Renal cell carcinoma (RCC)

Transcription

1 Renal cell carcinoma (RCC) Introduction The most common solid renal tumor. Accounts for 2 3% of all adult malignancies. It is the 3 rd most common urological tumor in men and the 2 nd in women. It is th e 6 th most common tumor overall in men and the 10 th in women. Predominantly affects adult men (3/2) in the 6 th 7 th decade of life. The most lethal urological tumor. Higher incidence in African Americans. Etiology The only environmental risk factor accepted to date is tobacco exposure, which increases RR times. It has also been related to asbestos and cadmium exposure. Obesity, living in urban areas, and low socioeconomic status have also been associated with increased risk. Thought to be related to v itamins A and E since its incidence is higher in employees of laboratories where both substances are synthesized. First degree family history increases RR 2.9 fold. Other causal factors: end stage renal disease with acquired cystic disease, familial syn (tuberous sclerosis, VHL disease), and high blood dromes pressure. Pathology Conventional renal cell carcinoma (70 80%): has a worse prognosis than papillary or chromophobe variants. The most common genetic alteration in this type of tumor is 3p25 26 mutation (VHL gene). Includes the subtypes: clear, granular, and mixed cell carcinomas. Papillary carcinoma (10 15%): associated with ESRD and acquired cystic disease. Has a greater tendency to be multicentric. The most common genetic alteration is chromosome 7 and 17 trisomy and the loss of the Y chromosome. It originates in convoluted tubule cells (similar to conventional carcinoma). There are two types: - Type I (basophilic): basophilic cells with scant cytoplasm. - Type II (eosinophilic): eosinophilic cells with abundant granular cytoplasm (more aggressive). Chromophobe cell carcinoma (3 5%): derived from the cortical portion of the collecting tubule. It has an eosinophilic variant that accounts for 30% of this type. The most common genetic alteration is the loss of heterozygosity on chromosomes 1, 2, 6, 10, 13, 17, and 21, with a hypoploid conten t. Has a higher incidence of p53 mutations and expression of the oncogene c Kit. Has a better prognosis than conventional renal cell carcinoma. Bellini duct carcinoma (1%): originates in the medullary collecting duct. Occurs at a younger age (3 rd 5 th decade of life). The most frequent genetic abnormalities are deletions in chromosome 1 and monosomy in chromosomes 6, 8, 12, 18, 21, and the Y chromosome. Highgrade, aggressive tumors unresponsive to conventional therapy. Medullary carcinoma (<1%): associated exclusively with the sickle cell trait. It affects African Americans in the 3 rd decade of life. It originates in the calyceal epithelium close to the papillae. It is very aggressive, usually metastasized at the time of diagnosis, and unresponsive to conventional therapies. Sarcomatoid variant: described in all variants; not considered a subtype. Unclassified carcinoma (<3%): poorly differentiated tumor, very aggressive and unclassifiable.

2 Staging (Fig. 1) Robson classification: Stage Tumor localization I II Organ confined tumor Tumor extends into ipsilateral adrenal gland or perirenal fat, but not beyond Gerota s fascia IIIa Tumor extends into renal vein or inferior vena cava IIIb Regional lymph node metastasis IIIc Regional lymph node metastasis and vein extension (IIIa + IIIb) IVa Tumor extends beyond Gerota s fascia IVb Distant metastasis TNM classification: Primary tumor Regional Lymph nodes Distant metastasis Tx T0 T1 T1a T1b T2 pt2a pt2b T3 pt3a pt3b pt3c T4 Nx N0 N1 N2 M0 M1 TNM stage grouping Stage I T1N0M0 Stage II T2N0M0 Stage III Stag e IV The 2009 TNM staging classifi cation system Primary tumor cannot be assessed. No evidence of primary tumor. Tumor 7 cm in greatest dimension, limited to the kidney. Tumor 4 cm in greatest dimension, limited to the kidney. Tumor >4 cm but 7 cm in greatest dimension. Tumor >7 cm in greatest dimension, limited to the kidney. Tumor >7 cm but 10 cm in greatest dimension Tumor >10 cm limited to the kidney Tumor extends into major veins or perinephric tissues, but not into the ipsilateral adrenal gland and not beyond Gerota s fascia Tumor grossly extends into the renal vein or its segmental (musclecontaining) branches or tumor invades perirenal and/or renal sinus (peripelvic) fat, but not beyond Garota s fascia. Tumor grossly extends into the vena cava below the diaphragm. Tumor grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava. Tumor invades beyond Gerota s fascia (including contiguous extension into the ipsilateral adrenal gland). Regional lymph nodes cannot be assessed. No regional lymph node metastasis. Metastasis in a single regional lymph node. Metastasis in more than 1 regional lymph node. No distant metastasis. Distant metastasis. T3N0 1M0, y T1 2N1M0 T4N0 2M0, T0 4N2M0 y T0 4N0 2 M1

