Clinical Policy Title: Fluorescence spectroscopy for prostate cancer diagnosis
Clinical Policy Number: 13.01.05
Effective Date:
Initial Review Date:
Most Recent Review Date:
Next Review Date:
April 1, 2017
November 16, 2016
November 16, 2016
November 2017
Policy contains:
 Digital rectal examination.
 Fluorescence spectroscopy.
 Fluorometry.
 Prostate specific antigen.
 Spectrofluorometry.
Related policies:
CP# 13.01.01
Genetic testing for prostate cancer prognosis
ABOUT THIS POLICY: Prestige Health Choice has developed clinical policies to assist with making coverage determinations. Prestige Health
Choice’s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS),
state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional
literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including
any state- or plan-specific definition of “medically necessary,” and the specific facts of the particular situation are considered by Prestige Health
Choice when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws
and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Prestige Health
Choice’s clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health
care providers are solely responsible for the treatment decisions for their patients. Prestige Health Choice’s clinical policies are reflective of evidencebased medicine at the time of review. As medical science evolves, Prestige Health Choice will update its clinical policies as necessary. Prestige Health
Choice’s clinical policies are not guarantees of payment.
Coverage policy
Prestige Health Choice considers the use of fluorescence spectroscopy for prostate cancer diagnosis to be
investigational and experimental, and, therefore, not medically necessary.
Limitations:
Coverage determinations are subject to benefit limitations and exclusions as delineated by the state
Medicaid authority. The Florida Medicaid website can be accessed at
http://ahca.myflorida.com/Medicaid/ .
Alternative covered services:
Digital rectal examination (DRE), fine needle biopsy, and prostate specific antigen (PSA)
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Background
Prostate cancer is the third most common cancer in the U.S. behind breast and lung. It is the most common
among men; an estimated 180,890 cases will be diagnosed in 2016. About 13% of U.S. males are expected
to be diagnosed with the disease during their lifetime (Howlader, 2016).
The most common means of diagnosing the disease is a Prostate Specific Antigen (PSA) test, for which
levels of 4.0 ng/ml or higher are considered abnormal, followed by a biopsy (or sometimes an ultrasound)
to confirm the presence and extent of cancer. Digital rectal exams, and other methods can detect prostate
cancer, although the literature supporting efficacy of all non-PSA screening approaches are of low to
moderate quality, and only relevant in high-risk populations (Carter, 2013).
Prostate biopsy has limited ability to accurately diagnose cancer. After surgery, just 32.2% of cancers were
detected correctly with a 12-core prostate biopsy using the same mapping, and just 43.3% of cancers were
assigned the same Gleason score (Serefoglu, 2013). Transrectal ultrasound (TRUS)-guided prostate biopsies
cannot differentiate cancer lesions from benign tissue and are only useful for locating boundaries of the
gland to guide biopsy (Crawford, 1998). Thus, there is a need to improve diagnostic accuracy.
Fluorescence spectroscopy is a type of electromagnetic spectroscopy that analyzes fluorescence from a
sample. It uses a beam of light, typically ultraviolet, that causes electrons in molecules to emit light. The
technique is also known as fluorometry or spectrofluorometry, and employs two types of instruments (filter
fluorometers and spectrofluorometers). It has been used for biochemical, chemical, and medical purposes.
Application of fluorescence spectroscopy in medicine is relatively new. In 1984, the first report of
fluorescence spectra measurement in cancerous and normal rat tissue, including prostate cancer, was
reported (Alfano, 1984). To date, the technique has been used most for diagnosing kidney and prostate
disease.
An early study confirmed that fluorescence spectroscopy was able to determine whether or not tissue was
malignant (Ramanujam, 2000). Subsequent reports used fluorescence spectroscopy to detect selenium
levels in serum, prostate tissues, and seminal vesicle tissues in prostate cancer patients (Sabaichi, 2006).
Another used the technique to measure in vivo fluorescence in photodynamic therapy of the prostate
(Finlay, 2006).
In addition to fluorescence spectroscopy, there are several types of spectroscopy that are now being used
for diagnostic purposes in medicine. These include elastic scattering spectroscopy, optical coherence
tomography, and Raman spectroscopy (A’Amar , 2013). Magnetic resonance spectroscopy has been found
to have high sensitivity and specificity in diagnosing prostate cancer (Mowatt, 2013), especially in low-risk
patients (Umbehr, 2009).
