Pathology Grand Rounds, November 2, 2023 - Bruce W. Wenig, MD

November 02, 2023

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Dr. Bruce M. Wenig, MD, Chair and Senior Member from Moffitt Cancer Center, presents on “Viral-Associated Cancers of the Head and Neck”.

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00:00Good afternoon and welcome
00:04to this Grand Round.
00:07Today's speaker is Doctor Bruce Wennig.
00:11He's an internationally renowned head
00:14and neck and endocrine pathology.
00:17Dr. Wennig completed his
00:19pathology residency at Mount
00:21Sinai Medical Center in New York,
00:24and he went on to do a fellowship
00:27in anatomic pathology at Cedar
00:30Sinai Medical Center in Los Angeles.
00:34And then he did a second fellowship in
00:39auto laryngologic pathology at AFIP
00:43at the Armed Forces Institute of Pathology.
00:46Dr. Wennig quickly became a staff
00:50pathologist in the Department of
00:53Endocrine and Autolaryngologic Pathology,
00:56where he served from 1987 to 1998,
01:03a little over 10 years.
01:05During this time,
01:06he rose through the ranks to become
01:10Assistant Chair of the Department
01:12and later Chief of the Division
01:15of Autolaryngologic Pathology.
01:18During this time,
01:19he also served as consultant at
01:22Walter Reed Hospital and the National
01:26Naval Medical Center in Bethesda.
01:28He served the US Naval Reserve Medical Corps.
01:34In 1998,
01:35Doctor Wenig got an opportunity
01:38to move back to New York as Vice
01:43Chair of Anatomic Pathology at
01:46Albert Einstein College of Medicine.
01:50Subsequently, he became Vice Chair of 8th
01:54Anatomic Pathology at Bethesdale Medical
01:57Center and then became the Chair of
02:01Pathology at Continuum Healthcare System,
02:04which oversaw or included multiple hospital
02:09Pathology departments in New York City.
02:13Subsequent to it's merger
02:15with Mount Sinai Hospital,
02:17Doctor Wennig became a Site Chair and a
02:20Vice Chair in the Department of Pathology.
02:24Since 2016, Doctor Wennig has been at
02:28Moffett Cancer Center where he is currently
02:31the Chair of the Department of Pathology. Dr.
02:36Wennig has been very generous with his time,
02:39serving at many leadership positions
02:44and in many committees with the
02:47College of American Pathology,
02:49United States and Canadian
02:51Academy of Pathology.
02:53He was Vice President and President
02:56of the North American Society of
03:00Hedonic Pathology and also served
03:02on the Committee of the American
03:06Joint Committee on Cancers, AJCC.
03:10He's on the editorial board of many high
03:14impact factor pathology journals and
03:16has won many scholarships and awards,
03:20the most recent of which is the Maude
03:25Abbott Lectureship at USCAP in 2021.
03:28His prolific career is highlighted by
03:32publication of close to 150 original
03:35articles and close to 100 chapters,
03:39books, monographs,
03:41including chapters on in the Fletcher book,
03:46The Millsburg, The Barnesburg,
03:49and he's been a significant contributor
03:54to The Who Blue Book since 2005,
03:58since the third series.
04:01And in the current fifth series,
04:03Doctor Wennig is a member of
04:06the editorial board.
04:08So he's a much sought after speaker.
04:11And those who attended his morning
04:14slide seminar have seen a glimpse
04:17of what a fantastic educator
04:19and teacher Doctor Wenig is.
04:21So with that,
04:22Bruce,
04:26thank you Doctor Preside.
04:27It's a pleasure and honor to be here.
04:30I've actually never been to Yale,
04:31even though I grew up and lived in New
04:34York and Westchester for many years.
04:36Been a long time since I've been
04:38in an old school amphitheater and
04:40it's wonderful you're part of my
04:42informality Since I've moved to Florida.
04:44I know where longer wear a coat nor a jacket.
04:48So what I'd like to talk to
04:49you about is is listed here.
04:50It's viral cancer,
04:52associated cancers of the head and
04:55neck within this hour's talk spend most
04:57of the time on HPV related cancers.
05:02By now you're probably aware of
05:03the clinical pathologic features,
05:05but we'll go through that.
05:06There's an ever increasing morphologic
05:08spectrum of these tumors that I
05:11want to share with you that if
05:12you do head and neck or if you do
05:15psychology of superficial lesions,
05:16you should be aware of the spectrum
05:19of HPV related changes and not
05:22dismiss a particular morphology
05:23because you don't think we're going
05:25to think about the possibility
05:27of being an HPV positive cancer.
05:32P16 is helpful, but it can be confusing.
05:36So I want to spend a little bit
05:38time on mechanism, What's positive,
05:40what's negative, you know,
05:41when it may be applicable and
05:44when it may not be.
05:46And the granddaddy of head
05:47and neck viral cancers,
05:49his nasopharyngeal carcinoma,
05:51different location,
05:52overlapping morphology and like
05:54HPB often is a cult primary
05:56presenting with the neck metastasis.
05:59And you may be confronted with a lesion
06:02that has overlapping morphology that
06:03if you only think of 1 and not the other,
06:06we may miss the diagnosis and the clinical
06:10therapeutic impact on that is important.
06:13And then obviously you know once we
06:15get through that talk about the occult
06:17metastatic cancer all within an hour.
06:19So I will try to make this
06:21you know as quick as possible.
06:23So medical mortality,
06:26we can report in 2018 show the
06:29trends in HPV positive human cancers
06:33and as you can see here in about
06:362010 or pharyngeal HPV cancer
06:39overtook cervical HPV as the most
06:42common human HPV related cancer.
06:45When you think about it,
06:46it makes sense because we have a Pap smear.
06:50So there's surveillance and early
06:52surveillance for cervical cancer.
06:54Conversely,
06:55there's no early manifestations
06:58of oropharyngeal cancer.
06:59They're clinically quiescent,
07:01often patients present with
07:03the neck metastasis.
07:04There's no way to screen for them.
07:05There's some,
07:06you know,
07:07ongoing saliva and testing that
07:09may portend the possibility of that,
07:12but it's not ready for prime time.
07:14So it makes sense that because
07:16there's no surveillance and with
07:18increased incidence it's going to
07:21overtake cervical cancer and all
07:23other cancers in terms of being the
07:25most common HPV related cancer.
07:27So when we think about head and neck
07:29squamous carcinoma and in spectrum of
07:31squamous carcinoma or the HPV cancers,
07:33you know this is the typical scenario,
07:36older tobacco abuser, alcohol abuser,
07:41right.
07:41So this is what we think
07:43about for conventional
07:44squamous cancer. But as you know
07:46by now the the demographics for
07:49the HPV is different, younger
07:53often Caucasian, often affluent and so
07:58that sets up a compare and contrast
08:01between HPV associated and HPV independent.
08:03And just to briefly go through this
08:06and I'll go through it in more detail.
08:08So tend to be younger risk factors
08:12are related to HPV and conversely
08:14non HPV is alcohol,
08:16is tobacco and alcohol the primary
08:19location for these orpharyngeal
08:21cancers at the base of the tongue
08:23and the tonsil and we'll go through
08:25that some of that morphology and
08:27why it may localize to there.