3 s Fig 1. TNM classification (2009): primary tumor.

4 Symptoms Over 50% are diagnosed incidentally. If symptoms appear, they are due to tumor growth, metastatic disease, paraneoplastic syndrome (20%), o r bleeding. The classic triad (pa in, mass, and hematuria) is uncommon (<10%). The most common symptoms are: pain (34%), hematuria (57%), weight loss (31%), Wunderlich syndrome (50% of cases have a hidden tumor). Paraneoplastic syndrome (20%): - Hypercalcemia (13%): production of PTH like or osteolytic metastases. - Polycyt hemia (1 8%): increased EPO production. - Amyloidos is (1 5%). - Anemia (20 40%). - Cachexia and febrile syndrome (20 33%) due to the formation of immunoglobulins. - AHT (25%): secondary to increased renin production. - Liver dysfunction or Stauffer s syndrome (3 20%). - Nephropathy (27%). - Other less common syndromes: hyperglycemia, Cushing s syndrome, neuromyopathy. Diagnosis Elevated alkaline phosphatase, high ESR, and anemia in the analysis indicate a poor prognosis. Plain abdominal X ray t o detect: - A mass effect in large tumors. - Diaphragm elevation. - Calcifications. - Metastatic bone lesions. Chest X ray: useful in the diagnosis of lung disease. Ultrasound: - Usually shows a solid iso or hypoechoic lesion. - Sometimes tumors must be differentiated from simple cysts, characterized by a smooth wall, round or oval morphology, and without internal echoes; transmission through a cyst has strong acoustic shadows behind the hypoechoic area. - If the lesion is not a cyst, the next exam should be a CT or MRI. CT: the single most important radiological examination in a diagnostic assessment. 10% of renal masses are indeterminate and require further testing (MRI/exploratory surgery). Allows assessment of local and distant venous extension. The diagnostic criteria based on Hounsfield units is as follows: - Any mass that is reinforced by more than 15 HU with iv administration of iodinated contrast media is considered a renal carcinoma. - Negative attenuation values in the CT (< 20 HU) are indicative of an angiomyolipoma. MRI: detects smaller lesions than CT and more adequately differentiates between cysts and solid lesions. Can be reserved for cases of locally advanced disease, venous compromise, or allergy to iodinated contrast. The tumors appear as: - Heterogeneous hypo or hyperintense masses in T1. - Hyperintense in T2. PET: good specificity, but low sensitivity. Bone scan: allows assessment of bone involvement in the extension study. Renal arteriography: is currently of limited value. Ultrasound or CT guided needle biopsy: their sensitivity and specificity vary between 80 95% with low morbidity (<5%). Indicated in the following cases: - Suspected renal abscess. - Infected cys t. - Differential diagnosis between RCC, suspected metastatic disease, or renal lymphoma.

