Multicentre Evaluation of Hepika Test Clinical Accuracy in Diagnosing HPV-Induced Cancer and Precancerous Lesions of the Uterine Cervix
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. Definition of the Reference Standard
2.3. Evaluation of Sample Adequacy and Cytology
- (a)
- Total number of optical fields 20× (FOV20×) in a slide = µm2 314,000,000 of circular area of slide containing the cells/µm2 350,000 of area of FOV20× = 897.
- (b1)
- Number of total cells estimated for FOV20× = Mean of the count of total cells found in 20 FOV20× of slide.
- (b2)
- Number of atypical cells estimated for FOV20× = Mean of the count of atypical cells found in 20 FOV20× of slide.
- (c1)
- Total cells present in a slide = (a × b1) = (897 × b1).
- (c2)
- Atypical cells present in a slide = (a × b2) = (897 × b2).
- (d1)
- Total cells present in residual sample = (c1/5 mL × n mL of residual liquid).
- (d2)
- Atypical cells present in residual sample = (c2/5 mL × n mL of residual liquid).
2.4. Hepika® Test (CE-IVD)
2.5. Human Papillomavirus (HPV) DNA Test
2.6. Statistical Analysis
3. Results
Adequacy of the Sample
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ADC | Adenocarcinoma |
AGC | Atypical glandular cells |
AIS | Adenocarcinoma in situ |
ASC-H | Atypical squamous cells–cannot exclude HSIL |
ASC-US | Atypical squamous cells of undetermined significance |
CC | Carcinoma |
CIN | Cervical intraepithelial neoplasia |
CIN1 | Cervical intraepithelial neoplasia grade 1 |
CIN2 | Cervical intraepithelial neoplasia grade 2 |
CIN2+ | Cervical intraepithelial neoplasia grade 2 or worse |
CIN3 | Cervical intraepithelial neoplasia grade 3 |
CIN3+ | Cervical intraepithelial neoplasia grade 3 or worse |
HG | High grade |
HK | Hepika |
HK+ | Hepika-positive |
HK− | Hepika-negative |
HPV+ | HPV-positive |
HPV− | HPV-negative |
HSIL | High-grade squamous intraepithelial lesion |
LG | Low grade |
LSIL | Low-grade squamous intraepithelial lesion |
LR+ | Positive likelihood ratio |
LR− | Negative likelihood ratio |
n | Number of cases |
N.P. | Not performed |
NEG | Negative |
NPV | Negative predictive value |
POS | Positive |
PPV | Positive predictive value |
SCC | Squamous cell carcinoma |
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Histology | HPV | Cytology | Total | % | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
POS | % | NEG | % | ADC | SCC | HSIL | LSIL | ASC-H | ASC-US | AGC | NEG | N.P. | |||
ADC | 4 | 1.5% | 2 | 1 | 1 | 4 | 1.5% | ||||||||
SCC | 6 | 2.2% | 1 | 0.4% | 3 | 3 | 1 | 7 | 2.6% | ||||||
AIS | 1 | 0.4% | 1 | 1 | 0.4% | ||||||||||
CIN3 | 60 | 21.9% | 1 | 43 | 9 | 2 | 5 | 60 | 21.9% | ||||||