08:29It's a rather unique type of epithelium
08:32called reticulated epithelium.
08:34As far as I'm aware that epithelium doesn't
08:37exist elsewhere which may explain some
08:40of the issues related to these HPV cancers.
08:43The other tobacco related or HPV
08:47independent can arise of any mucosal site,
08:51oral cavity,
08:52larynx of the more common locations.
08:54There is a pre malignant lesion association
08:57associated with the HPV independent cancers.
09:00We see dysplasia that predates or
09:03or precedes the invasive cancer.
09:06The same is not necessarily applicable
09:08for the HPV related cancers.
09:10The Histology is different the
09:12ones that are HPV related or
09:15predominantly uncharatinizing.
09:17That doesn't mean you can't get
09:19characterization as I will show you,
09:20but the independent ones
09:22are primarily keratinizing.
09:23We'll go through P16 and and
09:26and insight to HPV.
09:28You need to be aware and I'll I'll
09:30go through it again that there's this
09:33degrading of these non keratinizing
09:35cancers are not applicable and I'll
09:38explain why most people view them as
09:40poorly differentiated but they're
09:42in fact differentiated even though
09:45we don't see keratinization and the
09:47HPV cancers are radio responsive,
09:50radiosensitive and chemotherapeutically
09:52sensitive conversely the non or
09:54the HPV independent ones or not.
09:57And that contrasts in terms of you
10:01know biologic behavior in response
10:03to therapy before we get bogged
10:06down on a particular age.
10:08This graph just shows that HPV
10:10related cancers are not limited
10:12to a particular age group.
10:14You could see the trend here is that
10:16it can occur in older age patients.
10:18You know and maybe the poster
10:20child for that is Michael Douglas,
10:22would they have an HPV related cancer,
10:24older, white,
10:24affluent and not within the demographics
10:27that it was originally described.
10:29Before we get into some of the
10:32histological or pathologic details,
10:34yes, these are viral related,
10:37but tobacco smoking negatively
10:40impacts on response to to therapy.
10:43And these graphs,
10:44the top ones are you know HPV alone related,
10:48independent and the bottom two
10:51are with smoking,
10:52HPV with smoking and HP and this
10:54is patients who have greater than
10:5730 pack year history of smoking.
10:59So you could see the trend is that
11:02patients who had HPV and are tobacco
11:05abusers are poor responders to
11:07treatment and that's true across
11:10this all AJC staging levels.
11:12So this is a nice paper that details that.
11:16Just want to show you that HPV is
11:20negatively impacted by cofactors
11:23which include tobacco use.
11:25So I wanted to present this
11:26whole scenario with an
11:27actual case when I was in New York.
11:29This case came about.
11:31You know the demographics match what
11:33I showed you before 41 year old man.
11:36He presented with an enlarging left.
11:38Level 2 AI will show you
11:42the topographic anatomy.
11:43So for those of you who do head and neck,
11:47I don't know if there are any clinicians
11:48in the group or or listening,
11:50but neck mass does not mean anything.
11:54Neck mass in a particular anatomic
11:56location could mean everything.
11:58So if I know clinically it's
12:00a supraclavicular lymph node,
12:02that primary is most likely going
12:03to be somewhere outside the head
12:05and neck and below the clavicle.
12:07Conversely,
12:07if I know it's a level 2A or
12:10in the area of level 2,
12:12that's a common drainage location
12:14for an oropharyngeal cancer.
12:15So it's very important to be aware
12:17of the clinical presentation and
12:19nowhere in the neck that occurs.
12:21This patient had no history of any
12:24past cancers and no known history.
12:26And here's the seven levels of the
12:29topographic lymph node anatomy of the
12:31head and neck and and level 2A and 2B,
12:34which is a common but not unique
12:37dedicated drainage from the
12:39oropharynx is a common location for
12:42Nicole primary metastas to occur,
12:44whether in and around the parotid
12:46and we'll get to that later
12:49or separate from the parotid.
12:51So this patient on T1 and 2TT2 weighted
12:54images had a cystic lesion that had necrosis.
12:58So cystic necrotic mass.
13:00This is that patient's biopsy.
13:02It's an FNA.
13:03I'm not a cytopathologist.
13:04I don't pretend to be a cytopathologist,
13:06but even I can recognize that these
13:08are malignant basaloid cells.
13:10They're cohesive.
13:11There's no characterization.
13:13You know from day one that
13:15we're taught pathology.
13:16The more a tumor looks
13:17like it's all of origin,
13:18the better differentiated it is,
13:20the less it looks like it's all of origin,
13:22the less differentiated.
13:24So it makes sense to think
13:26about this as a metastatic,
13:28poor differentiated carcinoma and it
13:30is instance favor squamous cancer.
13:33The patient had a pet CT not only
13:36lights up that large cystic met,
13:38but there's another metastasis and
13:40at the ipsilateral base of the
13:42tongue there's increased uptake.
13:46So then the biopsy happened and this
13:49is tells you a lot about the nature
13:52of this tumor and low magnification.
13:54There's nobody in this room that
13:56can tell me where they can't.
13:58Yeah, I put the arrow where the cancer is,
14:00right? But the point being,
14:02it's small wall dyer's ring of which the
14:05Oropharynxis is extranodal lymphoid tissue.
14:08There's a lot of lymphoid infiltrate that
14:11can overrun the tumor and these tend
14:13not to induce a desmoplastic response.
14:16Maybe the body doesn't view this
14:18as being foreign.
14:19If you look at conventional
14:21squamous cancer would invades it's
14:23hard morphologically low power.
14:24You see the cancer and there's
14:25a decimal plastic response.
14:27So small tumor as I will show you,
14:30no desmoplasia coexisting benign
14:33lymphoplasmic cytic infiltrate.
14:36It's easy to overlook and if
14:37you look at the surface,
14:39there's no dysplasia we talked
14:41about no pre malignant lesion.
14:43But as we get to a little
14:45bit higher magnification,
14:45you could see the malignant basaloid
14:47cells that match what was in the neck.
14:49There's also some disc keratotic cells.
14:51So these are not completely
14:54devoid of characterization.
14:56And deeper in the block,
14:57you can see there's more tumor,
14:58but it's still small,
15:00certainly under a centimeter,
15:02your keratin positive and P16,
15:04I'm just showing you for now.
15:05We'll talk about that a little bit later.
15:08Often these arise in the tonsil or crypt,
15:11there's a different case.
15:13So if you think patient
15:14has a neck metastasis,
15:16you know if you don't do a
15:17tonsillectomy with do blonde clinicians
15:19do endoscopic blind biopsies.
15:21If they only took the biopsy
15:22up to that where the arrow is,
15:24they're going to miss the cancer.
15:25It's lurking in the sub in
15:27in the tonsilla crypt.
15:28This is a fairly obvious one.
15:30You could see it here.
15:31It's cystic and it's necrotic
15:35and when he's metastasized,
15:36they metastasize his cystic necrotic tumors.
15:39We'll talk later towards the end
15:42about occult metastatic cancers,
15:44but in the absence of a known
15:46primary a cystic lesion,
15:48some people might think about the
15:50concept of a carcinoma arising
15:52in a branchial cleft cyst,
15:53which doesn't exist as far as we know
15:56and we'll come back to that later.
