Diagnostic Accuracy of Prostate Histoscaning (P005)Arumainayagam N1, Mikhail M1, Shamsuddin A1, Nir D2, Winkler M1

1Charing Cross Hospital, Imperial Healthcare NHS Trust, London, UK2Imperial College London, UK

Introduction and Objectives

Methods

Prostate cancer is the most commonly diagnosed malignancy affecting men accounting for 25% of all new cancer cases in males (1), with 40,975 new cases diagnosed in 2010 ( a crude incidence rate of 133.7 cases per 100 000 males in the UK) and a life-time risk of developing the disease of 1 in 8. The current diagnostic paradigm for prostate cancer involves digital rectal examination (DRE) and prostate specific antigen (PSA) testing, in order to determine the need for transrectal ultrasound (TRUS) guided biopsy of the prostate. Whilst TRUS is able to display gross prostate anatomy, it is unable to reliably differentiate between normal prostate tissue and malignant regions within the gland.

Recent research has focussed on the use of imaging in an effort to rationalise the prostate biopsy technique towards a more targeted approach. An ideal imaging modality would only capture disease deemed to be clinically significant (by virtue of volume or Gleason grade), and thus reduce the over-diagnosis and over-treatment of clinically insignificant cancer. Such an ideal imaging test would be a ‘bed-side’ imaging modality, enabling the urologist and patient to reach a more informed choice regarding whether to proceed to biopsy at the initial consultation, as well as guiding regions needing specific targeting during biopsy.

Prostate HistoScaning (PHS) is a novel ultrasound-based tissue characterisation application that uses backscattered ultrasonography data (from TRUS) to detect specific changes in prostate tissue morphology, providing volumetric 3D images of the prostate and PHS detected tumour lesions. Given that PHS only requires TRUS data, it is a good potential candidate as a ‘point-of-care’ adjunctive imaging test to help clinicians and patients decide on the decision to proceed to biopsy, and guide the clinician towards targeting suspicious areas with the biopsy needle. Early studies using this technology reported encouraging results (2, 3), with more recent evaluation dampening this initial enthusiasm for PHS (4, 5).

We aimed to evaluate the accuracy of PHS using whole-mount radical prostatectomy specimens as the reference standard within our own institution.

The study was given approval by the institutional review board ethics committee and was conducted in accordance with STARD guidelines for the reporting of diagnostic tests (6). Men undergoing radical prostatectomy within our institution during a 16 month period (July 2010 to November 2011), were recruited to the study.

Inclusion criteria:All men with biopsy proven prostate cancer eligible to undergo radical prostatectomy were deemed suitable for inclusion.

Exclusion criteria:Any men who had previous treatment for prostate cancer (including hormonal manipulation)

All men recruited to the study, whilst under general anaesthesia for their radical prostatectomy operation underwent PHS following TRUS imaging immediately prior to undertaking surgery. All radical prostatectomy specimens subsequently were fixed in formalin and processed (5 mm step-sectioning) in the histopathology department at our institution and reported by an experienced uro-pathologist, who was blinded to the preceding PHS result.

Data acquisition and storage using the PHS software allowed future use of the axial PHS images generated to be directly compared with the subsequent radical prostatectomy specimen axial images (stored digitally). In each case PHS axial images were overlaid onto corresponding digital axial images of the radical prostatectomy specimen (see figure 1), to allow correlation of PHS lesions with those actually within the gland on prostatectomy (see figure 2 & 3).

Figure 2 – Corresponding radical prostatectomy specimen axial slice with inked margin of tumour lesion

Figure 3 – Digital overlay of corresponding axial images of PHA and radical prostatectomy specimen to determine correlation

Figure 1 – Example of PHS images(a) Coronal view with red arearepresenting positive PHS signal and grey zone representing the

level of the axial slice represented by (b)

Results

Level of Analysis

Sensitivity(95% CI)

Specificity(95% CI)

PPV(95% CI)

NPV(95% CI)

False Positive Rate

False Negative Rate

Positive Likelihood ratio(95% CI)

Negative Likelihood ratio(95% CI)

Accuracy(95% CI)

Octant 57 (53 - 60) 69 (62 -75) 75 (69 - 80) 50 (45 - 54) 31 53 1.81 (1.39 – 2.41)

0.63 (0.52 – 0.76)

61 (56 - 66)

Quadrant 62 (58 – 65) 73 (58 – 84) 89 (83 – 94) 35 (28 – 40) 27 38 2.25 (1.36 – 4.13)

0.53 (0.42 -0.73)

64 (58 – 69)

Hemi 98 (96 – 100) 40 (7 – 72) 97 (95 – 98) 50 (10 – 89) 60 2 1.63 (1.04 – 3.49)

0.06 (0.01 – 0.54)

95 (91 – 98)

Region of Prostate

Sensitivity(95% CI)

Specificity(95% CI)

PPV(95% CI)

NPV(95% CI)

