Recurrent Respiratory Papillomatosis (RRP) and Other HPV-Induced Lesions

A disorder in which wart-like tumors or other lesions grow recurrently within a person’s airway. These growths are caused by the human papillomavirus (HPV), and they may occur anywhere in a person’s airway, such as on the vocal cords (by far the most common site), in the supraglottic larynx, or in the trachea. If these growths are removed, they will almost always grow back, or recur; hence, “recurrent respiratory papillomatosis.”

Symptoms and risks of recurrent respiratory papillomatosis:

RRP can be life-threatening in young children, if not carefully followed and treated, since a child’s airway is relatively narrow and can potentially be obstructed completely by the disease’s proliferative growths; moreover, RRP in children tends to grow and recur more aggressively. In adults, RRP will usually only impair voice function (when the growths occur on the vocal cords), though it can also impair breathing in severe cases. Occasionally, RRP can also progress to cancer, and therefore patients found to be at high risk for this (see below) need to be monitored carefully.

Characteristics of the growths:

The growths usually associated with RRP are wart-like tumors, or papillomas, that protrude conspicuously from the surface on which they grow, often in grape-like clusters. These kinds of papillomas are usually seen in patients who have HPV subtypes 6 or 11, which are both lower-risk subtypes for incurring cancer. There are some HPV patients, however, who manifest their HPV infection with subtler, velvety growths within the airway—“carpet-variant” growths, so to speak. Although these “carpet-variant” growths do not have the wart-like appearance of the papillomas typically associated with RRP, there at least a few key points of similarity:

  1. Both the “carpet-variant” and wart-like growths are lesions that sometimes appear, either independently or together, in patients who have HPV;
  2. Both the “carpet-variant” and wart-like growths are stippled with polka-dot vascular markings, because each “loop” in the “carpet” or each “grape” in the wart-like cluster has its own fibrovascular core, seen as a red dot;
  3. Both the “carpet-variant” and wart-like growths can disrupt voice function;
  4. Both the “carpet-variant” and wart-like growths usually recur if they are removed.

Because of these similarities, we consider these “carpet-variant” growths, even when the sole expression of the infection, to be at least a cousin to RRP, within the family of HPV-induced lesions. Many patients with this “carpet-variant” condition have HPV subtypes such as 16 or 18 that are higher-risk for cancer; such patients need to be monitored with particular care.

Treatment for recurrent respiratory papillomatosis:

The primary treatment for RRP and other HPV-induced lesions is careful, conservative surgical removal of the growths. Because these growths almost always recur, surgery must usually be performed on a repeated basis, as frequently as every few weeks in children, but on average much less often in adults. A common interval between surgeries for adult patients is between every six months and every two years, depending on how quickly the RRP or other HPV-related lesion recurs and impairs the patient’s voice function again. There are also a few medical treatments that have been used in addition to surgery, including, among others, interferon, indole-3-carbinol, intralesional mumps or MMR (measles-mumps-rubella) vaccine, cidofovir, and bevacizumab.


Photos:



























Videos:

Papillomas of the Larynx and Trachea
This video shows wart-like growths in the voicebox and windpipe (larynx and trachea) caused by chronic infection with the human papillomavirus (HPV).
Pulsed-KTP Laser Coagulation of Vocal Cord Papillomas
See a video demonstration of laser coagulation of vocal cord papillomas.

Chondroma

A benign growth composed of cartilage cells.


Photos:

Chondroma of thyroid cartilage: Series of 4 photos

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CT scan of the larynx, showing the thyroid cartilage

Chondroma of thyroid cartilage (1 of 4)

CT scan of the larynx, showing the thyroid cartilage (outlined by gray dotted lines) and an abnormality deforming the thyroid cartilage on one side (between the white arrows). Note how the thyroid cartilage bulges on that side, as compared with the opposite side, and the black speck which indicates varying densities in the cartilage.
Chondroma of thyroid cartilage

Chondroma of thyroid cartilage (2 of 4)

Same patient, endoscopic view of the larynx, again showing the abnormality (at arrows). Here the abnormality looks similar to a saccular cyst, but the scan (and subsequent biopsy) shows that it is cartilaginous and a chondroma, not chondrosarcoma.
Closer view of the chondroma

Chondroma of thyroid cartilage (3 of 4)

Closer view of the chondroma, showing an almost bi-lobed appearance.
Chondroma of thyroid cartilage

Chondroma of thyroid cartilage (4 of 4)

Under strobe lighting, which shows that the left vocal cord (right of photo) is apparently at a lower level than the opposite cord.

