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Multifocal Lesions
How and why do they occur?
Professor Marc Goodman
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Multicentric lower genital tract neoplasia
• Defined by the existence of 2+ intraepithelial
lesions in different sites
Multicentric lower genital tract neoplasia
• Defined by the existence of 2+ intraepithelial
lesions in different sites
• Can occur synchronously or metachronously
Multicentric lower genital tract neoplasia
• Defined by the existence of 2+ intraepithelial
lesions in different sites
• Can occur synchronously or metachronously
• Multicentric lower genital tract intraepithelial
neoplasia is rare: ~4% in women with CIN
Multicentric lower genital tract neoplasia
• Defined by the existence of 2+ intraepithelial
lesions in different sites
• Can occur synchronously or metachronously
• Multicentric lower genital tract intraepithelial
neoplasia is rare: ~4% in women with CIN
• Pathogenesis
 Persistent HR-HPV
Multicentric lower genital tract neoplasia
• Defined by the existence of 2+ intraepithelial
lesions in different sites
• Can occur synchronously or metachronously
• Multicentric lower genital tract intraepithelial
neoplasia is rare: ~4% in women with CIN
• Pathogenesis
 Persistent HR-HPV
 Contemporaneous infection by multiple HR HPV
types
HPV Detection by Cancer Site
99%
97%
91%
91%
82%
75%
69%
70%
70%
63%
43%
32%
21%
Saraiya et al. JNCI 2015
Second cancers among 104,760 survivors of cervical
cancer with 40 years of follow-up
Site of Second Cancer
all cancers
rectum/anus
urinary bladder
uterine corpus
ovary
other female genital
pancreas
mouth
pharynx
larynx
trachea/bronchus/lung
breast
thyroid
melanoma
No Radiotherapy
SIR
1.06
1.28
1.93
0.11
0.62
5.00
1.26
1.98
2.28
1.99
1.93
0.85
0.60
0.70
95% CI
1.02-1.11
1.06-1.55
1.59-2.34
0.06-1.55
0.48-0.79
4.08-6.08
1.00-1.59
1.23-3.04
1.28-3.78
1.16-3.19
1.76-2.13
0.79-0.93
0.36-0.96
0.53-0.93
Chaturvedi et al. JNCI 2007
Second cancers among 104,760 survivors of cervical
cancer with 40 years of follow-up
Site of Second Cancer
all cancers
rectum/anus
urinary bladder
uterine corpus
ovary
other female genital
pancreas
mouth
pharynx
larynx
trachea/bronchus/lung
breast
thyroid
melanoma
No Radiotherapy
SIR
1.06
1.28
1.93
0.11
0.62
5.00
1.26
1.98
2.28
1.99
1.93
0.85
0.60
0.70
95% CI
1.02-1.11
1.06-1.55
1.59-2.34
0.06-1.55
0.48-0.79
4.08-6.08
1.00-1.59
1.23-3.04
1.28-3.78
1.16-3.19
1.76-2.13
079-0.93
0.36-0.96
0.53-0.93
HPV
Chaturvedi et al. JNCI 2007
Cervical HPV followed by Anal HPV
Index
HPV
(anus)
Any HPV
type
High-risk
HPV
Low-risk
HPV
Prior
HPV
(cervix)
Hazard Ratio
(95% CI)
P for
trend
None
1 type
2 types
3+ types
1 (ref)
17.3 (10.2-29.4)
45.5 (32.6-63.4)
44.7 (33.7-59.4)
<.001
None
1 type
2 types
3+ types
1 (ref)
17.9 (9.3-34.5)
26.2 (14.1-48.7)
41.8 (26.5-65.8)
<.001
None
1 type
2 types
3+ types
1 (ref)
16.2 (6.6-40.2)
64.1 (43.1-95.5)
47.4 (32.9-68.4)
<.001
1
10
100
