC in childhood is uncommon
• RCC as common as Wilms tumour during second decade of life
• Chidrens and young adults may respond to surgical treatment
better than elderly

4. India
• Incidence: 15-22/100,000/Yr, 2% of all malignant tumors,
• In India : Males: 1.2/100,000, Females : 0.5/ 100,000
• Indians living in western countries have higher incidence
• M:F = 2:1
• Age peak: 50 to 70 years
• India : mean age – 52 years

5. Incidence of Urologic Malignancies in India: Age
adjusted incidence rate (Per 100,000 populations)

6. classification

7. Etiology

8. Familial renal cancer and molecular genetics
• Genetics of clear cell carcinoma
– Von Hippel- Lindau disease VHL
– TP53
– PTEN
• Papillary renal carcinoma
– Type 1
– Type 2 heridetary leiomyomatosis and renal cell carcinoma
– XP11.2 translocation RCC
• Brit-Hogg-Dubbe syndrome
• Succinate dehydrogenase gene mutation
• Tuberous sclerosis

9. Von Hippel- Lindau disease VHL
• Autosaml dominant disorder – knudsons hypothesis
• VHL tumour suppressor gene
• 3p25-26
• Protein 213 aminoacids, 3 exons

10. Phenotypic genotypic correlation

11. • RCC in VHL
–Early age of onset
–Bilateral
–Multifocal involvement
–Most common cause of mortality
–Clear cell carcinoma
–Hypervascular

13. Hereditary papillary RCC (HPRCC)
• Type 1 papillary RCC
• Activation of proto oncogene
• C-MET protooncogene at 7q31
• Receptor thyrosine kinase for hepatocyte growth factor
• Autosomal dominant mode of transmission
• Trisomy of chromosome 7 was described as hallmark features
of papillary renal tumours

14. Type 2 heridetary leiomyomatosis and renal cell carcinoma
• Renal tumours are solitary, unilateral and most aggressive
• Collecting duct RCC are also common
• Large, prominent eosinophilic nuclei and nucleoli with perinuclear clearing
• Locus mapped in region of 1q42-44, site of fumarate hydratase gene
• Tumour suppressor gene
• Autosomal dominant inheritance
• RCC lower than cutaneous and uterine manifestations
• 20% of patient develop RCC
• Fumerate accumulation stabilize HIF1

15. XP11.2 translocations of RCC
• Tumours detected in young children and adolescent
• Tranlocations involving Xp11.2 and 1q21.2
• Associated with papillary cancers
• Fusion protein PRCC-TFE3
• Strong transcription activator of MET

16. Brit-Hogg-Dube syndrome
• Renal tumours are chromophobe RCC, oncocytoma, hybride or
transitional cell carcinomas
• Other features are cutaneous fibrofolliculomas, lung cyst,
sponataneous pneumothorax
• Penetrance of RCC 20-40%
• Bilateral and multifocal
• Average age of presentation 50yrs
• Mapped on 17p12, folliculine
• Folliculin may interface with mTOR pathway
• Autosomal dominant pattern

17. Tuberous sclerosis complex
• Predominant renal manifestation is angiomyolipoma, RCC 2-3%
• Othe manifestations are facial angiofibroma,
lymphangiomatosis of lung, neurological manifestations
• TSC1- hemartin, TSC2 – tuberin
• Both negatively egulate mTOT signaling

18. Tumour biology and clinical implications

19. • Immunobiology and immune tolerance
– Tumour associated antigens
• Carbonic anhydrase IX
• B7 family surface glycoprotein
• Spontaneous regression 0.3 to 7%

20. Pathology
• All RCC are by definition adenocarcinomas, derived from
renal tubular epithelial cells
• Gross – round or ovoid shape, circumscribed by
pseudocapsule
• Cystic degeneration 10-25% (associated with better
prognosis)
• Calcification can be stippled or plaque like – 10-20%
• Predilection for involvement of venous system 10%RCC

