Chap57N RCC

PCT - clear cell and papillary variants

DCT - chromophobe and collecting duct RCC

• - Tumor suppressor gene
• - Located at chromosome 3p25-26
• - As with most tumor suppressor genes, both alleles of the VHL gene must be mutated or inactivated for development of the disease; the observed inheritance patterns have conformed to Knudson’s hypotheses.

• To target the hypoxia-inducible factors 1 and2 (HIF-1 and HIF-2) for ubiquitin-mediated degradation,keeping the levels of HIFs low under normal conditions.
• Inactivation or mutation of the VHL gene leads to dysregulated expression of the HIFs, and they begin to accumulate in the cell.
• This, in turn, leads to a several fold upregulation of the expression of VEGF, the primary angiogenic growth factor in RCC, contributing to the pronounced neovascularity associated with clear cell RCC

• Round to ovoid and circumscribed by a pseudocapsule of compressed parenchyma and fibrous tissue rather than a true histologic capsule.
• Unlike upper tract TCC, most RCCs are not grossly infiltrative, with the notable exception of collecting duct RCC and some sarcomatoid variants.
• All RCCs are, by definition, adenocarcinomas, derived from renal tubular epithelial cells

With the exception of oncocytomas and some small (<1 cm) low-grade papillary adenomas, there are no reliable histologic or ultrastructural criteria to differentiate benign from malignant renal epithelial tumors

• Clear cell RCC (70%-80%)
• Multilocular cystic clear cell RCC (uncommon)
• Papillary RCC (10%-15%)
• Chromophobe RCC (3%-5%)
• Collecting duct carcinoma (<1%)
• Renal medullary carcinoma (rare) 
• Unclassified RCC(1%-3%)

• - Well circumscribed and a capsule is usually absent
• - Typically yellow when theyare bivalved and are highly vascular
• - Patients with clear cell RCC have a worse prognosis compared with papillary or chromophobe RCC, even after stratification for stage and grade. 
• - 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

• - Macroscopically, pRCC is well circumscribed with a pseudocapsule, yellow or brown in colour, and a soft structure.
• - more commonly found in patients with end-stage renal failure and acquired renal cystic disease.
• - tendency to multicentricity
• - The cytogenetic abnormalities associated with papillary RCC are characteristic and include trisomy of chromosomes 7 and 17 and loss of the Y chromosome

• -  derived from the cortical portion of the collecting duct
• - Chromophobe RCC cannot be graded (by the Fuhrman grading system), because of its innate nuclear atypia
• - a perinuclear clearing or “halo” is typically found and electron microscopic findings consist of numerous 150-to 300-nm microvesicles, which are the single most distinctive and defining feature of chromophobe cell carcinoma
• - Loss of chromosomes Y, 1, 2, 6, 10, 13, 17 and 21 are typical genetic changes
• - These microvesicles characteristically stain positive for Hale colloidal iron, indicating the presence of a mucopolysaccharide unique to chromophobe RCC

• -  a very rare tumour, comprising < 0.5% of all RCCs,
• - is predominantly diagnosed in young adults (median age 28 years) with sickle haemoglobinopathies (including sickle cell trait).
• - Renal medullary carcinoma is one of the most aggressive RCCs and most patients (~67%) will present with metastatic disease

• Despite treatment, median OS is 13 months in the most recent series.
• Due to the infiltrative nature and medullary epicentre of RMC, radical nephrectomy is favoured over partial nephrectomy even in very early-stage disease.

Many renal masses remain asymptomatic and non-palpable until they are advanced.

• Flank pain
• Gross hematuria
• Palpable abdominal mass

- rarely found - a too late triad.

• • palpable abdominal mass;
• • palpable cervical lymphadenopathy;
• • non-reducing varicocele and bilateral lower extremity oedema, which suggests venous involvement

• T1 - ≤ 7 cm, limited to kidney
• T1a - ≤ 4 cm
• T1b - 4 cm- 7 cm

• T2 - > 7 cm, limited to the kidney
• T2a - 7-10 cm
• T2b - > 10 cm

• T3 - extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota fascia
• T3a - into the renal vein or its segmental branches, or tumour invades perirenal and/or renal sinus fat
• T3b - into the vena cava below diaphragm
• T3c -  into vena cava above the diaphragm or invades the wall of the vena cava

