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Relationship of Human Papillomavirus to Schneiderian Papillomas


Relationship of Human Papillomavirus toSchneiderian Papillomas
Jordan S. Weiner, MD; David Sherris, MD; Jan Kasperbauer, MD; Jean Lewis, MD; Hongzhe Li, PhD; David Persing, MD, PhD

Objectives/Hypothesis: To classify a large group of Schneiderian papillomas (SPs) into their histologic subtypes and to determine the incidence of human pa­pillomavirus (HPV) in each subtype. Study Design: Pathologic review and polymerase chain reaction-based (PCR-based) examination of archived tissue. Methods: Slides of 114 tumors diagnosed as Schnei­derian, inverting, fungiform, or cylindric cell papillo­mas, or any associated carcinomas, were examined by a head and neck pathologist. Using PCR, consensus primers for the L1 region of HPV were used to deter-mine the presence of HPV in the tumors. This was also performed on normal turbinate control specimens. Results: Eighty-two (78%) were the inverting subtype, 21 (20%) the fungiform subtype, and 2 (2%) the cylin­dric cell type. Nine tumors were diagnosed as either verrucous or squamous cell carcinoma. Eighty-eight percent of the tumors had DNA of sufficient quality to be amplified using PCR. Of these, 5 of 69 (6.8%) in­verting, 17 of 17 (100%) fungiform, and 0 of 2 cylindric cell papillomas were positive for HPV. One of nine (11.1%) cancers was positive for HPV. No normal turbinate tissue contained HPV. HPV types 6b and 11 accounted for all cases of fungiform papillomas. Of the five HPV-positive inverting papillomas, three had HPV type 11 and two had HPV type 16. The single car­cinoma containing HPV contained HPV type 18. Con­clusions: The histologic subtype of SPs is important, as their etiologies appear to be different. HPV 6b and 11 appear to be involved in all cases of fungiform pa­pillomas but are only rarely involved in cases of in­verting or cylindric cell papillomas. HPV 16 may rarely play a role in cases of inverting papillomas, and HPV 16 and 18 may be involved in a subset of cases of carcinomas originating in an inverting papilloma.

INTRODUCTION

Schneiderian papillomas (SPs) are a group of un­usual nasal and paranasal sinus tumors of unknown etiology. They tend to occur in older, male patients and, in a previous report from our institution, are associated with tobacco usage in 75% of patients.1 Other risk factors such as alcohol consumption, occupation, or inflammatory con­ditions do not appear to be associated.1.2 Although they are benign, they have a significant propensity to recur (27%-78%)1-6 and are occasionally associated with malig­nancy (6%-17%).1-5 Treatment at present involves wide lo-cal excision of the tumors, at times necessitating medial maxillectomy, to ensure complete excision, as more limited resections have been associated with higher recurrence rates.1-5

There are three recognized subtypes of SP: inverting, fungiform, and oncocytic (cylindric) cell papillomas. In­verting papilloma represents 47% to 73% of the tumors, fungiform represents 19% to 50%, and oncocytic cell, 3% to 8%. The inverting and oncocytic cell subtypes originate on the lateral nasal wall or within the paranasal sinuses and have similar biologic behavior with high rates of recur­rence, as well as a known association with malignancy. In contrast, the fungiform subtype has a low recurrence rate, arises exclusively on the nasal septum, and is not associ­ated with malignancy.3

In search of an etiology, recent investigations have sought to identify human papillomavirus (HPV) in SE This virus plays a significant role in cervical neoplastic dis­ease,7-9 and recently, studies have been published examin­ing head and neck lesions for the presence of HPV.10,11 Stud­ies examining SP for HPV have made use of in situ hybridization (ISH) and polymerase chain reaction (PCR) techniques.6,12-19 The results have been mixed. Studies have found HPV DNA within fungiform papillomas in 50% to 100% of cases, and within inverted papillomas in 0% to 86% of cases. Studies that have shown HPV DNA to be present in a significant proportion of fungiform but in none of (or a very small proportion of) inverting and oncocytic cell sub­types16-19 raise the possibility of different etiologies for the three subtypes. However, two studies showed a relationship between HPV presence within inverted papillomas and re­currence,6,13 and five studies showed an association between the presence of HPV type 16 or type 18 (HPV-16 or HPV-18) and malignancy.12,13,15,19,20 Thus, to date, the role of HPV in the development and progression of SP is controversial.

