Definition
Non-visible hematuria (NVH), also known as microhematuria, is the presence of three or more red blood cells (RBCs) per high-power microscope field on a midstream, clean-catch urine sample.[1]Barocas DA, Boorjian SA, Alvarez RD, et al. Microhematuria: AUA/SUFU Guideline. J Urol. 2020 Oct;204(4):778-86.
https://www.auajournals.org/doi/10.1097/JU.0000000000001297
http://www.ncbi.nlm.nih.gov/pubmed/32698717?tool=bestpractice.com
A positive dipstick result for blood (trace blood or greater) does not confirm NVH, but should prompt further investigation with microscopy.[1]Barocas DA, Boorjian SA, Alvarez RD, et al. Microhematuria: AUA/SUFU Guideline. J Urol. 2020 Oct;204(4):778-86.
https://www.auajournals.org/doi/10.1097/JU.0000000000001297
http://www.ncbi.nlm.nih.gov/pubmed/32698717?tool=bestpractice.com
Significance
1% to 3% of patients with NVH have urinary tract cancer.[2]Tan WS, Feber A, Sarpong R, et al. Who should be investigated for haematuria? results of a contemporary prospective observational study of 3556 patients. Eur Urol. 2018 Jul;74(1):10-4.
https://www.doi.org/10.1016/j.eururo.2018.03.008
http://www.ncbi.nlm.nih.gov/pubmed/29653885?tool=bestpractice.com
[3]Samson P, Waingankar N, Shah P, et al. Predictors of genitourinary malignancy in patients with asymptomatic microscopic hematuria. Urol Oncol. 2018 Jan;36(1):10.e1-10.e6.
https://www.doi.org/10.1016/j.urolonc.2017.09.011
http://www.ncbi.nlm.nih.gov/pubmed/28988782?tool=bestpractice.com
Many cases of NVH are idiopathic; discrepancies between study populations may be attributable to factors including age, sex, ethnicity, occupation, and smoking status.[4]Tomson C, Porter T. Asymptomatic microscopic or dipstick haematuria in adults: which investigations for which patients? A review of the evidence. BJU Int. 2002;90:185-198.
http://www.ncbi.nlm.nih.gov/pubmed/12133052?tool=bestpractice.com
[5]Wollin T, Laroche B, Psooy K. Canadian guidelines for the management of
asymptomatic microscopic hematuria in adults. Can Urol Assoc J. 2009:3;77-80.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645872
http://www.ncbi.nlm.nih.gov/pubmed/19293985?tool=bestpractice.com
[6]Hiatt RA, Ordonez JD. Dipstick urinalysis screening, asymptomatic microhematuria, and subsequent urological cancers in a population-based sample. Cancer Epidemiol Biomarkers Prev. 1994;3:439-443. [Published correction appears in Cancer Epidemiol Biomarkers Prev. 1994;3:523.]
http://cebp.aacrjournals.org/cgi/reprint/3/5/439
http://www.ncbi.nlm.nih.gov/pubmed/7848421?tool=bestpractice.com
[7]Edwards TJ, Dickinson AJ, Natale S, et al. A prospective analysis of the diagnostic yield resulting from 4020 patients at a protocol-driven haematuria clinic. BJU Int. 2006;97:301-305.
http://www.ncbi.nlm.nih.gov/pubmed/16430634?tool=bestpractice.com
[8]Cohen RA, Brown RS. Microscopic hematuria. N Engl J Med. 2003;348:2330-2338.
http://www.ncbi.nlm.nih.gov/pubmed/12788998?tool=bestpractice.com
[9]Chou R, Dana T. Screening adults for bladder cancer: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2010;5:153:461-468.
http://www.ncbi.nlm.nih.gov/pubmed/20921545?tool=bestpractice.com
[10]Kang M, Lee S, Jeong SJ, et al. Characteristics and significant predictors of detecting underlying diseases in adults with asymptomatic microscopic hematuria: a large case series of a Korean population. Int J Urol. 2015 Apr;22(4):389-93.
https://www.doi.org/10.1111/iju.12697
http://www.ncbi.nlm.nih.gov/pubmed/25581719?tool=bestpractice.com
AUA: diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults
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The prevalence of NVH in the population varies from 2.4% to 31.1%, with higher rates in men older than 60 years and men who are current or past smokers.[1]Barocas DA, Boorjian SA, Alvarez RD, et al. Microhematuria: AUA/SUFU Guideline. J Urol. 2020 Oct;204(4):778-86.
https://www.auajournals.org/doi/10.1097/JU.0000000000001297
http://www.ncbi.nlm.nih.gov/pubmed/32698717?tool=bestpractice.com
[10]Kang M, Lee S, Jeong SJ, et al. Characteristics and significant predictors of detecting underlying diseases in adults with asymptomatic microscopic hematuria: a large case series of a Korean population. Int J Urol. 2015 Apr;22(4):389-93.
https://www.doi.org/10.1111/iju.12697
http://www.ncbi.nlm.nih.gov/pubmed/25581719?tool=bestpractice.com
History
The most important initial diagnostic step is a detailed history, with the aim of identifying risk factors for malignancy and medical renal disease. History may also indicate less serious causes (e.g., recent exercise or sexual activity, urinary tract infection, and menstruation).
