Human Papillomavirus (HPV)

A DNA virus that may cause cutaneous warts, genital warts, or the clinical condition recurrent respiratory papillomatosis (RRP) in susceptible individuals. Human papillomavirus (HPV) may occur in as many as 150 or more subtypes. The most common subtypes seen in patients with RRP are HPV 6 and 11. Other less common subtypes that can induce papillomas or other growths within the larynx include HPV 16, 18, 31, 44, 45, 55, 69, 84 & 11, 33 & 45 and some of these subtypes are associated with a higher risk of cancer formation. See the photo series below, displaying all of the subtypes mentioned above.

Common Questions About HPV

Q:  What is the relationship between the terms RRP, HPV, and Papilloma?

A:  The underlying disorder is HPV (human papilloma virus) infection of the airway, especially the larynx.  The virus “sets up house” chronically inside airway and stimulates a kind of proliferation called papillomas, or papillomatosis. Because these lesions tend to recur after surgical removal, the clinical syndrome has become referred to as recurrent respiratory papillomatosis (RRP).

Q:  HPV apparently has different subtypes.  What can you tell me about them?

A:  Human papilloma virus infection can consist of as many as 150 different subtypes.  Some are related to skin infection (causing warts).  Some are more common in genital or respiratory sites. Genital lesions are typically called condylomata, or genital warts.  In the airway, the lesions are typically called papillomas. Commonest subtypes in the airway are types 6 and 11. These two subtypes comprise the vast majority of our patients at Bastian Voice Institute (BVI). We have patients who have also tested positive for types 16, 18, 45, 55, and a few others.

Q:  I have a low-risk subtype of HPV.  Can you explain what this means?

A: The human papilloma virus (HPV) comes in 150 or more subtypes. Think of it like the many models of automobiles that all fall under the designation “Ford.”  Subtypes found most often in the respiratory and genital tracts are 6 and 11. HPV infection is associated with some degree of risk of stimulating, or converting to, a carcinoma.  Hence the higher risk of cervical cancer in women with HPV infection.  Some subtypes are considered to have a low risk of viral carcinogenesis; others have a high risk. At BVI, the majority of our many adult patients have 6 or 11, both of which are low-risk subtypes.  We also have one or two who have both 6 and 11.  Then we have a handful of patients with intermediate or high risk for cancer.  A few of these high-risk subtypes have in fact caused cancers in our population of ~150 adult patients with RRP. Thankfully, all have responded well to treatment and none to my memory have died from their cancer.


Photos:

Subtype 6

More common subtype seen in the airway. HPV 6 is associated with a lesser risk of cancer formation, as is HPV 11.

Papillomas, HPV subtype 6, before and after removal

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Papillomas: HPV Subtype 6 (1 of 4)

Papilloma, left vocal cord (right of image), standard light. Voice is grossly hoarse. This patient has HPV subtype 6.

Papillomas: HPV Subtype 6 (2 of 4)

Same lesion, under narrow band illumination.

Papillomas, removed: HPV Subtype 6 (3 of 4)

After removal and cidofovir injection, normalized larynx. Voice is normal.

Papillomas, removed: HPV Subtype 6 (4 of 4)

Same view, under narrow band illumination.

Subtle papillomas, HPV subtype 6

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Subtle papillomas, HPV subtype 6 (1 of 3)

After achieving a normal voice through several procedures, the patient came in for reexamination due to the return of mild huskiness. This distant panoramic view with standard illumination does not reveal any obvious papillomas.

Subtle papillomas, HPV subtype 6 (2 of 3)

At close range, using narrow band illumination, a subtle but definite HPV effect is seen. Notice the stippled vascular markings and the faintly increased pinkness at the margins of the cords, indicated by dotted lines.

Subtle papillomas, HPV subtype 6 (3 of 3)

With the vocal cords now at the pre-phonatory instant, these low-profile HPV-related papillomas are again seen, indicated by dotted lines.

Subtle papillomas and the importance of a motivated examination

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Standard light, HPV-6 infection (1 of 4)

Breathing position, standard light in a young woman with longstanding HPV-6 infection. Voice remains quite good, many months after her last microsurgery with cidofovir injection. The only obvious “lesion” is posterior right cord (left of image) but the characteristic punctate vascular marks are not seen. The black lines are purely for use to orient photo 4.