This study represents the largest study to date. One hundred fourteen SPs as well as 96 normal inferior turbinate specimens as controls were examined for the presence of HPV DNA. Two separate L1 consensus primer sets were used to detect HPV DNA. These were chosen be-cause of their proven success in detecting multiple differ­ent types of HPV.21,22

MATERIALS AND METHODS

Patients with SP were selected using a computerized search of all formalin-fixed, paraffin-embedded pathologic specimens at the Mayo Clinic from 1984 through 1996. Diagnoses included in­verting papilloma, cylindric cell papilloma, and fungiform papil­loma. A minority of the specimens represent squamous cell carci­noma (SCC) arising synchronously with benign papillomas or represent SCC or verrucous carcinoma (VC) arising at a site of previously excised SP. The slides were reviewed and the diagno­sis and histologic subtype confirmed by an experienced head and neck pathologist (J.E.L.). Blocks were chosen for sectioning which well represented the papillomatous neoplasm.

The blocks were sectioned using a disposable microtome blade. An unused portion of the microtome blade was used for each specimen and the blade changed after every two blocks to prevent block-to-block contamination. Sections were cut 20 µm thick. The ribbons were transferred directly into a microcen­trifuge tube without entering the water bath, also to prevent con­tamination. The tubes were assigned a laboratory reference num­ber so that histologic types were essentially randomly ordered and the investigator (J.s.w.) performing the analysis was blinded as to what type of tumor a given sample represented.

Digestion of the tissue to prepare the DNA for subsequent PCR was performed using a proteinase K digestion. To each sam­ple, 1 mL of proteinase K solution consisting of 885.5 µL H2O, 100 µL Buffer I (Perkin Elmer Corp., Branchburg , NJ ), 10 µL pro­teinase K (50 mg/mL), and 4.5 µL Tween 20. Samples were di­gested for 24 hours at 55 to 60°C with intermittent mixing.

Polymerase chain reaction was performed on all samples and controls using the MY09/MY11 and GP5+/GP6+ primer pairs de-scribed elsewhere.22,23 For the MY primers, a 100 µL reaction was performed containing 10 mM Tris-HCI pH 8.3, 50 mM KC1, 0.001% w/v gelatin, 12 mM MgC12, 200 mM dNTP, 7.5 U AmpliTaq Gold (Roche Molecular Systems, Alameda, CA), and 50 pmol of primers MY09, MY11, HMBBO1, BPCO4, and BGH2O. These primers are biotin-labeled as supplied in a kit by Roche Molecular Systems so that the PCR product could be detected by hybridization to an ar­ray of immobilized oligonucleotides. Using reverse-blot "strip" analysis, HPV genotype discrimination of greater than 27 HPV types can be performed in a single hybridization and wash cycle. In addition, the BPC04 and BGH2O primers24 amplify a 268-base­pair (bp) length of the human B-globin gene. This served to deter-mine whether DNA of sufficient quality was present for successful amplification of this length product. Samples negative for amplifi­cation of the B-globin product were discarded and fresh ribbons di­gested with proteinase K. The B-globin assay was repeated. If the tumor was still negative for (-globin product, it was eliminated from analysis as containing insufficient intact DNA for successful PCR. PCR was performed in a Perkin Elmer TC9600 using the fol­lowing cycling parameters: 95°C for 9 min and then 40 cycles of 95°C for 20 s, 55°C for 30 s, and 72'http://www.drsherris.com//C for 30 s. This was followed by a single, additional elongation step at 72C for 5 min.

For the GP5+/GP6+ primer set, a 50 µL reaction was per-formed with the following differences: 2.0 mM MgCl2 and 25 pmol of primers GP5+/GP6+ instead of the MY09/MY011 primers. Cycling conditions were as follows: 95°C for 9 min and then 40 cy­cles of 95'C for 30 s, 44'C for 60 s, and 72'C for 90 s. A final elon­gation step of 72°C for 10 min was performed.

