Papillomaviruses

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.

00:15 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.

00:28 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.

01:10 These most often are demonstrated in children and young adults likely due to to contact transmission in social settings or school settings.

01:21 The next form of disease with human papillomaviruses are the anal genital warts.

01:26 And this stems from the fact that human papillomavirus infection is the most commonly sexually transmitted disease in the world.

01:34 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.

01:51 That prevalence is trending downward in the States in other parts of the world where there are successful vaccination programs.

01:58 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.

02:49 It is known to disrupt or to infect disrupted epithelium of the skin and mucous membranes.

02:54 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.

03:16 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.

03:27 This mechanism is seen with with HSV infection.

03:31 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.

03:48 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.

04:22 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.

04:38 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.

05:06 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.

05:22 In addition, there are characteristic appearances on pathology, and one further can make diagnoses through serology and PCR.

05:30 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.

05:41 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.

06:06 This will be important when we eventually get to prevention and the vaccines which cover some, but not all of these.

06:13 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.

06:24 These are benign, as are most of the initial warts.

06:27 Tan colored to again, hypopigmented.

06:32 They feel soft, but they look like a flattened cauliflower.

06:36 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.

06:46 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.

07:02 And these, again, are benign warts with extraneous growth of squamous epithelium occurring typically in the perianal region.

07:11 And again, a picture's worth 1000 words on the lower part of the slide.

07:17 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.

07:30 Sometimes, this has additional effects on swallowing dysfunction if there is a significant amount of tissue growth.

07:37 So, this ends up being quite an issue for management for even otherwise healthy individuals.

07:44 Human papillomaviruses 16 and 18 are specifically able to cause cervical intraepithelial neoplasia.

07:51 These are the bad ones that we start to worry about and try to prevent with vaccines because they can progress to underlying carcinomas.

08:00 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.

08:14 disease is caused by human papillomavirus.

08:17 Serotypes 16 and 18.

08:19 Also include vulvar intraepithelial neoplasia or VII in and invasive vulvar cancer.

08:27 Although not all of those are caused by human papilloma virus, clinically and histologically.

08:32 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.

09:19 Again, almost all of them.

09:21 90% of those cancers are caused by serotypes 16 and 18.

09:25 Women have a higher incidence of anal cancer than men, especially those women who participate in receptive anal intercourse.

09:33 But then men who participate in sex with other men also can have anal cancers and anal HSIL lesions due to human papillomavirus.

09:45 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.

10:03 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.

10:16 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.

10:29 This is rare in developed countries or industrialized countries, where it accounts for less than 1% of all cancers.

10:36 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.

11:04 As you see in the photo in front of you, erythroplasia of Queyrat is a carcinoma in situ of the penis.

11:11 It's a flat red appearance which can be slowly progressive.

11:16 Perhaps the biggest thing to remember about human papillomavirus is that it can cause multiple types of cancer, especially the sexually transmitted serotypes.

11:26 16 and 18 and you can see them listed here.

11:29 Anal cervical core.

11:31 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.

13:21 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.

13:44 It's the only vaccine currently available in the United States, replacing prior forms of Gardasil which were quadrivalent.

13:51 The Gardasil nine targets, both the low risk serotypes six and 11, but also high risk serotypes.

13:59 16, 1831, 33 45 52 and 58.

14:05 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.

14:17 And those are the ones to remember that are protected effectively bird by Gardasil nine a bivalent vaccine called Cervarix also exists.

14:26 This was initially created to target and targeted specifically types 16 and 18 Ideally, vaccination should occur with pre-teen boys and girls.

14:38 It is a two dose series, especially when it is started by age 11 or 12.

14:43 The recommended range though is nine to 26 years of age for women and nine to 21 years for four men.

14:50 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.

15:29 What is an interesting development which is not yet available clinically is a therapeutic vaccine.

15:34 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.

21:01 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.