Brief review of Renal Cell Carcinoma, its pathogenesis, investigations, management, Prognosis and Follow up.

2. Renal Cell Carcinoma
Dr. Adnan Bilal
PG Urology
B.V.H

3. Contents
• Epidemiology
• Pathogenesis
• High Risk Groups
• Clinical Features
• Types
• Staging
• Diagnostic investigations
• Treatment
• Prognosis
• Follow up

4. Epidemiology
• Peak incidence: 6th to 7th decade of life.
• Male > female: 3 : 2
• Accounts for nearly 90% of all renal malignancies.

5. Risk Factors
• Modifiable:
– Smoking
– Obesity
– Hypertension
• Non Modifiable
– Having a first-degree relative with RCC 4 x RCC Risk ( Should be screened)
– Acquired polycystic disease 30 x RCC risk

6. Pathogenesis
• Renal cell carcinomas are adenocarcinomas of renal cortex
• Vascular tumors
• 20–25% metastatic at presentation
• Spread:
– By direct invasion through the renal capsule
– By direct extension into the renal vein.
• Distant Metastasis
Lung (Most Common), Liver, bone (osteolytic), ipsilateral adjacent lymph nodes, adrenal
gland, brain, the contralateral kidney, and subcutaneous tissue

7. Hereditary RCCs
• Von Hippel-Lindau
– Autosomal dominant, VHL Gene mutation, ch: 3p25-26
– Clear cell RCC, CNS hemangioblastomas, pheochromocytomas, retinal
angiomas, rarely pancreatic cysts or tumor's and epididymal cystadenomas
– Upregulation of VEGF
• Hereditary papillary renal cell carcinoma (HPRCC)
– Autosomal dominant, ch: 7 & 17
– Activation of the c- MET proto- oncogene > HGF > Epithelial proliferation and
differentiation

8. Hereditary RCCs
• Hereditary Leiomyomatosis
– Autosomal dominant, defect (Loss or mutation) in the fumarase hydratase gene
on chromosome 1q42-44
– Multiple cutaneous & uterine leiomyomas, Papillary RCC.
• Birt‐Hogg‐Dubé Syndrome
– Autosomal dominant, loss or mutation in the BHD gene chromosome 17p11.2.
– Fibrofolliculomas, lung cysts, pneumothoraxes, Clear cell RCC, Renal
Oncotytomas and Chromophobe RCC.

9. Hereditary RCCs
• Tuberous Sclerosis
– TSC1/2 genes Mutation
– AMLs, renal cysts, clear cell RCC, seizures, and developmental delay

10. Histological Types
• Three more common subtypes of RCC:
• Clear cell (80–90%)
– loss or inactivation of the VHL tumor suppressor
– Polygonal cells with a clear, glycogen, and lipid-filled cytoplasm
– Yellow to orange cut surface due to high lipid content
• Papillary (6–18%) (Type 1 and Type 3)
– MET proto-oncogene Mutation
– Papillary growth pattern with fibrovascular cores
– Multifocal and bilateral

11. Histological Types
• Chromophobe (4–6%)
– Arise from intercalated cells of collecting ducts
– Hypodiploidy
– Large polygonal cells with eosinophilic cytoplasm and a perinuclear halo
• Collecting duct carcinoma
– Arise from Medullary collecting duct
– Malignant glandular cells arranged in an irregular pattern within a fibrous stroma
(hobnail pattern)
– Association with sickle cell disease
– Poor prognosis

13. Clinical Presentation
• >50% are asymptomatic
• Classical triad:
– Hematuria
– Flank mass
– Flank pain
• Paraneoplastic Syndromes
• Examination:
– Abdominal mass
– Cervical lymphadenopathy
– A non- reducing varicocele, or lower limb oedema

14. Paraneoplastic Syndromes
• Ectopic hormone secretion by the tumor tissue (30%)

15. Differential Diagnosis
• Benign
1. Renal cysts
2. Angiomyolipoma
3. Oncocytoma
4. Renal Adenoma
5. Tuberculosis
6. Abscess / Pyonephrosis /
Hydronephrosis
1. RCC
2. Nephroblastoma
3. Urothelial based cancer
4. Renal Sarcoma
5. Ca associated with
neuroblastoma

17. Staging

18. Tumor Thrombus levels

19. Regional LNs

20. Fuhrman Grading
Based on the nuclear size, outline, and nucleoli.
• Low Grade:
– F1: Well differentiated
– F2: Moderately differentiated
• High Grade:
– F3 & F4: Poorly differentiated