15:59And then hydromagnification,
16:00you could see that this is
16:03predominantly non characterizing.
16:04There's a little bit of characterization,
16:06but that that's the primary cancer.
16:08Some other examples just showing
16:10even at the left low magnification
16:12you can identify the cell clusters,
16:15they're permeated by lymphocytes and
16:18plasma cells. There's no desmoplasia.
16:20On the right,
16:21there's a series of three images that
16:24just called, you know focus on those.
16:27The bottom one shows nucleopleomorphism.
16:30I've seen cases with a lot
16:32more nucleopleomorphism.
16:33There's at least one article in the
16:35literature that suggests that the
16:37presence of nucleomegaly and bizarre
16:39nuclei may portend a worst prognosis.
16:41I don't know if that's ever held up,
16:43but it's in the literature and
16:45for now we'll come back to this.
16:47The proof is in the P16
16:50and insight to HPV.
16:53These cancers are diffusely keratin positive
16:56whichever keratin you'd like to use,
16:58and diffusely P40 and P63.
17:01And this is important to know because if
17:04you have a metastatic cancer in the neck,
17:07that's basaloid nor endocrine cancers
17:10becoming the differential particularly
17:12small cell and they conversely
17:14are typically P40P63 negative,
17:17CK56 negative, so the NOR
17:19endercome markers will be positive.
17:21But in these non keratin cancers,
17:24conversely they're keratin positive
17:27P40P63 whichever one you want,
17:29if you use both, they'll be positive.
17:31They're negative for neuroendocrine markers,
17:33melanocytic markers and lymphoid markers.
17:36I mentioned before the
17:37issue of differentiation.
17:38So as you go from the left
17:41panel to the right panel,
17:43the more a tumor looks
17:44like it's cell of origin,
17:45the better differentiated it.
17:46So we're going from well
17:48differentiated to mildly differentiated
17:50to poorly differentiated.
17:51So if we use that concept for that
17:54neck metastasis in a different case but
17:57nonetheless a non keratizing carcinoma,
18:01the natural thought process is
18:03it's not baking carrot in and
18:06has to be poorly differentiated.
18:08But according to the CAP Synoptic protocol,
18:10these cancers don't get graded.
18:12And the reason for that although
18:15these terminologies were used,
18:16over time these are non carrotizing,
18:18they recapitulate the tonsilla
18:20crypt epithelium.
18:21So in fact they are differentiated cancers,
18:24albeit with no carrotization.
18:26So it's important to know that if
18:29you're staging these or grading them,
18:31you know that becomes a relatively
18:33minor issue in the synoptic reporting,
18:35but it is there are,
18:37they should not be graded.
18:39So I showed you pretty much the classic,
18:41if you will, type of HPV cancer.
18:44But there's a whole array of morphologies
18:46and maybe that'll even evolve over time.
18:48I will go through some of these,
18:50but by listing hybrid papillary basaloid,
18:53you know if you look at The Who,
18:56the spindle or sarcoma toid carcinomas
18:58or within the spectrum of HPV,
19:01I've never seen one that's been HPV positive.
19:03I don't know if Manju has ever seen that,
19:05but they're usually not.
19:06But I guess based on a few cases
19:08reported in the literature,
19:09they were within this
19:12classification Lymphopothelial like.
19:14So any tumor that is originating
19:16outside the nasopharynx that looks
19:19like a nasopharyngeal carcinoma
19:21previously called lymphopathelioma,
19:22but now the grading is different.
19:25We use the the terminology lymphopathelial
19:27like carcinoma because it looks like
19:30those lymphopathelial malignancies
19:31of the nasal pharynx and they may
19:34originate in the oropharynx and be HPV
19:36and not ebb positive and oosquamous
19:39and ciliated and neuroendocrine
19:42carcinomas can harbor transcription
19:43the active virus and we'll come
19:45back to that a little bit later.
19:48So here's a cancer that has more than
19:49just a little bit of characterization.
19:51It's got a mixed caronization,
19:53non caronization.
19:53People have applied the term hybrid.
19:56Is it important to give it a specific name?
19:58No,
19:58it's more important to recognize it as HPV.
20:00But I'm showing this to you because
20:02there is a spectrum of morphologies
20:04that we as pathologists need to be
20:06aware of in terms of, you know,
20:08what the diagnosis may be
20:10and you can see the P16.
20:12Tends not to be as positive or
20:14impositive in the carrotizing component,
20:16but certainly on the periphery
20:18and the non carrotizing.
20:19And this was backed up by insight to
20:22HPV papillary squamous carcinoma.
20:24And I use this very specific
20:27terminology for this entity.
20:29A lot of oral pathologists,
20:32and I'm not coming down oral pathologists,
20:34they're excellent, you know,
20:35and I've learned a lot at AFIP,
20:37but from the oral pathologists.
20:39But there's a tendency,
20:40at least the ones in Florida and maybe
20:43elsewhere to apply the term papillar
20:45squamous cancer for conventional
20:47squamous carcinoma that has papillary
20:49features or varrocoid features to me.
20:52If I use papillary squamous,
20:53I try to limit it to this
20:55entity as I will show you,
20:57which is an invasive cancer.
20:59You don't always see the invasion,
21:00which is a little bit problematic.
21:02It has an exophytic,
21:05papillary or exophytic appearance,
21:07fibrovascular cores and it's
21:09covered by malignant cells.
21:12So here's an example on the extreme
21:14left that filiform or papillary
21:16growth fibrovascular cores.
21:18The next image is a little bit
21:20more Oval shaped or exophytic and
21:22not as papillary if you will.
21:24But irrespective you could see
21:27the nature of the cytomorphology.
21:29So this is essentially what we might
21:32consider full thickness intrapothelial
21:34explasial carcinoma Insight.
21:36Here's a same example.
21:39And these are P16.
21:41You could see the grains on the
21:43right that it's a positive for HPV.
21:45So by convention,
21:46even the absence of invasion,
21:49they're considered to be at
21:52least superficially invasive.
21:54The majority are T2,
21:56which are more deeply invasive.
21:58If I'm thinking on biopsy
22:00about making this diagnosis,
22:01I'm either calling the clinician
22:03or looking in the chart to see
22:05if the patient already has nodal
22:06disease because not infrequently
22:08there's no little metastasis.
22:09They tend not to metastasize
22:11differently if you compare and
22:13they're not all of these papillaries,
22:15especially out outside of the oropharynx
22:17with this morphology will be HPV related.
22:20So the HPV ones have a much better
22:23prognosis because they're more radio
22:26responsive to the HPV independent.
22:28Another morphologic subtype is
22:30the basaloid squamous cancer.
22:32This is a high grade variant
22:35of squamous cell carcinoma.
22:36It's predominantly comprised
22:38of basaloid cells.
22:39The squamous component is the
22:41usually a minor component.
22:43It may be insight to or overt
22:45characterization and that
22:47varies from case to case.
22:48Many of them have just limited caronization,
22:51others have more overt carotenization
22:53and has a basaloid population.
22:56And here you can see a panel
22:59of images from the upper left
23:01showing a deeply invasive cancer.
23:04There is some keratinization there.