T4 - beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland

• • The sub-classification of T1 tumours using a cut-off of 4 cm might not be optimal in NSS for localised cancer.
• • The value of size stratification of T2 tumours has been questioned.
• • Since the 2002 version, tumours with renal sinus fat invasion have been classified as pT3a.
• • Renal sinus fat invasion might carry a worse prognosis than perinephric fat invasion but is nevertheless included in the same pT3a stage group.
• • Sub T-stages (pT2b, pT3a, pT3c and pT4) may overlap [99].
• • For adequate M staging, accurate pre-operative imaging (chest and abdominal CT) should be performed

- Found in 20% of patients with RCC - RCC was previously referred to as the internist’s tumor because of the predominance of systemic rather than local manifestations. Now, a more appropriate name would be the radiologist’s tumor. 

• Hypercalcemia 
• - 13% of patients with RCC
• - due to either paraneoplastic phenomena (PTH like peptides) or osteolytic metastatic involvement of the bone.

Hypertension - secondary to increased production of renin directly by the tumor; compression or encasement of the renal artery or its branches, effectively leading to renal artery stenosis;or arteriovenous fistula within the tumor

Polycythemia - due to increased production of erythropoietin, either directly by the tumor or by the adjacent parenchyma in response to hypoxia. 

Nonmetastatic hepatic dysfunction,or Stauffer syndrome.

Medical management predominatesand includes vigorous hydration followed bydiuresis with furosemide and the selective use of bisphosphonates,corticosteroids, or calcitonin (reviewed in Goldet al, 1996; Coleman, 2004; Pepper et al, 2007; Schwarzberg andMichaelson, 2009). Bisphosphonate therapy is now establishedas standard of care for patients with hypercalcemiaof malignancy, as long as renal function is adequate. Zoledronic acid, 4 mg intravenouslyevery 4 weeks

In general, treatment of paraneoplastic syndromesassociated with RCC has required surgical excision orsystemic therapy and, except for hypercalcemia, medicaltherapies have not proved helpful

• CECT - >15 HUs enhancement suggestive of RCC.
• MRI - for venous involvement if the extent of an inferior vena cava (IVC) tumour thrombus is poorly defined on CT.
• For the diagnosis of complex renal cysts (Bosniak IIF-III), contrast-enhanced ultrasonography showed high sensitivity (100%) and specificity (97%), with a negative predictive value of 100%.
• Chest CT is accurate for chest staging.
• There is a consensus that most bone metastases are symptomatic at diagnosis; thus, routine bone imaging is not generally indicated

• • to obtain histology of radiologically indeterminate renal masses;
• • to select patients with small renal masses for active surveillance;
• • to obtain histology before, or simultaneously with, ablative treatments;
• • to select the most suitable form of medical and surgical strategy in the setting of metastatic disease

• Treatment of localised RCC
• - Offer partial nephrectomy to patients with T1 tumours
• - If no adrenal gland involvement - do not perform ipsilateral adrenalectomy 
• - If large tumor, extended LN dissection 
• - RN in T2 tumors 

• Treatment of Locally advanced RCC - 
• - In patients with clinically enlarged lymph nodes, perform lymph node dissection for staging purposes or local control.

• For Metastatic disease - 
• - Cytoreductive nephrectomy (in favrourable and intermediate risk patients) is palliative and systemic treatments are necessary. 
• - Do not offer chemotherapy as first-line therapy in patients with clear-cell metastatic RCC.

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Offer active surveillance, radiofrequency ablation and cryoablation to elderly and/orcomorbid patients with small renal masses.

• In patients with clinically enlarged lymph nodes, perform lymph node dissection for staging purposes or local control.
• In case of venous involvement, remove the renal tumour and thrombus.

• Use ipilimumab plus nivolumab intreatment-naïve patients with clear-cell mRCC of IMDC intermediate and poor risk.
• Offer nivolumab after one or two lines of VEGF-targeted therapy in mRCC. 
• Do not rechallange patients who stop nivolumab plus ipilimumab because of toxicity with the same drugs in the future without expert guidance and support from a multidisciplinary team.

Use sunitinib or pazopanib in treatmentnaïvepatients with clear-cell mRCC ofIMDC favourable risk.

IMDC = The International Metastatic Renal Cell Carcinoma Database Consortium