Searches
Prestige Health Choice searched PubMed and the databases of:
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


UK National Health Services Centre for Reviews and Dissemination.
Agency for Healthcare Research and Quality’s National Guideline Clearinghouse and other
evidence-based practice centers.
The Centers for Medicare & Medicaid Services (CMS).
We conducted searches on September 30, 2016. Search terms were: “fluorescence spectroscopy prostate.”
We included:
 Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and
greater precision of effect estimation than in smaller primary studies. Systematic reviews use
predetermined transparent methods to minimize bias, effectively treating the review as a
scientific endeavor, and are thus rated highest in evidence-grading hierarchies.
 Guidelines based on systematic reviews.
 Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple
cost studies), reporting both costs and outcomes — sometimes referred to as efficiency studies
— which also rank near the top of evidence hierarchies.
Findings
While there are some promising findings discerning the ability of fluorescence spectroscopy to differentiate
benign from malignant tissue, use of this technique has been restricted. Current equipment is limited, and
there is a dearth of in vivo studies (Olweny, 2014). The American Urological Society’s guideline on early
detection for prostate cancer did not rate the efficacy of diagnostic tools other than PSA, based on lack of
evidence (Carter, 2013). The American College of Radiology’s most recent guideline on prostate cancer
detection and staging does not list fluorescence spectroscopy as a means of staging prostate cancer
(Eberhardt, 2012).
Small in vitro studies (n=12 and 20) of fluorescence spectroscopy used to differentiate malignant prostate
tissues documented sensitivity and specificity above 85% (Masilamani, 2011) and above 90% (AlSalhi,
2012). Another showed fluorescence spectroscopy identified levels of tryptophan in spectra in advanced
metastatic prostate cancers that exceeded moderately metastatic cancers and normal cells (Pu, 2013).
Fluorescence spectrography has also showed varying concentrations of fluorophores in prostate tissue
according to disease state (Werahara, 2015).
A review of 724 samples of capsular and parenchymal tissue samples from 37 patients with intermediateto-high grade prostate cancer used auto-fluorescence lifetime spectroscopy and light reflectance
spectroscopy to test accuracy of the Gleason score. The study resulted in agreement of 87.9%, 90.1%, and
85.1% for parenchymal tissues, and 91.1%, 91.9%, and 94.3% when capsular tissues were included, for
Gleason scores 7, 8, and 9 (Sharma, 2014).
One review used 50 prostate specimens from radical prostatectomy patients to obtain six (6) punch
biopsies from each, and four (4) measurement points for each biopsy, making a total of 1200 measurement
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points. Time-resolved fluorescence spectra resulted in a 93.4% correct classification (malignant vs. nonmalignant) of the 1200 samples, suggesting a helpful diagnostic tool for both pathologists and surgeons
(Gerich, 2011).
A study of concentrations of endogenous fluorophores in prostate tissue using an optical biopsy needle
guided by fluorescence spectroscopy in 208 males undergoing prostatectomy surgery found 72% sensitivity
and 66% specificity. The study also found a 93% negative predictive value to indicate benign tissue, leading
authors to conclude that this technique can increase the diagnostic accuracy of prostate biopsies
(Werahara, 2015).
A newly-constructed immunoassay system with surface plasmon field-enhanced fluorescence spectrometry
that detected PSA levels was able to make distinctions between cases of prostate cancer and benign
prostatic hypertrophy (Kaya, 2015).
Policy updates:
None.
Summary of clinical evidence:
Citation
Werahara (2015)
Feasibility study of
fluorescence spectroscopy
to diagnose prostate
cancer.
Olweny (2014)
Book chapter on light
reflectance spectroscopy
and autofluorescence for
kidney and prostate
disease.
Sharma (2014)
Using light reflectance
spectroscopy and autofluorescence lifetime
spectroscopy to diagnose
prostate cancer,
Gerich (2011)
Content, Methods, Recommendations
Key points:




Used guided optical biopsy needle to obtain biopsy core.
208 in vivo cores, 224 ex vivo cores analyzed.