Positive controls to assess the success of amplification con­sisted of DNA from the CaSki cell line known to contain HPV-16 DNA. Each PCR also included negative controls containing iden­tical reagents but lacking DNA. Following PCR, 15 µL of each sample was run on a 2% agarose gel (SeaKem GTG, FMC Bio-Products, Rockland , ME ) and stained with ethidium bromide to determine whether a band of the correct base-pair length was present. If the B-globin product was not amplified, dilution series with that sample were performed to determine whether in­hibitors present in the sample were responsible for the lack of successful amplification. If amplification was still unsuccessful, that sample was excluded from further analysis because of insuf­ficient amplifiable DNA.

Samples positive for HPV from the MY primer pair PCR were typed using the reverse blot method previously mentioned. A band appearing on the strip represented the presence of a spe­cific HPV type. Samples that were HPV negative using the MY primer set were then amplified using the GP primer set. Positive samples were sequenced following DNA purification using the Wizard Prep DNA purification kit. Sequence analysis by match­ing the product sequence with published DNA sequences (GeneBank) using commercial software (Wisconsin Package Ver­sion 9.1, Genetics Computer Group, Madison, WI), allowed assig­nation of a particular HPV type.

RESULTS

Table I shows the breakdown by histologic subtype of the tumors studied. Inverted papilloma was the most com­mon subtype found (78% of benign lesions), followed by fungiform (20% of benign lesions) and, last, by the rare cylindric cell papilloma (2%). Nine cases (8%) represented synchronous SCC or VC occurring with a benign papil­loma or represented recurrences in a patient with a previ­ously resected benign Schneiderian papilloma. Eight of the malignancies were associated with inverting papillo­mas; one occurred in a patient with a previously excised cylindric cell papilloma.

Table II shows the results of the (-globin assay to de­termine whether the DNA present in the specimen could be successfully amplified using the PCR technique. This was successful in 90% of the inverted papillomas and 85% of the fungiform papillomas, with an overall success rate of 89% for all the specimens. Specimens negative for B-globin were eliminated from further analysis.

TABLE I.
Histologic Subtypes.

Histologic Subtype

No. (%) of Cases

Benign neoplasms

Inverted papilloma

82

(78)

Fungiform papilloma

21

(20)

Cylindric cell papilloma

2

(2)

Total

105

Carcinoma (squamous cell or verrucous)

9

(8)

Total

114

Normal turbinate controls

96

TABLE II.
B-Globin Assay for DNA Amplifiability.

Histologic Subtype

(B-Globin Positive n (%)

Inverted papilloma

74

(90)

Fungiform papilloma

17

(85)

Cylindric cell papilloma

2

(100)

Carcinoma (squamous cell or verrucous)

9

(100)

Total

102

(89)

Normal turbinate controls

84

(88)

Table III compares the presence of HPV DNA in all tu­mors versus the turbinate control specimens using the MY09/MY11 primer set. Fourteen papillomas (13.7%) were positive for HPV DNA versus 0 of the turbinate controls (P < .00014). However, it should be noted that in one turbinate, a weak band of the correct length (450 bp) could be seen on the agarose gel. On the typing strips, no band was demonstrated. To be certain there was no HPV prod­uct, an attempt was also made to sequence the product, as was routine after amplification with the GP5+/GP6+ primer set. No HPV sequence was found; thus it was con­cluded that this could not be counted as the only HPV pos­itive-control sample.

Table IV compares the presence of HPV DNA in all tumors versus the turbinate control specimens using the GP5+/GP6+ primer set in the tumors already found to be HPV-negative using the MY09/MY11 primer set. An addi­tional 9 tumors (10.3%) were found to be positive versus 0 of the controls (P = .0032).

The data using the MY09/MY11 and GP5+/GP6+ primer sets were then combined to give the total HPV pos­itivity of the cases versus the turbinate control specimens (Table V). Overall, 23 of the tumors (22.3%) were HPV positive versus 0 of the controls (P < .001).

When the presence of HPV DNA in inverted and fungiform papillomas were compared individually to con­trols (Table VI), a stronger pattern emerged. Only a small fraction of the inverted papillomas were positive for HPV (6.8%), but compared to controls, this was statistically sig­nificant (P = .02). However, all 17 fungiform papillomas (100%) were positive for HPV DNA (P < .0001).

The rate of HPV positivity in the inverted papillo­mas versus the fungiform papillomas was compared (Table VII). Only 6.8% of the inverted papillomas versus 100% of the fungiform papillomas were positive for HPV DNA. This difference was strongly statistically signifi­cant (P < .0001).

