Herpes Virus Overview PDF

The herpes family is actually very large. There are lots of herpes viruses out there, herpes simplex, which we think of as sort of the recurrent form of herpes herpes labialis or genital herpes, herpes simplex type two. And then you can kind of switch those interchangeably. And we'll talk about that...

The herpes family is actually very large. There are lots of herpes viruses out there, herpes simplex, which we think of as sort of the recurrent form of herpes herpes labialis or genital herpes, herpes simplex type two. And then you can kind of switch those interchangeably. And we'll talk about that. Chickenpox. Varicella zoster is a herpes virus Epstein-Barr virus the virus that causes mononucleosis. And another condition we'll talk about today called hairy Lugo. That's a condition caused by EBV which is also in the herpes family. And all of this should be available to you. This is all on in your slides right. Next is CMV, cytomegalovirus, which we tend to see in patients who are immune compromised. It tends to come out in patients who are immune compromised. There are a couple HHV six and seven which are one is six disease and the other is probably Rosalia infinitum. And then HHV eight, which is a herpes virus that is associated with a malignant tumor of kind of vascular spindle cells with these slit like vascular spaces that we tend to see in patients who are immune compromised, specifically HIV positive patients. So let's talk about herpes simplex. So herpes simplex is a ubiquitous virus. It gets a very bad rep and it shouldn't. Over half of the population has been exposed to herpes. So half of this room has at least been exposed to herpes simplex. You may not know it. Not everyone is symptomatic, but it's just out there. And we need to stop stigmatizing this virus. It is a ubiquitous virus, very easy to catch. It's a DNA virus and it's trophic. What what that means is it thrives in epithelial cells and in cells of nerve ganglia, which is why it presents the way it does. And we'll get into this. So the first time your body sees the virus you are usually quite ill. Not everyone, but but many patients. The very first time you've been exposed to herpes simplex virus, you usually feel pretty crummy. You've been infected with a virus, so you may feel malaise, anorexia, low grade fever, muscle aches, you feel sick, and you also develop oral ulcerative lesions involving keratinocytes and non keratinocytes mucosa. That's a very important point. And we'll emphasize that in a moment even can come out onto the peripheral skin the lips. ET cetera. And then you get better over time. Week or two you're back up and running again. All the source of healed. You're feeling better, but the virus is still with you. It stays with you forever. It sneaks back up the nerve ganglia and it waits. If we're talking about herpes simplex one and it's an oral infection, it will live in our trigeminal ganglion. And it will wait until right before your wedding or right before a test in oral pathology or some other thing that's important, and it will kick you in. You're down and travel right back down. Those sensory nerves, and it tends to present as recurrent herpes labialis on the lips. However, you can also have a recurrent intra oral form as well. And that that is usually milder and very localized. Right. You've all heard of cold sores, the late term for recurrent herpes labialis. It's usually in an immune competent patient. Not a very serious thing. Kind of annoying. Irritating patients will say they have a little prodrome tingling sensation or pain, and then they will develop crops of vesicles that will coalesce and ulcerated and crust on the lips. Usually, sometimes you can see patients get them around the Neris. So lateral border of the nose. And then there is an intra oral form that occurs on keratin ized mucosa okay. And that's usually along the distribution of the greater palatine nerve. On the hard palate, HSV one is more amenable to infecting patients above the waist. HSV two below the waist. However, because of sexual practices and the ubiquitous nature of these viruses, you can have HSV two in the mouth and HSV one in the genital region. It doesn't matter, okay, they're very similar virus and they are very similar clinically and histopathological. In fact, in my lab, when I am doing an immuno stain for herpes, it's just pooled together. HSV one and two are one stain because they're very similar. It's just that one HSV one tends to favor and thrive better in the oral environment, where HSV two tends to thrive below the waist. So HSV one is usually contracted through routine household contact. Little children get this in preschool, I chew on a ball and then I give it to my friend because I'm generous and my friend chews on the ball and now we both have herpes. You can also have what we call subclinical infection, which means no one knows that I have herpes. I've chewed on the ball and I've given it to you, and of course you're going to chew on the ball. And so now you have herpes. But I didn't have any lesions that were obvious. So you felt very comfortable chewing on the ball. HSV one is usually responsible for oral and labial disease. You can have cutaneous disease, though, because you can auto inoculate and you can also get her conjunctivitis. So if you touch active lesions on your lips and then decide to poke around on your eyes, you can get conjunctivitis. That is her pet in nature. Half of people who are infected experience reactivation or recrudescence of latent infection, and the other half don't. Which is why I say you may not even know you've been exposed. There is a long list of things that people will say they swear will bring out an activation of latent herpes. Everything from hormonal changes to illness. Some people call them fever blisters. Right. I'm sure you've heard that term. Late term emotional factors, oral pathology, you know. Immune senescence as we become more mature and seasoned. Trauma. You know, if I'm doing dental procedures on a patient and tugging and pulling on the lip, well, then I may reactivate virus that's sleeping. However, the only absolutely unequivocal proven trigger experimentally is UV. So sun being out in the sun can cause reactivation. I already mentioned that patients can sometimes tell you they can tell it's coming. So first time your body sees the virus. And this is important if you see on an exam primary hepatic gingival stomatitis, that's exactly how you should write it on the exam. Because the primary is very different than the recurrent form of herpes. All right. So I do actually hold you accountable for full credit to distinguishing between primary herpes. When a patient presents with a fever and sores all over their mouth, as opposed to recurrent herpes when they have a little cold sore on their lip, that actually is different and it requires different intervention. All right. So first time your body sees the virus you may develop ulcers anywhere in the mouth. They can be on movable non keratin ized mucosa and on keratin ized mucosa. Now do you know what I mean when I'm saying keratin is in non keratinocytes. Because it's actually kind of important for this. So non keratin ized mucosa is pretty much everywhere except for the top of your tongue the dorsal tongue and your attached gingiva. Right. Those require a little extra keratin to protect you during function. Right. Everywhere else is pretty much non keratin ized right. The buckle