Mark Zafereo, M.D.
Disclaimer: The information contained within the Grand Rounds Archive is intended for use by physicians and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No warranties, either express or implied, are made with respect to accuracy, completeness or timeliness of this material. This material does not necessarily reflect the current or past opinions of the faculty of Baylor College of Medicine and should not be used as a basis for diagnosis or treatment, and is not a substitute for professional consultation and/or peer-reviewed medical literature.
Our patient is a 36-year-old gentleman with a history of juvenile onset recurrent respiratory papillomatosis. He was diagnosed with papillomatosis about age 4, and has had multiple endoscopic excisions since his early childhood. He has had a tracheostomy since 8 years of age due to significant burden of tracheal disease, but he is able to speak with a Passy-Muir valve. He presents 9 months after his last endoscopic excision with increasing dyspnea with exertion and hoarseness.
In the operating room, a direct laryngoscopy with bronchoscopy revealed recurrent papillomas of the mid surface of the right true vocal fold. These papillomas were removed with the laryngeal microdebrider. The rigid telescope was then passed through the vocal folds, where subglottic and upper tracheal papillomas were excised with the microdebrider. A rigid bronchoscope was then inserted, the tracheostomy was removed, and the patient was ventilated through the bronchoscope. Distal tracheal papillomas were excised during apneic ventilation with the cupped forceps. The patient was discharged home with a steroid taper and had significant improvement in his breathing and vocal quality following the procedure.
In 1923, Dr. Ullman inoculated his own upper arm with laryngeal papillomas from a 6-year-old boy’s larynx, and after 3 and a half months found several small, flat warts at the inoculated sites. Dr. Strauss visualized the HPV structure with the electron microscope in 1949. Dr. Strong began using the laser in the upper aerodigestive tract in the 1970s, and Drs. Lack and Mounts first detected HPV in laryngeal papillomas in the early 1980’s.
A little more on the human papillomavirus, which also has an interesting history. Genital warts were known to the ancient Greeks and Romans but believed to be the result of syphilis or gonorrhea until the 20th century. In 1907, Ciuffo established the infectious nature of warts by inoculating wart filtrates into skin and inducing papillomas. Dr. Richard Shope was able to isolate virus particles from tumors on captured wild rabbits and used these to inoculate domestic rabbits, which then developed similar tumors. He also noted that these tumors could progress to malignancy. The virus is thought to be the source of the myth of the jackalope, a rabbit with the antlers of an antelope. And in 1976, Zur Hausen assigned the first four types of HPV to cutaneous warts and also developed the connection between HPV and cervical cancer. Since that time, over 100 HPV types have been isolated and characterized.
Today, with viral probes, HPV has been identified in nearly all studied papillomatous lesions. It’s a small, circular, double-stranded, nonenveloped DNA virus, a member of the papovavirus family.
The genome consists of three regions: an upstream regulatory region, and two regions named according to the phase of infection in which they are expressed, the early (E) and late (L) regions. The two genes of the L region, L1 and L2, encode the viral structural proteins. E genes are numbered 1-7: E1 and E2 are involved in replication of the viral genome, E4 interacts with host cell intermediate filaments, and E 5-7 are involved in transforming activities. In high risk types of HPV (namely types 16 and 18), E6 and E7 have been shown to be potent oncogenes which accelerate proliferation of infected cells by disturbing the function of their respective tumor suppressor genes p53 and pRb (retinoblastoma gene). In lower risk forms of HPV (such as types 6 and 11) which are implicated in RRP, E6 has also been shown to bind with cellular proteins, although the physiologic relevance of these interactions is not well understood.
In a 10-year prospective epidemiological study of 73 children with RRP, Wiatrak et al found that patients with HPV type 11 and greater than 3 years of age were more likely to develop more aggressive disease, more frequent surgical procedures, greater need for adjuvant therapy, and a greater likelihood of tracheal disease.
There are now over 100 different HPV subtypes. Viruses that exhibit less than 90% identity in specific regions of the genome are defined numerically as separate subtypes. Subtypes correlate with tissue preference, disease severity, and the ability to effect cellular transformation. Both high and low risk HPV types are involved in genital HPV infections: 6 and 11 in condylomas and 16, 18, 31, 33, and 45 in cervical cancer. Types 6 and 11 are associated with lowest malignant potential and are most commonly identified in laryngeal papillomatous lesions and genital condylomas; types 31, 33, and 45 have intermediate malignant potential and are occasionally found in genital or oral malignancies; and types 16 and 18 have higher malignant potential, and induce cancer in the cervix, anogenital tract, oropharynx, and oral cavity.
