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Kidney cancer ( Renal cell carcinoma )

RCCs account for 2 % of the global cancer diagnoses and deaths but the incidence has increased In US cancer of the kidney and renal pelvis comprise the 6th most common newly diagnosed cancer in men and 10th most common in women In UK kidney cancer is the 7th most common cancer Globally highest rates are seen in European nations whereas low rates in African and Asian countries Seen more commonly in men ages 50-70 ( NICE 50- 80 ) Men affected more than women in a ratio of 2 : 1 In the US the median age of patients in the SEER database was 64 yrs Most kidney cancers are sporadic but about 4 % of RCCs can be hereditary
- if RCC diagnosed at age < 46 possibility of an underlying kidney cancer syndrome should be considered
- 10 familial syndromes the confer increased risk of developing RCC
- Von Hippel-Lindau disease is the most common form of hereditary RCC Mortality from kidney cancer has decreased as these are often picked up when they have not metastasized
 due to increased use of abdominal imaging ( for e.g US or CT scan of abdomen or chest ) Screening is not undertaken routinely unless a known heritable syndrome has been identified.

 

Most common is renal cell carcinoma ( RCC ) 
 RCC make up more than 90 % of all renal malignancies About 9 out of 10 kidney cancers are RCCs RCCs are cancers originating from renal epithelium RCC- also known as renal cell adenocarcinoma , hypernephroma or Grawitz tumour Most of these tumours are histologically believed to arise from the cells of the proximal convoluted tubule Of the RCCs 90 % are of clear cell (ccRCC ) 
Non-clear cell RCC – papillary and chromophobe subtypes with clear cell being the most common and most aggressive ccRCC ( 75 % ) being the most common type has received most attention and has worse disease specific survival as it tends to be discovered at a more advanced stage Most other kidney tumours are grouped as nccRCC Papillary RCCs are of 2 main types -1 & 2 with type 2 being more aggressive.

 

Rare non-clear cell RCC subtypes
- collecting duct carcinoma
- translocation RCC
- renal medullary carcinoma
- unclassified
- transitional cell carcinoma ( also called urothelial carcinomas which do not start in kidney but in the transitional cells in the lining of renal pelvis, nearly all renal pelvis cancers are of transitional type )
- Wilms’s tumour ( nephroblastoma ) most common kidney tumour in children
- renal sarcomas Benign kidney tumours
- angiomyolipoma ( most common benign kidney tumour )
- Oncocytoma.

 

Obesity
 Affects both men and women A study by Bergstrom et al has shown that each unit increase of BMI was linked to a 7 % increase in the relative risk of RCC diagnosis Morbidly obesity is associated with a 71 % increased risk compared to normal weight individuals in USA Obese individuals are technically challenging and several mechanisms have been proposed to explain increased risk of RCC.

 

Cigarette smoking major risk factor sufficient evidence to support causality risk directly related to duration and number of cigarettes ie dose ( risk is increased by about 50 % in males and 20 % in females compared to non-smokers ) passive smoking also increases the risk studies have shown a link between ccRCC and papillary RCC

 

Genetic predisposition for
 e.g Von Hipperl-Lindau disease
VHL -due to autosomal dominant constitutional mutation of VHL gene that predisposes to clear cell RCC and other proloferative vascular lesions.

 

Acquired cystic kidney disease Nearly 50 times increased risk ACKD is seen in patients with end stage renal disease on dialysis ( usually after 3 yrs of dialysis more than 50 % of patients will develop cystic changes ) Happen more in men , often B/L and multicentric RCC can happen any time in patients on dialysis with ACKD , even after renal transplant

 

Hypertension
 VITAL study revealed link between risk of RCC and hypertension with a hazard ratio of 1.70 A dose effect relation ship as with smoking is likely between severity of hypertension and risk of RCC Why this happens in people with hypertension is not very clear but one explanation is that the chronic renal hypoxia accompanying hypertension promotes tumour cell proliferation and angiogenesis by a transcription factor known as hypoxia inducible factor.

 

Classic triad
- gross haematuria
- abdominal pain
- palpable mass in the flank or abdomen

often represents advanced disease and seen only in about 10 % of cases
 Most cases ( > 50 % ) are detected incidentally during imaging – fo e.g a CT scan ordered for some other reason
 Early small RCCs are usually asymptomatic
 Isolated right sided varicocele or non reducing b/l varicocele , b/l lower extremity oedema can also reflect advanced disease ( varicocele develops as the tumour invades and grows into the renal vein and IVC causing a blockage of the testicular vein)
 Presentation can also be with para-neoplastic syndromes in up to 30 % fo patients ( these are symptoms caused by hormones or cytokines excreted by tumour cells or by an immune response against the tumour cell ) such as

- hypercalcaemia ( due to parathyroid related hormone peptide )
- unexplained fever
- erythrocytosis ( due to erythropoietin )
- Cushing’s syndrome ( due to ACTH )
- Hypertension due to renin over production
 About 25 % of cases are present as advanced /metastatic disease with symptoms as fever , weight loss , cough , adenopathy and bone pain
- bony metastasis can cause pathological fractures , spinal cord compression and hypercalcaemia
- pain ( excruciating , band like , sharp ) can be from vertebral collapse , spinal cord compression 
 Familial forms of RCC
- develop at a younger age
- often multiple and bilateral.