mucosa, unattached gingiva, ventral tongue, soft palate. ET cetera. Okay. So hard palate two I'm sorry. What is your question. So this one, the first and also. I'm sorry I. Said this lesion is different than cold sore. It's the same virus, but the recurrent form presents differently, right? The cold. A cold sore is different than this. You're not going to call this a cold sore, right? So that's what I mean. The recurrent form is different. So again hard palate is characterized right. So I don't know if there was some question about that. Any other question. Okay. We're all sticking together. All right. So the first time you see the virus you can get sores everywhere. You feel crummy fever, malaise, anorexia, muscle aches. You have a virus. And you and you develop these multifocal ulcerative lesions involving characterized and non characterized mucosa, including the labial vermilion the lipstick area of the lips. You can also see ulcerative lesions there. All right. That's primary. Her pedic gingival stomatitis. Here's another patient. Multiple ulcers involving the gingiva palatal mucosa. Labial mucosa. ET cetera. Very painful. Another patient I believe this was a. Yeah. Multiple errors. You can see marked gingival erythema. Ulcerative lesions. Patients feel pretty crummy. The patient deserves treatment. This is a treatable illness, right. If you catch them within the first three days of ulcerative active ulcerative lesions, systemic valacyclovir or acyclovir is indicated. It reduces viral shedding, helps expedite resolution, helps patients feel better, reduces infectivity. Fewer patients will be will benefit from their generosity. Okay. And you can appreciate again other patients just feel crummy. And then you have these multifocal lesions. And then oh here on the dorsal tongue. All right. And then the virus travels back the trigeminal ganglion and then waits. And you may or may not experience secondary or recurrent herpes lesions. In this case this is recurrent herpes labialis. Professor. Good question. How can you? The first lesson to a regular user, for example. So the question just to clarify is that, you know, you had multifocal ulcers in the mouth and you want to know how you tell that apart from other conditions, other ulcers. So what other conditions? I'm just not putting you on the spot. But let's think about this. The patient feels sick. They're ill. They have a fever. They have a may have a sore throat. They have muscle aches. This was acute onset. It's involving attached gingiva and multifocal movable areas of the oral mucosa. This is not an athlete's ulcer a canker sore. Those occur on non keratin mucosa. Right. And you don't typically there is a FAP. There is a condition where some patients do present with fever and APC ulcers. But that's a very unique and rare condition and it's recurrent. This is a one time deal. It's they've never felt like this before. They're very sick. And it does involve keratin ized mucosa. So that's actually a very important detail and why I keep emphasizing it. This one doesn't discriminate. It involves both keratin sized and non carotenoids. The first time your body sees the virus. All right then you feel better okay. But you can develop recurrent lesions that follow sensory nerves. The labial vermilion area is a classic site for recurrent herpes. It presents as these coalescing vesicles filled with fluid and viral particles. Active viral shedding is happening during this time, so patients should be discouraged from badgering this and then sharing that with other people poking their eyes. They should do good hygiene, good hand hygiene, simply to minimize the likelihood of contaminating other sites and or distributing the virus to others. All right. Question. One way to. You see. Is. Primary and secondary. Like you said, multifocal and then secondary. That's problem. Right. So you're right that it is typical, that it is a unilateral presentation. And we're getting to the intra oral form in just a moment. If we we'll come back. But you're ahead of us. But correct. You're absolutely correct. Yes. And an immune competent patient, it's usually even the same site. Right. If you've had patients with recurrent or if you have recurrent herpes labialis, it usually follows the same nerve sensory nerve and always presents on your lower left lip. You know, it tends to have a pattern of recurrence and a pattern of involvement at a particular site, and it tends to be an isolated lesion. Okay. Secondary. Secondary. Any other questions? Yes. More than that. But have you seen cases in the. Also. Yes. We haven't gotten to the intraoral part yet, so we're just talking about recurrent herpes labialis right now. But now that you mentioned it, there have been. Here you go. Is this what you were looking for? All right, so I mentioned recurrent herpes labialis because we are familiar with cold sores on the lip. However, you all need to be aware of the recurrent intra oral form of herpes, which is has a tendency to follow the distribution of the greater palatine nerve most often, but it almost always involves characterized mucosa, so the recurrent form of herpes tends to involve characterized mucosa. This is how you will not confuse it with an app that's ulcer, right? You'll see these little crops of very painful coalescing. They start out as vesicles and then rupture and eat these punctuate erythematosus, ulcerated lesions on characterized mucosa. All right. And we're still talking about immune competent patients here. Another example of recurrent intra oral herpes. Again as your colleague mentioned, unilateral presentation only involving intra oral sight on characterized mucosa right along the distribution of the greater palatine nerve. Very painful. Now, I don't know why I did this when I was putting this together, but I blacked out their eye because we were so careful about not showing faces unless patients have agreed to that. That's dumb, because we wouldn't have recognized this patient. Now their eye looks really weird. But in any case, the this is a patient demonstrating her petite conjunctivitis. And this is a result of auto inoculation. So again good hygiene is prudent in order to because these vesicles are filled with viral particles. And you can auto inoculate back in the day before dentists wore gloves, dentists were vulnerable to getting what's called her pedic whitlow, which is an epidemic. But nevertheless it was herpes of the the finger, the fingers, because of they put their hands and mouths right. And then you get these painful herpes lesions on the skin. Wrestlers can get something called scrum pox, which is the mats that they are wrestling on. If they're contaminated with herpes from one participant, you can get it in the skin. If you have open skin, open wounds and abrasions and things so you can auto inoculate. Now a lot of times a biopsy is not necessary. The lesions I've shown you are very classic. I would not recommend a biopsy because they presented exactly as you'd expect. Nevertheless, if ever a biopsy is indicated, this is one time when we really need the edge of the ulcer. Okay? That edge, the epithelium that meets up with the ulcer that's probably over here off the screen is the spot where we see those virally modified cells. That's where the the money is. If you want to make a diagnosis of herpes. And it has to be pretty early on really within a couple three days of ulcers, being present is when you're going to see the virally modified cells. So I