21. • Clear cell renal carcinoma
– 70-80% of all RCC
– Tumour typically yellow, highly vascular
– Clear cell, granular cell, or mixed
– Clear cell – round or polygonal with abundant cytoplasm
containing glycogen, cholesterol, cholesterol esters, and
phospholipids,
– All of which are readily extracted by the solvents used in routine
histologic preparations, contributing to the clear appearance of
the tumor cells

22. – Granular cells -- eosinophilic cytoplasm and abundant mitochondria,
can predominate.
– Two to 5 percent of clear cell RCC demonstrate sarcomatoid features
– Clear cell RCC is more likely to exhibit venous tumor extension than
any other subtype of RCC
– Chromosome 3 alterations and VHL mutations are common in clear
cell RCC, and mutation or inactivation of this gene has been found in
a majority of sporadic cases

24. • Papillary Renal Cell Carcinoma
– Second most common histologic subtype
– It represents 10% to 15% of all RCCs
– More commonly found in patients with end-stage renal failure and
acquired renal cystic disease
– Basophilic or eosinophilic cells arranged in papillary or tubular
configuration

25. – More than 50% or 75% of the tumor had to exhibit such architectural
features to qualify as a papillary RCC
– Multicentricity, which approaches 40% in many series
– Type 1 papillary RCC, the more common form, consists of basophilic
cells with scant cytoplasm
– Type 2 papillary RCC include potentially more aggressive variants with
eosinophilic cells and abundant granular cytoplasm

27. • Chromophobe Renal Cell Carcinoma
– Derived from the cortical portion of the collecting duct
– It represents 3% to 5% of all RCCs
– The tumor cells typically exhibit a relatively transparent cytoplasm
with a fine reticular pattern that has been described as a “plant
cell” appearance
– Perinuclear clearing or “halo” is typically found and electron
microscopic findings

28. – Microvesicles characteristically stain positive for Hale colloidal iron,
indicating the presence of a mucopolysaccharide unique to
chromophobe RCC
– Better prognosis for localized chromophobe RCC than for clear cell
RCC but a poor outcome in the subset of patients with sarcomatoid
features or metastatic disease

30. • Collecting Duct Carcinoma
– Less than 1% of all RCCs
– Occurred in younger patients, often in the third, fourth, or fifth
decades of life
– up to 50% have metastatic disease at the time of detection
– Ulex europaeus agglutinin 1 reactivity and positivity for E-cadherin
and c-KIT
– On microscopic examination, these tumors consist of an admixture of
dilated tubules and papillary structures typically lined by a single
layer of cuboidal cells, often creating a cobblestone appearance

31. • Renal Medullary Carcinoma
– Exclusively in association with the sickle cell trait
– Arise from the calyceal epithelium near the renal papillae
• Sarcomatoid Differentiation
– Sarcomatoid differentiation is characterized by spindle cell
histology, positive staining for vimentin, infiltrative growth
pattern, aggressive local and metastatic behavior, and poor
prognosis
– Found in 1% to 5% of RCCs, most commonly in association with
clear cell RCC or chromophobe RCC

32. • Unclassified Renal Cell Carcinoma
– Most are poorly differentiated and are associated with a highly
aggressive biologic behavior and a particularly poor prognosis

33. Clinical Presentation
• Kidney within the retroperitoneum, many renal masses remain
asymptomatic and nonpalpable until they are advanced.
• With the more pervasive use of noninvasive imaging for the
evaluation of a variety of nonspecific symptom complexes, more
than 50% of RCCs are now detected incidentally
• The classic triad of flank pain, gross hematuria, and palpable
abdominal mass is now rarely found - too late triad 10%
• In advanced stage: hematuria 60%, flank pain-40%, palpable
abdominal mass- 45%,
• Weight loss 35%, Anemia- 20%, varicocele, edema of leg (due to
invasion of renal vein or IVC)

36. • METASTATIC SPREAD
• 30% of cases have distant
metastasis at diagnosis
• Tumor < 3cm in diameter-
usually without metastasis
• Hematogenous metastasis -
Lung, liver, bone, CNS
• Lymphatic : to pelvic and para-
aortic lymph nodes
• Local : to regional lymph nodes:
para-aortic, paracaval, renal
hilar lymph nodes