CIN2 | 51 | 18.6% | 20 | 19 | 4 | 8 | 51 | 18.6% | |||||||
CIN1 | 34 | 12.4% | 7 | 19 | 2 | 6 | 34 | 12.4% | |||||||
NEG | 49 | 17.9% | 68 | 24.8% | 1 | 18 | 16 | 1 | 2 | 1 | 13 | 65 | 117 | 42.7% | |
Total | 205 | 74.8% | 69 | 25.2% | 2 | 5 | 92 | 63 | 10 | 2 | 2 | 32 | 66 | 274 | 100.0% |
0.7% | 1.8% | 33.6% | 23.0% | 3.6% | 0.7% | 0.7% | 11.7% | 24.1% | 100.0% |
HEPIKA Test | No. Cases | Histology | Residual Liquid Volume (mL) | Total Cells No. Estimation | Atypical Cells No. Estimation (%) | Optical Density E6#p53 | Optical Density E7#pRb |
---|---|---|---|---|---|---|---|
POSITIVE (27 Total) | 4 | ADC | 13 | 151,287 | 47,300 (43%) | 0.2985 | 0.2534 |
4 | SCC | 12 | 78,271 | 38,505 (58%) | 0.4731 | 0.3297 | |
9 | CIN3 | 13 | 142,661 | 24,224 (17%) | 0.2547 | 0.1993 | |
7 | CIN2 | 13 | 140,494 | 15,473 (12%) | 0.2190 | 0.2136 | |
3 | CIN1 | 8 | 138,842 | 14,055 (17%) | 0.1878 | 0.2133 | |
Total | 12 | 133,413 | 26,360 (26%) | 0.2769 | 0.2319 | ||
NEGATIVE (82 Total) | 1 | SCC | 15 | 47,235 | 33,508 (71%) | 0.1308 | 0.1430 |
1 | AIS | 15 | 219,621 | 173,463 (79%) | 0.2456 | 0.0967 | |
34 | CIN3 | 10 | 89,499 | 22,643 (26%) | 0.1015 | 0.1127 | |
25 | CIN2 | 11 | 98,123 | 16,122 (15%) | 0.1018 | 0.1099 | |
21 | CIN1 | 11 | 140,874 | 12,399 (9%) | 0.1027 | 0.1104 | |
Total | 11 | 106,357 | 20,003 (19%) | 0.1040 | 0.1114 |
Cytology | No. Cases | Hepika | HK+ | HK− | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
POS | % | NEG | % | HPV+ | % | HPV− | % | HPV+ | % | HPV− | % | ||
ADC | 0 | 2 | 0.7% | 2 | 100.0% | ||||||||
SCC | 2 | 2 | 0.7% | 3 | 1.1% | 2 | 40.0% | 3 | 60.0% | ||||
HSIL | 5 | 15 | 5.4% | 77 | 27.7% | 15 | 16.3% | 77 | 83.7% | ||||
LSIL | 92 | 8 | 2.9% | 56 | 20.1% | 8 | 12.5% | 53 | 82.8% | 3 | 4.7% | ||
ASC-H | 64 | 2 | 0.7% | 8 | 2.9% | 2 | 20.0% | 8 | 80.0% | ||||
ASC-US | 10 | 2 | 0.7% | 2 | 100.0% | ||||||||
AGC | 2 | 1 | 0.4% | 1 | 0.4% | 1 | 50.0% | 1 | 50.0% | ||||
NEG | 35 | 7 | 2.5% | 28 | 10.1% | 7 | 20.0% | 28 | 80.0% | ||||
N.P. | 66 | 3 | 1.1% | 63 | 22.7% | 3 | 4.5% | 63 | 95.5% | ||||
Total | 210 | 37 | 14.4% | 175 | 85.6% | 37 | 13.3% | 3 | 1.1% | 172 | 61.9% | 3 | 23.7% |
Histology | No. Cases | % | Hepika | HK+ | HK− | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
POS | % | NEG | % | HPV+ | % | HPV− | % | HPV+ | % | HPV− | % | |||
ADC | 0 | 1.5% | 4 | 100.0% | 4 | 100.0% | ||||||||
SCC | 4 | 2.6% | 5 | 71.4% | 2 | 28.6% | 4 | 57.1% | 1 | 14.3% | 2 | 28.6% | ||
CIN3–AIS | 61 | 22.3% | 11 | 18.0% | 50 | 82.0% | 11 | 18.0% | 50 | 82.0% | ||||
CIN2 | 51 | 18.6% | 8 | 15.7% | 43 | 84.3% | 8 | 15.7% | 43 | 84.3% | ||||
