00:01
The papillomaviridae viruses.
00:05
Papilloma viruses are small
and nonenveloped,
with an icosahedral capsid
with -- and this is important to remember --
circular, double-stranded DNA genome.
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They are transmitted through direct
or sexual contact with
actively expressed legions, which
mostly are warts.
00:23
And the incubation period
is quite prolonged
from 4-21 weeks.
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Human Papilloma Virus Epidemiology
Predisposing Conditions
for Human Papillomaviruses
Especially include immunosuppression,
such as those patients
living with HIV AIDS or solid organ
transplants such as a kidney transplant,
but also those with a atopic dermatitis
associated with a localized
inflammatory reaction,
which may have a permissive effect on the
emergence of the human papillomavirus.
00:53
The clinical disease is seen with human
papillomaviruses
primarily are cutaneous warts,
and those exist as common warts,
affecting the hands flat warts,
affecting the face and palmar,
or plantar warts affecting, of course,
the palms and soles of the hands and feet.
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These most often are demonstrated
in children and young adults
likely due to to contact
transmission in social settings or school
settings.
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The next form of disease
with human papillomaviruses
are the anal genital warts.
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And this stems from the fact
that human papillomavirus infection
is the most commonly sexually
transmitted disease in the world.
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There is a 10% prevalence
in the United States, 22% prevalence
in Africa, and over three fourths
of sexually active adults in the states
have been infected with at least one
serial type of human papillomavirus.
01:47
Genital causing general disease
during their lifetime.
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That prevalence is trending downward
in the States
in other parts of the world where
there are successful vaccination programs.
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But they those programs have a long ways
to go to eradicate
HPV sexually transmitted
disease completely.
02:06
Oropharyngeal HPV
infections more typically seen in men
than women and associated
especially with oral sex in men
who have sex with men,
but also with older age smoking
and actually by exposure to human
papillomavirus in aerosols produced
during surgical excision
or ablation of an HPV associated lesion.
02:28
Recurrent respiratory
papilloma ptosis is seen
especially those infants
who acquire HPV vertically
through passage through the birth
canal of an infected mother.
02:39
That ultimately becomes the most common
benign
laryngeal tumor in children.
02:45
additional clinical pathologic information
for human papillomavirus.
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It is known to disrupt
or to infect disrupted
epithelium of the skin
and mucous membranes.
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Such infections usually start off
as warts of rukus lesions
but are associated
with progression to at least six discrete types of cancer.
03:05
Over 200 serotypes or subtypes
of human papillomavirus exist
but relatively few account
for most of the diseases
seen with human papilloma virus infection.
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The infection then occurs via
direct skin contact or mucous
membrane contact, but it can be spread
to other body parts by the patient
themselves via auto inoculation.
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This mechanism is seen
with with HSV infection.
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For example, subclinical HPV infection
may occur,
but after an incubation period of two
to six months, there may be emergence
of a cutaneous or mucosal wart
and then eventually progression
to invasive disease
and potentially malignancy.
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Approximately two thirds of children
will have spontaneous remission of warts.
03:53
Typically, those children are younger,
so less than two years of age,
and it takes less than two years
for remission.
04:00
However, older children and adults
who may still yet
have spontaneous remission of their wards,
but it may take years
for that remission to occur.
04:09
Unfortunately,
though, recurrence is quite common.
04:14
Initial infection occurs at the cutaneous
and mucosal epithelial surfaces,
typically of genital tissue.
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And then viral proteins E6 and E7
are expressed, and these inactivate the
growth suppressors in the target tissues,
meaning that those same epithelial tissues
hen develop hyperplasia at the basal layer.
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And anytime one has hyperplasia of lesions,
then one is at risk for developing
malignancy.
04:46
To make a diagnosis of any
primary lesion with a human
papillomavirus, HPV,
is primarily a clinical diagnosis.
04:55
One can look at the lesions
are typically flat,
somewhat hypopigmented compared
to underlying skin,
and they occur in many different places.
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You can see an image of several
warts or several lesions
in the top on this slide,
with arrows identifying specific
hypopigmented, flat,
almost pale-looking HPV warts or lesions.
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In addition, there are characteristic
appearances on pathology,
and one further can make diagnoses
through serology and PCR.
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Pap smears, especially, will
demonstrate koilocytes,
which are dysplastic squamous
cervical cells with a
raisinoid nuclei.