Cancer risk factors
The risk of urinary tract malignancy increases with age >40 years, male sex, degree of hematuria, persistence of hematuria, history of visible hematuria, tobacco use, previous radiation exposure, family history of urothelial cancer (previously termed transitional cell carcinoma) or Lynch syndrome, and certain occupational exposures (dyes, benzenes, aromatic amines) and medications such as cyclophosphamide or ifosfamide chemotherapy, and aristolochic acid in some herbal weight loss preparations).[8]Cohen RA, Brown RS. Microscopic hematuria. N Engl J Med. 2003;348:2330-2338.
http://www.ncbi.nlm.nih.gov/pubmed/12788998?tool=bestpractice.com
Asymptomatic NVH is more likely to be associated with urinary tract malignancy in men.[11]American College of Obstetricians and Gynecologists' Committee on Gynecologic Practice, American Urogynecologic Society. Committee opinion no. 703: asymptomatic microscopic hematuria in women. Jun 2017 [Internet publication].
https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2017/06/asymptomatic-microscopic-hematuria-in-women
[3]Samson P, Waingankar N, Shah P, et al. Predictors of genitourinary malignancy in patients with asymptomatic microscopic hematuria. Urol Oncol. 2018 Jan;36(1):10.e1-10.e6.
https://www.doi.org/10.1016/j.urolonc.2017.09.011
http://www.ncbi.nlm.nih.gov/pubmed/28988782?tool=bestpractice.com
Obesity and hypertension are risk factors for renal cell carcinoma.[12]Escudier B, Porta C, Schmidinger M, et al. Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019 May 1;30(5):706-20.
https://www.esmo.org/guidelines/genitourinary-cancers/renal-cell-carcinoma
http://www.ncbi.nlm.nih.gov/pubmed/30788497?tool=bestpractice.com
If malignancy is suspected, based on a high-risk or intermediate-risk profile, then evaluation of the entire urinary tract, including upper tract imaging and cystoscopy for the lower tract, is required.[1]Barocas DA, Boorjian SA, Alvarez RD, et al. Microhematuria: AUA/SUFU Guideline. J Urol. 2020 Oct;204(4):778-86.
https://www.auajournals.org/doi/10.1097/JU.0000000000001297
http://www.ncbi.nlm.nih.gov/pubmed/32698717?tool=bestpractice.com
By contrast, the workup of low-risk patients can be more focused toward the suspected cause without a complete urinary tract survey. The UK National Institute for Health and Care Excellence recommends that people ≥60 years with unexplained NVH, and either dysuria or a raised white cell count on a blood test, should be referred using a suspected cancer pathway referral for bladder cancer (for a diagnosis or ruling out of cancer within 28 days of the referral).[13]National Institute for Health and Care Excellence. Suspected cancer: recognition and referral. Oct 2023 [internet publication].
https://www.nice.org.uk/guidance/ng12
Classification scheme
Considering the source of bleeding by anatomic site offers an organized approach. The upper urinary tract includes the kidneys (glomerular or nonglomerular) and ureters, with remaining structures in the lower urinary tract. These dividing lines are useful to apply during the history and physical exam, as well as when ordering diagnostic tests, because no single diagnostic test evaluates the urinary tract completely.
Diagnostic testing
Diagnostic testing must first confirm the presence of NVH. Thereafter, testing may distinguish an upper tract glomerular source from other causes, allowing a more refined workup. However, upper and lower tract diagnostic tests (imaging and cystoscopy) remain necessary in all patients with risk factors for urinary tract malignancy.
Screening
The most often identified cancer in patients with NVH is urothelial cancer.[7]Edwards TJ, Dickinson AJ, Natale S, et al. A prospective analysis of the diagnostic yield resulting from 4020 patients at a protocol-driven haematuria clinic. BJU Int. 2006;97:301-305.
http://www.ncbi.nlm.nih.gov/pubmed/16430634?tool=bestpractice.com
[14]Messing EM, Madeb R, Young T, et al. Long-term outcome of hematuria home screening for bladder cancer in men. Cancer. 2006;107:2173-2179.
http://onlinelibrary.wiley.com/doi/10.1002/cncr.22224/full
http://www.ncbi.nlm.nih.gov/pubmed/17029275?tool=bestpractice.com
[15]Friedman GD, Carroll PR, Cattolica EV, et al. Can hematuria be a predictor as well as a symptom or sign of bladder cancer? Cancer Epidemiol Biomarkers Prev. 1996;5:993-996.
http://cebp.aacrjournals.org/cgi/reprint/5/12/993
http://www.ncbi.nlm.nih.gov/pubmed/8959322?tool=bestpractice.com
[16]Sugimura K, Ikemoto S, Kawashima H, et al. Microscopic hematuria as a screening marker for urinary tract malignancies. Int J Urol. 2001;8:1-5.
http://www.ncbi.nlm.nih.gov/pubmed/11168689?tool=bestpractice.com
[17]Jones R, Latinovic R, Charlton J, et al. Alarm symptoms in early diagnosis of cancer in primary care: cohort study using general practice research database. BMJ. 2007;334:1040.
http://www.bmj.com/cgi/content/full/334/7602/1040
http://www.ncbi.nlm.nih.gov/pubmed/17493982?tool=bestpractice.com
The US Preventive Services Task Force recommends against routine screening, estimating a positive predictive value of 5% to 8% for NVH indicating bladder cancer.[9]Chou R, Dana T. Screening adults for bladder cancer: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2010;5:153:461-468.
http://www.ncbi.nlm.nih.gov/pubmed/20921545?tool=bestpractice.com
[18]Nielsen M, Qaseem A; High Value Care Task Force of the American College of Physicians. Hematuria as a marker of occult urinary tract cancer: advice for high-value care from the American College of Physicians. Ann Intern Med. 2016;164:488-497.
http://annals.org/article.aspx?articleid=2484287
http://www.ncbi.nlm.nih.gov/pubmed/26810935?tool=bestpractice.com
American College of Physicians: hematuria as a marker of occult urinary tract cancer
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