Amyloidosis

A condition in which abnormal proteins (called amyloids) become deposited in the spaces between cells. In some cases, the cause of amyloidosis is a systemic disorder in which the body over-produces proteins–for example, multiple myeloma, a blood disease; in this scenario, the amyloid deposits can be dispersed widely across the body. In other cases, the amyloid deposits do not seem to reflect systemic disease and can be more organ-specific.

Amyloidosis in the larynx:

In laryngeal amyloidosis, the deposits seem to be localized either just to the larynx, or to the larynx and pharynx. One sees what looks like yellowish candle wax within the tissues. The amyloid deposits are quite firm, and when biopsied, there is little bleeding.

Treatment for laryngeal amyloidosis:

Because of their infiltrative nature, amyloid deposits typically cannot all be dissected out of the larynx; instead, then, an operating physician will aim to debulk the deposits in areas where they impair breathing or the voice. That is, when deposits are widespread in the larynx, there does not seem to be any point in removing them except in locations where removal will improve function. Often, repeated procedures are required over many years’ time, though occasionally the condition seems to stop progressing.


Photos:

Amyloidosis, before and after debulking: Series of 4 photos

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ubmucosal amyloid deposits in pharyngeal walls and epiglottis

Amyloidosis, before debulking (1 of 4)

Panoramic view. Submucosal amyloid deposits in pharyngeal walls and epiglottis, with examples at arrows.
anterior subglottis

Amyloidosis, before debulking (2 of 4)

View of anterior subglottis shows diffuse infiltration of yellowish, submucosal amyloid.
deposit at anterior commissure tethering upper surface of left vocal cord

Amyloidosis, before debulking (3 of 4)

Phonation under strobe light shows deposit at anterior commissure tethering upper surface of left vocal cord, and resultant vibratory asymmetry.
Amyloidosis, after debulking

Amyloidosis, after debulking (4 of 4)

Some months later, after laser debulking at short arrow, showing improvement of vibratory closure after tethering reduced. Note increase of nearby supraglottic amyloid deposit does not need to be addressed because it has no functional consequence to the patient, who has other asymptomatic deposits in subglottis, epiglottis, and nasopharynx.

Amyloidosis: Series of 1 photo

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Amyloid deposits

Amyloidosis (1 of 1)

Amyloidosis, before and after debulking: Series of 8 photos

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large spherical mass of amyloid material bulging submucosally

Amyloidosis, before debulking (1 of 8)

Panoramic view of a large spherical mass of amyloid material bulging submucosally (contour at dotted line) in the false and aryepiglottic cords. The patient has only a harsh stage whisper, and glottic voice only with inspiratory (inhaling) phonation. The posterior vocal cord and ventricle of the opposite side (left of photo) are visible, but the amyloid mass obscures all but a few millimeters of the posterior cord on its side.
Amyloidosis, before debulking

Amyloidosis, before debulking (2 of 8)

Closer view.
edge of the amyloid mass

Amyloidosis, before debulking (3 of 8)

View yet further down, showing the upper trachea (top-center of photo), the posterior end of one of the vocal cords (left of photo), and the edge of the amyloid mass (bottom-right of photo, again marked by a dotted line). The mass is again obscuring a view of the vocal cord on its side; in fact, it is pressing the cord downward, which affects the voice.
mass overlies most of both vocal cords

Amyloidosis, before debulking (4 of 8)

Phonation, while attempting to see the vocal cords beyond the large overhanging mass. The vocal cords are each marked with an F, one of the posterior ventricles with a V, and the amyloid mass with an A. This mass actually overlies most of both vocal cords and presses them both downward.
Amyloidosis after debulking

Amyloidosis, after debulking (5 of 8)

Twenty-four hours after laser removal, i.e., debulking.
deepest recess of the dissection

Amyloidosis, after debulking (6 of 8)

Looking into the deepest recess of the dissection. The parallel lines indicate the upper border of the thyroid cartilage.
Amyloidosis after debulking

Amyloidosis, after debulking (7 of 8)

After debulking, both vocal cords are now visible from this angle (compare with photo 2). Remaining swollen overhanging tissue did not appear to be infiltrated with amyloid deposition.
Complete healing

Complete healing (8 of 8)

Many months after debulking, and with complete healing, the voice can pass for normal, and the laryngeal vestibule is no longer filled with the enormous bulk of amyloid. The nubbin at anterior false cord would only need removal if it became large enough to interfere with voice.

