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renal cell carcinoma (hypernephroma, Grawitz tumor)

also see kidney cancer Etiology: 1) hereditary syndromes - von Hippel-Lindau syndrome (most common hereditary form) - hereditary papillary renal carcinoma - familial renal oncocytoma associated with Birt-Hogg-Dube syndrome - hereditary renal carcinoma - horseshoe kidney 2) risk factors - obesity - smoking [15] - occupational exposure - trichloroethylene, benzene, benzidine, cadmium, herbicides, vinyl chloride [11] - renal cysts [15] - renal dialysis increases risk for renal cysts [15] Epidemiology: - 3rd most common genitourinary neoplasm - 3% of adult malignancies [11] - 58,000 cases yearly [1] - 13,000 cancer-related deaths annually [1] - most common kidney neoplasm - 2x male predominance - peak age 5th - 6th decade, median age = 64 years [11] - most are found incidentally on imaging performed for other reasons [1] Pathology: 1) 1% are bilateral 2) 5% are multifocal 3) most originate in the renal cortex 4) may metastasize to a) lung (75%) b) soft tissues (36%) - renal veins - inferior vena cava - periaortic & retroperitoneal lymph nodes c) bone (20%) c) liver (18%) d) brain &/or spinal cord (8%) e) skin (8%) [15] Microscopic Pathology: - histologic subtypes: a) clear cell or conventional (majority, 75% [15]) b) granular c) papillary d) chromophobe e) collecting duct f) sarcomatoid Genetics: - type 1 (RCC1) associated with defects in VHL - associated with defects in RNF139 gene - associated with defects in FLCN gene - translocation (3;8)(q14.2;q24.1) of RNF139 with FHIT - der[17]t[X;17][p11;q25] fusion of TFE3 transcription factor gene (Xp11) with ASPSCR1 gene at 17q25 - chromosomal translocation t(2;3)(q35;q21) involving HSPBAP1 with the putative pseudogene DIRC3 is found in familial renal cell carcinoma 1 - chromosomal translocation t(2;3)(q35;q21) involving DIRC2 is found in familial renal cell carcinoma 1 (RCC1) - chromosomal translocation t(X;1)(p11.2;q21.2) involving PRCC & TFE3 - chromosomal translocation t(X;X)(p11.2;q13.1) involving NONO with TFE3 - chromosomal translocation t(6;11) involving TFEB [24] - other implicated genes GBA3, PHF17, IGF2BP3, ZNF608, SULF1, TBRG1, TTYH2, CA12, XRRA1, VTCN1, OGG1, EREG, DLEC1, BAP1, PBRM1 Clinical manifestations: 1) patients often asymptomatic until malignancy is advanced [1] - 25-30% asymptomatic, diagnosis is incidental 2) classic triad - flank pain, palpable abdominal mass, hematuria (9%) [1] 3) abdominal pain - mid abdominal tenderness to palpation [29] 4) lower extremity edema may be up to hips (see Complications:) 5) acute varicocele, usually left-sided 6) associated paraneoplastic syndromes - erythrocytosis - headache, blurred vision, facial plethora [1] - hypertension associated with elevated erythropoietin - AA amyloidosis - polymyalgia rheumatica - hepatic dysfunction - hypercalcemia - polyneuropathy [15] - dermatomyositis [15] 7) weight loss 8) fever, night sweats 9) also see kidney cancer Laboratory: 1) complete blood count (CBC) - may be polycythemia (erythrocytosis) secondary to unregulated erythropoietin secretion by tumor 2) serum chemistries a) serum calcium: may be hypercalcemia due to unregulated production of calcitriol by tumor b) serum alkaline phosphatase may be elevated with bony metastases c) liver function tests d) renal function tests e) electrolytes [11] 3) urinalysis: hematuria 4) PCR/southern blot/northern blot/in-situ hybridization 5) serology: antiantibodies: C19orf29, CCDC34 Radiology: 1) renal ultrasound - can distinguish benign cysts from complex cysts & solid masses [1] - unreliable for tumors < 3 cm in size [1] - fine needle aspiration for smaller lesions - large solid mass or complex cyst likely to be malignant - fine needle aspiration not needed prior to surgical resection [1] 2) computed tomography of abdomen, pelvis & thorax (with contrast) a) indicated if lesion is not clearly a benign cyst - NEJM knowledge+ elects for CT over initial ultrasound in woman of child-bearing age [1] - more sensitive & specific for assessment of local invasiveness, lymph node involvement, metastases [NEJM knowledge+] b) distortion of renal contour c) no sharp interface with surrounding parenchyma d) heterogenous e) enhanced by contrast - specialized renal protocol CT scans include: - a noncontrast phase - a postcontrast nephrographic phase - a delayed excretory phase is often included [15] f) typically has ball shape, may be exophytic [15] g) allows for staging h) pathognomonic CT findings obviate need for renal biopsy [1] 3) magnetic resonance imaging may be alternative to CT [15] 4) chest X-ray may show pulmonary metastases 5) bone scan if bone pain [1] 6) PET scanning not useful in evaluation of primary RCC due to increased radiotracer activity within collecting system - PET scanning may be useful for evaluation of metastases [15] Staging: Fuhrman nuclear grade [3] 1) round uniform nuclei, ~10 microns diameter, small or absent nucleoli 2) slightly irregular nuclei, ~15 microns diameter, nucleoli visible at 400x 3) moderate to markedly irregular nuclei, ~20 microns diameter, large nucleoli visible at 100x 4) moderate to markedly irregular nuclei, also multilobular, multinucleated, or bizarre nuclei & marked chromatin clumping AJCC/TNM staging [2] TX: primary tumor cannot be assessed. T0: no evidence of primary tumor. T1: tumor ~7 cm & confined to kidney. T1a: tumor ~4 cm & confined to kidney. T1b: 4 cm < tumor <= 7 cm & confined to kidney. T2: tumor > 7 cm & confined to kidney. T3: tumor extends into major veins; invades adrenal or perinephric tissues; does not extend beyond Gerota's fascia. T3a: invades adrenal or perirenal/renal sinus fat; T3b: grossly extends into renal vein or muscle containing segmental branch or vena cava below diaphragm. T3c: extends into vena cava above diaphragm or invades wall of vena cava. T4: tumor invades beyond Gerota's fascia. NX: regional lymph nodes cannot be assessed. N0: no regional lymph node metastases. N1: metastasis in single regional lymph node. N2: metastases in more than one regional lymph node. MX: distant metastasis cannot be assessed. M0: no distant metastasis. M1: distant metastasis. Complications: - thrombosis due to hyperviscosity of polycythemia (stroke) - metastases in 33% of patients in RCC [15] - predilection for vascular invasion - 20-50% of metastases are identified after nephrectomy [15] - 25% with metastatic relapse after nephrectomy [16] - venous tumor thrombus extending into the renal vein & inferior vena cava - obstruction of inferior vena cava resulting in lower extremity edema - paraneoplastic syndromes [1] - anemia - hepatic dysfunction in the absence of liver metastases - fever - hypercalcemia - erythrocytosis - AA amyloidosis - thrombocytosis - polymyalgia rheumatica [1] Differential diagnosis: - complex renal cysts [15] - renal oncocytoma [15] - renal angiomyolipoma [15] Management: 1) also see kidney cancer 2) nephrectomy for resectable RCC a) radical nephectomy is the primary treatment b) partial nephrectomy may be appropriate for patients with tumors < 4 cm that are not adjacent to the renal pelvis [1] - active survelliance is an option for tumors < 4 cm [1] c) renal artery embolization may be an option for patients unable to tolerate surgery [15] d) adjvant chemotherapy or radiation therapy not recommended for early stage localized RCC [1] 3) resecting primary renal cell carcinoma may improve response to chemotherapy in metastatic disease [1] 4) resistance to radiation therapy & chemotherapy 5) radiation therapy a) pain, bleeding, symptomatic CNS or bone involvement [1] b) renal cell carcinoma is radioresistant 6) radiofrequency ablation may be an option for tumors < 3 cm - metastatic renal carcinoma developed in 3 of 106 patients [26] 7) adjuvant therapy in patients with resected non-metastatic renal cell carcinoma* does not improve outcomes [1,13] - observation is standard of care in resected non-metastatic renal cell carcinoma [1] - evidence of renal vein involvement does not justify adjuvant chemotherapy [1] - sunitinib FDA-approved for adults at risk for recurrent renal cell carcinoma following nephrectomy [18] 8) targeted agents as adjunctive treatment to surgery for metastatic disease - surgical resection may play a role in resection of metastatic as well as primary RCC [1] - cytoreductive nephrectomy may not be standard of care [22,23] - VEGF inhibitors - sunitinib [10,22] - sunitinib alone not inferior to nephrectomy followed by sunitinib in metastatic renal-cell carcinoma [23] - sorafenib - bevacizumab - pazopanib (Votrient) - axitinib (Inlyta) [11] - cabozantinib (Cabometyx) [19] - tivozanib (investigational) - mTOR inhibitors - temsirolimus, everolimus [1, 11] 9) immunotherapy a) interleukin-2 & interferon alfa beneficial for ~10% of patients with metastatic renal cell carcinoma [1] - aldesleukin [11] - sunitinib superior to interferon-alfa for metastatic renal cell carcinoma [12] b) anti-PDCD1 &/or anti-CD274 antibody may induce tumor regression & prolonged stabilization in patients with advanced renal cell carcinoma, cutaneous melanoma, or non-small-cell lung cancer [4,5] c) nivolumab (Opdivo) + ipilimumab (Yervoy) superior to sunitinib [17] d) lenvatinib + pembrolizumab superior to sunitinib [28] - progression-free survival 23.9 vs 9.2 months [28] e) axitinib in combination with pembrolizumab (73% response) [20] f) atezolizumab in combination with bevacizumab for treatment of metastatic renal cell carcinoma improves survival by 3 months vs sunitinib [21] g) interferon alfa-2A (Roferon A) h) interferon alfa-2B (Intron A) [11] 10) other chemotherapeutic agents [11] - vinblastine - gemcitabine - 5-fluorouracil - paclitaxel - carboplatin - ifosfamide - doxorubicin - floxuridine 11) zoledronate for bone metastases inhibits osteoclastic activity 12) prognosis: - 5 year survival after radical nephrectomy [11] - T1 - 95% - T2 - 88% - T3 - 59% - T4 - 20% - survival is 77% for tumors <4 cm, 54% for tumors 4-7 cm, 46% for tumors >7 cm [15] - renal cell carcinoma is an immunogenic tumor, & spontaneous regressions have been documented [11] 13) screening not recommended for older patients with end stage renal disease or who are not renal transplant candidates [1]

Interactions

disease interactions

Specific

papillary renal cell carcinoma renal cell carcinoma, chromophobe type renal cell carcinoma, clear cell type; clear cell (conventional) renal cell carcinoma renal cell carcinoma, sarcomatous type

General

adenocarcinoma malignant kidney neoplasm (kidney cancer)

Database Correlations

OMIM 144700

References

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