05:39
It almost sounds like a chocolate
bar and it's not.
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Raisinoid nuclei with hyperchromasia.
05:45
And on the side slide's picture
to the lower right,
you can see with the red arrow
identify 1 such site
with prominent nuclei.
05:56
So, let's look specifically at the diseases
caused by the human papillomaviruses
and the types of diseases depend on
what serotype we're talking about.
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This will be important when
we eventually get to
prevention and the vaccines which cover
some, but not all of these.
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Starting then with serotypes 1-4,
these human papillomaviruses
all cause skin warts, such as
you see in the picture
of the plantar aspect of a foot.
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These are benign, as are
most of the initial warts.
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Tan colored to again, hypopigmented.
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They feel soft, but they look like
a flattened cauliflower.
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So, a description would be a plantar
wart, cauliflower-liked,
skin-colored or soft tan colored lesion,
usually on the plantar aspects
of the hands and feet.
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These represent epidermal hyperplasia
and hyperkeratosis.
06:51
Human papillomaviruses types 6 and 11
will cause warts as well, but localized to
the anogenital side, and this is known as
condylomata acuminata.
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And these, again, are benign
warts with extraneous
growth of squamous epithelium occurring
typically in the perianal region.
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And again, a picture's worth 1000 words
on the lower part of the slide.
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Type 6 and 11 also can cause
laryngeal papillomas,
and although these are benign
and growing in laryngeal tissue,
they can grow to quite extensive sizes
and extensive numbers,
and actually can cause airway obstruction.
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Sometimes, this has additional effects
on swallowing dysfunction
if there is a significant amount
of tissue growth.
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So, this ends up
being quite an issue for management for
even otherwise healthy individuals.
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Human papillomaviruses 16 and 18
are specifically able to cause cervical
intraepithelial neoplasia.
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These are the bad ones that we start
to worry about and try to prevent
with vaccines because
they can progress to underlying carcinomas.
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You can see a picture on the
lower part of the slide
showing early such lesions, and
this is mucosal dysplasia,
looking both inflamed and also,
again, that sort of paler appearing,
flat-based lesion.
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disease is caused by human papillomavirus.
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Serotypes 16 and 18.
08:19
Also include vulvar
intraepithelial neoplasia or VII in
and invasive vulvar cancer.
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Although not all of those are caused
by human papilloma virus,
clinically and histologically.
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5% of all genital cancers
in women are caused by HPV
infection, especially serotypes 16 and 18
that vulvar intraepithelial neoplasia
can progress from an initial low
grade lesion to a high grade squamous
epithelial lesion known as hs idl
that would be the b flat areas
seen in the photo of the vulva
and perineum just immediately to the left.
08:59
But then they further can progress
to invasive cancer,
which would be the white raised areas.
09:04
As noted on the photo
and you can see arrows pointing
to both of those types of lesions types 16
and 18 of human papillomavirus
also can cause anal high grade squamous
INTRAEPITHELIAL lesions
and full fledged anal cancer.
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Again, almost all of them.
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90% of those cancers
are caused by serotypes 16 and 18.
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Women have a higher incidence
of anal cancer than men,
especially those women who participate
in receptive anal intercourse.
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But then men who participate in sex
with other men
also can have anal cancers and anal
HSIL lesions
due to human papillomavirus.
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The presence or co-infection of HIV
raises the incidence
and progression of those lesions.
09:52
Mostly serotypes
16 of human papillomavirus
also is associated with oral
pharyngeal cancer, especially occurring
at the base of the tongue
and in the torso regions.
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In the photo in front of you
and circled shows in a lesion
or cancer of the pure form es sinus.
10:12
Not all laryngeal cancers are caused
by human papillomavirus.
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And fortunately in this case
human papillomavirus infected or positive
tumors have a better prognosis
if they occur in the laryngeal area.
10:25
Type 16
also is associated with penile cancer.
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This is rare in developed countries
or industrialized countries,
where it accounts for less
than 1% of all cancers.
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However, in many parts of Africa, Asia
and South America,
sorry, ten
to 20% of cancers
in men are associated with HPV type. 16
50% of
overall all penile cancers are associated
with human papillomavirus.
10:53
And it presents
typically as a painless lump or sometimes
an ulcerative lesion on the penis, most
especially prominent at the glans penis.