Proteinaceous deposits of primary laryngeal amyloidosis can occur anywhere and “everywhere” in the larynx: Series of 4 photos

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narrowed airway and protruding lesions

Airway Passage (1 of 4)

This middle-aged woman has experienced gradual deterioration of voice across several years. Note the narrowed airway and protruding lesions.
irm submucosal masses

Submucosal Masses (2 of 4)

In a closer view, one gets the sense of firm submucosal masses (most prominent deposits circled, at arrows). Note the yellowish cast as well. Vocal cord margins are marked with dotted lines.
diffuse subglottic infiltration

Diffuse Subglottic Infiltration (4 of 4)

Just below the vocal cords, diffuse subglottic infiltration is also seen, with the most prominent deposit posteriorly at the arrow.
yellowish amyloid deposits

Amyloid Deposits (3 of 4)

At closer range, the yellowish cast typical of amyloid deposits is seen better.

Videos:

Amyloidosis
This video gives an example of amyloidosis, which is a condition in which abnormal proteins (called amyloids) become deposited in the spaces between cells.

Verrucous Carcinoma

Verrucous carcinoma is a variant of squamous cell carcinoma (SCCA). In the head and neck, this uncommon subtype of SCCA is seen most often in the oral cavity or on the vocal cords. Visually, it tends to have an exophytic (outward-growing) and wartlike, irregular surface. This variant of SCCA is typically less aggressive than other squamous cell carcinomas. Local recurrence tends to be the issue more than distant metastasis. Surgery tends to be the most effective treatment, though of course every patient’s circumstance is individualized and considered in the light of three treatment options: surgery, radiation therapy, and chemotherapy.


Photos:


Sarcoma

A malignant tumor that originates in mesenchymal tissue. Mesenchymal tissue comprises muscle, bone, fat, connective tissue, blood vessels, and cartilage. If, instead, a malignancy originates in lining or covering tissues—which includes skin, bronchial tubes, the lining of the mouth, throat, and gastrointestinal tract, and breast and salivary gland ducts—then that tumor is called a carcinoma.

Carcinomas are far more common than sarcomas, and sarcomas involving the larynx are rare, with chondrosarcoma (“chondro-” refers to cartilage origin) heading the list. The clinicians at our laryngology practice have seen hundreds of carcinomas in their career, but probably no more than 20 sarcomas.


Photos:


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 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.








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.





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.




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.



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.





Subtype 44



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.




Subtypes 33 & 45



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.



Subtype 69



HPV 84 & 11


Carcinoma in situ (CIS)

A lesion comprised of “cancer cells,” but with those cells limited to the lining mucosa and without evidence of extension to adjacent structures. In other words, there is no sign of invasion beyond the mucosa. Carcinoma in situ (CIS) is typically a localized and highly curable precursor to invasive cancer. CIS is sometimes called intraepithelial carcinoma.

In laryngology, CIS is found primarily on the vocal cords themselves, where a tiny, early lesion can change the quality of the voice. In other locations, CIS would ordinarily be “silent.”

Cancer

A malignant growth or tumor caused by abnormal and uncontrolled cell division. The hallmark of cancer is its potential ability to invade neighboring tissue or to spread (metastasize) to other parts of the body through the lymphatic system or the bloodstream. Early cancers may have done neither, remaining localized to the tissue of origin. The majority of cancers in the head and neck are classified as carcinomas.


Photos of cancer:

Vocal cord cancer, before and after surgery

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Squamous cell carcinoma

Vocal cord cancer (1 of 4)

Squamous cell carcinoma, right vocal cord (left of image), standard light.
Vocal cord cancer

Vocal cord cancer, 1 week after surgery (2 of 4)

One week after laser excision. See irregular granulation especially at lower margin of excision.
one month after excision

Vocal cord cancer, 1 month after surgery (3 of 4)

Approximately one month after excision, healing progressing.
Vocal cord cancer

Vocal cord cancer, after complete healing (4 of 4)

After complete healing, patient has a voice that passes for normal. Under strobe light, right cord oscillates well except at very high vocal pitch. Note, however, the mild pseudo-bowing of the right cord due to tissue loss, and that there is a mucosal wave on the left, but not on the right.

Glottic Cancer, Laser Removal

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Glottic cancer, laser removal (1 of 3)

Early right vocal fold carcinoma, operative view (OR).

Glottic cancer, laser removal (2 of 3)

Same lesion, at the start of laser removal (OR).

Glottic cancer, laser removal (3 of 3)

Same larynx, after removal is complete. With healing over the next several months, the deficit “fills in” and voice result is often surprisingly good (OR).









 




















Videos:

Early Vocal Cord Cancer
This video provides an introduction to early vocal cord cancer (stages 1 and 2) and compares the two main treatment options, laser surgery and radiation therapy.