23:07Typically they have these lobules
23:08that are kind of jigsaw shaped
23:11with Central Comedotype necrosis
23:13seen here and across the panel.
23:15I just wanted to point out that
23:18these may have what looks like we
23:20duplicated basement membrane material.
23:22So if you had a biopsy just in
23:24this area which is showing this
23:26basaloid reduplicated base membrane material,
23:29a natural consideration would be a salivary
23:32gland tumor such as adenoid cystic carcinoma.
23:35The majority of adenoid cystic
23:37carcinomas are cytologically low grade.
23:39They're basaloid, they're densely cellular,
23:42but there's very little pleomorphism,
23:44very few mitosis and no necrosis.
23:47But the basaloid squamous cancers,
23:49if just by like markoscopy chose
23:51to make a differential diagnosis,
23:53are typically markedly pleomorphic,
23:56mitotically active with necrosis
23:59and interesting every now and then.
24:01Rosettes and palisinin may occur in
24:03things that are not nor endocrine
24:05olfactory neuroblastoma.
24:07This was a case of sinonasal basaloid,
24:09squamous that had rosettes and palisinin
24:12but nor endocrine markers were negative.
24:15The degree of squamous
24:17differentiation can vary,
24:18you know starting in the left panel,
24:19very little, little bit more in the center
24:22you know and a lot towards the right.
24:25So there is always some component usually
24:28of squamous whether it's intrapathelial
24:30dysplasia or over carbonization.
24:32You may or may not find something
24:34nice like this is carcinoma in site 2.
24:37And so if you take a tumor that's
24:40basaloid reduplicated membrane
24:42material that is very neurotrophic,
24:45the thought might be an anoid
24:48cystic carcinoma,
24:49but you can see that in
24:52basaloid squamous cancers.
24:53So these are like the non keratin cancers,
24:59CK56P40P63 positive,
25:00neuroendocrine markers negative and
25:02if it's related to HPV it will be P16
25:06positive and HPV insight 2 positive.
25:10It is important to recognize
25:12the presence or absence of HPV.
25:15Your pharyngeal ones are
25:16strongly associated with it.
25:18The non pharyngeal ones are typically not,
25:21but every now and then can be.
25:23The ones that are HPV associated
25:26have a much better overall prognosis.
25:29So if you're ever confronted with this,
25:31if you do have neck pathology
25:34irrespective of location,
25:35it's always important to exclude the
25:37possibility then it might be HPV related
25:40because it directly relates to prognosis.
25:43Is a nice paper by Bill Westra
25:47showing the significant difference
25:50in survival whether it's HPV positive
25:53or HPV negative and and I just get
25:56ahead a little bit ahead of myself.
25:58P6 clean alone is not diagnostic for
26:01HPV for the presence of HPV virus.
26:05So you need we need to be careful
26:09about using P16 just to complete this
26:11story based Lloyd's claim is here's
26:13an example where there is what looks
26:15like we duplicated base membrane material,
26:17there is necrosis,
26:18there is nuclear pleadomorphism.
26:20Generally that's unusual and anoid
26:22cystic but it can occur so this might
26:25engender consideration And then the
26:27tumor is diffusely Sox 10 positive.
26:30So the tox 10 if you're not familiar
26:32is an excellent myopathelial marker.
26:35Anoid cystic carcinoma is predominantly
26:38A myopathelial derived tumor.
26:40So if you see this and you do a Sox 10,
26:43the natural thought could be it's
26:45an anoid cystic cancer.
26:47Well,
26:47we need to be aware that Sox 10 can
26:51be seen and is seen consistently
26:53in basaloid squamous cancer.
26:55Why is that important?
26:55We want to make the right diagnosis.
26:57So if you think about that then you
26:59reflex the HPV and it's positive the
27:02patient potentially has a better
27:04overall prognosis.
27:05The last of this group of morphologies
27:08that I wanted to show is the
27:11endosquamous or ciliated.
27:12You know,
27:12when I was training and for many
27:15years after we were taught,
27:17anything that's ciliated is benign.
27:18So we know that's not true anymore.
27:20So if you look at the left panel,
27:22there's a separation on the extreme
27:24left of a glandular lesion and on the
27:27right non glandular but more solid.
27:29This that is a combined ananosquamous
27:32and on the right I don't know how well
27:34IT projects, but there's a basaloid,
27:37malignant basaloid component both in
27:40the this area more solid and this is
27:42the it's a little bit cystic there,
27:45but this one has the cilia.
27:46So that's the ciliated ananosquamous
27:50and I don't know how well IT projects
27:53to P16 highlights the cilia and
27:56these can be occult primaries,
27:59metastatic in the neck.
28:00So if you're not aware of this
28:02morphology and you see this,
28:04you might think you know this
28:05is not an HPV related cancer.
28:07But if you did the HPV in site too,
28:09it would be positive neurendocrine
28:12carcinomas and that terminology
28:13only includes small cell and
28:16large cell.
28:16It's not a neurendocrine tumor.
28:18So neurendocrine carcinoma and
28:20attempt to classify these across
28:23the spectrum of organ sites.
28:25Neurendocrine carcinoma speaks to small cell,
28:27large cell in the head and neck
28:30particularly there is a subset that
28:32are HPV related and there's about four
28:34articles in the literature collating them.
28:36There's about 19 cases you know.
28:38Many of them when the primaries
28:40identified is in the tonsil,
28:42the base of the tongue, many of them
28:45presented as occult primaries in the neck.
28:47It's important to recognize these
28:50has got a high mortality rate.
28:53So unlike any other HPV related cancer,
28:57this is the exception to the rule
28:59in terms of being radio responsive
29:01and having a better prognosis.
29:03So irrespective of the presence of the virus,
29:06these are bad actors and I'll try to
29:10explain why that is in a little bit.
29:12So just some examples of that submucosal
29:14tumor with trabecular growth,
29:16it has some of the growth pattern of
29:18a neuroendocrine tumor on the right.
29:19The small round cell malignancy that that
29:23will be part of a broad differential
29:26with individual cell necrosis,
29:28cytocarinate, not CK 5-6 but Cam 5.2.
29:31I don't know how well IT projects.
29:33It's usually a paranuclear dot
29:35like staining pattern,
29:36synaptifies and cormoran and insm
29:391 positive and the the markers
29:42that are associated with the non
29:44Karanisin carcinoma are negative.
29:46Now in some of these reports
29:48there was a commingling of the
29:50non karatinizing with squamous
29:51differentiation and the NOR endocrine.
29:54So in those reports,
29:55there was a mixture of cells that
29:57were CK56 and P40P63 positive
30:00and others that were not.
30:04And here's an example of that tumor
30:07showing P16 and the HPV positive.
30:09So why is it that those tumors that are
30:13HPV positive tend to be radio sensitive,
30:16whereas the independent ones that
30:18include neuroendocrine tumors are not.
30:21So it relates to the cell cycle and where
30:23in the cell cycle those tumor cells are
30:26in terms of their radio sensitivity.
30:28So in this quadrant in the M phase
30:31or mitotic phase are the cells
30:33of the HPV related cancer,
30:35their chromatin is condensed,
30:38they're more targetable.