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As you see in the photo
in front of you,
erythroplasia of Queyrat is a carcinoma
in situ of the penis.
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It's a flat red appearance
which can be slowly progressive.
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Perhaps the biggest thing to remember
about human papillomavirus is that it can
cause multiple types of cancer, especially
the sexually transmitted serotypes.
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16 and 18 and you can see them
listed here.
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Anal cervical core.
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Penile vaginal vulva
one virus in one actually
two sub serotypes of one virus can cause
an incredible array of invasive disease
of how
do we prevent human papilloma
virus disease
both hygienic or barrier precautions
and then of course, vaccines
starting with hygienic measures.
11:52
Use of barrier contraception
condoms is the most effective way
to prevent transmission
of human papillomaviruses.
12:00
Further, those lesions which are cutaneous
or mucosal need to be left alone.
12:05
So so counseling our patients
do not scratch cut or pick at the wart.
12:10
And those who have a hard time avoiding
that need to avoid nail biting
and picking a cuticles.
12:16
The virus itself can persist in moist
specimens such as seen in towels,
wash cloth, moist clothing,
but also in retained blood and body
fluids
such as seen on nail clippers or razors.
12:30
So so share to avoid sharing those fomite
transmitting things is is beneficial
and then keeping the feet dry
the air wear foot protection
when using a public locker room
in the pool or in the showers
which are community based.
12:47
prevention of human papillomavirus disease
via vaccines is the most effective
if one can get vaccine delivery into the
the at risk and targeted population,
especially for the serotypes of human
papillomavirus, which are associated
with the various cancers
of cervical vulvovaginal,
anal oropharyngeal,
even head and neck cancers, penile cancers
and including the precancerous lesions
so so those, you know,
low intensity intraepithelial lesions
which have not yet progressed
and certainly for genital warts.
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So it makes sense to create vaccines
to target the higher
risk serotypes and especially these
sexually transmitted serotypes.
13:29
So the current
cream of the crop, I guess
for HPV vaccination
is a nine veiled recombinant vaccine
known as are produced by Gardasil
and is Gardasil nine.
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It's the only vaccine currently available
in the United States,
replacing prior forms of Gardasil
which were quadrivalent.
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The Gardasil nine targets,
both the low risk
serotypes
six and 11, but also high risk serotypes.
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16, 1831, 33 45 52 and 58.
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Hard to remember all those,
but I would suggest keeping in mind
that that are the classic four
which are six, 11, 16 and 18,
such as initially included
in the quadrivalent Gardasil vaccine.
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And those are the ones to remember
that are protected effectively bird
by Gardasil nine a bivalent vaccine called
Cervarix also exists.
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This was initially created to target
and targeted specifically types 16 and 18
Ideally, vaccination
should occur with pre-teen boys and girls.
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It is a two dose series, especially when
it is started by age 11 or 12.
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The recommended range though
is nine to 26 years of age for women
and nine to 21 years for four men.
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The better coverage exists
if one can vaccinate a teen or a pre-teen.
14:57
So under age 13,
prior to their age of sexual maturity,
as well have they may have a better
immune response and have better protection
against those high risk serotypes
that the vaccine protects against.
15:10
Even for those individuals
who are vaccinated, however,
continue
pap testing of the cervical tissues
is necessary to detect
emergence of disease caused by other non
vaccine
subtypes as well to detect disease caused
in those already
infected prior to vaccination.
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What is an interesting development
which is not yet
available
clinically is a therapeutic vaccine.
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So an individual who developed disease
associated with a vaccine preventable
HPV serotype could be vaccinated
to boost an immune response
and hopefully help address
or treat that preexisting lesion.
15:50
treatment options for human
papillomaviruses
depend on the site
and really on the type of lesion,
beginning
with cutaneous warts of the most common,
including common plantar and flat words
most often want to take a wait
and see approach because most of these
spontaneously resolved
if given enough time.
16:10
However, they can be treated
if they become painful,
if they are in a cosmetically difficult
part of the body, such as the face
if they are persistent or if the patient
is immunosuppressed or immuno compromised.
16:24
If treatment is indicated,
the first line approach
is topical,
salicylic acid every day for three months.
16:30
Certainly available over the counter
in most parts of the world.
