HPV Genotyping by Molecular Mapping of Tissue Samples in Vaginal Intraepithelial Neoplasia (VaIN) and Vaginal Squamous Cell Carcinoma (VaSCC)
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Selection of Subjects and Specimens
2.2. HPV Genotyping Using Liquid-Based Cytology (LBC) Specimens with the Genosearch-31+4 Method
2.3. Sandwich Cutting Method for FFPE (Formalin Fixed and Paraffin Embedded) Tissue Specimen Analysis
2.4. Immunohistochemical Staining for p16 and Ki67
2.5. Manual Microdissection and DNA Extraction from Tissue Specimens
2.6. HPV Genotyping Using FFPE Tissue Specimens
2.7. Statistical Analysis
3. Results
3.1. Diagnosis and Determination of Vaginal and Cervical Intraepithelial Lesions with P16 and Ki67 Immune-Staining of Tissue Specimens
3.2. The Prevalence of HPV Infection in Cases with Vaginal Intraepithelial Neoplasia (VaIN)
3.3. Comparison of the Prevalence of HPV Genotypes in Tissue Specimens and in Cervicovaginal Scraped Cells
3.4. Determination of HPV Genotypes Responsible for VaSCC, VaIN, and CIN by Molecular Mapping
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
HPV | human papillomavirus |
Vag-SIL | vaginal squamous intraepithelial lesion |
VaIN | vaginal intraepithelial neoplasia |
VaSCC | vaginal squamous cell carcinomas |
CIN | cervical intraepithelial neoplasia |
GS-31+4 | Genosearch-31+4 |
HR | high risk |
pHR | possibly high risk |
LR | low risk |
dsDNA | double-stranded DNA |
pRb | retinoblastoma protein |
SCJ | squamous-columnar junction |
LCM | laser capture microdissection |
FFPE | formalin-fixed and paraffin-embedded |
PCR | polymerase chain reaction |
H&E | hematoxylin and eosin |
IHC | immunohistochemistry |
PBS | phosphate buffered saline |
HRP | horseradish peroxidase |
DAB | 3,3′-diaminobenzidine |
DW | distilled water |
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Cases with a Single Lesion | Cases with Multiple Lesions | ||||||||
---|---|---|---|---|---|---|---|---|---|
Diagnosis | VaIN1 | VaIN2/3 | VaSCC | VaIN1+CIN1/Con | VaIN1+CIN2/3 | VaIN2/3+CIN/Con | Total | ||
N = 23 | N = 14 | p¹ | N = 7 | p2 | N = 7 | N = 16 | N = 3 | N = 70 | |
Age | 43.8 (27–67) | 48.3 (22–55) | >0.1 | 81.7 (76–88) | 0.013 | 36.6 (19–55) | 37.8 (22–80) | 42.4 (32–50) | 48.6 (19–88) |
HPV prevalence (%) | 95.7 (22/23) | 100 (14/14) | >0.1 | 85.7 (6/7) | 85.6 (6/7) | 100 (16/16) | 100 (3/3) | 95.7 (67/70) | |
HR-HPV (%) * | 17.4 (4/23) | 85.7 (12/14) | 57.1 (4/17) | 28.6 (2/7) | 93.8 (15/16) | 66.7 (2/3) | 55.7 (39/70) | ||
Possible HR-HPV (%) * | 34.8 (8/23) | 0 (0/14) | 28.6 (2/7) | 57.1 (4/7) | 43.8 (7/16) | 33.3 (1/3) | 31.4 (20/70) | ||
LR-HPV (%) * | 43.5 (10/23) | 14.3 (2/14) | 0 (0/7) | 42.9 (3/7) | 25.0 (4/16) | 66.7 (2/3) | 30.0 (21/70) | ||