Sensitivity 72%, specificity 66%, neg. predictive value for in vivo.
Sensitivity 75%, specificifity 80%, neg. predcitvie value for ex vivo.
Key points:


Equipment currently in use is limited.
Dearth of in vivo studies on ability of fluoriescence spectroscopy to diagnose prostate
cancer.
Key points:




Both methods used to assess 185 prostate capsular tissues, 539 parenchymal tissues.
Tissues taken from prostate cancer patients with Gleason Score (GS) 7, 8, or 9.
Accuracies for parenchymal tissues at GS 7, 8, 9 were 87.9%, 90.1%, and 85.1%.
Accuracy for capsular tissues at GS 7, 8, and 9 were 91.1%, 91.9%, and 94.3%.
Key points:
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Citation
Assessment of the
differentiation of benign
and malignant tissue.
Content, Methods, Recommendations
 50 prostate specimens were obtained after radical prostatectomy.
 6 punch biopsies from each specimen, and 4 measurement points for each biopsy, using
time-resolved fluorescence spectra.
 Of 1200 points, 93.4% were correctly classified.
Glossary
Digital rectal examination (DRE) – A means of checking the prostate gland for cancer, through use of a
lubricated gloved finger inserted into the patient’s rectum.
Fluorometry – See fluorescence spectroscopy.
Fluorescence spectroscopy – A type of electromagnetic spectroscopy that analyzes fluorescence from a
sample, by using a beam of light, typically ultraviolet, that causes electrons in molecules to emit light. Also
known as fluorometry or spectrofluorometry.
Prostate specific antigen (PSA) – A blood test of a protein produced by cells of the prostate gland,
commonly used as in screening for prostate cancer.
Spectrofluorometry – See fluorescence spectroscopy.
References
Professional society guidelines/ other:
Carter HB, Albertsen PC, Barry MJ, Zietman AL. Early detection of prostate cancer: AUA guideline. J Urol.
2013;190(2):419 – 26.
Eberhardt SC, Carter S, Casalino DD, et al. ACR Appropriateness Criteria® prostate cancer - pretreatment
detection, staging, and surveillance. Reston VA: American College of Radiology; 2012. 12 pp.
https://www.guidelines.gov/summaries/summary/43879/acr-appropriateness-criteria--prostate-cancerpretreatment-detection-staging-and-surveillance. Accessed October 3, 2016.
Gerich CD, Opitz J, Toma M, et al. Detection of cancer cells in prostate tissue with time-resolved
fluorescence spectroscopy. Proceedings of Society of Photo-Optical Instrumentation Engineers (SPIE) 7897.
Optical Interactions with Tissue and Cells XXII, 78970R. February 22, 2011.
http://proceedings.spiedigitallibrary.org/proceeding.aspx?articleid=1348599. Doi: 10.1117/12.876094.
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Howlader N, Noone AM, Karpcho M, et al. SEER Cancer Statistics Review, 1975-2013. Bethesda MD:
National Cancer Institute. http://seer.cancer.gov/csr/1975_2013/. April 2016. Accessed September 30,
2016.
Olweny EO, Cadeddu JA. Light Reflectance Spectroscopy and Autofluorescence (Kidney and Prostate).
Chapter in: Advances in Image-Guided Urologic Surgery, September 4, 2014.
http://link.springer.com/chapter/10.1007%2F978-1-4939-1450-0_8#page-1. Accessed September 30, 2016.
Peer-reviewed references:
A’Amar OM, Liou L, Rodriguez-Diaz E, De las Morenas A, Bigio IJ. Comparison of elastic scattering
spectroscopy with histology in ex vivo prostate glands: potential application for optically guided biopsy and
directed treatment. Lasers Med Sci. 2013;28:1323 – 29.
Alfano RR, et al. Laser induced fluorescence spectroscopy from native cancerous, and normal tissue.” IEEE J
Quantum Electron. 1984;20(12):1507 – 11.
AlSalhi MS, Masilamani V, Atif M, Farhat K, Rabah D, Al Turki MR. Fluorescence spectra of benign and
malignant prostate tissues. Laser Phys Lett. 2012;9(9):631 – 35.
Crawford ED, Hirano D, Werahera PN, et al. Computer modeling of prostate biopsy: tumor size and location
– not clinical significance – determine cancer detection. J Urol. 1998;159(4):1260 – 64.