16:34
But for more advanced disease,
cryotherapy can be considered
the challenge though, with either of these
especially is for those warts on the face
because there may be pigment free changes
and unfortunate cosmetic challenges
specifically for facial warts
using retinoic acid such as tretinoin
using topical makeup mode, which is a
a toll like receptor seven agonist
that actually boosts the immune response
to to locally treat the virus infection
itself, which is causing the world's
and and potentially eye
considering topical flora urushiol
for refractory lesions
which are cutaneous warts
also considered in topical immunotherapy
and also into lesion of the Amazon
or flu oral urushiol.
17:24
Unfortunately with all of these
reinfection or recurrence is common
over one third
so 35% or so after one year.
17:33
treatment of vulvovaginal imperil
anal warts again
one can start with a wait and see approach
because spontaneous resolution
still can occur without treatment.
17:43
However, only in up to 40% of patients
are so less likely
than with the prior cutaneous warts
when treating medical therapy
as first line option,
multiple treatments are available
and no one specific intervention is best
for all situations.
17:59
For non-pregnant women,
one can consider topical portfolio,
a toxin in mode,
silica kittens and topical interferon.
18:11
Other invasive therapies
include cryoablation
such as laser ablation, surgery,
electric pottery and also cam therapy in
which is a resident or a blistering
agent from the blister beetle.
18:25
And it causes a cancer lysis.
18:26
It is not yet approved.
18:28
It has been used commonly
by dermatologists around the world
It is unfortunately increasingly difficult
to find, yet it's quite effective
if the patient is immunocompromised
or if the lesion is occurring in an AIDS
typical or not typical fashion,
such as a postmenopausal woman
and or if the ward itself is refractory
to treatment,
then biopsies
indicated to evaluate for progression
to a pre malignant
or an active malignant lesion.
18:56
Treatment of cervical HPV infections
really depends on classifying the lesion
into a low grade squamous INTRAEPITHELIAL
lesion, LCL, or skin grade one
or a high grade intraepithelial lesion,
HSA cell or grades C and two and three.
19:14
And this really depends on the degree
of dysplasia seen on pathology
The low grade squamous epithelial lesions
have a low potential
for progression to malignancy,
but it is not zero.
19:26
So those are lesions which ultimately
require repetitive evaluation.
19:30
The high grade
squamous epithelial lesions,
of course, have a much higher potential
for progression to malignancy
and thus deserve a much more aggressive
intervention.
19:42
Complex algorithms exist
with up to six clinical actions
based on the risk of developing either
high grade
epithelial disease and or invasive cancer.
19:54
Fortunately, patients under age
25 years of life
have a lower risk for this progression
and thus can be addressed
with a lower or less aggressive algorithm.
20:05
However, patients aged 25 to 65
or even older have a much higher risk
and deserve a more aggressive
range of actions to be considered.
20:16
The interventions also will be guided by
cytology results,
such as seeing a pap smear.
20:21
And also there are 13 high risk high
HPV serotypes.
20:26
So if one has a has been able to confirm
which serotype is present,
that may guide a higher
or more aggressive algorithm of approach
the high risk serotypes that exist
or that are known
of course include 16 and 18
that those are perhaps the two
most important to remember
because they are sexually transmitted.
20:49
But the other types are 31 33 35, 39, 45,
51 52 56,
58 59 and 68.
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So so all 13 types can be associated
with, with advanced disease.
21:07
In general,
as we look at cervical HPV
infections, the low grade squamous
and epithelial lesions
can simply be followed by annual testing,
certainly testing or repeat
testing one year after initial diagnosis
that the high grade squamous
intraepithelial lesions
initially diagnosed by cytology
need to be followed by biopsy
and then typically addressed with a loop
electro
surgical excision procedure or sleep.
21:35
Importantly,
this procedure needs to get wide.
21:39
So it so needs to include
the entire transformation
zone of infected epithelial tissue,
which may not yet
have transformed into malignant tissue
but but will do so if not captured.
21:50
So it is possible to both be diagnostic
and potentially therapeutic
with an aggressive
and sufficiently wide margin
electro surgical excision procedure
For patients with oropharyngeal papilloma is including
recurrent respiratory papilloma ptosis.
22:09
The approach is a potassium titanium
phosphate laser surgery.
22:12
So just as basically remember,
laser surgery is necessary
for oral pharyngeal disease
caused by human papillomavirus.
22:20
Keep in mind that the most likely patient
suffering from this
is the person who acquired disease
as an infant
born to a mother who had active disease
with a vertical transmission.