 

Physical examination has limited role in RCC but beware of findings as
 palpable abdominal mass palpable cervical lymphadenopathy non-reducing varicocele and b/l lower extremity oedema which indicates venous involvement.

 

FBC LFT , LDH , CRP Bone pofile Urinalysis US can be the first line investigation and can suggest a diagnosis CT allows for assessment of local invasiveness , lymph node involvement or distant metastases MRI can give additional information in investigating local advancement and venous involvement by tumour thrombus Contrast enhanced abdominal and pelvic CT is valuable in accurate staging
IV contrast material demonstrates enhancement Renal tumour core biopsy confirms the diagnosis Histological diagnosis typically established after surgical removal of the tumour or after biopsy.

 

NICE USC guidance -Refer using a USC pathway for an appointment within 2 weeks if they are aged 45 and above and have
 unexplained visible haematuria without urinary tract infection OR visible haematuria that persists or recurs after successful treatment of urinary tract infection.

 

Regardless of tumour histology surgery is the preferred treatment for non-metastatic disease Majority of patients are diagnosed when the tumour is still amenable to surgical treatment For patients with non- metastatic RCC ( TNM stages I -III ) radical nephrectomy or partial nephrectomy is the only acceptable curative treatment Use of targeted agents in metastatic disease has been the major advancement in recent decades Metastatic RCC is refractory to conventional chemotherapy Options for systemic therapy in cases of relapse or stage IV disease include kinase inhibitors , mTOR inhibitors and monoclonal antibodies against VEGF or PD- L1 ( programmed death ligand ) The IHC stain for the immunosuppressive marker NICE recommends sunitinib as a 1st line treatment for people with advanced and or metastatic disease for whom immunotherapy is suitable.

 

RCC is an aggressive disease Prognostic determinants include
○ tumour stage , grade
○ local extent of the tumour
○ presence of regional nodal metastases
○ evidence of metastatic disease at presentation Some example of predicting prognosis using tools
○ Memorial Sloan Kettering Cancer Centre prognostic model 
○ International Metastatic Renal Cell Carcinoma Database Consortium Lung metastasis is the most common site of distant recurrence About 20 % to 30 % of patients with localized tumour will experience a relapse -median time to relapse after surgery is 1-2 yrs with most relapses within 3 yrs

References

  1. Padala, Sandeep Anand et al. “Epidemiology of Renal Cell Carcinoma.” World journal of oncology vol. 11,3 (2020): 79-87. doi:10.14740/wjon1279
  2. Epidemiology and Etiology of Kidney cancer Epidemiology and Etiology of Kidney Cancer (urotoday.com)
  3. Gray RE, Harris GT. Renal Cell Carcinoma: Diagnosis and Management. Am Fam Physician. 2019 Feb 1;99(3):179-184. Erratum in: Am Fam Physician. 2019 Jun 15;99(12):732. PMID: 30702258.
  4. Pandey J, Syed W. Renal Cancer. [Updated 2021 Feb 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK558975/
  5. Kabaria, Reena et al. “Renal cell carcinoma: links and risks.” International journal of nephrology and renovascular disease vol. 9 45-52. 7 Mar. 2016, doi:10.2147/IJNRD.S75916
  6. Chow, Wong-Ho et al. “Epidemiology and risk factors for kidney cancer.” Nature reviews. Urology vol. 7,5 (2010): 245-57. doi:10.1038/nrurol.2010.46
  7. Motzer, R. J., Jonasch, E., Boyle, S., Carlo, M. I., Manley, B., Agarwal, N., Alva, A., Beckermann, K., Choueiri, T. K., Costello, B. A., Derweesh, I. H., Desai, A., George, S., Gore, J. L., Haas, N., Hancock, S. L., Kyriakopoulos, C., Lam, E. T., Lau, C., Lewis, B., Madoff, D. C., McCreery, B., Michaelson, M. D., Mortazavi, A., Nandagopal, L., Pierorazio, P. M., Plimack, E. R., Ponsky, L., Ramalingam, S., Shuch, B., Smith, Z. L., Somer, B., Sosman, J., Dwyer, M. A., & Motter, A. D. (2020). NCCN Guidelines Insights: Kidney Cancer, Version 1.2021, Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw18(9), 1160-1170. Retrieved Jun 12, 2021, from https://jnccn.org/view/journals/jnccn/18/9/article-p1160.xml
  8. Cairns, Paul. “Renal cell carcinoma.” Cancer biomarkers : section A of Disease markers vol. 9,1-6 (2010): 461-73. doi:10.3233/CBM-2011-0176
  9. PDQ Adult Treatment Editorial Board. Renal Cell Cancer Treatment (PDQ®): Health Professional Version. 2021 Mar 17. In: PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK65815
  10. Hsieh, James J et al. “Renal cell carcinoma.” Nature reviews. Disease primers vol. 3 17009. 9 Mar. 2017, doi:10.1038/nrdp.2017.9
  11. Suspected cancer: recognition and referral NICE guideline [NG12]Published: 

  12. NCCN guideline version 4.2021 Kidney Cancer https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf

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