Specifically in the larynx, a series of studies have documented HPV types 6 and 11 DNA by PCR in about 20%of macroscopically normal-appearing upper aerodigestive tract mucosa. Nunez and others identified HPV DNA in 25% of postmortem laryngeal specimens. HPV can be identified in a slightly higher percentage of laryngeal carcinoma, a still higher percentage of verrucous carcinoma, and in nearly all cases of laryngeal papillomatosis.
HPV infects basal cells of the epithelium, which are the only dividing cells of the epithelium. The viral particles are bound to cell-surface receptors, enter the cell, and are transported to the nucleus, where the viral genome is released and undergoes replication. Viral DNA enters the cell and is transcribed into RNA, which is then translated into viral proteins. Then superficial keratinocytes which contain the virus are released by shedding. There can be either an active infection in which the late genes are expressed and virions are produced, or a latent infection in which some early genes are expressed but no viral production occurs and tissue remains clinically and histologically normal. The reasons why either an active or latent infection occur are not completely understood, but one hypothesis is host immunity. This also explains why reactivation of viral expression and clinical recurrence of laryngeal papillomatosis can occur after years of remission, and it is thought that adult-onsets cases could either represent new infection or activation of virus present since birth. In 2006, Dr. Sisk at Mississippi showed a 2% incidence of HPV DNA in tonsillectomy specimens, which compares to an incidence of RRP of 2-4/100,000 (0.004 percent) and, again, suggests that there are other factors such as host immunity and mucosal injury involved in RRP pathogenesis. Malignant transformation has been shown to occur with higher risk types of HPV, but a similar process may also occur to cause papilloma formation in lower risk types.
Host immunity also likely plays a role in maternal HPV infection. Although most sexually active women acquire HPV infection, by 2 years >90% of women do not have detectable virus. A small subset of women develop persistent infection, with persistent infection often defined as > 1 visit at least 4 months apart with the same HPV type detected, and the dynamics of acquisition of the virus and clearance and immune response to an exposure are not well understood. In a national study published in JAMA in 2007, the prevalence of genital HPV among women age 14-49 was 27%, so clearly there are many more children who are exposed to HPV than who develop papillomatosis.
While adult RRP is thought to be related to reactivation of latent infection or newly acquired sexually transmitted disease, juvenile onset is believed to be transmitted during gestation or passage through the birth canal. There has been significant research in both the otolaryngology and OB-GYN literature on the transmission of HPV from mother to child and the risk of subsequent development of RRP. Vaginal delivery, firstborn child, young mother, and low socioeconomic status have been cited as risk factors. All these risk factors are related to exposure to HPV: primigravida mothers are more likely to have a longer second stage of labor and prolonged exposure to the virus; and young mothers and those with low socioeconomic status are associated with increased risk of condylomatous lesions. While it is believed that the virus is transmitted by vertical transmission from mother to child during birth, the risk of transmission to the child in a mother with an active condylomatous lesion who undergoes a vaginal delivery has been estimated from to be as high as 3%. Factors other than maternal HPV infection that may influence transmission include patient immunity; timing, length, and volume of virus exposure; and trauma to the child during the birthing process. In support of this argument, there was a study by Dr. Tenti and others in the OB-GYN literature showed that 30% of infants exposed to HPV in the birth canal had evidence of HPV in their nasopharynx, but only a small fraction of these developed RRP. Caesarian section has been hypothesized to reduce the transmission of HPV, but there is also a higher morbidity and economic cost compared to a vaginal delivery. But caesarian delivery does not prevent papillomatosis in all cases, and there are rare cases of neonatal papillomatosis which suggest that the disease may develop in utero in some cases. In addition to that, HPV DNA has been recovered in both umbilical cord blood from infants delivered to mothers with HPV infection and in amniotic fluid samples from infected mothers. So in summary, taking all of what is known about HPV transmission and modes of delivery, there is currently not sufficient evidence to warrant caesarian sections in all pregnant women with condylomata.
