renal cell carcinoma (hypernephroma, Grawitz tumor)
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Introduction
also see kidney cancer
Etiology
- 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
- 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% are bilateral
- 5% are multifocal
- most originate in the renal cortex
- may metastasize to
- lung (75%)
- soft tissues (36%)
- renal veins
- inferior vena cava
- periaortic & retroperitoneal lymph nodes
- bone (20%)
- liver (18%)
- brain &/or spinal cord (8%)
- skin (8%)[15]
Microscopic pathology
- histologic subtypes:
- clear cell or conventional (majority, 75%[15])
- granular
- papillary
- chromophobe
- collecting duct
- 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
- patients often asymptomatic until malignancy is advanced[1]
- 25-30% asymptomatic, diagnosis is incidental
- classic triad
- abdominal pain
- lower extremity edema may be up to hips (see Complications:)
- acute varicocele, usually left-sided
- 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]
- erythrocytosis
- weight loss
- fever, night sweats
- also see kidney cancer
Laboratory
- complete blood count (CBC)
- may be polycythemia (erythrocytosis) secondary to unregulated erythropoietin secretion by tumor
- serum chemistries
- serum calcium: may be hypercalcemia due to unregulated production of calcitriol by tumor
- serum alkaline phosphatase may be elevated with bony metastases
- liver function tests
- renal function tests
- electrolytes[11]
- urinalysis: hematuria
- PCR/southern blot/northern blot/in-situ hybridization
- serology: antiantibodies: C19orf29, CCDC34
Radiology
- 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]
- computed tomography of abdomen, pelvis & thorax (with contrast)
- 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+]
- distortion of renal contour
- no sharp interface with surrounding parenchyma
- heterogenous
- enhanced by contrast
- typically has ball shape, may be exophytic[15]
- allows for staging
- pathognomonic CT findings obviate need for renal biopsy[1]
- indicated if lesion is not clearly a benign cyst
- magnetic resonance imaging may be alternative to CT[15]
- chest X-ray may show pulmonary metastases
- bone scan if bone pain[1]
- 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]
- round uniform nuclei, ~10 microns diameter, small or absent nucleoli
- slightly irregular nuclei, ~15 microns diameter, nucleoli visible at 400x
- moderate to markedly irregular nuclei, ~20 microns diameter, large nucleoli visible at 100x
- 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]
Differential diagnosis
Management
- also see kidney cancer
- nephrectomy for resectable RCC
- radical nephectomy is the primary treatment
- 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]
- renal artery embolization may be an option for patients unable to tolerate surgery[15]
- adjvant chemotherapy or radiation therapy not recommended for early stage localized RCC[1]
- resecting primary renal cell carcinoma may improve response to chemotherapy in metastatic disease[1]
- resistance to radiation therapy & chemotherapy
- radiation therapy
- radiofrequency ablation may be an option for tumors < 3 cm
- metastatic renal carcinoma developed in 3 of 106 patients[26]
- 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]
- 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)
- sunitinib[10][22]
- mTOR inhibitors
- temsirolimus, everolimus [1, 11]
- immunotherapy
- 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]
- 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]
- nivolumab (Opdivo) + ipilimumab (Yervoy) superior to sunitinib[17]
- lenvatinib + pembrolizumab superior to sunitinib[28]
- progression-free survival 23.9 vs 9.2 months[28]
- axitinib in combination with pembrolizumab (73% response)[20]
- atezolizumab in combination with bevacizumab for treatment of metastatic renal cell carcinoma improves survival by 3 months vs sunitinib[21]
- interferon alfa-2A (Roferon A)
- interferon alfa-2B (Intron A)[11]
- interleukin-2 & interferon alfa beneficial for ~10% of patients with metastatic renal cell carcinoma[1]
- other chemotherapeutic agents[11]
- zoledronate for bone metastases inhibits osteoclastic activity
- 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]
- 5 year survival after radical nephrectomy[11]
- screening not recommended for older patients with end stage renal disease or who are not renal transplant candidates[1]
More general terms
More specific terms
- 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
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2021.
Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022 - ↑ 2.0 2.1 AJCC Cancer Staging Manual. 6th ed. Springer 2002.
- ↑ 3.0 3.1 Bostwick & Eble, eds. Urologic Surgical Pathology. Mosby 1997
- ↑ 4.0 4.1 Topalian SL et al Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer N Engl J Med, June 2, 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/22658127 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1200690
Brahmer JR et al Safety and Activity of Anti-PD-L1 Antibody in Patients with Advanced Cancer N Engl J Med, June 2, 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/22658128 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1200694 - ↑ 5.0 5.1 Journal Watch: Aging/Geriatrics July 2, 2012 ASCO 2012 Report: Genitourinary Cancer Massachesetts Medical Society http://oncology-hematology.jwatch.org
- ↑ Krajewski KM, Giardino AA, Zukotynski K et al Imaging in renal cell carcinoma. Hematol Oncol Clin North Am. 2011 Aug;25(4):687-715 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21763963
- ↑ Flanigan RC, Salmon SE, Blumenstein BA et al Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001 Dec 6;345(23):1655-9. PMID: https://www.ncbi.nlm.nih.gov/pubmed/11759643
- ↑ Motzer RJ, Hutson TE, Tomczak P et al Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17215529
- ↑ Stephenson AJ, Chetner MP, Rourke K et al Guidelines for the surveillance of localized renal cell carcinoma based on the patterns of relapse after nephrectomy. J Urol. 2004 Jul;172(1):58-62. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15201737
- ↑ 10.0 10.1 Escudier B Medscape Oncology: Oct 10, 2014 Medscape Medical News from the: European Society for Medical Oncology (ESMO) Congress 2014 Refining Sunitinib Use Extends Survival in RCC http://www.medscape.com/viewarticle/832897?nlid=67605_481&src=wnl_edit_medp_honc&uac=40275SJ&spon=7
- ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 Sachdeva K. Harris JE Medscape: Renal Cell Carcinoma http://emedicine.medscape.com/article/281340-overview
- ↑ 12.0 12.1 Motzer RJ, Hutson TE, Tomczak P et al Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug 1;27(22):3584-90 PMID: https://www.ncbi.nlm.nih.gov/pubmed/19487381
- ↑ 13.0 13.1 Janowitz T, Welsh SJ, Zaki K, Mulders P, Eisen T. Adjuvant therapy in renal cell carcinoma-past, present, and future. Semin Oncol. 2013 Aug;40(4):482-91 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23972712
- ↑ Hazar DB, Eneanya ND, Kilcoyne A, Rosales IA. Case Records of the Massachusetts General Hospital. Case 35-2015: A 72-Year-Old Woman with Proteinuria and a Kidney Mass. N Engl J Med. 2015 Nov 12;373(20):1958-67. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26559575 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMcpc1505527
- ↑ 15.00 15.01 15.02 15.03 15.04 15.05 15.06 15.07 15.08 15.09 15.10 15.11 15.12 15.13 15.14 15.15 15.16 15.17 15.18 Thomas S, Grimm L, Brady MP Renal Cell Carcinoma: Recognition and Follow-up. Medscape. April 18, 2016 http://reference.medscape.com/features/slideshow/renal-cell-carcinoma
- ↑ 16.0 16.1 Rothaus C Systemic Therapy for Metastatic Renal-Cell Carcinoma. NEJM Resident 360. Jan 25, 2017 https://resident360.nejm.org/content_items/2197/
- ↑ 17.0 17.1 Chustecka Z Immunotherapy Changes First-Line Paradigm in Advanced RCC. Medscape. Sep 11, 2017. Coverage from the European Society for Medical Oncology (ESMO) 2017 Congress https://www.medscape.com/viewarticle/885477
Motzer RJ, Tannir NM, McDermott DF Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. March 21, 2018 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/29562145 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1712126 - ↑ 18.0 18.1 FDA News Release. November 16, 2017 FDA expands approval of Sutent to reduce the risk of kidney cancer returning. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm585657.htm
- ↑ 19.0 19.1 Minerd J MedPage Today. January 14, 2018 Cabozantinib Bests Everolimus in RCC with Bone Metastases. Subgroup analysis of METEOR trial showed improved survival. https://www.medpagetoday.com/hematologyoncology/renalcellcarcinoma/70501
Escudier B, Powles T, Motzer RJ et al Cabozantinib, a new standard of care for patients with advanced renal cell carcinoma and bone metastases? Subgroup analysis of the METEOR trial J Clin Oncol. 2018 Jan 8:JCO2017747352 PMID: https://www.ncbi.nlm.nih.gov/pubmed/29309249 - ↑ 20.0 20.1 Bankhead C Combo Therapy Highly Active in Untreated RCC. Objective responses with anti-VEGF/Anti-PD-1 pairing in three-fourths of patients. MedPage Today. Feb 11, 2018 https://www.medpagetoday.com/meetingcoverage/mgucs/71090
Atkins MB, et al Safety and efficacyo of axitinib in combination with pembrolizmab in patients with advanced renal cell cancer. Genitourinary Cancers Symposium (GUCS) 2018; Abstract 579.