30:39There's other factors related in this
30:42in terms of microenvironment and P53,
30:45but in simplistic terms because
30:47they're in the M phase and their
30:50chromatin is condensed and made,
30:52the more targetable and
30:54responsive to radiation.
30:55Conversely in the S phase or synthesis
30:58phase are the non for the HPV
31:01independent and neurentocrine cancers,
31:03their chromatin is more widely dispersed,
31:05less amenable to targetable by by
31:09radiation and and therefore that
31:12in part explains the differential
31:14in terms of response to treatment.
31:18So even if the neurentocrine has HPV,
31:20it still falls within this S phase
31:23and is less of a targetable agent.
31:26OK,
31:26shifting gears almost back to
31:29basic Histology.
31:31This is the reticulated epithelium.
31:33Can't see it at this magnification,
31:35but here is the surface squamous
31:38epithelium and it's a transition zone,
31:40not unlike the transition zone
31:42in the urban cervix,
31:44except the transition here is to this
31:48reticulated epithelium and former
31:50terminologies or lympho epithelium.
31:53This you don't see,
31:54and I didn't have a higher magnification,
31:57but the cohesiveness and
32:01intercellular connections,
32:02desmosomes that you see in the
32:05surface epithelium are completely
32:06gone in this reticulated epithelium.
32:09That's why it's more permeated
32:11by lymphocytes,
32:12plasma cells and antigen processing
32:15cells and just to show you that.
32:17And then these are diffusely
32:19carried and positive.
32:21So why is this epithelium and this
32:25location the target area for HPV?
32:28So there are many theories.
32:29One is the permeability of this epithelium
32:32makes it more susceptible to infection.
32:36Some people claim that the deep
32:38and vagination of the ***** make
32:40it a excellent reservoir for HPV,
32:43and that's probably true.
32:45But arguably the most important
32:46thing is immunity.
32:48This epithelium is PDL 1 positive.
32:52The presence of PDL 1 suppresses
32:54T cell response,
32:55which in turn allows for persistence
32:58of HPV and allowing for the HPV and
33:02the immortalization of cells to cancers
33:05to be under evade immune surveillance.
33:09So it's a combination of regions,
33:12but likely the most cogent one is this,
33:15you know,
33:16the PDL one and the immune suppression.
33:19This very nice paper by Bill Westra.
33:21If you don't follow the literature,
33:23you know Bill is one of the
33:26original authors on many
33:28papers of of identifying HPV,
33:30including the very first one that
33:32showed A cause and effect between
33:34the can't the virus and cancer.
33:36But this is a nice diagram diagrammatic
33:39depiction of this reticulated epithelium.
33:42There's a loss,
33:43there's no intercellular connections,
33:45It's very permeable.
33:46You can see even in this diagram
33:49the lymphocytes and antigen processing cells.
33:52The other component of this is
33:53the fact that in this epithelium,
33:55unlike other epithelium,
33:57there are lymphatics and vascular spaces.
34:00So when you see a tumor that looks like this,
34:02that's completely what we might in term
34:05carcinoma in site 2 with no violation
34:07of the base membrane because of that
34:09permeability and because of the intra
34:12epithelial lymphatics and vascular spaces.
34:14This could be the solnitis for the
34:17cancer that gives rise to metastasis,
34:19very tiny primary,
34:21multiple neck nodes.
34:23And in that original graph I showed
34:26between comparing and contrasting
34:28HPV positive HPV negative,
34:30the HPV positive cancers tend to be
34:32smaller tumors with a higher end stage,
34:35many more positive nodes.
34:39So relative to this epithelium,
34:42which as far as I know is unique in the body,
34:45we never applied the term carcinoma.
34:47Insight to how often do you see a tumor
34:49that's relegated to what we might
34:51consider the the insight to component.
34:53It's uncommon,
34:54but you can put the whole tonsil through
34:56and this might be the only nitus,
34:58but that's the primary focus for
35:01the metastatic cancer because of
35:03the nature of that epithelial.
35:04So cap guidelines for HP for P16 testing,
35:10these were published in 2018.
35:12They're currently undergoing A revision.
35:15I'm not sure when they're going
35:16to be published,
35:17but probably sometime either late this year,
35:20which is only another month or so or 2024.
35:24But most of the criteria are
35:27still applicable and the most
35:29important one arguably is the P16.
35:31Yes, it's an excellent screening tool.
35:34It needs to be nuclear inside
35:36a plasmic in at least 70%.
35:38So what's 69% and what I mean I personally
35:42have a hard time trying to quantitate,
35:45you know P67,
35:47you know digital pathology and and you
35:49know what will be helpful in that.
35:51But the point being it's got
35:53to be the majority of cells,
35:54nuclear and cytoplasm.
35:57So P16 is a tumor suppressor gene.
36:00When it binds to CDK 4/6,
36:03it keeps cycling the one in check,
36:06which in turn keeps retinoblastoma
36:09in its hypophosphorylated state,
36:11which in conjunction with this transcription
36:14factor leads to cell cycle arrest.
36:17And the reason I'm showing you
36:19is I'm not a basic scientist but
36:22explains P16 overexpression.
36:24So anything that alters retinoblastoma
36:27in here it's hyperphosphilated
36:29releases that block and so at
36:31least the cell cycle progression.
36:33There's an inverse relationship between
36:37P16 and P53P53 in its normal state,
36:40low or no P16 overexpression
36:43retinoblastoma in its abnormal
36:45state increase PP 16 expression.
36:50So getting a little bit ahead of myself,
36:52anything that alters retinoblastoma
36:54will lead to increase in P16 as we
36:58identify immunistic chemical that
37:00doesn't mean there's a virus there and
37:03that means that P16 cannot in and of
37:06itself depending on what you're looking at,
37:08be the arbiter in terms
37:10of being HPV positive.
37:12And here's one example.
37:13I'll just start at the top part,
37:15the A.
37:16So the oncogenic stress on the left is
37:18the virus you know impacts on P16
37:21through retinoblastoma and P53
37:23leads to over expression of P16.
37:26In another schematic you could see
37:28that the virus infects the cells,
37:31makes its way into nucleus.
37:32Impacts on E6 and E7E7 directly on
37:37retinoblastoma increased in P16.
37:40But E 6 is not just there and
37:43doesn't have a negative impact.
37:45It impacts on P53 and also on maintaining
37:49telomerase activity in the infected cell,
37:52which keeps telomerase length intact,
37:56which allows for immortalization of the cell.
37:59So both retinoblastoma the E7 and
38:02the E6 by different mechanisms lead
38:05to immortalization of the cell.
38:08So back to P16. It's widely available.
38:11It's easy to interpret.
38:13It is considered a surrogate
38:16marker for HPV 16.
38:18We can do it on psychology,
38:21we can do it on tissue,
38:23and it is considered reliable
38:25but not uniformly predictor of a
38:28carcinoma rising in the oropharynx.
38:31So I don't think anybody,
38:32if you're a pathologist and
38:34there's no brown stain,
38:35would think that's a positive stain.
38:36It's a dead negative stain.
38:40I'm sure in this group you
38:41would not call that positive,
38:42but there are people who see any
38:47staining and we'll call it P16 positive,
38:50seen that in in patient review cases.
38:53And I'm not denigrating anybody,
38:55it's just not understanding
38:56of that the interpretation.