5 Prognostic factors Stage: the single most important prognostic factor as there is a strong prognostic correlation. Loco regional or s ystemic extension significantly lowers chances for survival: Tumor localization % sur v ival ( 5 years) Localized tumor Tumor extends into ipsilateral adrenal or perirenal fat Tumor extends into major veins <25 Tumor extends beyond Gerota s fascia <20 Distant metastasis <20 Fuhrman nuclear grade: independent prognostic factor of survival. Nuclear grade I Uniform nuclear margin, nuclear size <10mm, absent nucleolus II Irregular nuclear margins, nuclear size >15mm, small nucleolus III Irregular nuclear margins, nuclear size 20mm, prominent nucleolus IV Multilob ulated nucleus, nuclear size >20, chromatin bodies Histological subtype: sarcomatoid differentiation, Bellini s carcinoma, and medullary carcinoma have worse survival rates. DNA ploidy: mainly in organ confined tumors. Aneuploidy is significantly associated with a worse prognosis. Other prognostic factors: general malaise, symptomatic presentation, constitutional syndrome, and synchronous metastases are poor prognostic factors. The presence of anemia, elevated ESR, elevated alkaline phosphatase, and elevated LDH at the time of diagnosis are also signs of a poor prognosis. Treatment of organ confined tumors Active surveillance: - Indications: homogen ous tumors with well defined margins, <3 cm, and in elderly patients with high surgical risk. - Rate of tumor growth: cm/year (30% do not grow during follow up). - Monitoring with contrasted imaging techniques is recommended every 6 12 months. Nephron sparing surgery (open or laparoscopic): - Imperative in bilateral tumors or tumors in a single kidney patient. - Compromised renal function or systemic disease (AHT, DM) is considered a relative indication. - If there is a normal contralateral kidney, it is considered an elective indication. - Tumors up to 7 cm can be removed by means of this technique. - Complications: urinary fistula (3 8%) and bleeding (most common complication). - Efficacy: the 5 year disease free survival rate is %. - Local recurrence rate: 5 10%. Ablative therapies: cryosurgery and radiofrequency. - May be percutaneous or laparoscopic. - Indications: advanced age; significant comorbidity; solid, peripheral exophytic tumors <3.5 cm and far from the vascular and collecting systems. Also in recurrences after conservative surgery. - Recurrence: 5 15%. Short follow up techniques. Radical nephrectomy: indicated in cases in which conservative surgery is not possible. - Lymphadenectomy: controversial. Recommended in cases with ganglionary involvement or in palliative cytoreductive surgery. - Removal of the adrenal gland: in cases with macroscopic or radiological implications.

6 Treatment of locally advanced and metastatic tumors Radical nephrectomy with lymphadenectomy or adrenalectomy or thrombectomy. Cytoreductive nephrectomy: nephrectomy for metastatic RCC. Indicated in patients with good general health, little metastatic disease, and scant liver or bone involvement. Resection of metastasis: - Indicated in solitary lesions, pulmonary lesions, and patients who have been diseasefree for a long period (metachronic metastasis). - Contraindicat ed in multiple, liver or bone metastases; in synchronic tumors; or in patients who have been disease free for only a short time. Systemic therapy: - Chemotherapy: low response rate (2 6%) due to the expression of a P glycoprotein (mul in 80 90% of renal tumors. tidrug resistant protein) - Radiation therapy: only useful for symptomatic palliative treatment of bone metastases. - Immunological treatment: Cytokines: - Interferon α: overall response = 12% (1.8% complete response). Mean survival of 5 15 months. - IL 2: overall response = 15% (6 8% complete response). Mean survival of months. High toxicity when taken alone (Muscle weakness syndrome). - Com bination of both: overall response = 19%. Does not improve survival rates. Adoptive immunotherapy: transfer of autologous lymphocytes. Has shown no benefits over cytokine therapy. Vaccines: no clinical trials have proven their clinical usefulness. Target therapies: currently the first line of adjuvant treatment. All are aimed at dis the VEGF pathway: rupting - Bevacizumab: monoclonal Ab that binds to VEGF, inhibiting its signal. Does not improve survival, but increases time to progression. Not used in monotherapy. - Sunitinib: oral agent that inhibits the tyrosine kinase receptor. Improves survival and produces tumor regression in 30 40% of cases. - Sorafenib: oral agent that inhibits the kinase RAF receptor. Has been shown to improve the progression free rate, disease stabilization, and tumor regression. - Temsirolimus: intravenous agent that inhibits m TOR. Blocks HIF 1. Improves survival rates. - Everolimus: the most recent oral agent; used as a 2 nd line treatment. - Multimodal therapy: most cases are treated with more than one treatment modality: a combination of primary tumor surgery +/ metastasis surgery +/ systemic therapies.