will try and show you these if I can. I don't know how this pointer and I don't get along. I did put some arrows just in case. But you see these giant looking epithelial cells with multiple nuclei. We call it nuclear molding. The nuclei look like they're spooning. You know what that means. Like where you like when you put spoons in a in the dish tray at the end of the night after you've done your dishes, one spoon next to the other. So they kind of mold up against each other. That is a viral psychopathic effect. And then look how the cells are kind of rounding up and letting go. This is another entity in which you see a kantha lysis cells rounding up and letting go of their neighbors. But we wouldn't confuse this with this is acute onset. I wasn't sick with this three days ago, and now here I am in your chair, feeling crummy. And when you did the biopsy, you're looking at these weird nuclear changes, right? That's classic for herpes. All right. Any questions about that? Yeah. So? That's always a secondary. It is. So that's a that's the secondary manifestation. Yeah. So they must have acquired the virus from me when I showed up in their chair and they did dentistry on me without gloves, and they came in contact with my viral shedding because either I had active lesions present, or maybe I was had asymptomatic viral shedding. And then presumably they contracted the virus. And then this is the recurrent form in them. Right. Because it's where they were infected. But let's say I have the vision and my lips and I touch my. It's a secondary form. There's. There's no way for the virus to find a pet in the another branch of the nerve. Not typically. It usually follows. The question is, can the virus kind of seek out other sites in you? Not typically. It's usually auto inoculation that brings it to a new a new place in an immune competent patient. If your immune system is sturdy and strong, it usually sticks to the plan. If you are immune compromised, though, all bets are off, you can have ulcerative lesions even involving non keratin ized mucosa. That's why very sick patients immune compromised either due to bone marrow transplants or medicine. They're taking some suppressive medications or because they have HIV Aids. These patients can have ulcerative lesions anywhere. And often these are swabbed and cultured in order to see whether it could be some herpes virus family member that's mimicking a traumatic ulcer or an ulcer or something of that nature. Yes. It's usually intra oral and fever, and you can have associated oral ulcers, but you usually feel pretty crummy. And there's almost always mucosal involvement. These are all great questions. Yes. Yeah. Well. So the question is that's tricky right. So auto inoculation the vesicles need to be ruptured typically. I suppose it's trickier to auto inoculate from just say asymptomatic shedding from one place to another. So usually the viral particles are very concentrated in those vesicles. And so generally it's discouraged you kind of futz with those and then touch other places. Instead you wash with soap and water and then you don't have to worry about. All right, I'm going to I'll take one more question, and I'm glad to answer questions later, but I have so much to talk about. Yes. Well, there the question is when? When are the vesicles most infective? So you're technically capable of sharing this virus or auto inoculating until the crops of vesicles stop forming and crust completely. So any time during that stage you are shedding in. You can theoretically have asymptomatic viral shedding as well. I am going to move on. Not that I'm glad to answer questions, but I don't want to hold you a minute later and we have so many things to talk about. So HSV two is essentially the same virus. It is just more amenable to residing thriving below the waist in the genital regions. Recurrence is common, very similar to intra oral recurrent herpes or recurrent herpes labialis. The real issue is during childbirth vaginal birth. If the pregnant person is delivering the baby vaginally and have active hepatic lesions, there is a concern about transmitting the virus to the infant. The immune susceptible infant right. And rarely could you transmit this in utero. Just one picture showing that the lesions are very similar on genital lesions as they are orally. Now chicken pox I don't know if any of you have had chicken pox. I assume many of you have, and if you haven't, you I assume were vaccinated against it. So chickenpox is a herpes virus. And I think it's very cool because it behaves exactly like the herpes simplex virus. The first time your body sees chicken pox, you feel pretty crummy. If you've had it, you know you had a fever, runny nose, muscle aches, itchy little crops of vesicles that keep coming out in waves, even sometimes oral lesions. And then you get better, right? And now the virus lives in our spinal ganglia, and it comes back in a milder form as shingles. Right. Just like the recurrent. You know, they have a very similar pattern. Right. So it's easy to remember a chicken pox virus, varicella very easy to share sneezing and so forth. Right. We've gone through all of these. You can be contagious a little ahead of time two days before you get the rash. And and then until all those crops of lesions have crusted you can have intra oral involvement. Not typical for a patient to show up in our practice though, saying, hey, what's in my mouth when they're feeling so crummy elsewhere, right. But but just so you know, patients with varicella can develop oral involvement. There's a child who presented with multiple vesicular lesions on the skin associated with varicella zoster, another patient presenting with multiple vesicular lesions. Again you know that reactivation of latent virus zoster virus we call shingles or herpes zoster. Usually in immune competent patients the reactivation involves only one dermatology. So one sort of general sensory area along the dorsal ganglion patients will. It's a tricky thing to diagnose because the feeling is very odd for patients. And they will say, oh, I just have this sensation in my shoulder or my side or my face and it it hurts. It's got this kind of it's difficult to describe. And patients have been inadvertently put into a category of maybe an inflammatory Madonna genic lesion when it involves the maxilla, say, for example, thinking, oh, maybe this is a tooth related problem because it is nerve related pain, right? So this the pain can be kind of tricky to characterize. And sometimes it takes until you see the vesicles before you can say, oh it was shingles right. Who gets shingles? Well, any one of us could get shingles even if you were vaccinated against chickenpox, because that is the activated virus, right? Activated latent virus. So you're all eligible for shingles. Good to know. But what will make us have shingles would be immune suppression, immune senescence as we become older chemo reductive therapy the list goes on. So here's a nice I love a good cartoon. Here's a patient with chickenpox and then just showing you reactivation years later of shingles. Here's a patient with kind of an axillary distribution of shingles. You can see these kind of crops of vesicles. Now this kind of I think we spoke about this a moment ago. She stepped up but. This patient presented with shingles, herpes zoster with oral involvement. And it looks a heck of a lot like recurrent into oral herpes follows the kind of stays to the midline, doesn't