Single HPV type (%) | 95.7 (22/23) | 78.6 (11/14) | 85.7 (6/7) | 14.3 (1/7) | 25.0 (4/16) | 0 (0/3) | 62.9 (38/70) | ||
Multiple HPV types (%) | 0 (0/23) | 21.4 (3/14) | 0 (0/7) | 71.4 (5/7) | 75.0 (12/16) | 100 (3/3) | 32.9 (23/70) |
Cases with a Single Lesion | Cases with Multiple Lesions | ||||||||
---|---|---|---|---|---|---|---|---|---|
Diagnosis | VaIN1 | VaIN2/3 | VaSCC | VaIN1+CIN1/Con | VaIN1+CIN2/3 | VaIN2/3+CIN/Con | Total | ||
N = 23 | N = 14 | p¹ | N = 7 | p2 | N = 7 | N = 16 | N = 3 | N = 70 | |
Age | 43.8 (27–67) | 48.3 (22–55) | >0.1 | 81.7 (76–88) | 0.013 | 36.6 (19–55) | 37.8 (22–80) | 42.4 (32–50) | 48.6 (19–88) |
HPV prevalence (%) | 95.7 (22/23) | 100 (14/14) | >0.1 | 85.7 (6/7) | 85.6 (6/7) | 100 (16/16) | 100 (3/3) | 95.7 (67/70) | |
HR-HPV (%) * | 17.4 (4/23) | 85.7 (12/14) | 57.1 (4/17) | 28.6 (2/7) | 93.8 (15/16) | 66.7 (2/3) | 55.7 (39/70) | ||
VaIN1 CIN1/Con | VaIN1 CIN2/3 | VaIN2/3 CIN/Con | |||||||
0 (0/7) 28.6 (2/7) | 6.25 (1/16) 87.5 (14/16) | 66.7 (2/3) 33.3 (1/3) | |||||||
Possible HR-HPV (%) * | 34.8 (8/23) | 0 (0/14) | 28.6 (2/7) | 57.1 (4/7) | 43.8 (7/16) | 33.3 (1/3) | 31.4 (20/70) | ||
VaIN1 CIN1/Con | VaIN1 CIN2/3 | VaIN2/3 CIN/Con | |||||||
42.9 (3/7) 28.6 (2/7) | 43.8 (7/16) 12.5 (2/16) | 33.3 (1/3) 33.3 (1/3) | |||||||
LR-HPV (%) * | 43.5 (10/23) | 14.3 (2/14) | 0 (0/7) | 42.9 (3/7) | 25.0 (4/16) | 66.7 (2/3) | 30.0(21/70) | ||
VaIN1 CIN1/Con | VaIN1 CIN2/3 | VaIN2/3 CIN/Con | |||||||
42.9 (3/7) 28.6 (2/7) | 25.0 (4/16) 0 (0/16) | 33.3 (1/3) 33.3 (1/3) | |||||||
Single HPV type (%) | 95.7 (22/23) | 78.6 (11/14) | 85.7 (6/7) | 14.3 (1/7) | 25.0 (4/16) | 0 (0/3) | 62.9(38/70) | ||
Multiple HPV types (%) | 0 (0/23) | 21.4 (3/14) | 0 (0/7) | 71.4 (5/7) | 75.0 (12/16) | 100 (3/3) | 32.9(23/70) |
Case | VaIN | HPV Type in Tissue | HPV Type in Scraped | Discordance in HPV Type | HR-HPV May Exist |
---|---|---|---|---|---|
No. | by Uniplex E6/E7 PCR | Cells by GS31+4 | in Tissue and Cell Samples | in Preclinical Lesions | |
1 | VaIN1 | HPV81 * | Negative | NE | |
2 | VaIN1 | HPV81 * | HPV56,58 | NE | 56, 58 |
4 | VaIN1 | HPV84 | HPV51,58 | Completely | 51,58 |
7 | VaIN1 | HPV90 | HPV16,90 | Partly | 16 |
8 | VaIN1 | HPV81 * | HPV51,66,89,42 | NE | 51 |
11 | VaIN1 | HPV66 | HPV66,89 | Partly | |
16 | VaIN1 | Negative | HPV31 | Completely | 31 |
18 | VaIN1 | HPV16 | HPV31,82 | Completely | 31 |
27 | VaIN1 | HPV53 | HPV53 | No | |
28 | VaIN1 | HPV90 | HPV55,61 | Completely | |
29 | VaIN1 | HPV53 | HPV53,62 | Partly | |
30 | VaIN1 | HPV68 | HPV52 | Completely | 52 |
33 | VaIN1 | HPV66 | HPV18,51,61,66,84,90 | Partly | 18, 51 |
36 | VaIN1 | HPV66 | HPV66 | No | |
39 | VaIN1 | HPV61 | HPV39,61 | Partly | 39 |