Stobe light, vocal cord margin irregularity (2 of 4)

With such a clear voice, this prephonatory instant under strobe light reveals a surprising degree of vocal cord margin “serpentine” irregularity. Black lines again support orientation with photo 4.

Narrow band light, vascular marks seen (3 of 4)

At very close range and also using narrow band light, the tiny punctate vascular marks are seen in the lesion first seen in photo 1. Faint vascularity like that demonstrated here can be a correlate of relatively stable, inactive disease, which has clinically been the case here.

Narrow band light, papilloma formation (4 of 4)

This narrow band view includes only the anterior half of the vocal cords from the black lines of photos 1 and 2 to the anterior commissure (at x). Inside the faint circles, note the vascular markings that suggest papilloma formation to explain the serpentine margin.

HPV Vascular Effect

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Two papillomas (1 of 3)

Approximately one month after removal of papillomas and Avastin injection in a man who has battled aggressively-recurring disease caused by HPV, type 6. In this view using narrow band light, only two small papillomas are visible.

Stippled vascularity (2 of 3)

At closer range, careful inspection shows no papilloma (yet), but only the stippled vascularity typical of HPV infection.

HPV vascular effect (3 of 3)

HPV vascular effect is seen even more clearly.

Type 6 HPV Papillomas Firmer Than Most

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Stippled vascularity not seen (1 of 4)

Diffuse involvement of true and false cords with papilloma caused by HPV 6. After hundreds of procedures from childhood through early adulthood, the stippled vascularity is not extremely evident in this standard-light view.

HPV vascular effect (2 of 4)

At closer range, still under standard light, the characteristic vascularity—what we term “HPV vascular effect”—is only beginning to be evident (arrows).

Vascularity clearly seen (3 of 4)

At still closer range, and now under narrow-band light, stippled vascularity is clearly seen (arrows).

Under narrow-band light (4 of 4)

Even closer view still under narrow-band light: the stippled vascularity is now unmistakable.

HPV 6: Going, Going, Gone?

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“Curative mode” plan (1 of 7)

Known HPV 6-induced laryngeal papillomas, with resulting gross hoarseness. The plan is “curative mode” defined as 3 or more successive, surgical cleanouts with adjuvant injection to see if the disease can be put into remission or at the least “tamed” to less rapid recurrence.

Closer view (2 of 7)

At closer range. Still, the full extent of disease becomes more obvious at the anterior right vocal cord (left of photo at arrow) in the next photo, when viewed under narrow band illumination (NBI).

Narrow-band illumination (3 of 7)

Now under NBI, the right anterior vocal cord (left of photo) involvement is seen clearly.

Post surgery (4 of 7)

A few days after surgical removal using the usual “basement membrane peel” technique of removal and in this case cidofovir injection. Voice is already dramatically improved, the right cord (left of photo) retains vibratory ability, and the grey wound base is seen clearly.

Towards “management mode” (5 of 6)

Voice had been “normal” until recent weeks, and so the patient therefore waited longer than intended for followup surgery, to the point that we are drifting out of “curative mode” and over into “management mode.” Here, under standard light, the disease is not that obvious.

Same view under NBI (6 of 7)

Under NBI at closer range, the carpet of HPV upper surface and one actual papilloma are more evident, but it is still not quite clear why the patient says voice has been getting slightly hoarse.

Stippled vascularity seen (7 of 7)

At closer range, faint HPV-induced vascular stippling is seen along the margin of the right vocal cord (left of photo) within the dotted line, and this explains his subtle and increasing hoarseness. Another surgical cleanout with adjuvant medication is scheduled.

Subtype 11

One of the more common subtypes seen in the airway. HPV 11 is associated with a lesser risk of cancer formation, as well as HPV 6.

Papillomas, HPV Subtype 11, Before and After Removal

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Papillomas: HPV Subtype 11 (1 of 4)

Papillomas at posterior vocal cords, with left side (right of image) much larger than right. This patient has HPV subtype 11.

Papillomas: HPV Subtype 11 (2 of 4)

Closer view, under narrow band illumination, which accentuates the vascular pattern.

Papillomas, removed: HPV Subtype 11 (3 of 4)

Two weeks after microsurgical removal, cidofovir injection, and return of normal voice.