tend to cross the midline, very focal along the distribution of the greater palatine nerve. However, in patients with shingles, there is almost always, almost always overlying skin involvement. So you would not typically confuse this with recurrent intra oral herpes. Shingles usually only happens once or maybe twice if you're unlucky in your lifetime, and if it does involve the head and neck area with intra oral involvement like this, expect skin involvement too. And you do not expect that with recurrent herpes simplex. Okay, that's how you're going to tell it apart. All right. So that's shingles and chicken pox. Herpes family. Yes. Yes you can. Yeah. Because you have been vaccinated with the live attenuated virus and so you won't get chicken pox, but you can get shingles because of that. So when you become a certain age and you're asked if you want a shingles shot, yes. Is the answer to prevent it. But you are you are not spared from getting shingles just because you were vaccinated. Yeah. Excellent. Yeah. All right. So now we're going to move on to the herpes virus family member that also causes mononucleosis. It's called EBV x bar virus. Now unlike herpes which has a tendency to to thrive in epithelial cells and nerve ganglia, this particular virus likes bad T cells and epithelium. And many of you may maybe have had mononucleosis at some point in your lifetime. But this virus, like all herpes viruses, once you've had it, it lives in your body and you can see this virus causing trouble later. So things that it can get up to include serving as a cofactor in malignancies. So EBV associated tumors including certain lymphoma proliferative diseases. Also nasopharyngeal carcinoma has a very strong association with Epstein-Barr virus. There's an undifferentiated salivary carcinoma that's involved associated with EBV. And then there's this thing we're going to talk about today that's called hairy lookalikes. So first let's talk about the first time the patient sees the virus. They may have they call infectious mononucleosis. Right. This patient is demonstrating posterior auricular lymphadenopathy. Right. We can see that enlarged lymph node behind the ear lobe. And then these kind of enlarged diffuse erythematosus tonsils with this exudate. Most patients with mono have a sore throat. Right. They feel pretty crummy kind of nonspecific viral symptoms. But nevertheless this patient had mononucleosis. Now I mentioned that EBV can come along later after you've been exposed to the virus. You may not even know you were exposed, but it can come along later and reveal itself in other ways. It can serve as a troublemaker, instigating malignant transformation, and it can also cause this entity. Now, I apologize in advance for the name. I did not name it, but it is very important that we all agree. Right now. This is not hairy tongue, okay? This involves the tongue. And it can sometimes, you know, you're trying to keep all these terms straight. Harry Lucas, unfortunately, is completely different than Harry ten, and it's important that you keep these two terms straight. This is one time when the term Lucas is a diagnosis. Sorry for that too. All right. So. What is Harry Lucas? It is characterized by these white lesions on the side of the tongue. I feel when I show you the examples, I feel like there's often these kind of vertical, kind of linear presentation that's kind of distinctive. We do see Harry Lucas more commonly in immunocompromised patients, particularly patients with HIV Aids, post organ transplant. And we have established in my lab and others, you can develop Harry Lucas, an otherwise healthy patient who has just older and has some immune senescence. So as we become more seasoned, our immune system becomes less capable of keeping everything in order. And so you can have Harry Lucas to simply as a result of old age. All right. The cause is from EBV infection and what we do about it. Well, first you biopsy it because these are lesions at high risk sites for oral cancer. Right. So you're going to biopsy these lesions. However I just want to point out some features that make me suspicious that this is Harry Lucas. Do you see what I mean when I tell you it has this kind of vertical kind of orientation, this kind of linear stripes? I've seen several examples of this clinically in my clinical practice, and then certainly many examples. People have sent photos and things of that nature to me, and that's a very typical presentation. So just keep that with you and carry it around as you're kind of keeping your differential forming and so forth. But this involves the lateral tongue. You will biopsy this lesion because we have all been taught that this is a high risk site and it's a high risk presentation. It's not uncommon because this is. Typically seen in patients whose immune system is suppressed. It's also not uncommon to see a secondary fungal infection called candidiasis. In conjunction with this. We'll talk about that infection in a bit. But just so you know, it's not unusual to see that. Now, I always say that under the microscope, once you biopsy it, you are looking for a red, white and blue appearance. Okay. So what I mean by that is that you have a thick layer of hair keratin at the top. It looks pink or we'll call it red. Just for my my little demonstration. Then you have this band of cells here that are kind of pale. They're admittance. That's white. All right. And blue is just the basal cell layer. That's kind of normal. It's in this band of pale cells here, these edema to cells where we look at the nuclei using in situ hybridization studies. So all these blue dots that you see here are EBV positive cells. So we do in situ hybridization to confirm that this is Harry Lucas. All right. So you would need that information from me as a pathologist. I will run that test, even though I might suspect it's an EBV related lesion because it's red, white and blue. But nevertheless, I always run the in situ hybridization study. So those blue dots, everything is pale. That is a very sensitive, very carefully orchestrated assessment. Then those blue dots that you see in the nuclei are actually confirming that this is an EBV associated infection. And so what EBV associated lesion. And so what that means. What do you do about that now that you know this is hairy Lucas, which means it's an EBV related lesion. Well you need to have a conversation with your patient because why do they have this lesion. It usually means their immune suppressed look through their medications. Are they doing injections with Humira for their psoriatic arthritis. Are they taking steroids for other conditions. Do they use an inhaler. Maybe the steroid is suppressing their immune system locally. Are they do they could they have HIV and not know it. Could they be undiagnosed or are they on heart therapy. High you know highly active retroviral therapy. But the therapy is suppressing their immune system too much. And their infectious disease specialist might need to do some tinkering. This could be a sign that they are too immune suppressed. Right. Because the they are developing sort of these opportunistic type changes. Another opportunistic infection that we don't see very often. So this is if you remember the very first day of the class, I told you when I would say something is rare and unusual. This is not that common. You're probably not going to run into this very often in your practice. But for the sake of completeness, I wanted to mention