40 | VaIN1 | HPV61 | HPV31,61 | Partly | 31 |
45 | VaIN1 | HPV58 | HPV58 | No | |
50 | VaIN1 | HPV67 | HPV67 | No | |
52 | VaIN1 | HPV73 | HPV73 | No | |
53 | VaIN1 | HPV90 | Negative | Completely | |
55 | VaIN1 | HPV56 | HPV52,56 | Partly | 52 |
59 | VaIN1 | HPV71 | Negative | Completely | |
62 | VaIN1 | HPV34 | NE | NE | |
5 | VaIN2/3 | HPV52 | HPV52 | No | |
12 | VaIN2/3 | HPV18 | HPV18 | No | |
14 | VaIN2/3 | HPV16 | HPV16,84,89,90 | Partly | |
17 | VaIN2/3 | HPV52 | HPV52,84 | Partly | |
25 | VaIN2/3 | HPV42 | HPV6,42 | Partly | |
57 | VaIN2/3 | HPV42 | HPV42 | No | |
6 | VaIN2/3 | HPV16 | HPV16,89 | Partly | |
19 | VaIN2/3+VaIN1 | HPV58+HPV31 | HPV31,54,58,90 | Partly | |
23 | VaIN2/3+VaIN1 | HPV51+HPV90 | HPV39,51,90 | Partly | 39 |
41 | VaIN2/3 | HPV16 | HPV16 | No | |
42 | VaIN2/3 | HPV16 | HPV68 | Completely | |
44 | VaIN2/3 | HPV56 | HPV56 | No | |
51 | VaIN2/3 | HPV16 | HPV16 | No | |
54 | VaIN2/3 | HPV58 | HPV39,58 | Partly | 39 |
64 | VaSCC | HPV16 | HPV16 | No | |
65 | VaSCC | HPV45 | NE | NE | |
66 | VaSCC | HPV58 | HPV16,52,58 | Partly | 16,52 |
67 | VaSCC | HPV68 | NE | NE | |
68 | VaSCC | HPV53 | NE | NE | |
69 | VaSCC | HPV67 | HPV6,52 | Completely | 52 |
70 | VaSCC | Negative | NE | NE |
VaIN | HPV Type in Tissue | Acompanied | HPV Type in Tissue | Discordance for HPV Type | HPV Type in Cells | Discordance for HPV Type | HR-HPV May Exist |
---|---|---|---|---|---|---|---|
Lesion | by E6/E7 PCR | Lesion | by E6/E7 PCR | VAIN vs. CIN/Con | by GS-31+4 | Tissue vs. Cells | in Preclinical Lesions |
VaIN1 | HPV53 | CIN3 | HPV52 | Yes | HPV16,39,52,90 | Partly | 16,39 |
VaIN1 | Negative | CIN2 | HPV18 | Yes | HPV18 | No | |
VaIN1 | Negative | CIN2 | HPV52 | Yes | HPV16,52 | Partly | 16 |
VaIN1 | HPV81 | CIN1 | HPV90 | Yes | HPV51,52,58,59,90 | Partly | 51,52,58,59 |
VaIN1 | Negative | CIN1 | Negative | No | Negative | No | |
VaIN1 | Negative | CIN3 | HPV51 | Yes | HPV51 | No | |
VaIN1 | HPV42 | CIN2 | HPV52 | Yes | HPV42,52 | No | |
VaIN1 | HPV53 | CIN1 | HPV68 | Yes | HPV52,53,68 | Partly | 52 |
VaIN1 | HPV42 | CIN2 | HPV58 | Yes | HPV31, 51 | Completely | 31, 51 |
VaIN1 | HPV67 | CIN2 | HPV52 | Yes | HPV52 | Partly | |
VaIN1 | HPV67 | CIN1 | HPV67 | No | Negative | Completely | |
VaIN1 | HPV81 | CIN3 | HPV16 | Yes | HPV16,35,51,53 | NE | 35,51 |
VaIN1 | HPV71 | CIN1 | HPV84 | Yes | HPV11,16,53,54,62,84 | Partly | 16 |
VaIN1 | HPV52 | CIN2 | HPV66 | Yes | HPV16,52,66 | Partly | 16 |
VaIN1+metaplasia | HPV66+HPV74 | CIN1 | HPV53 | Yes | HPV42,52,53 | Partly | 52 |
VaIN1 | HPV53 | Condyloma | HPV11 | Yes | HPV56,53,73 | Partly | 56 |
VaIN1 | HPV90 | CIN1+CIN1 | HPV52+HPV68 | Yes | HPV52,68 | Partly | |
VaIN1 | HPV34 | CIN2 | HPV39 | Yes | NE | NE | |
