Valor de VPH en patología no cervical: Vulva, Vagina, Pene, Ano, ORL

Valor de VPH en patología no
cervical: Vulva, Vagina, Pene,
Ano, ORL
Dr. Jaume Ordi
Servicio de Anatomía Patológica
Hospital Clínic. Barcelona
[email protected]
-1-
Neoplasias
asociadas a HPV
Cervix
Forman D, et al.
Vaccine 2012; 30
Suppl 5. F12-F23
-2-
Neoplasias
asociadas a HPV
-3-
Neoplasias
asociadas a HPV
• Cérvix
• Vulva
• Vagina
• Pene
• Ano
• Región ORL
• Conjuntiva
• Piel
-4-
Neoplasias
asociadas a HPV
• Carcinomas escamosos
-5-
Detection of HPV:
molecular techniques
-6-
Relationship with
HPV: histological characteristics
• HPV negative
• HPV positive
-7-
Relationship with
HPV: p16INK4a & p53
p16 (+)
p16 (-)
p53 (-)
p53 (+)
-8-
Detection of HPV:
IHC (indirect)
p53
E6
-9-
Detection of HPV:
IHC (indirect)
p53
p53
E6
Proteosome
- 10 -
Detection of HPV:
IHC (indirect)
p53
E7
Proteosome
p16
p16
p16
p16
cdk
Cyclin D
p16
1
P
p16
p16
p16
p16
p16
p16
p16
E2F
- 11 -
Rb
INK4a
p16
Immunostaining
• Positive result: Continuous staining of basal cells
• Negative result: Negative or focal, patchy staining
- 12 -
Carcinoma
de vulva
- 13 -
SCCs of the vulva
Uterine cervix
Vulva
Vulva and vagina
Cérvix
0
50
100
150
200
250
Carcinomas Vulva and Uterine Cervix.
Hospital Clinic. Barcelona
Lorenzoni et al, Cancer trends in the
Maputo province, Mozambique. Manuscript
in preparation
- 14 -
SCCs of the vulva:
HPV
HPV +
17%
HPV –
83%
Santos M, et al. Am J Surg Pathol
2006; 30: 1347
De Sanjosé S, Alemany L, Ordi J, et al. , et al Eur J
Cancer. 2013; 49:3450-61
- 15 -
SCCs of the vulva:
HPV and age
De Sanjosé S, Alemany
L, Ordi J, et al. , et al
Eur J Cancer. 2013;
49:3450-61
- 16 -
SCCs of the vulva:
HPV types
1; 6%
1; 6%
HPV16
2; 13%
HPV33
HPV31
HPV51
12; 75%
Santos M, et al. Am J Surg
Pathol 2006; 30: 1347
De Sanjosé S, Alemany L, Ordi J,
et al. , et al Eur J Cancer. 2013;
49:3450-61
- 17 -
p16
p53
p16
p53
p16
p53
Prediction of HPV
positivity
p16 (+++)
p53 (-)
basaloid/warty histology
Sensitivity
100%
93.8%
62.5%
Specificity
98.7%
35.5%
93.4%
Positive PV
94.1%
23.4%
66.7%
Negative PV
100%
96.4%
92.2%
Santos M, et al. Am J Surg Pathol
2006; 30: 1347-1356
- 21 -
SCCs of the vulva:
HPV and p16
De Sanjosé S, Alemany L,
Ordi J, et al. , et al Eur J
Cancer. 2013; 49:3450-61
- 22 -
Associated skin
lesions
Premalignant and other
associated skin lesions
Hr-HPV
Positive (n=13)
Negative (n=68)
p value
VIN basaloid/warty type
7
(53.8 %)
0
(0 %)
<0.001
VIN differentiated type
0
(0 %)
31
(45.6 %)
0.001
Lichen simplex chronicus
2
(15.4 %)
43
(63.2 %)
0.002
Lichen sclerosus
0
(0 %)
27
(39.7%)
0.004
Santos M, et al. Am J Surg Pathol 2006; 30: 1347-1356
- 23 -
Associated skin
lesions
Premalignant and other
associated skin lesions
Hr-HPV
Positive (n=13)
(53.8 %)
Negative (n=68)
0
VIN basaloid/warty type
7
VIN differentiated type
0
(0 %)
31
(45.6 %)
0.001
Lichen simplex chronicus
2
(15.4 %)
43
(63.2 %)
0.002
Lichen sclerosus
0
(0 %)
27
(39.7%)
0.004
Santos M, et al. Am J Surg Pathol 2006; 30: 1347-1356
Santos M, et al Int J Gynecol Pathol 2004; 23:206-214
- 25 -
(0 %)
p value
<0.001
p16
p53
p16
p53
HPV-associated lesions:
Standardized nomenclature (LAST)
• 2-tiered nomenclature : LSIL and HSIL (may be further
qualified with the appropriate -IN terminology (CIN, VIN,
VaIN, AIN, PAIN, PeIN)
Darragh TM, et al. Consensus recommendations from the
College of American Pathologists and the American Society for
Colposcopy and Cervical Pathology; Arch Pathol Lab Med. 2012; 136:
1266-1297.