Papillomas, removed: HPV Subtype 11 (4 of 4)

Closer view of left posterior vocal cord, narrow band illumination. Notice that there are a few dot-like vascular marks. These are typical of HPV effect, and may presage recurrence.

Papillomas, HPV subtype 11

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Papillomas: HPV Subtype 11 (1 of 3)

Panoramic view, standard light, shows papillomas on the aryepiglottic cord, false cords, anterior face of arytenoid, and at anterior commissure. This patient has HPV subtype 11.

Papillomas: HPV Subtype 11 (2 of 3)

Closer view, standard light, shows more clearly the papillomas on the anterior face of the right arytenoid and at the anterior commissure.

Papillomas: HPV Subtype 11 (3 of 3)

Still closer view, to see more clearly the anterior commissure papilloma.

Papillomas, HPV subtype 11

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Papillomas: HPV Subtype 11 (1 of 2)

Vocal cords, narrow band light, showing papillomas on the upper surface of the anterior vocal cords. This patient has HPV subtype 11.

Papillomas: HPV Subtype 11 (2 of 2)

Tracheal view, standard light, showing scattered papillomas (arrows). The carina is in the distance.

Subtype 16

Less common in the airway than the more common subtypes 6 and 11. HPV 16 is associated with a higher risk of cancer formation, along with HPV subtypes 18, 31, 45, 55, and others.

Lesions of HPV Subtype 16

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Lesions of HPV Subtype 16 (1 of 3)

Recurring inflammatory and leukoplakic lesions caused by HPV subtype 16. A left vocal cord cancer (right of image) was removed several years earlier, and the patient developed a right vocal cord cancer almost a year later.

Lesions of HPV Subtype 16 (2 of 3)

Slightly magnified view, focusing on the anterior (frontward) ends of the vocal cords. The cords' stippled vascularity, which often accompanies HPV infection, is more apparent here.

Lesions of HPV Subtype 16 (3 of 3)

A similar view to image two, but with narrow-band illumination, which accentuates the vascular pattern. Biopsy/removal of these lesions revealed high-grade dysplasia; re-biopsy almost a year after this examination returned a diagnosis of cancer.

Cancer, HPV Subtype 16, Before and After Radiation

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Cancer: HPV Subtype 16 (1 of 5)

Cancer, in a patient with HPV subtype 16. The divot and blood seen on the left vocal cord (right of image) are the result of a biopsy performed elsewhere (not by BVI physician) earlier the same day as this examination.

Cancer: HPV Subtype 16, after radiation therapy (3 of 5)

Six weeks after the end of radiation therapy, the tumor is no longer seen. However, part of the left cord (right of image) is missing, due to sloughing of the tumor that had eaten away part of the cord’s normal tissue.

Cancer: HPV Subtype 16, after radiation therapy (4 of 5)

Phonation. Strobe light, open phase of vibration, shows that the margin of the left cord (right of image) is at a lower level than the right’s, due to loss of some of the bulk of the cord where the tumor died and sloughed away.

Cancer: HPV Subtype 16, after radiation therapy (5 of 5)

Strobe light, closed phase of vibration. The more normal right cord (left of image) unsuccessfully attempts to reach the left cord’s residual upper surface mucosa. Voice is functional but hoarse.

Subtype 18

This is less common in the airway than the more common subtypes 6 and 11. HPV 18 is associated with a higher risk of cancer formation, along with HPV subtypes 16, 31, 45, 55, and others.

HPV 18—High Risk Subtype

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Papillomas seen (1 of 4)

Middle-aged man with chronic hoarseness and the lesions seen here, diagnosed by the pathologist as papillomas.

Stippled vascularity (2 of 4)

Closer view. Stippled vascular markings consistent with HPV effect are seen more clearly here.

Surgical removal (3 of 4)

Soon after microlaryngoscopic removal, and in preparation for followup cidofovir injection.

Cidofovir injection (4 of 4)

Needle (arrow) and blanching and swelling of the left cord as cidofovir is injected. The same technique can be used for Avastin.

Subtype 31

This is less common in the airway than the more common subtypes 6 and 11. HPV 31 is associated with a higher risk of cancer formation, along with HPV subtypes 16, 18, 45, 55, and others.