21. Diagnostic investigations
• CT Abdomen and pelvis with IV contrast
• MRI renal imaging: For patients with contrast allergy, renal failure, or
pregnancy.
• Urine cytology and culture
• Full Blood Count
• Serum creatinine and electrolytes, calcium, clotting studies, and LFTs

22. Diagnostic investigations
• If RCC:
– Staging Chest CT
– Bone Scan (if indicated)
• IVC involvement:
– Doppler USS / MRI
• Renal Scan / eGFR:
– If any sign of impaired renal function
• Bone scan:
– If bony metastasis suspected

23. Biopsy
• Indeterminate renal mass
• Select patients with small renal masses for active surveillance
• Obtain histology before (advantageous), or simultaneously with
ablative treatments
• To decide most suitable form of medical and surgical strategy in the
setting of metastatic disease

24. Treatment
• Surgical (Mainstay)
– Partial Nephrectomy ( Open, Lap or Robotic)
– Radical Nephrectomy (Open, Lap or Robotic)
• Ablative Options
– Cryotherapy (Intra-op USG, Percutaneous, Lap)
– Radiofrequency ablation (Image Guided)
• Active surveillance
• Systemic Therapy
• Renal Artery embolization

25. Low Risk: 4-6 Intermediate Risk: 7-9 High Risk: 10-12

26. Partial Nephrectomy
• Gold standard for all T1a and selected T1b tumors
– Single anatomical/ functioning kidney / bilateral tumor
– VHL Syndrome
– Contralateral kidney threatened
– T1 (up to 7cm) tumors with a normal contralateral kidney, unless close to the
pelvicalyceal system.
• CT renal angiogram helps identify anatomy
• Complications:
• Urinary leak (Needing drainage or stent)
• Hyperfiltration injury

27. Radical Nephrectomy
• Gold Standard for T2-4 & T1 tumors not suitable for PN
– Adrenalectomy is not needed unless involved
– LN sampling only if involved for staging purpose
– Lap for T2/T3a
– Open for very large or T3c / T4
– Disease involving IVC or surrounding organs or abdominal wall needs multidisciplinary
approach
• Complications:
– Bleeding, Embolism of tumor thrombus & bowel, pancreatic, splenic, pleural injury

30. Infra- hepatic tumor thrombus

31. Retro-hepatic Tumor Thrombus

32. Supra diaphragmatic and atrial tumor thrombus

33. Cryotherapy
<−20 °C
3.1 mm

34. Radiofrequency Ablation
High•
frequency, Alternating
current
45 and 55 °C = IR cell damage
55–60 °C = Cell Death

35. Renal Artery
Embolization
Gross hematuria in patients
who are unfit for curative
surgery

36. Active Surveillance
• For Unfit patients or small renal masses (<T1a) thought to be benign
• Metastasis is rare in masses <3cm
• For every 1cm increase metastasis prevalence increases by 3.5%

37. Cytoreductive Nephrectomy
• As a palliative procedure in the setting of metastatic disease for
managing patients with severe hemorrhage or unremitting pain.
• No additional benefit of CN + Systemic therapy over systemic therapy
alone.

38. Metastatectomy
• For patients having a solitary or oligometastatic renal cell carcinoma if
technically feasible.
• Improved survival benefit when combined with adjuvant therapy.

39. Systemic Therapy
• For Metastatic Renal Cell CA
• Immunotherapy ( Presence of Cytotoxic T cells in resected tumors)
– Interferon and Interleukin 2
• VEGFR Inhibitor ( VHL Syndrome : Target angiogenesis)
– Tyrosine kinase inhibitors
– Sunitinib, Sorafenib, Pazopanib, Axitinib, cabozantinib and Tivozanib
– Monoclonal antibodies
– Bevacizumab
– mTOR inhibitors
– Temsirolimus and Everolimus

40. Systemic Therapy
• Checkpoint inhibitors (Target T cell suppressive regulators)
– Nivolumab (Atezolizumab, ipilimumab : Newer agents)
• Chemotherapy
– Ineffective due to high multidrug resistance P glycoprotein expression
• Palliative
– Dexamethasone 4mg QID

41. Prognostic factors (Disease recurrence
and survival rate)
• TNM classification
• Histological grading(Fuhrman grade
• Pathological subtype
• Patients overall health status
• Comorbidity
 presence of sarcomatoid or rhomboid pattern
 Tumor necrosis
 Microvascular invasion

44. Follow up

45. Thanks !