CMV. I think the most important thing for you to know is if there is a non healing ulcer in your patient's mouth, you need to explain it right. And I think any one of us understand that could be malignancy right. It could be squamous cancer or other cancer. It could be an infectious etiology okay. So CMV is just like EBV. It kind of hangs around if you've ever been exposed to it. And it comes out when we are very immune suppressed. And it often presents just as a nonspecific ulcer that just comes and sits and doesn't heal. Okay. So you will remember that I'm not going to hold you accountable for much regarding this. I just want you to know it for your clinical practice. Okay? The interesting thing about CMV is that how we talked about EBV likes T cells and B cells and epithelial cells. This particular virus similarly likes those cells, but it also likes salivary gland epithelium and also the cells that line blood vessels. So that's where you go looking for it. And what are you looking for. It is actually a little bit interesting. These this a virus has a very unique inclusion in the nucleus when it affects infect cells. And so it has a very distinctive appearance. So anyway you're looking for ulcerations. It is ubiquitous in Aids patients. So be mindful of that. So here you go I just want you to see what the cells look like. This is just for your interest. We call them owl eye inclusions. So as a pathologist when you look through the microscope it's shocking because you feel like the cells are looking back at you. They have these giant inclusions. You can see them from the back row. Yes. That is not the nucleus. That's a huge viral inclusion. There's another there's another one. So these are just viral modifications of the cells. Very typical for CMV. And again this is just for your knowledge. There's another one. See? Looks right back at you. All right. A couple more things before you take our break. How are we doing? Two, three. How long do we talk? We have an hour to talk. I'm done at ten of three, right? Okay. A couple more things, and then we'll take a break. So just a quick run through this. I just wanted to mention Enteroviruses because Enteroviruses tend to have, you know, like most viruses, when you're sick with a virus, you feel crummy, you have a fever, you have muscle aches, malaise, etcetera, runny nose sometimes, etcetera. But enteroviruses often also come with oral ulcers. And so I just wanted to talk about a couple of these happened and hand, foot and mouth disease. We don't typically tease these apart from each other because they're very closely related. Yes. When you are infected with one enterovirus, you are unlikely to ever get that one again because you're immune to it. But there are like 100 of them, so you're bound to run into another at some point. They're easy to transmit in crowded areas. Think amusement parks, for example. Like, imagine that you've taken your young children to Disney World, and, you know, someone probably licked the thing, that stroller that you rented to purchase. And now you're walking through Disney World and then maybe touch your face or something. And then, wow, hand, foot and mouth disease is no fun, just so you know. So her band, Gina patients will present with a sore throat, fever, muscle aches, just like any other virus. Very nonspecific. And then you also get a few vesicular ulcerative lesions, most commonly on the palate. You can get them other places, but not on keratin ized mucosa. So you should not confuse this with herpes. Right. You see these ulcerative lesions mostly on the palate. This patient also has one on the labial mucosa. Just a few little ulcers. They feel really crummy. But it's not involving the attached gingiva. It's not involving the kind of palate hard palatal mucosa where we tend to see herpes also. So just soft palatal mucosa just a few a few little ulcers. And this is typical for her. And again it's not very likely that a patient will show up in your practice complaining of these things because they also feel pretty crummy. And usually patients will decline to come for a routine dental visit if they have a systemic illness. But just for your knowledge now, hand, foot and mouth disease is really unique, very similar except for that you tend to have in addition to the oral lesions, you also have skin lesions they present on the palms of the hands and the feet. And you see these red vesicular lesions on the hands very distinctive. And also on the feet. Here's a couple of other examples. Little vesicles. And then you also get oral ulcers. So that one's pretty easy to remember. Right hand foot and mouth disease. Um. All right. This, I think, is the last thing I'll talk about before the break. Maybe or just maybe a couple of things I think I'll do. Measles and mumps. We'll just run through these quickly. You know, you would think we don't have to talk too much about measles and mumps because many people are vaccinated against measles. Mumps and rubella is a part of the vaccination regimen when you're a young person and then boost it again before you do things like enter dental school and things of that nature. However, there are parents who are not vaccinating children, and so we are seeing some of these cases come along. And just for your knowledge, I think it's important for you to at least be aware of the presentation. All right. So measles is an RNA permissive virus and it's transmitted very easily, very easily transmitted through respiratory secretions. And patients feel crummy. They develop light sensitivity. And I've never seen them in person. But I do have an example that I stole from somewhere. I hope I gave credit, but I will show it you. You get oral changes called complex spots. They're these tiny little white spots in the mouth that are apparently pathogenic for measles. But because they are very transient, they only are present for a very brief time. And because patients are so sick elsewhere, it's not like what you would say to diagnose measles, right? You're not going to say, oh, I see complex spots and I know that's measles. It's just interesting that there is an oral manifestation associated with measles. It's just very rare to see it because patients are usually actually very sick with measles. There's an infectious prodrome, which is why it is so easy to catch. That begins until day four of the rash. So you're infectious until about 4 or 5 days into this terrible rash that you get all over your skin. So see these little kind of polka dots on the mouth? They're supposed to be those black spots. I've never seen them. I'm not asking you about them or anything. I just want you to know about them, all right? You should know you should be educated. All right? And then mumps is another one you should know about. Mumps is also an RNA premix of virus. But this particular virus likes glandular tissue. Okay. So major glands and also genital glandular tissue. So it's an acute illness. Patients feel really horrible typically affects children and young adults although adults can get it if you were not vaccinated. Again super easy to catch from respiratory secretions. You have a fever, malaise, headache, all of the things you get whenever you have a virus and then you develop acute, painful swelling of glandular tissue. So the parotid glands in particular, but also genital glandular tissue. And you're more likely to have disseminated symptoms if you get this as an adult. So here's an archival image of a couple of