High-risk HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68
Goodman et al. JID 2011
Cervical HPV followed by Anal HPV
Index
HPV
(anus)
Any HPV
type
High-risk
HPV
Low-risk
HPV
Prior
HPV
(cervix)
Hazard Ratio
(95% CI)
P for
trend
None
1 type
2 types
3+ types
1 (ref)
2.6 (1.4-4.6)
2.3 (1.3-4.0)
0.005
None
1 type
2 types
3+ types
1 (ref)
1.7 (0.8-3.9)
2.5 (1.3-4.8)
0.002
None
1 type
2 types
3+ types
1 (ref)
3.2 (1.4-7.3)
2.8 (0.9-5.3)
0.56
1
10
High-risk HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68
Goodman et al. JID 2011
Anal HPV followed by Cervical HPV
Index
HPV
(cervix)
Any HPV
type
High-risk
HPV
Low-risk
HPV
Prior
HPV
(anus)
Hazard Ratio
(95% CI)
P for
trend
None
1 type
2 types
3+ types
1 (ref)
9.4 (4.8-18.5)
7.4 (3.6-15.1)
14.2 (9.8-20.7)
<.001
None
1 type
2 types
3+ types
1
10.6
4.0
12.8
(ref)
(3.8-29.4)
(1.0-16.2)
(6.1-26.8)
<.001
None
1 type
2 types
3+ types
1 (ref)
8.5 (3.4-21.2)
10.1 (4.3-23.4)
14.9 (9.6-22.9)
<.001
1
10
100
High-risk HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68
Goodman et al. JID 2011
Anal HPV followed by Cervical HPV
Index
HPV
(cervix)
Any HPV
type
High-risk
HPV
Low-risk
HPV
Prior
HPV
(anus)
Hazard Ratio
(95% CI)
P for
trend
None
1 type
2 types
3+ types
1 (ref)
0.8 (0.3-2.1)
1.4 (0.6-3.0)
0.18
None
1 type
2 types
3+ types
1 (ref)
0.3 (0.06-1.9)
1.8 (0.5-6.1)
0.38
None
1 type
2 types
3+ types
1 (ref)
1.3 (0.3-5.2)
1.0 (0.4-2.9)
0.38
0.1
1
10
High-risk HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68
Goodman et al. JID 2011
Multicentric lower genital tract neoplasia
• Defined by the existence of 2+ intraepithelial
lesions in different sites
• Can occur synchronously or metachronously
• Multicentric lower genital tract intraepithelial
neoplasia is rare: ~4% in women with CIN
• Pathogenesis
 Persistent HR-HPV
 Contemporaneous infection by multiple HR HPV
types
 Shared risk factors, e.g., smoking
Second cancers among 104,760 survivors of cervical
cancer with 40 years of follow-up
Site of Second Cancer
all cancers
rectum/anus
urinary bladder
uterine corpus
ovary
other female genital
pancreas
mouth
pharynx
larynx
trachea/bronchus/lung
breast
thyroid
melanoma
No Radiotherapy
SIR
1.06
1.28
1.93
0.11
0.62
5.00
1.26
1.98
2.28
1.99
1.93
0.85
0.60
0.70
95% CI
1.02-1.11
1.06-1.55
1.59-2.34
0.06-1.55
0.48-0.79
4.08-6.08
1.00-1.59
1.23-3.04
1.28-3.78
1.16-3.19
1.76-2.13
079-0.93
0.36-0.96
0.53-0.93
Tobacco
smoking
Chaturvedi et al. JNCI 2007
Second cancers among 104,760 survivors of cervical
cancer with 40 years of follow-up
Site of Second Cancer
all cancers
rectum/anus
urinary bladder
uterine corpus
ovary
other female genital
pancreas
mouth
pharynx
larynx
trachea/bronchus/lung
breast
thyroid
melanoma
No Radiotherapy
SIR
1.06
1.28
1.93
0.11
0.62
5.00
1.26
1.98
2.28
1.99
1.93
0.85
0.60
0.70
95% CI
1.02-1.11
1.06-1.55
1.59-2.34
0.06-1.55
0.48-0.79
4.08-6.08
1.00-1.59
1.23-3.04
1.28-3.78
1.16-3.19
1.76-2.13
0.79-0.93
0.36-0.96
0.53-0.93
Reproductive
factors (younger at
first delivery,
higher parity)
OC use?