As evident from the last several slides, there are factors other than HPV which dictate which patients with HPV exposure develop RRP. In a prospective study from Israel of 20 children with RRP who underwent immunologic evaluation at 6-month intervals, children with decreased lymphocyte mitogen stimulation response and decreased ratio of CD4 to CD8 cells were significantly more likely to have more extensive burden of disease and more frequent procedures. So as is theorized for other HPV-induced disease like oropharyngeal cancer, host immunity likely plays a role in papillomatosis, as the vast majority of patients who are exposed to the virus do not develop disease.
The most common site for RRP by far is the larynx, involved in over 97% of cases, with the true vocal cords the most common subsite. In a multicenter study by Kashima from John Hopkins, the second most common site was the mucociliary junction of a tracheostomy site. It was also common for papillomas to form in the midthoracic trachea in these patients at a level corresponding to the tip of the tracheostomy tube, where a squamociliary junction is formed because of abrasion of the tracheostomy tube. In this study, papilloma distal to the undersurface of the vocal folds was rare in patients without a tracheostomy. Other common sites were the nasal vestibule, the nasopharyngeal surface of the soft palate, the midzone of the laryngeal surface of the epiglottis, upper and lower margins of the ventricle, undersurface of the vocal folds, the corina, and bronchial spurs. All of these sites have in common the junction of ciliated pseudostratified columnar or respiratory epithelium, with stratified squamous epithelium. For example, in the nasopharynx, the ciliated epithelium of the nasopharynx meets the squamous epithelium of the oropharynx at the site of velopharyngeal closure. In the larynx, the upper half of the epiglottis is lined by squamous epithelium which brushes the posterior pharynx during swallowing, and the lower half by ciliated epithelium. The false vocal folds are lined by squamous epithelium on the upper surface and ciliated epithelium on the undersurface (roof of the ventricle). And this also speaks to a physiologic explanation for why laryngopharyngeal reflux, which causes areas of respiratory epithelium to undergo squamous metaplasia and form new squamocolumnar junctions, may encourage the growth and recurrence of latent HPV which is already present in the mucosa.
These are images of areas of transitional epithelium between the true vocal folds and the false vocal folds. The blue arrow is indicating the point where the transition takes place. You can see that an epithelium change takes place at that point from ciliated pseudostratified columnar (below the arrow, covering the false cords) to the non-keratinized stratified squamous (above the arrow, covering the true vocal folds). This epithelium makes functional sense because when we phonate, we will cause rubbing of the two vocal cords. If there was no stratified squamous epithelium, we would be causing damage every time we talk. The red arrow is indicating the vocalis muscle. On the right is a closer view of the transition point (black arrow) between the true vocal cords (yellow arrow) which is non-keratinized stratified squamous and the false vocal cords (green arrow) which is ciliated pseudostratified columnar. The cilia are noted by the red arrows. Again, the reason for the difference is physiologic, in that the non-keratinized stratified squamous epithelium protects against abrasion and strong flow of air. And this is a final close up of the epithelium of the larynx including the false vocal cords with the characteristic ciliated pseudostratified columnar appearance.
Histologically, RRP appears as sessile or pedunculated masses, pink to white in color, that often occur in irregular exophytic clusters. The masses consist of fingerlike projections of keratinized stratified squamous epithelium supported by a core of highly vascularized connective tissue stroma. Again, exophytic projections of keratinized stratified squamous epithelium overlying a fibrovascular core, and on the right, koilocytes, which are vacuolated cells with clear cytoplasmic inclusions, suggesting the presence of a viral infection. Epithelial maturation abnormalities also occur, including hyperplasia of the basement membrane; dyskeratosis, which is premature keratinization in cells that are not in the keratinizing surface layer of the skin; and hyperkeratosis, which is thickening of the epithelium.
RRP demonstrates a bimodal distribution with a juvenile onset in children less than 5 years of age and an adult onset in young adults between 20 and 40 years of age. The national registry for juvenile onset RRP estimates about a 2/100,000 incidence in the pediatric population and about a 2/100,000 in the adult population. And the disease is rarely fatal but carries significant morbidity on an individual level and high cost to society with annual health expenditure total cost estimated at $150 million. The juvenile form, as in our patient today, is typically more aggressive than the adult form, with more than half of children with RRP requiring more than 10 procedures to control their disease, and 7% requiring more than 100 procedures during their lifetime.