38:58So we need to be very rigid not
39:00only in our diagnostic criteria
39:02but our interpretation.
39:03So this is a blush.
39:05It's not a positive stain.
39:08That's a positive stain.
39:11That's not a positive statement, right.
39:13It's kind of positive, but not strongly.
39:16There's some nuclear,
39:17not cytoplasmic and some
39:19cells are not positive.
39:20So you might call that equivocal
39:22because it's not that negative or blush,
39:24but it's not positive.
39:26That's the kind of scenario where
39:28you need to confirm with something
39:31more sensitive and specific.
39:32And you've seen this before,
39:34but I just want to point to the bottom here.
39:36This E6 and E7 we target by immuno,
39:39by insight to hybridization that's the
39:42gold standard in in a tumor not the P16.
39:47And the reason I mentioned that I
39:49would just to show you there's AP 16,
39:50you've seen this before.
39:53Before I go you to the illustration,
39:55the bottom B part is an oncogenic
39:59stress that's not HPV related
40:02that has altered retinoblastoma.
40:04And has led to P16.
40:07So it's not HPV related.
40:09And the reason I point that out,
40:11these cases actually happen.
40:12So this is a Periparadid level 2,
40:15a typical location for an
40:18oropharyngeal cancer to metastasize to.
40:20It looks here's the parotid and
40:23primary squamous cancers of the
40:25parotid are extraordinarily rare.
40:27If you ever have a case like that
40:30it's likely a cutaneous cancer
40:31directly invading the parotid.
40:33Or the patient had a history of a
40:35had an ex famous cancer somewhere
40:37on the face that's now metastatic.
40:39So if you remember that thinking about
40:42a primary, you know, becomes challenging.
40:44Do they occur?
40:45Yeah.
40:46But you really need to see good evidence of
40:48that. Now here's the parotid,
40:49There are many intra and
40:51periparatal lymph nodes.
40:52They do drain the pharynx and you
40:55have a non caranoisin cancer and
40:57this thing is diffusely P16 positive.
40:59So you tell the tell the clinician or
41:03radiation oncologist you have a metastatic
41:06orpharyngeal P16 positive cancer.
41:09They tell the patient,
41:10they start you know setting the
41:13patient up for targeted therapy
41:15except that the HPV is dead negative.
41:17So this points out what I've been
41:20trying diagrammatically to show.
41:21P16 can be over expressed in the
41:25absence of virus and about 20 to
41:2830% of cutaneous squamous cancers.
41:30But this is not the only one
41:32can be P16 positive.
41:33So really the gold standard and we've
41:36moved to doing every single case,
41:39even conventional ones with P16
41:41and insight and certainly in the
41:44presence of a cold metastatic
41:45cancer with no known primer,
41:47you can't rely solely on the P16 and
41:49it has to be backed up by the insight
41:52to and in fact I don't even do P16,
41:55I go right to the insight to
41:56because that's where the money is.
41:58So that's negative.
41:59I don't care what the P16 look like.
42:04What about psychology?
42:05Do the same guidelines that
42:0870% apply to cytology?
42:10And the simple answer is no,
42:12there are no guidelines.
42:13So here this cell block,
42:15you know these tumors could be this
42:17occult metastatic in the neck,
42:18no known primary, they're P16.
42:22How do you interpret P16?
42:24You interpret it just on
42:25the cells that you have,
42:26we don't have the entire lesion.
42:28So what's 70% and what is
42:3070% mean in this context?
42:32And it's very challenging and
42:34this is where you know the insight
42:36to becomes critical because
42:37if you have limited material,
42:40you know let's just say 1010 cells
42:42that are diagnostic in a cluster,
42:44you know and they're positive
42:46or they're negative,
42:46it doesn't mean that there's
42:49not HPV there because they may
42:51be very gated response to P16,
42:54you know and the insight to HPV
42:56could be done on limited material.
42:58And as long as you find a single
43:00grain and they're more here,
43:02it becomes diagnostic or or positive
43:05for insight to HPV and diagnostic
43:08for an HPV related cancer. OK.
43:12We shift gears to the nasal pharynx,
43:15and I know conceptually we all
43:17know where the nasal pharynx is,
43:19but aside from being somewhere
43:20in the back of the throat,
43:22it actually has to find anatomic location.
43:25You know it it borders or butts
43:28up to the base of the skull.
43:31So cancers originating of nasal pharynx,
43:33particularly keratinizing,
43:34often kind of invade towards the base
43:37of the skull and then they become incurable.
43:41It's got a virtual floor in the uvula,
43:43so only when we swallow does
43:45it have an actual floor.
43:46The interior is the opening
43:48to the nasal cavity.
43:50I just want to point out the lateral
43:52wall where most nasopharyngeal
43:54carcinomas develop.
43:55It's the opening of the Eustachian too.
43:58And cancers in this location for
44:01some reason like this area that
44:04there's a rage raised cartilaginous
44:07plate that's posterior to the
44:09opening in the Eustachian tube
44:10Cancers like to originate.
44:12Behind that there's an indentation
44:15called fossil Rosenmuel.
44:16It tends to push the Eustachian to forward,
44:20shuts off the the opening to the ear canal.
44:23So anecdotally,
44:24unilateral otitis medium
44:26responsive to antibiotic therapy,
44:28is nasopharyngeal carcinoma.
44:29For this reason.
44:31So tiny cancer puts the station forward.
44:34Wonderful milieu for infection,
44:36except there's no infection,
44:39but there's otitis media
44:41unresponsive to antibiotic therapy.
44:44So the classification of nasopharyngeal
44:47carcinoma now is 2 broad categories,
44:50not 3 keratinizing,
44:52well moderately poorly
44:54differentiated and non keratinizing,
44:56which used to be divided up
44:58in WHO two and three.
45:00Now it's one differentiated used to
45:04be called transitional carcinoma
45:06and undifferentiated used to
45:09be called lymphobothelioma.
45:11Those two morphologies can be
45:15identical to HPV related cancers
45:18and there is a basaloid squamous
45:20carcinoma that of the nasopharynx
45:22that can be EBV positive.
45:24So just you know compare and contrast chart,
45:27you could see that the keratinizing
45:30which is weakly associated with
45:32EBV which makes it not radio
45:34responsive has the worst
45:35prognosis but the best terminology
45:37well differentiated keratinase,
45:39squamous carcinoma sounds like a
45:40tumor that's going to do better
45:43than an undifferentiated carcinoma
45:44except that the non caratizing and
45:47undifferentiated strong association
45:49with EBV are radio responsive have
45:51a better five year survival rate.
45:53So we've gone through caratizing,
45:55I need to show you but there's
45:57this is a dead ringer for a non
45:59caratizing carcinoma and oropharynx.
46:01It's a non carat nasal pharyngeal
46:03carcinoma and non caratizing
46:05differentiated it'd be keratin positive,
46:08P40P63 positive.
46:09Nerner can markers negative but
46:12HPV negative and Eber Epstein
46:15Barr encoded RNA positive.
46:19So those are easy to identify.
46:21The less distinguishable if you will,
46:25tumor type is the undifferentiated
46:28and both of these do not elicit
46:30a decimal plastic response.