Hysterectomy and
ovarian ablation
through irradiation
may alter hormone
exposure
Chaturvedi et al. JNCI 2007
Second cancers among 104,760 survivors of cervical
cancer with 40 years of follow-up
Site of Second Cancer
all cancers
rectum/anus
urinary bladder
uterine corpus
ovary
other female genital
pancreas
mouth
pharynx
larynx
trachea/bronchus/lung
breast
thyroid
melanoma
No Radiotherapy
SIR
1.06
1.28
1.93
0.11
0.62
5.00
1.26
1.98
2.28
1.99
1.93
0.85
0.60
0.70
95% CI
1.02-1.11
1.06-1.55
1.59-2.34
0.06-1.55
0.48-0.79
4.08-6.08
1.00-1.59
1.23-3.04
1.28-3.78
1.16-3.19
1.76-2.13
079-0.93
0.36-0.96
0.53-0.93
Reproductive
factors
BMI
Tobacco smoking
Chaturvedi et al. JNCI 2007
Age-specific incidence of vaginal, vulvar, anal, and rectal cancer in
Swedish women with and without a history of grade 3 CIN
RR 6.7 (1.9-18.0)
RR 2.6 (1.2-5.1)
RR 2.8 (1.3-5.4)
RR 1.2 (0.6-1.9)
Edgren et al. Lancet 2007
Multicentric lower genital tract neoplasia
• Defined by the existence of 2+ intraepithelial
lesions in different sites
• Can occur synchronously or metachronously
• Multicentric lower genital tract intraepithelial
neoplasia is rare: ~4% in women with CIN
• Pathogenesis
 Persistent HR-HPV
 Contemporaneous infection by multiple HR HPV
types
 Shared risk factors, e.g., smoking
 Iatrogenic factors, e.g., radiotherapy
Second cancers among 104,760 survivors of cervical
cancer with 40 years of follow-up
Site of Second Cancer
all cancers
colon
stomach
rectum/anus
urinary bladder
uterine corpus
ovary
other female genital
pancreas
mouth
pharynx
larynx
trachea/bronchus/lung
breast
thyroid
melanoma
No Radiotherapy
SIR
1.06
0.93
0.96
1.28
1.93
0.11
0.62
5.00
1.26
1.98
2.28
1.99
1.93
0.85
0.60
0.70
95% CI
1.02-1.11
0.80-1.08
0.72-1.29
1.06-1.55
1.59-2.34
0.06-1.55
0.48-0.79
4.08-6.08
1.00-1.59
1.23-3.04
1.28-3.78
1.16-3.19
1.76-2.13
079-0.93
0.36-0.96
0.53-0.93
Radiotherapy
SIR
1.34
1.22
1.31
1.90
1.90
0.91
0.97
4.73
1.35
1.30
1.57
1.92
2.74
0.71
1.26
0.68
95% CI
1.31-1.38
1.13-1.32
1.17-1.47
1.74-2.09
1.74-2.09
0.81-1.02
0.86-1.10
4.19-5.32
1.19-1.53
0.90-1.85
1.00-2.37
1.30-2.75
2.58-2.91
0.67-0.76
0.97-1.62
0.55-0.85
Radiation
Chaturvedi et al. JNCI 2007
Hazard ratios for second cancers for women who received radiotherapy
versus those who did not receive radiotherapy
HRs highest among
younger women at
cervical cancer diagnosis
Chaturvedi et al. JNCI 2007
Multicentric lower genital tract neoplasia
• Defined by the existence of 2+ intraepithelial
lesions in different sites
• Can occur synchronously or metachronously
• Multicentric lower genital tract intraepithelial
neoplasia is rare: ~4% in women with CIN
• Pathogenesis
 Persistent HR-HPV
 Contemporaneous infection by multiple HR HPV
types
 Shared risk factors, e.g., smoking
 Iatrogenic factors, e.g., radiotherapy
 Immune incompetence
Do immune-compromised women have more multifocal
HPV-related disease than immune-competent women?