TABLE III.
MY09/MY11 Consensus Primer Set
on All Tumors Versus Turbinate Controls.

Tumors n (%)

Turbinate Controls (n)

Negative

88

(86.3)

84

Positive

14

(13.7)

0

P < .00014 (Fisher exact test).

TABLE IV.
GP5+/GP6+ Consensus Primer Set on MY Negative Samples.

Tumors n (%)

Turbinate Controls (n)

Negative

79

(89.7)

84

Positive

9

(10.3)

0

P = .0032 (Fisher exact test).

The presence of HPV DNA in carcinomas was com­pared with turbinate control specimens (Table VIII). Al-though HPV DNA was found in one of nine cases (11%) of carcinoma, this was not statistically significant compared with controls (P = .097).

Human papillomavirus typing (Table IX) showed that within the fungiform papillomas, nine contained HPV type 6b (HPV-6b) (53%) and eight contained HPV type 11 (HPV-11) (47%). Of the five inverted papillomas positive for HPV, three were positive with HPV-11 and two were positive with HPV-16. Of the nine carcinomas (SCCa or verrucous), only one carcinoma contained HPV DNA; this contained HPV-18.

DISCUSSION

The search for a viral etiology for Schneiderian pa­pillomas is part of a growing trend seeking to identify in­fectious agents with etiologic involvement in neoplasia. This is typified by the establishment of HPV as a major causative role in cervical neoplasia.25 Since Brandsma et al.26 demonstrated the presence of HPV DNA in Schnei­derian papillomas in 1987, there has been significant in­terest worldwide in assessing a possible role of HPV in SP. Because of the continuing mixed results of reports con­cerning the presence of HPV DNA in SP, we elected to study a large group of Mayo Clinic patients with SP to de­termine the incidence of HPV DNA in the tumors. We also thought it vitally important to include control nasal tissue in the study because of the tremendous sensitivity of PCR, as well as the possibility of laboratory contamination. In addition, although Buchwald et al.27 did not find HPV DNA in normal nasal mucosa by PCR and ISH, we wanted to confirm that in our population of patients, HPV infec­tion of the nasal mucosa was not prevalent in normal in­dividuals. With no HPV DNA confirmed in 84 normal turbinate specimens, it is likely that HPV DNA identified in tumors plays a role in their development.

The study of Schneiderian papillomas is complicated by the fact that there are three distinct histologic sub-types that were recognized by Hyams3 in 1971. This clas­sification scheme has been validated by the distinctly dif­ferent clinical behavior of the fungiform papillomas versus the inverting and cylindric cell papillomas. How-ever, many studies continue to refer only to inverting pa­pillomas. The reader cannot distinguish, then, whether the tumors studied did, indeed, represent only inverting papillomas, or whether the study also included tumors that may be subclassified as fungiform papillomas. For this reason, the present study includes classification of the papillomas by an experienced head and neck patholo­gist into the three subtypes so that discussion of possible etiologies can be subtype-specific.

TABLE V.
MY09/MY11 and GP5+/GP6+ Combined Data.

Tumors n (%)

Turbinate Controls (n)

Negative

79

(77.7)

84

Positive

23

(22.3)

0

P < .0001 (Fisher exact test).

TABLE VI.
Human Papillomavirus Positivity by Tumor Subtype
Versus Controls.

Inverted Papillomas

Fungiform Papillomas

Turbinate Controls

Negative

69

0

84

Positive

5

(6.8%)

17 (100%)

0

P Value

.02

<.0001

Our finding of 78% of the benign tumors belonging to the inverting subtype, 20% belonging to the fungiform subtype, and 2% belonging to the cylindric cell subtype is consistent with previous studies.