Papillomas, HPV Subtype 31, Going Into Remission

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Papillomas: HPV Subtype 31 (1 of 4)

Standard light, showing lesions on the vocal cords, in particular the stippled vascular pattern we call "HPV effect." The patient's voice was nearly gone, with numerous syllable drop- outs and a very effortful quality. Compare with photo 3.

Papillomas: HPV Subtype 31 (2 of 4)

Closer view, using narrow-band light to accentuate the vascular pattern of "HPV effect." Biopsy and additional testing of these lesions showed squamous papilloma with moderate dysplasia, and HPV subtype 31 was confirmed, which is high risk for eventually causing cancer. After the patient underwent several injections of cidofovir, the lesions persisted but seemed to become more indolent. On compassionate grounds, this fairly young person was then prescribed celecoxib for six months.

Papillomas, in remission: HPV Subtype 31 (3 of 4)

Three years after photos 1 and 2, standard light view. Within two months of the start of celecoxib, voice improved very noticeably, and the "HPV effect" vascularity resolved. Still, it is unknown what roles in this recovery were played by the patient's immune system, the cidofovir, and the celecoxib, respectively.

Papillomas, in remission: HPV Subtype 31 (4 of 4)

Closer view than photo 3, under narrow-band light.

HPV 31 As A Cause of “Chronic Laryngitis” 

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Hazy leukoplakia, HPV suspected (1 of 4)

This 20-something nonsmoker without reflux symptoms is chronically hoarse. HPV infection is suspected for the following reason: While hazy leukoplakia can be occasionally seen as a result of excessive voice use, it would be most unusual to this degree, and this far lateral to the vocal cord margin. Biopsy shows only chronic inflammation, and HPV testing is positive for subtype 31.

Leukoplakia remains (2 of 4)

Several months later, the inflammatory reaction with leukoplakia remains.

Leukoplakia demarcated (3 of 4)

Narrow band illumination here makes the leukoplakia patches more demarcated.

HPV effect confirmed (4 of 4)

Within the circle, one can see faint HPV-effect on vasculature (stippling).

HPV 31 → Cancer → Cure

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Carcinoma in situ (1 of 4)

This man developed hoarseness spontaneously a year before this visit. He had accumulated 30 pack-years as a smoker, but had quit 7 years earlier. Removal of “polyps” elsewhere returned a diagnosis of carcinoma in situ (CIS), the earliest stage in the development of cancer.

HPV subtype 31 (2 of 4)

Under narrow band light, note some unusual “suspicious” capillaries, and the stippled “HPV effect” at the arrow. These findings triggered HPV subtyping and identification of high-risk subtype 31.

Excisions (3 of 4)

After 2 prior excisions elsewhere with positive margins, somewhat aggressive excision was performed in the operating room, attempting to avoid the need for radiotherapy in this fairly young man. The specimen showed severe dysplasia/ CIS, but with negative margins. After some months, voice became very functional.

Seven years later (4 of 4)

Seven years later, at an annual visit, there are no stippled or other abnormal vascular marks. Voice has been very acceptable to the patient, if occasionally faintly husky.

Subtype 44

HPV 44

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Voiceless 50-year-old man (1 of 6)

This 50-year-old man is virtually aphonic. The vocal cord abnormality is already visible in this distant view.

Vascular stippling (2 of 6)

At closer range and under standard light, the vascular stippling is becoming more visible. The two small 'X's are for reference with Photo 3.

Narrow band light, vascularity (3 of 6)

At even closer range under narrow band light, the vascularity is even more evident. The two small 'X's are for reference with Photo 2.

4 months later, recurrent papillomas (4 of 6)

This man had marked improvement of voice after surgery 4 months earlier but within weeks, voice began to deteriorate due to regrowth of his papillomas.

Open position, narrow band light (5 of 6)

Still in open (breathing) position but now under narrow band light. The stippled vascular markings typical of HPV effect are seen more clearly.

Closing for voicing (6 of 6)

As the cords come into approximation for voicing, still under narrow band light, the recurrent lesions are again seen.

Subtype 45

This subtype is less common in the airway than the more common subtypes 6 and 11. HPV 45 is associated with a higher risk of cancer formation, along with HPV subtypes 16, 18, 31, 55, and others.