• Women with compromised immune systems are 4x more
likely to be infected with HPV than immune competent
women
• HIV-infected women have reduced capacity for viral
clearance
• HIV-positive women, especially those with severe
immunosuppression, are 5x more likely than HIV-negative
women to develop lower genital tract neoplasia
• Severity of HPV-related cervical disease has been linked
to increasing immunosuppression
Cross-sectional analysis of lower genital tract intraepithelial
neoplasia in immune-compromised women with an abnormal Pap
Immune Compromised (N=33)
Immune Competent (N=310)
Site of
High Grade
Low Grade
Low Grade
High Grade
Neoplasia
N Percent
N Percent
N Percent
N Percent P-value
VIN
7
21%
18
55%
40
13%
72
23% <0.0001
19
6%
0.0036
VAIN
11
33%
3
9%
23
7%
56
CIN
5
15%
2
6%
23
7%
18%
0.21
8%
AIN
0
0%
3
9%
35
11%
26
0.45
Immune compromised women include 16 HIV+ and 17 transplant, lupus, diabetes
Multifocal disease involving at least 2 anogenital sites was more common
among the immunocompromised patients (61% vs 30%)
Likes et al, Arch Gynecol Oncol 2013
HPV-related cancers among US organ
transplant recipients
N
Outcome
In situ cancers
Cervix
71
Vagina
34
Vulva
284
Anus
53
Penis
58
Invasive cancers
Cervix
52
Vulva
66
Anus
103
Penis
25
Oropharynx 144
Incidence
rate
SIR
95% CI
144.9
10.4
86.5
6.3
11.4
3.3
2.6-4.2
10.6 7.4-14.8
20.3 18.0-22.8
11.6 8.7-15.2
18.6 14.1-24.0
15.8
20.1
12.3
4.9
17.2
1.0
7.3
5.4
3.9
2.2
0.8-1.3
5.6-9.2
4.4-6.6
1.8-2.5
1.8-2.5
Age at Transplant
dx,
to cancer
median median
yrs
yrs
38
50
42
43
59
2.6
3.4
4.1
4.4
5.7
44.5
52
54
56
56
3.8
4.1
5.3
3.5
3.5
Time from transplant to
diagnosis similar for in situ and
invasive cancers
Increased incidence of cancer
associated with earlier age at
transplant and increased time
since transplant: cumulative
duration of immunosuppression
contributes to risk of HPVassociated cancer
Madeleine et al, Am J Transplant 2012
Incidence rate ratios (IRRs) for immunosuppressive medications and risk for
HPV-related cancers among US organ transplant recipients
In situ
Medication
Cyclosporin
Tacrolimus
Azathioprine
Mycophenolate
IRR
95% CI
IRR
95% CI
IRR
95% CI
IRR
95% CI
Invasive
Cervix
Vulva
Anus
Penis
Cervix
Vulva
Anus
Penis
Oropharynx
N=71
1.1
0.6-1.9
0.8
0.4-1.4
1.2
0.7-1.9
0.7
0.4-1.3
N=284
1.4
1.1-1.8
0.7
0.6-0.9
1.8
1.4-2.2
0.8
0.6-1.0
N=53
1.1
0.6-1.8
0.8
0.5-1.4
1.4
0.8-2.4
1.0
0.6-1.7
N=58
2.3
1.3-4.2
0.4
0.2-0.7
2.4
1.4-4.1
0.6
0.3-1.0
N=52
1.4
0.8-2.4
0.7
0.4-1.2
1.4
0.8-2.5
0.6
0.3-1.1
N=66
1.1
0.7-1.9
0.9
0.6-1.5
2.0
1.2-3.2
0.9
0.5-1.4
N=103
1.4
0.9-2.1
0.6
0.4-1.0
1.7
1.1-2.5
0.7
0.5-1.1
N=24
1.2
0.5-2.7
1.0
0.4-2.3
1.2
0.5-2.6
1.2
0.5-2.6
N=144
0.6
0.4-0.8
2.1
1.5-2.9
0.7
0.5-1.0
0.9
0.6-1.3
Older immune suppressive drug regimens, such as
calcineurin inhibitors (cyclosporin) and anti-metabolites
(azathiopine) associated with 2x increased incidence of
anogenital cancers
Opposite impact of two calcineurin inhibitors for several
cancers suggest different pathways
Madeleine et al, Am J Transplant 2012
Multicentric lower genital tract neoplasia
• Defined by the existence of 2+ intraepithelial
lesions in different sites
• Can occur synchronously or metachronously