False Positive Rate

False Negative Rate

Positive Likelihood Ratio(95% CI)

Negative Likelihood Ratio(95% CI)

Accuracy(95% CI)

Anterior Prostate

16 (12 – 18) 96 (91 – 99) 85 (62 – 96) 46 (44 – 48) 4 84 4.26 (1.25 – 18.08)

0.88 (0.83 – 0.97)

51 (46 – 53)

Posterior Prostate

92 (88 – 95) 33 (24 – 40) 73 (70 – 76) 67 (49 – 81) 67 8 1.37 (1.15 – 1.59)

0.25 (0.11 – 0.52)

72 (67 – 77)

Level of Analysis

Sensitivity(95% CI)

Specificity(95% CI)

PPV(95% CI)

NPV(95% CI)

False Positive Rate

False Negative Rate

Positive Likelihood ratio(95% CI)

Negative Likelihood ratio(95% CI)

Accuracy(95% CI)

Octant 62 (55 – 68) 72 (64 – 79) 75 (68 – 81) 58 (51 – 65) 28 42 2.20 (1.67 – 2.89)

0.53 (0.44- 0.65)

66 (61 – 71)

Table 1: Accuracy of PHS at varying levels of analysis when all cancer considered significant

Table 2: Comparison of Accuracy of PHS between Anterior and Posterior Prostate (using Octant division of prostate)

Table 3: Accuracy of PHS at Octant Level when only ≥ 0.2cc lesion considered significant

Methods

Performance of PHS with changing definitions of ‘clinically significant cancer’: The primary endpoint was to calculate the accuracy of PHS at an octant level for:(a) when all cancer on radical prostatectomy was considered significant(b) when only those tumours ≥ 0.2cc on radical prostatectomy were considered significantIn addition to the octant division, accuracy values were calculated when the prostate was divided into quadrant and hemi-gland sectors for analysis, when detecting all cancer (see figure 4 below for schematic representation of prostate gland sectors for analysis).We also aimed to evaluate whether there was any difference in accuracy values for PHS when detecting tumours in the anterior and posterior prostate (using the octant scheme of dividing the prostate). For each patient total tumour volume on PHS was also compared with total tumour volume on radical prostatectomy specimen.All statistical analysis used was performed with statistical software (SPSS v17.0 SPSS Chicago III and MedCalc version 13).

Figure 4 – division of the prostate for statistical analysis:OctantQuadrantHemi-gland

Conclusions

PHS shows promise as a possible bed-side imaging modality capable of detecting prostate cancer.Our results show that it performs better in the posterior part of the prostate (i.e. the peripheral zone), where most prostate cancers occur. However it is not reliable in detecting tumours in the anterior part of the prostate.When raising the threshold for defining clinically significant cancer as only lesions ≥ 0.2cc, accuracy values showed a modest improvement, with overall accuracy rising from 0.61 to 0.66. The results in this study indicate that PHS has potential to serve as an imaging test to detect clinically significant prostate cancer.However, the values from our series would indicate that it does not yet have the required accuracy to facilitate targeted prostate biopsy or be used as a triage test in order for men to defer biopsy in the presence of a normal scan - future advances and improvements in PHS technology may hopefully deliver this.

References(1) Cancer Research UK Prostate Cancer Statistics http://www.cancerresearchuk.org/cancer-info/cancerstats/types/prostate/incidence/ (2) Salomon G, Spethmann J, Beckmann A, Autier P, Moore C, Durner L, et al. Accuracy of HistoScanning for the prediction of a negative surgical margin in patients undergoing radical prostatectomy. BJU international. 2013 Jan;111(1):60-6 (3) Braeckman J, Autier P, Soviany C, Nir R, Nir D, Michielsen D, et al. The accuracy of transrectal ultrasonography supplemented with computer-aided ultrasonography for detecting small prostate cancers. BJU international. 2008 Dec;102(11):1560-5 (4) Javed S, Chadwick E, Edwards AA, Beveridge S, Laing R, Bott S, et al. Does prostate HistoScanning play a role in detecting prostate cancer in routine clinical practice? Results from three independent studies. BJU international. 2013 Nov 13. (5) Schiffmann J, Tennstedt P, Fischer J, Tian Z, Beyer B, Boehm K, et al. Does HistoScanning predict positive results in prostate biopsy? A retrospective analysis of 1,188 sextants of the prostate. World J Urol. 2014 Aug;32(4):925-30.(6) Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, et al. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. BMJ (Clinical research ed). 2003 Jan 4;326(7379):41-4.

Statistical analysis to evaluate the relationship between PHS total tumour volume and final histopathology tumour volume was also undertaken:Figure 5 – Plot of PHS total tumour volume vs RP specimen total tumour volumeFigure 6 – The difference of the logarithm of PHS and RP tumour volume vs logarithm of RP tumour volume

This study was partly funded by the Imperial College Healthcare Charity