different children showing marked enlargement of glandular tissue. They look absolutely miserable. Just look miserable. All right. So I think we need a break. So we'll do just five minutes since I do still have some things to talk about. And we'll come back and talk about HPV. All right. That went by really fast, but I don't want to run out of time to go over everything, so I will. If you're still needing more time, you can just step out and otherwise I will get started. So the next thing I want to talk about is human papillomavirus. And HPV is something that your patients will most definitely ask you about because HPV has become very familiar in the in the public domain. I think there's been a lot of conversation about HPV, and we owe a lot to a famous actor, Michael Douglas, because he famously he's married to Catherine Zeta-Jones, right. And he famously said that he developed oral pharyngeal cancer from oral sex. And he is not wrong. He that is true. However, you know, when you look in the literature about HPV related oral precancer and cancer, they do tend to lump oral cancer in with oropharyngeal literature. So I will disclose that oropharyngeal cancer and precancer related to HPV is much more common than oral cavity HPV related dysplasia and oral squamous cell carcinoma. However, we do see HPV related oral precancer and cancer all the time in my biopsy service, so it does exist. It's just much more common in the oral pharynx. Okay, so what does HPV? I'm sure you know about it. It's a virus that likes epithelium. And you can remember that very easily because HPV causes the benign subtypes cause warts right. Very typical. And so you can imagine something causing that's trophic for surface skin and mucosa will form a very bumpy rough corrugated surface lesion. Right. So it only replicates in the basal keratinocytes. And there are over 130 HPV types that have been identified. There's a great paper. It's a little old now but it was in the Lancet I think that looked at clearance rates of high risk and I assume low risk HPV types. And basically the take home message is that most patients, even if they are infected with a high risk HPV type, most patients actually clear the virus or it's below a detectable level. Based on all of our ability to detect within a few to several months of contracting it. So your immune system does a pretty good job of clearing the virus. The problem is that if it doesn't. Right. So. The issue is when you have a exposure to a high risk HPV type and you become a chronic carrier of that virus, you cannot get rid of it, then you are more likely to develop HPV related precancer and cancer. And locations where patients develop these lesions include cervical cancer or pharyngeal and oral cavity cancer. We don't know whether you know if you have an infection with, say, high risk HPV 16, if it also helps confer immunity to other types. And then again, we don't know whether you can become kind of reinfected with that type. If you've been exposed to it again. So you can be a transient carrier of HPV. If you're you have a sort of a positive antibody titer. And but again, most of the time you clear the virus. It's just when you're a chronic carrier that you have to worry. There are all kinds of HPV types. Low risk types are associated with little warty lesions we develop in the oral cavity called squamous papilloma. Other HPV types are associated with Veruca vulgaris, which is a wart that you usually see on the skin. However, you can get Veruca in the mouth if you like to bite your warts off your fingers, so you can occasionally get a Veruca in the mouth, although the virulence rate is very low. Condor is also a benign HPV associated wart like proliferation. However, it's usually seen in immune compromised patients, and it has a higher association with sexual transmission. And then hex disease is a HPV associated condition where patients develop multifocal kind of papilloma in the mouth related to very particular low risk types. And that's usually seen in patients who live in close quarters or who crowded have a crowded living condition. So these are squamous papilloma I always feel like they're very social. They wave to you with those finger like projections. I think they're beautiful. I actually really like warts. And I feel like they're just like, this one is really lovely. I mean, that's a beautiful squamous papilloma. They have this kind of pebbly or finger like surface texture which is typical. They can either be sessile like me, which is kind of broad and attached, or they could be peduncle and kind of on a stalk. Right. The one on the top has sort of a cauliflower like look. And if you look very closely you can see there's a little satellite lesion as well. A couple other examples. Very beautiful squamous papilloma involving the ventral tongue. And each of these patients one on the dorsal tongue standing tall. And just another look at that cauliflower like one on the palate. All right. So these are all squamous papilloma. This is a coming autumn. So this is kind of lomita tend to be larger lesions. And those papillary projections are more blunted. They're more rounded and smooth. And so they tend not to have those very pointy finger like projections. Again this is just a benign HPV associated wart like lesion that has been associated with low risk HPV types. But in this case, most likely these lesions tend to be seen more commonly in immune compromised patients and as a result of sexual transmission. One thing I do like about warty lesions, and I'm sure you will appreciate this too. They look exactly like you'd expect them to under the microscope. All right, so you have the gross specimen here showing these finger like projections. It looks exactly like you'd expect under the microscope. Right. There's a lot of epithelium because this is an epithelial trophic virus. Right. So the epithelium is hyperplastic a little more than you'd expect. Right. And you see it has these undulating finger like projections overlying these fibro vascular connective tissue. Cause the papillae contain kind of dilated vascular channels. So those are all caused by low risk types. If your patient has a watery lesion like this and they're so panicked oh my gosh, am I going to get oral cancer. No. These are caused by low risk HPV types. They're not caused by high risk types. This is not a high risk lesion. So this is not something to lose sleep over. The issue is high risk HPV. Now high risk HPV is simply you've been exposed to a different type of HPV that has a higher risk of inducing malignant transformation. These lesions don't look like the warts that we looked at okay. They look exactly like the white and red lesions we've already learned about and you're already worried about. Okay, it will present as a demarcated lookalike in the mouth. And you don't like those already because we've talked about that right. We're worried about those because demarcation is a concerning thing. Right. And if it's a white lesion it should explain itself. So high risk HPV lesions don't you won't confuse them with a wart. You'll confuse them with a white lesion. You can't explain. And the way we recognize that it's an HPV related lesion is using special tests in my lab okay. So how do you get HPV. Well from contact with others. Right. So sexual contact or the low risk HPV types are probably through social contacts. You get warts from touching someone who has a war, not necessarily through sexual through sexual discourse. You