To maximize the chances of successful PCR, this study made us of the DNA polymerase AmpliTaq Gold. AmpliTaq Gold is a DNA polymerase that does not become active until it is heated to 95°C for 9 min. This is equiva­lent to a "hot start" PCR by preventing amplification of nonspecific products before cycling begins. According to the manufacturer, this technique is said to increase both specificity and sensitivity (confirmed in our laboratory, data not published). We were able to successfully amplify the (-globin gene in 89% of the cases. Two issues are par­ticularly important in the likelihood of successful amplifi­cation of DNA: specimen age and amplification product size. In a study designed to assess the effects of sample preparation (including age) and PCR product size, Greer et al.28 showed that increasing sample age had a negative impact on the successful amplification of DNA targets greater than 268 bp. In their study, the amplification of a 536-bp segment of the human (-globin gene from forma­lin-fixed, paraffin-embedded tissues was successful in less than 40% of 10-year-old specimens. This is in contrast to greater than 90% success if the amplification product was 268 bp long. These data have widespread implications be-cause many PCR-based HPV studies, including this one, use the MY09/MY11 primer set (a primer set that ampli­fies a 450-bp product) on archived, formalin-fixed, paraf­fin-embedded tissues. Thus the successful amplification of a 268-bp B-globin does not guarantee successful amplifi­cation of a 450 bp HPV product. This provides an advantage to the GP primer set, since it amplifies a 150-bp prod­uct; this increases the likelihood of success using forma­lin-fixed, paraffin-embedded tissues.

TABLE VII.
Combined Data for Inverted Versus Fungiform Papillomas.

Inverted Papillomas Fungiform Papillomas

Negative 69 0

Positive 5 (6.8%) 17 (100%)

P = .0001 (Fisher exact test).

Laryngoscope 109: January 1999 24

 

TABLE VIII.
Human Papillomavirus Positivity of Carcinomas
Versus Turbinate Controls.

Carcinomas

Turbinate Controls

Negative

8

84

Positive

1 (11.1%)

0

P = .097 (Fisher exact test).

Using the MY09/MY11 L1 consensus-primer set, we were able to demonstrate HPV DNA in 13.7% of all SPs, and in none of the controls (P < .00014). When the GP5+/GP6+ primer set was added, the overall HPV posi­tivity rose to 22.3% of all SPs versus 0% of controls (P< .0001). This number is consistent with many reports of HPV in "inverted" papillomas. However, when the in­verted papilloma data are separated from the fungiform papilloma data, a striking pattern emerges. All 17 fungi-form papillomas (100%) were positive for HPV DNA ver­sus only 6.8% of the true inverted papillomas (P < .0001). It should be mentioned that in subsequent experiments (work in progress), using type-specific primer sets de-signed to detect HPV-6b/11, HPV-16, and HPV-18, we have demonstrated HPV-11 DNA in three normal turbinate control specimens. If the presence of HPV DNA in invert­ing papillomas (6.8%) is compared with that of controls (3.6%), there is no statistically significant difference.

These results are nearly identical to those of Buch­wald et al.,19 who studied 78 patients with SP in Den-mark. The authors classified the papillomas according to the system of Hyams,3 and using both ISH and PCR tech­niques, demonstrated HPV DNA in only 6% of inverted papillomas, in 69% of fungiform papillomas, and in none of the cylindric cell papillomas. Our results are also nearly identical to those of Gaffey et al.,17who studied 28 SP us­ing ISH and PCR. They found HPV in only 5% of invert­ing papillomas and in 100% of fungiform papillomas.

In contrast to our study and those mentioned above, a number of studies have identified HPV DNA in a significant number of inverted papillomas. One such study, performed by Beck et al.,20 demonstrated HPV DNA by PCR using con­sensus primers for the L1 region in 63% of inverted papillo­mas. They did not mention fungiform papillomas, however, raising the possibility that this histologic subtype was in­cluded in the analysis. Bernauer et al.,13 in a study of 21 in­verted papillomas using consensus primers for the L1 region, found HPV DNA in seven (33%). Although those au­thors, like Beck et al., did not mention the fungiform sub-type, they did state that features of inversion into the un­derlying stroma were identified, a classic feature of inverting papilloma. Similar results were obtained by Kashima et al.,12 who found HPV DNA in 24% of inverting papillomas and 15% of fungiform papillomas. Likewise, McLachlin et al.15 found HPV DNA in 3 of 15 (20%) inverted papillomas and in 3 of 5 (60%) fungiform papillomas. Wu et al.,14 using type-specific primers for HPV type 57b (HPV-57b), demonstrated HPV-57b DNA in 86% of inverted pa­pillomas. Our laboratory used these primers and found no HPV-57-positive papillomas (data to be published in a fu­ture report using multiple type-specific primer sets.) This, combined with the fact that HPV-57 should be detected by the consensus primers MY09/MY11 and GP5+/GP6+, makes it unlikely that HPV-57 plays a role in the tumors studied in this study.