Papillomatosis is the most common benign neoplasm of the larynx among children, accounting for up to 84% of laryngeal tumors in the pediatric age group. It represents the second most common cause of hoarseness in children, the most common being acute laryngitis. Hoarseness is the generally the first clinical symptom followed by stridor. Especially in the juvenile form at initial diagnosis, respiratory distress is common. Because hoarseness in children is common and RRP is rare and slowly progressive, many cases are not recognized until the papillomas obstruct the airway. There are reports of neonatal papillomatosis, and while congenital airway anomalies are much more common, RRP should remain in the differential for infants with stridor at birth.
Physical exam is primarily flexible endoscopy, though some advocate a mirror exam with no flexible fiberoptic endoscopy to reduce any risk of transmission to the nasopharynx. And there is no uniform staging system.
RRP has a fairly classic appearance, but other laryngeal pathology that causes hoarseness includes laryngitis, trauma, laryngeal cancer (as in the top left), intubation granuloma (top center), vocal cord nodules (top right), Reinke’s edema (bottom left), vocal cord cysts (bottom center), and vocal cord polyp (bottom right.)
Surgery remains the definitive treatment for the disease: it reduces tumor burden, decreases spread of disease, ensures patent airway, and improves voice quality. Subtotal removal with preservation of normal structures, especially the anterior and posterior commissures, often is the best approach. Complications of injuring normal tissue include glottic and subglottic stenosis, web formations, and a diminished airway. Another argument for subtotal removal is that even if you are to remove all clinically evident disease, latent virus likely remains in adjacent tissue, and the injury to surrounding normal tissue may create an environment suitable for implantation of viral particles and new areas of disease. Surgical resection of disease in the anterior commissure is often staged to prevent the apposition of two raw mucosal surfaces. At least 1 mm of untreated mucosa should be left in the anterior commissure to avoid webs. And timing is important, with a balance between symptom control and avoiding respiratory distress and increasing complications with increased number of procedures. Surgical management includes removal of gross disease with the endotracheal tube followed by extubation and apneic excision of smaller and posterior lesions. Jet ventilation is another option, eliminating the fire hazard of endotracheal intubation and allowing good visualization, but also risks transmission of HPV into the distal airway.
There are a variety of surgical techniques, and epinephrine and steroids are often used postoperatively, especially in children. Phonomicrosurgical excision is one option, and while relatively uncommon in practice, was actually the Academy’s Voice Committee’s preferred method for adult RRP in their 2002 report, citing lowest risk of scar formation and easier complete resection of disease, as opposed to a debulking, and thereby preventing morbidity associated with recurrent procedures.
These are some pictures from Dr. Zeitels. At top left is the initial presentation of glottal papillomatosis. Top right illustrates subepithelial infusion of epinephrine into the superficial lamina propria, separating the disease from the superficial lamina propria and enhancing visualization by positioning the disease toward the center of the laryngoscope and separating it from the vestibular fold. Bottom left shows the effect of external counterpressure on the cartilaginous laryngeal framework. A large microflap is dissected that encompasses all of the epithelial disease and maximally preserves normal superficial lamina propria so that the resection should be between the epithelial basement membrane and superficial lamina propria. Bottom right illustrates the maintained microvasculature of the superficial lamina propria after resection. In their study, Zeitels and Sataloff had very good results with this technique. 6 patients who had not undergone previous surgery did not recur within 2 years, and 10/16 patients who presented with recurrent disease did not have a recurrence within 2 years. When there was involvement of the anterior commissure, 2 or 3 procedures were done in a staged fashion to avoid anterior commissure webbing. The patients in this study were all adults without massive or transglottal papillomas.
More pictures from Dr. Zeitels. The left picture illustrates a large papillomatous lesion of the left vocal fold encompassing all of the musculomembranous region and extending into the ventricle. On the right, after subepithelial infusion, the ventricular component is well visualized.