can also transmit HPV vertically from mother to newborn. And I mentioned horizontal transmission sort of casually. Oh, I just put this in this, an ancient article. So I actually had this in here for a bit, but I just want put it in there more to remind me to tell you that just because you see a papilloma in a child's mouth does not mean that this is a sexually transmitted wart. As I've already said, you can get the low risk. HPV types are not typically transmitted like squamous papilloma. That's not a sexual contact. So you know we're all mandatory reporters right. So I just want you to know that having a squamous papilloma in the mouth and a child does not mean there was some disagreeable interaction. All right. So misinformation regarding HPV is that if you have HPV you're going to get cancer. I've already told you there are many low risk types. They cause warts and other things that many of us have been exposed to. We don't need to worry that those are the types that cause cancer. And even if you have a high risk type, you're very likely to clear it. If you have a good immune system, it's just that every now and then you don't, right? Most of the time HPV is associated with oropharyngeal cancer, but people who have HPV associated oral pharyngeal cancer, we will notice it on our head and neck exams. It metastasizes often before you even know you have a lesion, an oral pharyngeal lesion, and even though it metastasize, it's already metastasized to a lymph node that you and I can feel in our exams. Those patients still do better, they have a better prognosis if it's HPV related oropharyngeal cancer than if it's not. So it's actually a pretty a better actor will say over 90% of all tonsil cancers in men under the age of 40 are associated with HPV. Just so you know. HPV and oral cancer strongly associated with a number of sex partners patients have. There's weak to no association with smoking. Again, as I've emphasized, it's mostly oropharyngeal and tonsils, although and I've already mentioned the thing about Mets and that patients do better, but we do see it in the mouth. This was a little quick and dirty study done by some colleagues in my lab, where I look at slides and we just looked at pulled 20 cases from our lab. And these are precancerous lesions, just like the dysplasia we you already learned, except for instead of being caused by, say, smoking or betel quit or other things, this was caused by HPV. So we looked at these lesions and a couple did go on to turn into squamous cell. So they we don't quite know how these lesions behave. But this is just a lookup. Right. So absolutely that's what you should think of it clinically when you biopsy it you will see dysplasia. All I care is that you know it's dysplasia okay. I'm just showing you an example of a dysplasia that happened to be HPV related for your knowledge okay. So don't panic. I'm not going to ask you to distinguish between dysplasia. That's non HPV related from dysplasia. That is if you know this is dysplasia I am thrilled okay. I'm just telling you this one happens to be HPV related. And the reason I know look how bizarre the dysplasia is. In the upper right corner there is a weird apoptotic cell here, a cell undergoing kind of programed cell death, these strange, brightly pink pair of keratin on the top. And this disordered penis, it's a cis carcinoma in situ. So we do p16 which is a stain that we can do that confirms that HPV is driving the process. And that brown band positivity here is positive. Just so you know. And then we do inside two for high risk HPV. And all those blue dots that you see are positive. So I just want you to know you can have HPV associated dysplasia. We just don't know quite what it means yet. We don't know whether this will behave the same as which is better right. That like the HPV associated dysplasia and cancer in the oropharynx, we also don't know whether this will stop happening. Right? Many young people, our children and young adults are vaccinated now against high risk HPV types. So it is very possible that we will see a decline in HPV associated oropharyngeal and oral cancer. So we'll hope for the best, right? All right. A little quick. Yes. Question. How can you go? This virus and hypoplastic. Problem because I know this is not. A hypoplastic papilloma. What do you mean? So. So there's the squamous papilloma that I was talking to you about. Those are caused by HPV. It's just they're caused by low risk HPV types. Um, I mean, there are a variety of tumors that can have a papillary architecture, but, you know, maybe like selenium from things we don't cover in our course. But nevertheless, there are some papillary tumors that have a kind of a papillary architecture but are not papilloma. Right. And so just a papilloma, a papillary architecture in and of itself doesn't mean HPV related. Right? It's just we know that these lesions are definitely HPV related based on our insight two studies. So I have to think. That's what. I'm a little confused. Can we talk about this offline? I'm glad to talk about this with you after. I'm a little confused. I'm not sure why. Why? We would need to chase that. Unless you're. But let's talk about it. I will, we will discuss. Just for the sake of time, we'll move forward. But I do want to briefly talk about HIV, because although we're all familiar with human immunodeficiency virus and what how it how it occurs and what the underlying etiology is, what's important to us as dentists and clinicians is the oral manifestations of immune suppression. Right. So you well know that HIV is an RNA retrovirus. It binds to CD4 positive T cells. It's transmitted by sexual contact and blood transfusions and trans placental. But the oral manifestations of HIV Aids are manifestations of things that occur because of immune suppression. All right. So. Having herpes virus present in weird places. We already said we're not going to call it herpes recurrent intraoral herpes unless it's on the keratin mucosa in the mouth. Right? But what if herpes is presenting on my dorsal tongue or on the side of my tongue? That's unusual. Right? So herpes simplex in unusual locations, another herpes simplex virally associated malignancy called Kaposi's sarcoma is unique to patients with HIV Aids or those with significant immune suppression similar to HIV Aids. EBV associated lesions like Harry Lucas, which you learned about lymph. Proliferative disease. And then we can see reactivation of latency and V that when I told you it's like an owl looking back at you. Right. So you get all of these complications. And one thing you can see in HIV positive patients who are not controlled is candidiasis. So what is candidiasis? Candidiasis is an organism that's either a part of your normal flora or it isn't. You either have it or you don't. And if you have it, it doesn't bother you until it does. Right? So not everyone can get thrush or candidiasis. It's the same term, but it's just thrushes, a late term. We call this candidiasis as clinicians, right? Candidiasis is an overgrowth of Candida organisms, usually Candida albicans. But there are a number of candidates species and it presents in a couple different ways clinically. If you are immune suppressed or if you are. Let's say you recently took antibiotics and it wiped out your normal flora, bacterial microorganisms that keep everything in kind of a nice homeostasis. When you wipe those out, then the candidate organisms take advantage and they kind of overgrow