46:32But in this panel you could see the
46:34clusters of cells and higher magnification,
46:36large nuclei, vesicular coma and
46:39prominent nucleoli but very cohesive.
46:42But if they sheet out like you see here
46:44which may not be identifiable readily,
46:46looks like a histiocytic response.
46:48But here where they become more obvious
46:50because they're more clustered.
46:52The differential includes lymphoma
46:54and Melanoma. So you know,
46:56in anyone case you might think it's cohesive,
46:58it's not, it's got to be carcinoma.
47:01But I've seen cohesive lesions prove
47:02to be Melanoma or even lymphoma.
47:04In the most common lymphoma this
47:07location is the diffuse large B cell.
47:10These are Carrot MP 63 and Ebro positive.
47:12So that blocks in the diagnosis.
47:15The basaloid is a rare tumor type.
47:19I have to have one a couple months ago,
47:21so I thought I'd share it.
47:22You know, relatively typical nasaloid,
47:26squamous carcinoma, morphology,
47:28keratin, P63,
47:29Sox 10 as I showed you before
47:32and Ebro positive.
47:33But if I'm looking at this,
47:35even if the clinician swears up and down,
47:37it's nasal pharynx that's just
47:39next to the oral pharynx.
47:41So it might be extending back.
47:42So it's always important to probably
47:44not probably to do HPV to exclude the
47:48possibility that this is HPV and not EBV.
47:52The cold metastatic cancers in the neck.
47:54There's a topographic anatomy on the left.
47:57The diagram on the right is from Leon
48:00Barnes 3 tone Bible on Hananic Pathology.
48:03Unfortunately Doctor Barnes
48:04passed away a few years ago.
48:06He had retired years ago.
48:08So I think this is a 2010 was the 3rd
48:10edition, maybe a little bit later.
48:12But you could see,
48:14you know the the,
48:15the point of the images that there is
48:18often dedicated drainage from ukosocytes
48:20of the head and neck to site specific
48:23topographic anatomy of lymph nodes.
48:25That's why we need to bug our
48:27clinical colleagues to say
48:29where in the neck is dislocated.
48:31Because if I know it's level 6,
48:33I'm thinking thyroid.
48:34If it's super clavicular,
48:35I'm thinking something below the diaphragm
48:39thorax or AB Mario Luna who also passed.
48:44I don't know if that name means anything.
48:45One of the godfathers of head and neck
48:47pathology along with Doctor Barnes,
48:49Back, Doctor Beth Sackins and Dr.
48:50Himes.
48:51This is his chapter in Doctor
48:53Barnes book 2009.
48:54If you look at the OR,
48:56what he did was meta analysis showing
49:00that the most common morphologic
49:02subtype of occult metastatic cancer,
49:05this is the cervical neck,
49:07is a squamous carcinoma.
49:09And when they identified literature,
49:12the primary there was most often from what
49:15we call Waldorf's tonsil ring oropharynx,
49:18base of tongue Palatine tonsil,
49:21nasopharyngeal tonsil,
49:22otherwise known as the adenoids and the
49:27identification of a primary was about 30%.
49:31That's here.
49:32So the primary detected in about 30%
49:34of these cold metastatic cancers,
49:36at least according to this meta analysis,
49:39most of them above the clavicle
49:41but some below the clavicle.
49:43So you have in the literature evidence
49:46that the primary was never identified.
49:49In all these cases, we know it
49:51originates in the Waldorf's tonsil.
49:54So these are metastatic
49:56carcinoma of unknown primary.
49:58These are clinically and
50:01radiographically obvious cancers,
50:03proven by biopsy or cytology.
50:06No history or previous malignancy,
50:08no history of any site specific,
50:11no clinical laboratory evidence of
50:13a primary and that can engender the
50:16consideration of a brachiogenic
50:18carcinoma whose criteria were
50:20defined in 1950 and haven't changed.
50:22Except that we don't believe this.
50:25I mean, I was taught that at
50:27a FIPI drank that kool-aid.
50:28I have never made that diagnosis.
50:31If you see something in the
50:32neck that's malignant,
50:33it's metastatic cancer and not
50:35arising from a brachioclepsis even
50:38if it fits all these criteria.
50:41So brachioclepsis,
50:42you know they have a bimodal
50:45age distribution.
50:46They overlap the majority with
50:48the typical demographics of an
50:50HPV related carcinoma.
50:52If you're thinking about making that
50:55diagnosis in somebody who's over 40 years,
50:58only about 5% of branchioclepsis
51:00arise in that.
51:02So you need to be a little bit
51:03wary and pay attention to age.
51:05When you have one of these lesions in,
51:06that doesn't mean it can't occur,
51:08but you know,
51:09we need to be careful about that.
51:11Here are examples of of infected
51:14or inflamed branchioclepsis,
51:16benign epithelium.
51:17You know,
51:18maybe there's a blush here and a blush here,
51:20but typically P16 negative.
51:22This is another case, a real case.
51:26You can see the epithelium is attenuated.
51:28It's not really overtly malignant,
51:31but it was diffusely P16 positive.
51:34But these are typically uniformly
51:36HPV negative.
51:38So if you're thinking about making a
51:41diagnosis of a branchial Clef cyst with P16,
51:45you still can do it,
51:46but you need to reflex to insight
51:48to the make sure there's no HPV.
51:50I've seen cases, believe it or not,
51:52with really bland morphology and then
51:54we put the whole lesion through,
51:57there was no overtly subtologic
51:59malignancy that had HPV.
52:02So these HPV, the more I see them,
52:05the less I understand,
52:07You know,
52:07This is why we like to do a
52:09lot of stains to try to help us
52:11define what these are and further
52:12understand what's going on.
52:13There is literature that supports,
52:16you know,
52:17branchioclepsis with HPV and those
52:19with not the majority or not and and
52:22as we're standing here talking about
52:24this branchial clepsis are not HPV related.
52:26So if you find HPV,
52:28you know even unfortunately if
52:30there's no bland Histology and
52:32had a case about a year ago,
52:34we're compelled to call it carcinoma,
52:35metastatic carcinoma.
52:37So before I end I just wanted to share,
52:39I saw it with a case history.
52:41I want to end with a case history
52:4339 year old female enlarging
52:45right sided neck mass level 2A,
52:47no known history.
52:48I don't know if an FNA was done probably
52:53that's usually the first diagnostic modality
52:56here you can just show or show before.
52:58And as we get to higher magnification
53:00you can appreciate that there's
53:01a little bit of lymph node.
53:03But most of it is a face and it's
53:05replaced by this sheet like diffuse
53:08cell morphology with enlarged nuclei,
53:10vesicular chrominent and prominent nucleoli.
53:13This is a dead ringer for
53:16nasopharyngeal carcinoma,
53:17non carbonizing undifferentiated type.
53:19Then keratin and P63 is positive
53:23but the Eber is negative.
53:25And I just this is part of the rationale
53:28for showing you the morphologic spectrum.
53:31P16 was diffusely positive,
53:32a more important HPP was positive.
53:34So you have a tumor that looks like
53:37nasopharyngeal cancer that if it was Eber
53:39positive would be nasopharyngeal carcinoma.
53:41The nasopharynx is a different anatomic
53:43location to target by radiation.