Lasers are another tool for excision. In 1917, Einstein described the basic physics of stimulated emission of radiation; however, it was not until 1954 that Townes and Gordon built a microwave laser called a Maser. The carbon dioxide laser is most commonly used. The CO2 laser is a type of ablative laser with a wavelength of 10,600 nm, a wavelength which is absorbed by water. It works by a process known as photothermolysis, whereby the laser’s energy is absorbed by intracellular water, thus vaporizing cells. A microspot micromanipulator can enable initial debulking in a defocused mode and then focusing to a 250-nm spot size to excise papillomas from problem areas such as the commissures. The CO2 laser is both precise and enables good hemostasis, but there is the potential for thermal damage, airway fire, and dissemination of HPV particles, and it is an expensive technology. In a large study out of San Francisco, Dr. Dedo treated 244 patients with the CO2 laser. They used frequent 2 month surgical intervals to aggressively evaluate and treat any recurrences and had a 50% rate of remission at 2-month follow-up. They had a fairly high rate of 27% anterior glottic webs, and they illustrate a technique for releasing the more posterior aspect of the scarring with a mucosal flap. In (A) a flap is created with scissors from mucosal edge of one vocal cord. In (B) the CO2 laser is used to resect the anterior triangle of the scar so the flap is flexible and has space to rotate into. And in (C) the flap is rotated into position, allowed the raw undersurface to adhere to the adjacent raw surface.
The microdebrider was introduced for RRP in the late 1990s, and has arguably become the most popular tool for RRP excision. Web-based survey of all ASPO members in 2004 reported 53% using the microdebrider compared to 42% using the CO2 laser. The same study reported 63% reported using spontaneous or apneic ventilation, 24% using jet ventilation, and 10% laser-safe endotracheal tubes.
There was a small randomized prospective study of 34 patients in Alabama directly comparing the microdebrider with the CO2 laser showed shorter procedure times, less expense, better voice quality, and no difference in pain with the microdebrider, but the choice of surgical instrumentation, whether the laser, microdebrider, or phonomicrosurgery depends largely on the lesions and anatomy as well as a surgeon’s personal preference and expertise, and ideally one could use several or all of these techniques in their practice depending on the particular patient and anatomy.
There are very few randomized and/or prospective studies evaluating adjuvant therapy for RRP, and this is an important point, because the natural history of the disease can include remissions and reactivations, so without a placebo, it’s difficult to determine whether an effect is due to the drug or a remission which would have occurred in the absence of the drug. Overall, about 20% of patients are treated with adjuvant therapies, and common criteria for using adjuvant therapies include patients who are requiring more than 4 surgical procedures per year, patients with distal spread of disease, and those with rapidly progressive disease leading to airway compromise. In a 2004 ASPO survey, 75 practitioners were using cidofovir, 25 interferon, 15 indole-3-carbinol, and 11 heat shock protein E7. However in data from the national registry for juvenile onset RRP, alpha interferon is still the most commonly used adjuvant therapy at 42% of patients, compared to 29% with indole-3-carbinol and 17% for cidofovir.
Interferons are a class of proteins manufactured by cells in response to a variety of stimuli including viral infection. The enzymes produced block viral replication and make cell membranes less susceptible to viral penetration. It has shown mixed clinical success and some unfavorable side effects with acute flu-like reactions and chronic hepatic and renal dysfunction. In the late 1980s, Drs. Donovan and Goepfert here in Houston participated in a randomized crossover trial of 66 patients with severe juvenile-onset papillomatosis where half of the cohort was initially treated with interferon for 6 months and then observed for 6 months, and the other half were observed for six months, and then treated with interferon for 6 months. While not all patients responded, there was an overall statistically significant improvement in disease burden for patients during the time they were being treated with interferon. And a subset of patients who were observed after discontinuation of the drug showed significant worsening of their disease burden.
Briefly focusing specifically on cidofovir, which is an antiviral agent which is currently FDA approved for CMV retinitis but not papillomatosis. Case series report up to 50% remission with cidofovir, illustrating the problem with case series in evaluating papillomatosis, Dr. McMurray from Wisconsin recently published a randomized, placebo-controlled study in Annals which showed a significant improvement in disease-burden in the cidofovir group, but a similar significant improvement in disease burden in the placebo group, such that there was no difference in improvement between patients who received the cidofovir and those who received placebo. There is also concern for nephrotoxicity and carcinogenicity with cidofovir, and accordingly the RRP task force only recommends it in moderate and severe cases.