Atkins MB, Plimack ER, Puzanov I et al. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Lancet Oncol 2018; PMID: https://www.ncbi.nlm.nih.gov/pubmed/29439857 - ↑ 21.0 21.1 Fuerst ML with Expert Critique by Bowman IA Immunotherapy Plus Antiangiogenic Therapy Slows Growth of Advanced Kidney Cancer. Adding atezolizumab to bevacizumab delayed cancer growth by about 3 months longer than targeted therapy with sunitinib MedPage Today. 03.22.2018 https://www.medpagetoday.com/reading-room/asco/immunotherapy/71920
- ↑ 22.0 22.1 22.2 Mulcahy N In Advanced Kidney Cancer, Surgery No Longer Sole Standard of Care. Medscape. Jun 03, 2018. https://www.medscape.com/viewarticle/897536
- ↑ 23.0 23.1 23.2 Mejean A, Ravaud A, Thezenas S et al Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma. N Engl J Med 2018; 379:417-427 PMID: https://www.ncbi.nlm.nih.gov/pubmed/29860937 Free full text https://www.nejm.org/doi/full/10.1056/NEJMoa1803675
- ↑ 24.0 24.1 Dahl DM, Simeone JF, Iliopoulos O et al Case 36-2018: A 29-Year-Old Man with an Incidentally Discovered Renal Mass. N Engl J Med 2018; 379:2064-2072. Nov 22, 2018 PMID: https://www.ncbi.nlm.nih.gov/pubmed/30462933 https://www.nejm.org/doi/full/10.1056/NEJMcpc1802832
- ↑ Morais C, Johnson DW, Vesey DA, Gobe GC. Functional significance of erythropoietin in renal cell carcinoma. BMC Cancer. 2013 Jan 10;13:14. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/23305401 Free PMC Article
- ↑ 26.0 26.1 Johnson BA, Sorokin I, Cadeddu JA Ten-year outcomes of renal tumor radio frequency ablation. J Urol 2019 Feb; 201:251-258. PMID: https://www.ncbi.nlm.nih.gov/pubmed/30634350
- ↑ Hu SL, Chang A, Perazella MA et al The Nephrologist's Tumor: Basic Biology and Management of Renal Cell Carcinoma. J Am Soc Nephrol. 2016 Aug;27(8):2227-37. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/26961346 Free PMC Article
- ↑ 28.0 28.1 28.2 Motzer R, Alekseev B, Rha SY et al Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med 2021; 384:1289-1300 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33616314 https://www.nejm.org/doi/full/10.1056/NEJMoa2035716
- ↑ 29.0 29.1 NEJM Knowledge+
- ↑ Renal Cell Cancer (PDQ): Treatment http://www.nci.nih.gov/cancertopics/pdq/treatment/renalcell/HealthProfessional
Patient information
renal cell carcinoma patient information