37. • Stauffer syndrome
– Non metastatic hepatic dysfunction
– 3-20% of cases
– Almost all patients with Stauffer syndrome have an elevated serum alkaline
phosphatase level, 67% have elevated prothrombin time or
hypoalbuminemia, and 20% to 30% have elevated serum bilirubin or
transaminase levels
– Other common findings include thrombocytopenia and neutropenia, and
typical symptoms include fever and weight loss, many patients are found to
harbor discrete regions of hepatic necrosis .
– Biopsy - demonstrates nonspecific hepatitis associated with a prominent
lymphocytic infiltrate
– Elevated serum levels of IL-6 - this and other cytokines may play a pathogenic
role
– Hepatic function normalizes after nephrectomy in 60% to 70% of cases.
– Persistence or recurrence of hepatic dysfunction is almost always indicative
of the presence of viable tumor and thus represents a poor prognostic
finding

38. Screening and Clinical Associations

39. Investigations
• Intravenous pyelography
– Lack of sensitivity and specificity of intravenous pyelography for the
detection of parenchyma tumors is well documented
– Miss small anterior or posterior lesions that do not distort the
collecting system or the contour of the kidney.
– Features suggestive of malignancy
• Calcification within the mass
• Increased tissue density
• Irregularity of the margin and
• Distortion of the collecting system

40. • Ultrasonography
– Performed because it is noninvasive, accurate, and relatively
inexpensive
– Reliable for differentiation of solid tissue from fluid and can
establish the diagnosis of a simple renal cyst
– Criteria for simple cysts have been defined and include a
• Smooth cyst wall, a
• Round or oval shape without internal echoes, and
• Through-transmission with strong acoustic shadows posteriorly.
– If these criteria are met, observation is sufficient in an
asymptomatic patient
– Renal mass that is not clearly a simple cyst by strict ultrasound
criteria should be evaluated further with computed tomography
(CT)

41. • CT scan
– Any renal mass that enhances with intravenous administration of contrast
material on CT by more than 15 Hounsfield units (HU) should be
considered an RCC until proved otherwise (Hartman et al, 2004).
– Solid masses that also have substantial areas of negative CT attenuation
numbers (below −20 HU) indicative of fat are diagnostic of AMLs
– 10% to 20% of solid renal masses CT findings are indeterminate, and
additional testing or surgical exploration is needed to establish a definitive
diagnosis

42. • Magnetic resonance imaging (MRI)
• Renal arteriography has a limited role in the diagnostic
evaluation of renal masses and is primarily reserved for
patients with concomitant renal artery disease
• Renal mass biopsy is now being revisited for the evaluation
of renal masses
– False-negative rate of renal mass biopsy was thought to be 18%
– Overall accuracy is greater than 80%.
– Assessment of tumor grade and histologic type, which reflects tumor
aggressiveness, is also accurate in the majority of cases
– The risks of clinically significant perinephric bleeding and
pneumothorax also appear to be low (<1%), and needle tract seeding is
exceedingly rare when centrally located, infiltrative renal masses are
excluded.

43. • Renal mass biopsy is now being considered more frequently,
particularly in
– Younger, healthy patients who are unwilling to accept the uncertainty
associated with renal mass biopsy are still typically managed
primarily based on radiographic and clinical considerations.
– Suspicion of renal abscess
– When RCC must be differentiated from metastatic malignant disease
– Renal lymphoma

47. staging

53. • Prognostic Factors – MSKCC Scoring System
• Poor-prognosis patients are defined as those having ≥ 3 more
factors: these are predictors of short survival:
• Serum LDH > 1.5 times the upper limit of normal
• Hemoglobin (g/dl) : < lower limit of normal
• Corrected serum Calcium > 10 mg/dL (2.5 mmol/L)
• Interval less than a year from original diagnosis to start of systemic
therapy
• Karnofsky Performance Score ≤ 70
• ≥ 2 sites of organ metastasis