A little about disease course and prognosis. Younger age and HPV type 11 are associated with more aggressive disease. As previously mentioned, in a 10-year prospective epidemiological study of 73 children with RRP at the children’s hospital of Alabama, Dr. Wiatrak found that patients with HPV type 11 were more likely to develop more aggressive disease, more frequent surgical procedures, greater need for adjuvant therapy, and a greater likelihood of tracheal disease. According to the national registry for juvenile onset papillomatosis, during childhood most patients reach a level of stable disease but persistent disease, a small percentage of patients develop progressive disease, and about 20% go into remission. Then during adolescence the disease often goes into a more quiescent state. Most researchers believe that tracheostomies can contribute to distal spread of disease and that it is a procedure to be avoided in children with RRP unless absolutely necessary for airway protection. There is some controversy, as some argue that these patients have a more aggressive papillomatous course and thus are more likely to need a tracheostomy, but there is evidence that a tracheostomy predisposes to papillomatosis. A large study from Russia published in 2005 showed about 10% lower airway involvement with RRP, with over 90% of these patients having had a previous tracheostomy. Of these 9% with lower airway involvement, 20% had pulmonary involvement. With pulmonary involvement, mortality is high ranging from 25-75% in the literature. In an ASPO survey, half of practices reported that a patient had died under their care, most commonly from pulmonary failure, but other causes of death were anesthesia-related complications and malignant transformation.
There are two prophylactic HPV vaccines that have been developed, one is a quadrivalent vaccine manufactured by Merck against types 6, 11, 16, and 18; and the other is a bivalent vaccine manufactured by GlaxoSmithKline against types 16 and 18. Both vaccines use the L1 protein of the outer surface of the virus as the immunogen, and are combined with an aluminum adjuvant to boost immunity. While potentially effective for cervical or oropharyngeal cancer, the bivalent vaccine would not be effective for RRP, as it does not protect against types 6 and 11. The quadrivalent vaccine was licensed for use in the US in 2006, and is administered as a series of three injections at 0, 2, and 6 months. While there are no vaccine studies specific to RRP, we can perhaps extrapolate some data from studies of the vaccine with cervical cancer.
Merck funded a large international multicenter study published in the New England Journal in 2007. It was a randomized, double-blind phase III study of over 12,000 women between 15 and 26 years of age who received either 3 doses of the vaccine or placebo, and the endpoint was high-grade cervical neoplasia. The women were followed for 3 years after receiving the vaccine, and the rates of development for the vaccine and placebo groups were used to develop a vaccine efficacy, which was 98% for the prevention of cervical intraepithelial neoplasia in women who were HPV naïve at the beginning of the study.
A more recent international, multicenter study which is currently in press in the Lancet was conducted, also a randomized, double-blind study, looking at 4,000 slightly older women, age 24-45, reporting a 91% efficacy for HPV naïve women for developing cervical disease related to HPV types 6, 11, 16, and 18. There was no difference in the number of adverse events between those patients who received the vaccine versus the placebo.
So, in conclusion, RRP is a disease that while rarely fatal, causes significant mortality. Surgical management is the mainstay of treatment, and regardless of the instruments that are used, the principle of preservation of normal mucosa so as not to cause further propagation of disease is important. And, it’s an exciting area of medicine in that a potential cure in the form of prevention with a vaccine is perhaps on the near horizon. And one future challenge that remains is to find medical therapy that can consistently halt progression or induce remission in patients who have already developed disease.
A 36 year-old gentleman with a history of juvenile onset recurrent respiratory papillomatosis who has undergone multiple endoscopic excisions since his early childhood. He has had a tracheostomy since his early childhood due to significant burden of tracheal disease, but is able to speak with a Passy-Muir valve. He presents 9 months after his last endoscopic excision with increasing dyspnea with exertion and hoarseness.
In the operating room, a direct laryngoscopy with bronchoscopy revealed recurrent papillomas of the mid surface of the right true vocal fold. The papilloma was removed with laryngeal microdebrider. The rigid telescope was then passed through the vocal folds, where subglottic and upper tracheal papillomas were excised with the microdebrider. A rigid bronchoscope was then inserted, the tracheostomy was removed, and the patient was ventilated through the bronchoscope. Distal tracheal papillomas were excised during apneic ventilation with the cupped forceps.
The patient was discharged home with a steroid taper and had significant improvement in his breathing and vocal quality following the procedure.
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