TABLE IX.
Human Papillomavirus (HPV) Typing Versus Tumor Histology.

HPV Type

Fungiform Papillomas (n)

Inverted Papillomas (n)

Carcinomas (n)

6b

9

0

0

11

8

3

0

16

0

2

0

18

0

0

1

The question arises of how to reconcile the conflicting results between the groups finding HPV DNA in signifi­cant percentages of inverting papillomas and those groups which do not, including the present study. Several explanations are possible. One is differences in methodol­ogy. Could certain techniques be more sensitive than oth­ers? This is possible, but two facts suggest that this is not the case. First, in the present study, PCR using two sepa­rate, widely used sets of L1 consensus primers was per-formed. It has been demonstrated that the use of two or more consensus primer sets has a higher sensitivity in HPV detection than any one set alone.29,30 In addition, studies have shown that the smaller the PCR product is, the more likely it is to be successfully amplified from for­malin-fixed, paraffin-embedded specimens.24.28.31 This makes the GP5+/GP6+ primer set ideal, as it amplifies a 150 bp segment of DNA. Second, HPV DNA was detected in 100% of the fungiform papillomas. This demonstrates the efficiency of the double primer set technique in de­tecting HPV DNA in samples containing it.

If differences in technique cannot explain the disparate results of different groups of researchers, perhaps epidemio­logic factors play a role. It is not yet known where the origin of HPV infection of the head and neck is, or what the route of transmission is. Certainly, the possibility that the source is from anogenital locations exists, given the predominance of the same HPV types in SP and in anogenital HPV-related diseases. If this is the case, differences in the epidemiology of anogenital HPV infection could explain differences in HPV DNA positivity in inverting papillomas. Clearly, there may be more than one mechanism of alteration of cell growth and differentiation (i.e., HPV infection in some tumors, and other factors, such as smoking, in others). A third possible expla­nation is that there may be novel HPV types in this group of tumors that are not detected using the current conventional "consensus" primers. At the present time, this is an unverifi­able hypothesis. Fourth, the role of the immune system, which may allow some patients to "clear" their viral infection while others develop chronic infection, is unknown.

This study confirms a strong relationship between HPV infection with HPV-6b/11 and fungiform papillomas, given that 100% of the fungiform papillomas studied were HPV DNA positive. This is consistent with most previous studies. The high rate of positivity may be related to the high sensitivity of a "two consensus-primer sets" ap­proach. This study supports the concept that, at least in a large group of tumors treated at the Mayo Clinic, two dif­ferent etiologies exist for fungiform papillomas versus in­verting and cylindric cell papillomas. Only a small minor­ity of inverting papillomas appear to be HPV related in this population. Other factors such as cigarette smoking may be more important in this population.

The presence of HPV-16 in two of the five inverted papillomas that were HPV DNA positive, and of HPV-18 in the only carcinoma that was HPV DNA positive, de-serves mention. HPV-16 and HPV-18 have been consis­tently identified in cervical carcinomas, whereas HPV-6b and HPV-11 play a role in benign genital warts and mild dysplasia.32 In particular, HPV-18 appears to predominate in high-grade and biologically more aggressive cervical carcinomas.33 Although it was only identified in this one tumor, these data would suggest that HPV-16 and HPV-18 may play a role in a subset of inverted papillomas and re­lated malignancies. A similar trend has been noted by other authors.12.13.15.19,20

Further work is required to confirm the absence of HPV infection in the majority of inverting and cylindric cell papillomas, as well as to study the clinical behavior of inverting papillomas and carcinomas which are HPV pos­itive versus those which are not. In addition, the potential role of the immune system in the persistence of HPV in­fection and development of tumors should be studied to better understand the pathogenesis of this interesting group of nasal tumors.

CONCLUSION

Studies of Schneiderian papillomas need to carefully distinguish the different histologic subtypes, as their eti­ology, clinical behavior, and required treatment are likely to be different. HPV-6b and HPV-11 appear to be involved in all cases of fungiform papillomas but are only rarely in­volved in cases of inverting or oncocytic cell papillomas. HPV-16 may rarely play a role inverting papillomas, and HPV-16 and HPV-18 may be involved in a subset of cases of carcinomas originating in an inverting papilloma.

ACKNOWLEDGMENT

The authors gratefully acknowledge the significant assistance of Ms. Renee McGovern in conducting the lab-oratory work.

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