- 27 -
p16
- 28 -
p53
Carcinoma
de vagina
- 29 -
SCCs of the vagina
Vagina
Vulva
Cérvix
0
50
100
150
200
250
Carcinomas Vulva, Vagina y Cérvix Uterino. Hospital Clinic.
Barcelona
- 30 -
SCCs of the vagina: HPV
• 32 invasive SCC of HCP / HVH
HPV 7; 22%
1; 4%
1; 4%
1; 4%
HPV +
25; 78%
2; 8%
HPV 16
HPV 35
1; 4%
HPV 51
1; 4%
HPV 52
HPV 58
18; 72%
HPV 59
HPV 68
Fuste V, et al. Histopathology 2010; 57: 907
- 31 -
Carcinoma
de pene
- 32 -
Penile cancer and HPV
• Two etiologic pathways for penile cancer and PeIN
• HPV infection
• Other factors including chronic inflammation, phimosis, and
lichen sclerosus
• HPV DNA is found in 47%-50% of all penile tumors
• HPV16 the most frequent type
• Significant contribution of low-risk HPV types
- 33 -
Carcinoma
anal
- 34 -
Anal cancer and HPV
• Increasing incidence in the past decade: growing
number of cases in high-risk groups (men who have sex
with men, immunosuppressed individuals, HIV infection)
• In women, associated with
anal touching during sex,
recent anal sex, and no
condom use during anal sex
(Moscicki et al, 2013)
• Overall HPV prevalence 84.2% (95%CI: 81.5%-86.9%)
• HPV16, 87.1%
- 35 -
Carcinomas
de la
región ORL
- 36 -
SCC of
head & neck and HPV
• Oropharynx
• Tonsil
45%
HPV
58%
• Oral cavity
0- 8%
• Nasopharynx
0-8%
• Larynx
0- 7%
• Sinonasal tract
20%??
- 37 -
Tobacco, alcohol
SCC of
head & neck and HPV
• High number of sexual
partners
• HPV 16 infection
• Independent of smoking and
alcohol
- 38 -
Sinonasal SSCC and HPV
H&E
p16
ISH
Larque AB, Hakim S, Ordi J et al, Mod Pathol 2014
- 39 -
mRNA HPV 16
Laringeal SCC in HIV+ patients
Sex
Case 1
F
Age
36
Alcohol
Smoking
consumption
Packs/year
Per day
23
No
Risk factor
Years
HIV
IVDA
a)
9
Heterosexual
b)
Antiretroviral
Other lesions
treatment
e)
Lamivudin
HCV+ , Carcinoma
Estavudin
uterine cervix,
VIN3
Case 2
M
54
20
No
Homosexual
12
Lamivudin
f)
-
Estavudin
indinavir
Case 3
M
42
36
No
Homosexual
16
Lamivudin,
Pulmonary
Estavudin,
tuberculosis
indinavir, ritonavir
Case 4
F
41
10
No
IVDA
a)
7
Lamivudin,
zidovudin,
e)
g)
HCV+ , PML ,
CIN3
h)
abacavir
Case 5
M
46
25
No
Heterosexual
18
Zidovudin
B-cell lymphoma,
Didanosin,
rynopharynx
nevirapin
Case 6
F
37
100
120 gr
IVDA
a)
9
Tenofovir,
emtricitavin,
nevirapin
Moyano S, Ordi J, et al. HIV Med 2009; 10: 634-639
HCV+
e)
VPH y pronóstico en
neoplasias malignas
- 42 -
SCC of head & neck:
survival
HPV +
(n=12)
Stage
I
II
III
IV
HPV (n=48)
p
.977
1
4
4
3
(8.4)
(33.3)
(33.3)
(25.0)
5
13
17
13
(10.4)
(27.1)
(35.4)
(27.1)
- 43 -
Alos L, et al. Cancer 2009; 115:27012709
Larque AB, et al. Mod Pathol 2014;
in press
Oropharyngeal SCC:
survival
• Better response to chemotherapy induction (82% vs. 55%)
• Better response to radio-chemotherapy treatment (84% vs.
57%)
Fakhry C, et al J Natl
Cancer Inst 2008; 100
Lassen P, et al. J Clin
Oncol 2009; 27:1-7
- 44 -
Vaginal SCC:
Stage at Diagnosis
Alonso I, et al.