VaIN1 | HPV34 | CIN3 | HPV52 | Yes | HPV34,52 | No | |
VaIN1 | HPV53 | CIN2 | HPV39 | Yes | HPV16,42,89 | Completely | 16 |
VaIN1 | HPV84 | CIN3 | HPV52 | Yes | NE | NE | |
VaIN1 | Negative | CIN2 | HPV51 | Yes | HPV51 | No | |
VaIN1 | HPV66 | CIN3+CIN1 | HPV16+HPV66 | Yes | HPV16,52,59,53,66,82 | Partly | 52,59 |
VaIN2/3 | HPV66 | CIN1 | HPV67 | Yes | HPV82 | Completely | |
VaIN2/3 | HPV16 | Condyloma | HPV6 | Yes | HPV6,16 | No | |
VaIN2/3+VaIN1 | HPV51+HPV71 | CIN2 | HPV51 | Yes | HPV51,71,68 | Partly | 68 |
HPV Type | VaIN1 | VaIN2/3 | VaSCC | Total | CIN1 | CIN2/3 | Total | ||
---|---|---|---|---|---|---|---|---|---|
N = 49 * | N = 17 | p | N = 7 | No. | N = 10 | N = 16 | No. | ||
High-risk HPV | HPV16 | 1 | 6 | 1 | 8 | 2 | 2 | ||
HPV18 | 1 | 1 | 1 | 1 | |||||
HPV31 | 1 | 1 | |||||||
HPV39 | 2 | 2 | |||||||
HPV45 | 1 | 1 | |||||||
HPV51 | 2 | 2 | 3 | 3 | |||||
HPV52 | 1 | 2 | 3 | 1 | 6 | 7 | |||
HPV56 | 1 | 1 | 2 | ||||||
HPV58 | 1 | 2 | 1 | 4 | 1 | 1 | |||
HPV68 | 1 | 1 | 2 | 2 | 2 | ||||
Possibly high-risk HPV | HPV34 | 3 | 3 | ||||||
HPV53 | 6 | 1 | 7 | 1 | 1 | ||||
HPV66 | 5 | 1 | 6 | 1 | 1 | 2 | |||
HPV67 | 3 | 1 | 4 | 2 | 2 | ||||
HPV73 | 1 | 1 | |||||||
Low-risk HPV | HPV42 | 2 | 2 | 4 | |||||
HPV61 | 2 | 2 | |||||||
HPV71 | 3 | 3 | |||||||
HPV81 | 5 | 5 | |||||||
HPV84 | 2 | 2 | 1 | 1 | |||||
HPV90 | 5 | 5 | 1 | 1 | |||||
Negative | 6 | 0 | 1 | 7 | 1 | 0 | 1 | ||
Any HPV type | 43 (87.8%) | 17 (100%) | 6 (85.7%) | 66 (90.4%) | 9 (90.0%) | 16 (100%) | 25 (96.1%) | ||
HR-HPV type | 6 | 14 | <0.001 | 4 | 24 | 3 | 15 | 18 | |
Possibly HR-HPV type | 18 | 1 | 0.015 | 2 | 21 | 4 | 1 | 5 | |
LR-HPV type | 19 | 2 | 0.084 | 0 | 21 | 2 | 0 | 2 | |
Total | 49 | 17 | 7 | 73 | 10 | 16 | 26 |
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Zhang, S.; Saito, M.; Okayama, K.; Okodo, M.; Kurose, N.; Sakamoto, J.; Sasagawa, T. HPV Genotyping by Molecular Mapping of Tissue Samples in Vaginal Intraepithelial Neoplasia (VaIN) and Vaginal Squamous Cell Carcinoma (VaSCC). Cancers 2021, 13, 3260. https://doi.org/10.3390/cancers13133260
Zhang S, Saito M, Okayama K, Okodo M, Kurose N, Sakamoto J, Sasagawa T. HPV Genotyping by Molecular Mapping of Tissue Samples in Vaginal Intraepithelial Neoplasia (VaIN) and Vaginal Squamous Cell Carcinoma (VaSCC). Cancers. 2021; 13(13):3260. https://doi.org/10.3390/cancers13133260
Chicago/Turabian StyleZhang, Shitai, Mayumi Saito, Kaori Okayama, Mitsuaki Okodo, Nozomu Kurose, Jinichi Sakamoto, and Toshiyuki Sasagawa. 2021. "HPV Genotyping by Molecular Mapping of Tissue Samples in Vaginal Intraepithelial Neoplasia (VaIN) and Vaginal Squamous Cell Carcinoma (VaSCC)" Cancers 13, no. 13: 3260. https://doi.org/10.3390/cancers13133260