56. Management of localized RCC
SURGERY -
•Radical nephrectomy
•Nephron sparing partial nephrectomy
OTHER MODALITIES
•Radiotherapy
•Chemotherapy
•Targeted molecular therapy

58. • it includes a systematic approach with careful mobilization of
Gerota’s fascia and early vascular control.
•
• For left-sided exposure, the lienorenal ligament is incised to
mobilize the spleen cephalad.
• On the right side, the hepatic flexure of the colon is mobilized.
• The plane between the mesentery of the colon and Gerota’s fascia
is then developed using a combination of sharp and blunt
dissection.
• On the right side, the vena cava is exposed by Kocherizing the
duodenum.
• Using blunt dissection, the retroperitoneal fat overlying the renal
vessels is separated, exposing the renal hilum.

59. TYPES – POLAR NEPHRECTOMY
WEDGE RESECTION
ENUCLEATION

61. Thermal abalition therapy
• Cryo /RFA : altrnative to NSS
• done by lap / percuteniously
• local recurence is high
• Ideal candites : advance age with significant co morbidity
• local recurence after previous nss
• multiple lesion in wich nss is combersome

62. Locally advance disease
• Stages II and III. Locally advanced tumors are managed with
radical nephrectomy, which can require resection of adjacent
organs, and with tumor thrombectomy from the renal vein and
possibly the inferior vena cava.
• Between 40% and 60% of patients can be cured with such an
aggressive surgical approach.

64. • After surgical excision, up to 30% of patients with localized tumors
experience relapse.
• The lung is the most common site of distant recurrence, seen in
50% to 60% of patients.
• The median time to relapse after surgery is approximately 2 years,
with most relapses occurring within 5 years.
• Interferon alpha and high-dose interleukin-2 (IL-2) have been
tested as adjuvant treatments following resection of stage 1-2
kidney cancer. However, no benefit has been seen in randomized
trials.

65. • (NCCN) Kidney Cancer Panel has recommended that patients
be seen every 6 months for the first 2 years after surgery and
annually thereafter.
• Each visit should include a history, physical examination, and
comprehensive metabolic panel (eg, blood urea nitrogen,
serum creatinine, calcium levels, LDH, and liver function tests).
Abdominal and chest imaging studies should be done
approximately 2 to 6 months after surgery and as clinically
indicated thereafter.

66. • Overall invoveloment of venous system in rcc is 4% to 10%
• Clinical suspicion in case of rcc with lower extremity edema ,
isolated rt sided varicocele .
• Staging of ivc thrombus
• level 1 ; ADJUCENT to renal ostium of renal vein
• Level 2 extending up to lower aspect of liver
• Level 3 intrahepatic portion of ivc
• Level 4 aboveb diaphragm

68. • Stage IV. Cytoreductive nephrectomy before systemic therapy
is recommended in patients with a surgically resectable
primary tumor.
• Metastasectomy should be considered in patients with
favorable features such as a solitary metastasis or a long
interval between initial diagnosis and the development of
metastatic disease.
• In these patients, the 5-year disease-free survival rate can be
as high as 30%.

70. • Systemic therapy is recommended for patients with residual
metastatic disease,
• though patients with low-volume indolent metastases may
initially undergo a period of observation.
• Several systemic agents exist today that are non-curative and
therefore require long-term sequential therapy with multiple
agents and management of toxicity.

71. • Immunotherapy
• IL-2. In selected patients with relapsed or medically unresectable stage IV
clear-cell RCC.
• high-dose IL-2 can be considered as a first-line treatment option.
• Although no demonstrable OS benefit has been seen, durable complete
remissions occur in 7% to 8% of patients.
• Thus, despite the associated toxicity of capillary leak syndrome, IL-2
remains a viable treatment option reserved for patients with good
performance status and acceptable comorbid disorders.
• Unfortunately, there are no predictive biomarkers upon which to base the
selection of patients for treatment with high-dose IL-2.

72. • Bevacizumab plus interferon alpha:
• This combination has been associated with a 31% objective
response rate with a median PFS of 10.2 months.