• Multicentric lower genital tract intraepithelial
neoplasia is rare: ~4% in women with CIN
• Pathogenesis
 Persistent HR-HPV
 Contemporaneous infection by multiple HR HPV
types
 Shared risk factors, e.g., smoking
 Iatrogenic factors, e.g., radiotherapy
 Immune incompetence
 ‘Monoclonal spreading’
Monoclonal spreading
• Multicentric lesions may originate from a
distinct epithelial cell population that was
infected and transformed by HR-HPVs before
being disseminated throughout the epithelium of
the genital mucosa
• All lesions would be expected to be derived from
one initially transformed cell clone
Monoclonal spreading
In 6 of 7 women with
invasive cervical cancer who
later developed vaginal or
vulvar carcinomas
(metachronously distinct),
viral genome integration
sites were identical,
suggesting a common clonal
origin
Were vulvar and vaginal lesions derived from quiescent dysplastic HPVtransformed cells that were not detected by the conventional histopathologic
analysis because they were locally disseminated early in the neoplastic process?
Vinokurova et al. JNCI 2005
Biopsy Study: Observational study of 690 women referred to
colposcopy after abnormal cervical cancer screening results
Adding a second biopsy, targeting even minimally abnormal-looking areas of the cervical
transformation zone, increased the sensitivity to detect a prevalent HSIL significantly from
61% to 86%. Adding a third biopsy increased the sensitivity further to 96%. The incremental
benefit of taking multiple biopsies was present regardless of referral cytology, HPV-16 status,
and colposcopic impression
Wentzensen et al, JCO 2015
Should taking additional biopsies when multiple lesions are
present become the standard practice of colposcopic biopsy?
• Collection of additional lesion-directed biopsies during
colposcopy increased detection of histologic HSIL,
regardless of patient characteristics
• Allows earlier management decisions and provide greater
reassurance for women with negative results
• Limited benefit from additional non-directed biopsies
• For clinical recommendations, the benefits and harms of
taking additional biopsies need to be considered
• More sensitive screening and biopsy approaches may
preferentially detect lesions with a low risk of
progression to cervical cancer
Summary
• Multicentric lesions occur synchronously
or metachronously (more common)
• Rare event occurring in <5% of lower
genital tract malignancies
• Shared risk factors
• Iatrogenic factors
• Immune incompetence
• Monoclonal spreading
Acknowledgements
CDC Cancer
Mona Saraiya, Meg Watson, Zahava
Berkowitz, Justin Miyamoto
CDC HPV Lab
Elizabeth Unger, Martin Steinau,
Daisy Lee, Mariella Zamaroon,
Julia Gargano
Battelle
Christopher Lyu, Dale Rhoda,
April Greek
Florida
Youjie Huang, Jill Mackinnon,
Carlos Alvarez
Florida Central Lab
Ed Wilkinson, Martha Campbell,
Thompson Amy Wright
Louisiana
Ed Peters, Lauren Cole
Michigan
Glenn Copeland, Lara Ashley, Won
Silva
Iowa
Charles Lynch, Freda Selk
Los Angeles
Maria Sibug-Saber, Wendy Cozen
Hawaii
Brenda Hernandez
Kentucky
Claudia Hopenhayn, Amy Christian,
Tom Tucker HPV Typing of
Cancers Workgroup Multiple
Pathology Labs in 7 Cancer
Registries