CIN1 | 34 | 12.4% | 7 | 26.6% | 27 | 79.4% | 7 | 20.6% | 27 | 79.4% | ||||
NEG | 117 | 42.7% | 5 | 4.3% | 112 | 95.7% | 3 | 2.6% | 2 | 1.7% | 46 | 39.3% | 66 | 56.4% |
Total | 274 | 100.0% | 40 | 14.6% | 234 | 85.4% | 37 | 13.5% | 3 | 1.1% | 168 | 61.3% | 66 | 24.1% |
Histology | Sensitivity [% (95% CI)] | Specificity [% (95% CI)] | PPV [% (95% CI)] | NPV [% (95% CI)] | LR+ [% (95% CI)] | LR− [% (95% CI)] | Prevalence |
---|---|---|---|---|---|---|---|
CARCINOMA | 81.8% (48%–98%) | 88.2% (84%–92%) | 22.5% (16%–31%) | 99.1% (97%–100%) | 6.94 (4.50–10.70) | 0.21 (0.06–0.72) | 4.0% |
CIN3+ | 27.8% (18%–40%) | 90.1% (85%–94%) | 50.0% (36%–64%) | 77.8% (75%–80%) | 2.81 (1.61–4.90) | 0.80 (0.69–0.93) | 26.3% |
CIN2+ | 22.8% (16%–31%) | 92.1% (86%–96%) | 70.0% (55%–81%) | 59.4% (57%–62%) | 2.86 (1.52–5.39) | 0.84 (0.75–0.93) | 44.9% |
Hepika POS | DOR | p Value | ||
---|---|---|---|---|
Histology | No. Cases | % | (95% CI) | |
CARCINOMA | 9 | 81.8 (9/11) | 33.68 (6.95–163.07) | p < 0.001 |
CIN3+ | 20 | 27.8 (20/72) | 3.50 (1.75–6.99) | p < 0.001 |
CIN2+ | 28 | 22.8 (28/123) | 3.41 (1.65–7.05) | p < 0.001 |
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Gustinucci, D.; Ciccocioppo, L.; Coppola, L.; Negri, G.; Zannoni, G.; Passamonti, B.; Cesarini, E.; Ianzano, C.; Andreano, T.; Pireddu, A.; et al. Multicentre Evaluation of Hepika Test Clinical Accuracy in Diagnosing HPV-Induced Cancer and Precancerous Lesions of the Uterine Cervix. Diagnostics 2021, 11, 619. https://doi.org/10.3390/diagnostics11040619
Gustinucci D, Ciccocioppo L, Coppola L, Negri G, Zannoni G, Passamonti B, Cesarini E, Ianzano C, Andreano T, Pireddu A, et al. Multicentre Evaluation of Hepika Test Clinical Accuracy in Diagnosing HPV-Induced Cancer and Precancerous Lesions of the Uterine Cervix. Diagnostics. 2021; 11(4):619. https://doi.org/10.3390/diagnostics11040619
Chicago/Turabian StyleGustinucci, Daniela, Lucia Ciccocioppo, Luigi Coppola, Giovanni Negri, Gianfranco Zannoni, Basilio Passamonti, Elena Cesarini, Ciro Ianzano, Tiziana Andreano, Anjuta Pireddu, and et al. 2021. "Multicentre Evaluation of Hepika Test Clinical Accuracy in Diagnosing HPV-Induced Cancer and Precancerous Lesions of the Uterine Cervix" Diagnostics 11, no. 4: 619. https://doi.org/10.3390/diagnostics11040619
APA StyleGustinucci, D., Ciccocioppo, L., Coppola, L., Negri, G., Zannoni, G., Passamonti, B., Cesarini, E., Ianzano, C., Andreano, T., Pireddu, A., & Giorgi-Rossi, P. (2021). Multicentre Evaluation of Hepika Test Clinical Accuracy in Diagnosing HPV-Induced Cancer and Precancerous Lesions of the Uterine Cervix. Diagnostics, 11(4), 619. https://doi.org/10.3390/diagnostics11040619