and you develop a fungal infection. Right a candidiasis. And so candidiasis presents this way which is the pseudo membranous form. Pseudo membranous candidiasis is I'm sorry, but we liken all kinds of things to food and pathology. It kind of looks like cottage cheese. Okay. You have these sort of curd like plaques that theoretically you can wipe away with a little force and some gauze. It will leave pinpoint bleeding at the base. That's very typical for the pseudo membranous form of candidiasis. So again, if you recently had antibiotics and it suppressed your bacterial overgrowth, that kind of keeps the Candida in check in your mouth. That's a time when you might see a flare of candidiasis. I see it in diabetic patients. I see it in patients with hypo salivation because our saliva is an excellent protector, right. Kind of keeps our oral flora and balance. And certainly you can see it in an immune suppressed patient. Other things that you could see in immune suppressed patients are florid papilloma ptosis. So HPV low risk types. But instead of getting one kind aloma or one squamous papilloma you develop crops of papilloma. And we call that florid papilloma ptosis. You can also see this, paradoxically on patients when they are undergoing retroviral therapy, because this seems to evade that retroviral therapy a little bit. This purple lesion that you see, the soft subsub mucosal sessile purple mass that you see on the palate. This is in an HIV positive patient. And this is a very concerning finding. This is that very bottom entity on my list at the very beginning that HHV eight related lesion called capaci sarcoma. Now Kaposi's sarcoma can be seen on the skin, typically in patients of Mediterranean ancestry and on the extremities. It's less worrisome. But in patients who are immune suppressed and develop these lesions in the mouth, that can be very concerning because it generally suggests HIV Aids that has either not been diagnosed and treated right, or a patient who has stopped taking their medication because having a flare of this does suggest that the patient is immune suppressed. So actually, a 24 year old female presented to my clinic not too long ago with lesion on her leg and then multiple sorry, sorry, multiple lesions in her mouth of capaci sarcoma. So. And she did not know that she had HIV. So it is if you see this very important to have patients get tested for HIV, especially if they are not already under the care of an infectious disease specialist. All right. So these purple lesions are pathogenic for Kaposi's sarcoma biopsies indicated though. And you will see kind of slit like channels with spindle cells and extra red blood cells in between. Very typical for capillaries. We already talked about this entity earlier today. So very familiar to you. You already recognize red white blue right. That kind of row of pale cells. That's where the EBV positive cells will live. They have this kind of altered chromatin and have a very distinctive look. But it's the changes on the tongue. They're actually a little painful. And patients develop these kind of white plaques on the tongue that kind of have a very subtle vertical linear presentation in my opinion. Other things you can see in HIV positive patients include necrotizing ulcerative gingivitis. We used to call it acute necrotizing ulcerative gingivitis. Some of you may have learned this as a nug, but now we just say nug. It's just nug no a necrotizing ulcerative gingivitis. And this is caused by skyrockets that are in the oral cavity. This used to be called trench mouth during World War one because it was it is kind of transmissible. It is a bacterial infection essentially. And when you're under significant stress, like, you know, dealing with combat and so forth in a trench, you're under stress. So and probably immune suppressed. And we're probably smoking. And so lots of reasons why it was very common during the First World War. But you can see it now very typically in smokers and also in HIV positive patients. And so what is NUG. What does it look like? Well, as I mentioned, patients feel crummy. They tend to have a fever and develop this very distinctive fetid odor, oral mal odor that you will recognize. And characteristic punched out papillae. The entire dental papillae tend to be punched out. And by that it's because they're necrotic. You have necrotic ulcerative lesions in the entire dental papilla. Very painful. Gentle debridement is the recommended treatment together with antibiotics and chlorhexidine rinses. And so this is again usually seen in patients who are immune suppressed. If you see this in a patient no smoking can't really explain it. I would recommend consultation with their physician to rule out HIV. You need to explain it. Why would an otherwise healthy person develop necrotizing ulcerative gingivitis? Classic presentation. Multifocal. Ulcerative necrotic. Punched out papillae. Other examples. It can progress it. It can extend into the periodontal. It can extend into the lips onto the palate. We call it nup necrotizing ulcerative periodontitis. Right. And necrotizing ulcerative stomatitis if you want if it's kind of multifocal and spreading beyond the gingiva. All right, a couple other things to touch base on before you push off. Are we doing good? So this next thing we'll talk about is a bacterial infection. Even though the term says microcystis, which strongly suggests fungus, it's not a fungus. Acting on psychosis is actually a bacterial infection characterized by these very beautiful colonies of bacterial microorganisms that kind of develop these sort of delicate projections at the surface. And then your body mounts this amazing host response with all these neutrophils that come around. We actually see actinium psychosis with some frequency. Those of you who plan to do apical ectomy procedures in your clinical practice will remove the inflammatory apical lesion, the closest or granuloma, for example. It's not unusual for me to see actinium psychosis under the microscope. If it's removed locally, there isn't much more to do about it, but it can become a problem that requires intravenous antibiotic intervention in very serious situations. But. You can see these colonies of bacterial microorganisms can be so large, you can actually see them with your unaided eye when you're doing an incision and drainage procedure in a patient who has a soft tissue abscess with actinium psychosis, you see these little yellow flecks in the pus that's draining. And they're actually we call them sulfur granules because they're bright yellow, but they represent big colonies of actinium lysis. So here is actually a patient with an oral cutaneous sinus tract that has perforated the skin. Remember that infections tend to channelize through the bone, following the path of least resistance until they reach a surface. And usually we have an intra oral manifestation. Looks like a little pimple on the gums, and that is called a. Sinus tract. And what's the orifice called? Ulysses. Do you remember that from the midterm populist par uglies? That's that little pimple like focus of granulation tissue at the orifice of a sinus tract, right? Well, you can also have that channelized to the skin. So this was an oral cutaneous fistula. And this is a colony, large colony of bacterial microorganisms. This is what actin mices look like. They're really pretty. And they're always in the sea of neutrophils that come around. Your body gets very upset about them. It