Evers DJ, Hendriks BHW, Lucassen G, Ruers TJM. Optical spectroscopy: current advances and future
applications in cancer diagnostics and therapy. Fut Oncol. 2012;8(3):307 – 20.
Finlay JC, Zhu TC, Dimofte A, et al. Interstitial fluorescence spectroscopy in the human prostate during
motexafin lutetium-mediated photodynamic therapy. Photochem Photobiol. 2006;82(5):1270 – 78.
Kaya T, Kaneko T, Kojima S, et al. High-sensitivity immunoassay with surface plasmon field-enhanced
fluorescence spectroscopy using a plastic sensor chip: application to quantitative analysis of total prostatespecific antigen and GalNAcB1-4GlcNAc-linked prostate-specific antigen for prostate cancer diagnosis. Anal
Chem. 2015;87(3):1797 – 803.
Masilimani V, Rabah D, Alsahi M, Trinka V, Vijayaraghavan P. Spectral discrimination of benign and
malignant prostate tissues – a preliminary report. Photochem Photobiol. 2011;87(1):208 – 14.
Mowatt G, Scotland G, Boachie C, et al. The diagnostic accuracy and cost-effectiveness of magnetic
resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localization of
prostate abnormalities for biopsy: a systematic review and economic evaluation. Health Technol Assess.
2013;17(20):1 – 281.
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Pu Y, Xue J, Wang W, et al. Native fluorescence spectroscopy reveals spectal differences among prostate
cancer cell lines with different risk levels. J Biomed Ops. 2013;18(8). Doi: 10.1117/1.JBO.18.8.08702.
Ramanujam N. Fluorescence spectroscopy of neoplastic and non-neoplastic tissues. Neoplasia. 2000;2(12):89 – 117.
Ramashvili L, Bochorishvili I, Gabunia N, et al. Laser induced fluorescence studies of blood plasma and
tumor tissue of men with prostate cancers. J Cancer Ther. 2012;5:1021 – 30.
Sabaichi AL, Lee JJ, Taylor RJ, et al. Selenium accumulation in prostate tissue during a randomized,
controlled short-term trial of I-selenomethione: a Southwest Oncology Group Study. Clin Cancer Res.
2006;12(7 Pt 1):178 – 84.
Serefoglu EC, Altinova S, Ugras NS, Akincioglu E, Asil E, Balbay MD. How reliable is 12-core prostate biopsy
procedure in the detection of prostate cancer? Can Urol Assoc J. 2013;7(5-6):E293 – 98.
Shahzad A, Knapp M, Edetsberger M, Puchinger M, Gaubitzer G, Kohler G. Diagnostic application of
fluorescence spectroscopy in oncology field: hopes and challenges. Applied Spectroscopy Reviews.
2010;45(1):92 – 99.
Sharma V, Olweny EO, Kapur P, Cadeddu JA, Roehrborn CG, Liu H. Prostate cancer detection using
combined auto-fluorescence and light reflectance spectroscopy: ex vivo study of human prostate. Biomed
Opt Express. 2014;5(5):1512 – 29.
Umbehr M, Bachmann LM, Held U, et al. Combined magnetic resonance imaging and magnetic resonance
spectroscopy imaging in the diagnosis of prostate cancer: a systematic review and meta-analysis. Eur Urol.
2009;55(3):575 – 90.
Werahara PN, Jasion EA, Liu Y, et al. Human feasibility study of fluorescence spectroscopy guided optical
biopsy needle for prostate cancer diagnosis. Conf Proc IEEE Eng Med Biol Soc. 2015;2015:7358-61. Doi:
10.1109/EMBC.2015.7320091.
CMS National Coverage Determinations (NCDs):
No NCDs identified as of the writing of this policy.
Local Coverage Determinations (LCDs):
No LCDs identified as of the writing of this policy.
Commonly submitted codes
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Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not
an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill
accordingly.
CPT Code
0443T
Description
Real time spectral analysis of prostate tissue by fluorescence spectroscopy
Comments
ICD-10 Code
Z12.5
Description
Screening for neoplasm of prostate
Comments
Description
Comments
HCPCS Level II
Code
N/A
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