Gynecol Oncol,
2012;125:194-9
HPV positive
HPV positive
HPV negative
- 45 -
HPV negative
Vaginal SCC:
HPV and Prognosis
Disease Free Survival
Variable
HR
95% CI
p-value
HPV positivity
0.45
(0.22-0.92)
.029
Age ≥ 68 years
1.85
(0.89-3.85)
.098
HPV positivity
0.49
(0.24-1.00)
.050
FIGO stage III-IV
2.33
(1.17-4.65)
.017
HR
95% CI
p-value
HPV positivity
0.35
(0.13 to 0.94)
.038
Age ≥ 68 years
1.36
(0.51 to 3.59)
.539
HPV positivity
0.36
(0.14 to 0.93)
.035
FIGO stage III-IV
3.88
(1.49 to 10.10)
.005
Overall survival
Variable
- 46 -
Alonso I, et al. Gynecol
Oncol, 2011, 2012;
125:194-9
Uterine cervix:
HPV and prognosis
Histological type
SPF10 GP5+/6+ HPV E7
ADC, mucinous
-
-
-
ADC, mucinous
-
-
-
ADC, mucinous
-
-
-
ADC, mucinous
-
-
-
SCC, keratinizing
-
-
-
SCC, non-keratinizing
-
-
-
SCC, non-keratinizing
-
-
-
Adenosquamous
-
-
-
Rodriguez-Carunchio L,
et al, Manuscript in
preparation
- 47 -
p16
- (+ focal)
+
- (+ focal)
+
- (+ focal)
Vulvar SCCs:
Stage at Diagnosis
Alonso I et al. Gynecol
Oncol 2011; 122:509514
Diseasefree
survival
Overall
survival
- 48 -
Vulvar SCC:
HPV and Prognosis
Ref
Year
n
Overall survival at 5 years
HPV-associated
HPV- independent
p
Monk
26
1995
55
72%
44%
0.010
Pinto
22
2002
16
63%
71%
0.447
van de Nieuwenhof
18
2009
130
80%
78%
0.646
Lindell
85
2010
75
85%
40%
0.030
Alonso
20
2011
98
67 %
71%
0.789
Choschzick
89
2011
39
40%
75%
>0.05
Del Pino M, Rodriguez-Carunchio L, Ordi J.
Histopathology 2013, 62: 161-175
- 49 -
Conclusiones finales
• Una proporción variable de tumores del área ano-genital
está causada por VPH (20% en vulva, 50% en pene y
80-90% en vagina y ano). Marcadas diferencias en
región ORL (50-60% en orofaringe y amígdala, 20% en
región rinosinusal y 0-5% en laringe y cavidad oral)
• VPH de tipo mucoso o genital adquiridos mediante
transmisión sexual
• HPV16 es el tipo más prevalente en todas las áreas
(≈75%)
- 50 -
Conclusiones finales
• La morfología (basaloide, condilomatosa [warty] y no
queratinizante) tiene sólo una fiabilidad relativa para
identificar a los tumores asociados a VPH
• La sobreexpresión de p16 tiene una sensibilidad y
especificidad mucho más alta que la histología aunque
presenta algunas inespecificidades
• La detección molecular del DNA del VPH mediante de
PCR es la técnica más sensible
- 51 -
Conclusiones finales
• Los tumores asociados a VPH, al menos en aquellas
localizaciones en las que la cirugía es difícilmente
curativa, (región ORL, vagina, cérvix) tienen un
pronóstico mejor que los carcinomas negativos para
VPH
• Existe debate sobre el interés de determinar VPH en
estos tumores: aunque tiene significado pronóstico, su
tratamiento es, en la actualidad, idéntico
- 52 -
Department of Obstetrics
and Gynecology
Department of Pathology
Hospital Clínic
Aureli Torné, Marta del Pino, Pere
Fuste, Imma Alonso, Roser
Nonell, Montse Cardona, Ágata
Rodríguez, Nadia Abu-Ligha,
Dept. of Otolaryngology
Jose L. Blanch
Isam Alobid
Hospital Oncologico Lisboa
Ana Felix
Institut Català d’Oncologia
Silvia de Sanjosé
Maria Alejo
Omar Clavero
Elena Gonzalvo
Montse Tortosa
Alfons Nadal
Josep Ramírez
Paola Castillo
Roser Esteve
Silvia Alòs
Francisco Pérez
Naiara Vega
Hospital Vall d’Hebró
Lorena Marimon
Leo Rodríguez
Amaia Sagasta
Àngel Garcia
Assumpta Pérez
Santiago Ramón y Cajal