53:45So it's important to separate
53:46it out from oral pharynx.
53:48It's Eber negative,
53:49so you know you need if you're doing this.
53:52If you're a psychologist and
53:53you have a case like this,
53:55just remember, you know,
53:56don't get stuck on a particular diagnosis.
54:00You do the Ebert's negative,
54:01you can reflex, you should reflex the HPV.
54:04So this is an HPV associated
54:08lymphopelial carcinoma.
54:09The patient did have tonsil removed
54:11and just these images show the
54:14primary which is identical to the
54:16metastasis with the P16 and HPV.
54:19So the morphologic lesions overlap.
54:21So to conclude,
54:23undoubtedly viruses cause
54:26cancer and neck cancers.
54:29Depending on the location,
54:31whatever terminology you use,
54:33just be consistent.
54:34So The Who recommends squamous carcinoma,
54:37HPV positive and EV positive.
54:40But if you prefer different terminology,
54:43always use that terminology.
54:45So our clinical colleagues are aware
54:47they may and often present as a cold
54:49primary for the reasons I show you.
54:51So tiny primary multiple net
54:54metastases that can be large,
54:56so small tumors give rise to
54:59large metastatic cancers.
55:00For the reason I mentioned,
55:01there's no such animal as carcinoma
55:03insight to relative to the oropharynx.
55:05That's because of the unique Histology
55:07of the reticulated epithelium,
55:09the grading.
55:10These are differentiated cancers,
55:11so stay away from poorly differentiated
55:14and certainly in synoptic reporting the
55:17the correct check mark is not applicable.
55:20Lesions that morphologically
55:21look like carcinoma site to may
55:24metastasize because of the epithelium.
55:26It has a broad morphologic spectrum.
55:28Ancillary testing is critical.
55:30The SP 16 is a good Screener but
55:32it needs to be backed up by insight
55:35to for the reason I mentioned.
55:37If these viral related cancers have
55:40overall better prognosis than non viral
55:42with the exception of neuroendocrine
55:45cancer and the the recommendation if
55:47you make a diagnosis of neuroendocrine
55:48carcinoma you do not need to cap
55:51recommendation to reflex to HPV.
55:54But if you're uncertain to diagnosis
55:56and it's part of your immuno
55:58your work up and you've gotten
55:59it at the initial testing,
56:01you may get that stain back but it
56:04doesn't positively impact survival.
56:07I showed you the overlapping
56:09morphologies with HPV and EBV,
56:11so unknown primary with
56:13particular morphology you might
56:14order at the same time HPV and Eber testing,
56:18there's no correlation to the small size
56:21in the large metastasis and that occult
56:23primary even when the tonsil comes out.
56:25And I can assure you haven't
56:27looked at a lot of tonsillectomies,
56:29takes a lot of time to look because that
56:32primary can be at one slide in one focus.
56:34P16 is helpful then because it'll light
56:36it up at least it'll point you in the
56:39right direction and that all confers
56:41different stagings according to the AJCC.
56:43So the 8th edition now has
56:46two or pharyngeal ones,
56:47HPV related HPV independent dedicated
56:50nasopharyngeal one and now there's
56:53a a separate classification for
56:55metastatic cancers of unknown primary.
56:58Before I conclude,
56:59I just want to share some of the things
57:02are on the horizon, liquid biopsy,
57:05so NAV DX which is a proprietary company,
57:09I'm not sure anybody clinically is using
57:12it here are they do you know they are OK,
57:15so you're ahead of the game for us.
57:17So that is going to become
57:19probably standard of care.
57:21You know, it assists.
57:22It looks at circulating tumor cells or HPV,
57:24you know just listed here early cancer
57:27detection confirms HPV genotype.
57:30You can assess tumor response,
57:33identify residual disease
57:35and detect early recurrence.
57:37And I just took this off their website.
57:38So you've probably seen this before.
57:40It's an easily interpreted graph
57:42that they provide and what always
57:45comes up are HPV vaccinations.
57:47And yes,
57:48the quadrivalent vaccine began was initiated
57:51in girls I think in 2006 and in boys in 2011.
57:57Does that impact on prevention?
57:59We don't know at this point.
58:02So the epidemiology remains to be determined.
58:05So this is ongoing.
58:06And with that,
58:07I thank you.
58:07Thank you for the invitation to be here.
58:09I'd be happy to take any questions
58:19and I finished on time.
58:30So the question is,
58:31have I ever seen HPV positive cancer
58:33that was P16 negative? Yes, I have.
58:36That's why we do both together because
58:39I learned the valuable lesson.
58:41I also learned the lesson.
58:43You know, my immediate response to
58:46a clinician telling me to do P16 on
58:50intrapacial dysplastic lesion that
58:52has nothing to do with HPV is no,
58:55I'm not going to do that.
58:56Why am I going to do that?
58:57I mean, I'd say it kindly to them, right?
58:59I explain what's the rationale,
59:01how you going to treat that differently?
59:02They're not HPV, but I've been fooled,
59:06so I don't do it in every case.
59:07In particular,
59:08I have two cases of young people of
59:11invasive Karyn Eisen squams cancers,
59:14the larynx,
59:15they're HPV positive and I
59:16don't know they were P16.
59:18But to go back to your question,
59:20rarely one or two cases P16
59:23navigative HPV positive and because
59:26of that we we run both together.
59:28Have you seen
59:29one? I don't
59:33believe
59:43so. OK.
59:46So I would suggest if it's it looks HPV
59:49and it's in the neck P16 negative and E,
59:57yes, so,
01:00:08so you get a tonsil biopsy,
01:00:13you don't see
01:00:16it. Yeah, absolutely.
01:00:19So, and that's what I was referring to so.
01:00:22A patient with a neck mask
01:00:23to do a tonsillectomy,
01:00:24you put the whole thing through and
01:00:26there's nothing really that screams cancer.
01:00:29So I'm not going to do it on 20 slides,
01:00:31but in going through that I might find more,
01:00:34so I didn't compare and contrast.
01:00:36So the reticulated epithelium
01:00:37is usually not cohesive.
01:00:39It can be cohesive at times,
01:00:41but it's very low NC ratio
01:00:43and not hypochromatic.
01:00:44So if I see something that's
01:00:45more even a tiny nest and there's
01:00:47nucleoplemorphism in hypochromatia
01:00:49and I'm not convinced, yes,
01:00:51I will do AP16 and if that's positive,
01:00:55that's your primary.
01:00:55But I would like to back it up with insight.
01:01:03I don't see any chat questions.
01:01:06So thank you for your time.
01:01:16Chad, questions.
01:01:19Yes. Yeah, I have one to ask.
01:01:22Are you there? Yeah, I'm here,
01:01:24but I can't hear you.
01:01:27The question is, can
01:01:30HPV be transmitted mouth to mouth by kissing?
01:01:35Did anybody understand that?
01:01:45You should look at the chat if you can.
01:01:50So the question is, can HPV transmitted
01:01:52mouth to mouth so low risk can.
01:01:56I don't know about high risk, I I don't
01:02:01you know, maybe you can through saliva.
01:02:03So it's certainly a possibility,
01:02:05but I don't have an absolute answer for that.
01:02:19Oh, thank you.