Papillomas, HPV Subtype 45

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Papillomas: HPV Subtype 45 (1 of 2)

Papillomas in the supraglottis, left of image. The pink, velvety area of papillomas is outlined by small arrows.

Papillomas: HPV Subtype 45 (2 of 2)

Closer view of the vocal cords, showing leukoplakia. This is presumably a second expression of the HPV infection, though the typical dotted or pointed vascular marks of HPV are not seen in the area of the leukoplakia.
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HPV type 45 detected (1 of 7)

Panoramic view shows marked enlargement from tumor of false cords. Biopsy shows squamous cell and cancer HPV type 45 is also detected as the likely cause.

Closer view of HPV effect (2 of 7)

Closer view of the true vocal cords showing HPV effect of vascular stippling.

Narrow band illunination (3 of 7)

Narrow band illumination accentuates HPV vascular effect.

Post radiotherapy, glottic web seen (4 of 7)

After radiotherapy with complete response. A glottic web is now seen as a radiation side effect/complication.

Post-radiation web (5 of 7)

Closer view of post-radiation web.

Post-microlaryngoscopy, release of glottic web (6 of 7)

After microlaryngoscopy and release of glottic web. Tumor is gone.

HPV effect no longer seen (7 of 7)

Closer view of final result; patient has very good voice. Note that the HPV-related stippled vascularity is no longer seen.

Subtypes 33 & 45

HPV and Cancer: Types 33 and 45

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Hoarse voice (1 of 5)

Chronic hoarseness in a younger woman, diagnosed elsewhere with “nodules.”

Narrow band light (2 of 5)

At closer range, under narrow band light. Note the two distinct vascular patterns: a finer, stippled one of anterior 1/3 and a more coarse and aberrant one on the mid and posterior fold. The pathology report shows invasive carcinoma-in-situ, which was removed using the CO2 laser.

Post excision (3 of 5)

One week after excision of the lesion.

Healed (4 of 5)

After healing, the right fold normalizes remarkably and the patient’s voice sounds normal to her and to the clinician.

"Cured" (5 of 5)

Two years later, laser excision alone (no doubt along with the patient’s immune system) has produced a durable remission/ “cure.”

Subtype 55

This subtype is less common in the airway than the more common subtypes 6 and 11. HPV 55 is associated with an intermediate degree of risk of cancer formation, as compared to other subtypes of HPV.

Papillomas, HPV Subtype 55, Going Into Remission

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Papillomas: HPV Subtype 55 (1 of 4)

Papillomas of the vocal cords, in a patient with HPV subtype 55, which is intermediate-risk for progressing to cancer.

Papillomas: HPV Subtype 55 (2 of 4)

Same exam, with narrow-band lighting, which accentuates the vascular pattern of the papillomas.

Papillomas, in remission: HPV Subtype 55 (3 of 4)

Same patient, years later, in remission, and with normal voice. No sign of papillomas here or anytime during the prior three and a half years, after meticulous removal and Cidofovir treatment.

Papillomas, in remission: HPV Subtype 55 (4 of 4)

Same exam as photo 3, with narrow-band lighting. The vascular dots on the vocal cords are not HPV-related.

Subtype 69

HPV Subtype 69 (High-Intermediate Risk)

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Standard lighting (1 of 2)

Here, right vocal cord (left of photo) is unaffected, while left cord is entirely covered with papillomas caused by HPV 69.

Narrow band lighting (2 of 2)

At close range, under narrow band light, the vascular pattern is more strikingly revealed.

HPV 84 & 11

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Chronic hoarseness, papilloma (1 of 5)

60-something man with chronic hoarseness due to these lesions, seen under standard light. Biopsy shows "papilloma" and HPV testing reveals subtypes 84 & 11.

Stippled vascularity, leukoplakia (2 of 5)

At closer range under narrow band light, the stippled "HPV effect" vascularity is seen more clearly. The lesion marked by 'X' in this photo and photo 1 shows a subtle degree of leukoplakia.

Post treatment, voice is very good (3 of 5)

After several micro laryngoscopes, first using cidofovir as an adjuvant, and then avastin, the larynx looks quite clear. Voice is also very good.

Closed phase (4 of 5)

Under strobe light, closed phase of vibration.

Open phase (5 of 5)

Open phase of vibration.