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Report on the immunohistochemical detection of genus-specific papillomavirus antigen with an immunoperoxidase technique - in a papilloma of the caruncle, in which papillomavirus-specific DNA was previously successfully, demonstrated in a virological examination by means of hybridization of nucleic acid.
OBJECTIVE: To evaluate the pathological features and variations of sinonasal inverted and oncocytic papillomas and correlate the microscopic findings with the clinical behavior. STUDY DESIGN: A retrospective review and pathological assessment. METHODS: A retrospective review and pathological assessment were performed on 40 patients with a diagnosis of inverted papilloma treated by the senior author (w.l.) between 1994 and 2001. RESULTS: Forty cases were identified and reviewed. Seven patients developed recurrences (18%), and four underwent malignant transformations (10%). Pathological assessment revealed 34 (85%) inverted papillomas and 6 (15%) oncocytic schneiderian papillomas. Dysplasia was present in 26 cases (65%), including 9 cases (22%) of high-grade dysplasia (moderate to severe). Metaplasia of the sinonasal mucosa adjacent to inverted papillomas and oncocytic schneiderian papillomas was seen in 18 (45%) cases. Recurrence developed in two patients with oncocytic schneiderian papillomas (33%) and five patients with inverted papillomas (15%). Four cases (10%) of carcinoma ex papilloma were seen; one arose from oncocytic schneiderian papilloma (17%), and three arose from inverted papilloma (9%). Oncocytic schneiderian papilloma was more often mixed with typical inverted papilloma, rather than presenting in its pure form. CONCLUSIONS: Although oncocytic schneiderian papilloma is uncommon relative to inverted papilloma, the results suggest that they have higher rates of both recurrence and malignant transformation. The common admixture of oncocytic schneiderian papilloma with inverted papilloma speaks for a common etiological factor of these two lesions. A larger number of cases for analysis would be necessary to confirm the trend noted in our data. Nonetheless, pathological findings consistent with oncocytic schneiderian papilloma should be explicit in any classification system and justify aggressive treatment and careful postoperative surveillance.
Five solitary squamous papillomas of bronchus with variable degrees of dysplasia, one combined with a laryngeal papilloma and with a neuroendocrine carcinoma in the contralateral lung, and five papillomas combined with invasive squamous cell carcinomas were investigated for their expression of human papilloma virus DNA by in situ hybridization. Benign squamous cell papillomas showed an association with papilloma virus type 11 and rarely type 6, whereas types 16 or 18, sometimes in combination with types 31/33/35 were found in papillomas associated with carcinomas. In one patient a benign papilloma containing human papilloma virus type 18 and 31/33/35-positive preceded a recurrence combined with carcinoma by 2 years; this recurrent papilloma and the carcinoma were also positive for human papilloma virus 18 DNA. We suggest that human papilloma virus typing should be performed in every squamous cell papilloma of bronchus. Patients with papillomas exhibiting human papilloma virus 16 or 18 positivity are at high risk for the development of squamous cell carcinoma. Furthermore, virus typing may be of prognostic importance in relation to the development of squamous carcinoma.
Papilloma virus DNA from a laryngeal papilloma was cloned in phage lambda L 47 and characterized after cleavage with different restriction enzymes. Hybridization with the DNAs of human papilloma virus types 1, 2, 3, 4, 5, and 8 showed no homology under stringent hybridization conditions. Human papilloma virus type 6 DNA, however, was partially identical to laryngeal papilloma virus DNA; different restriction enzyme fragments hybridizing with the other DNA were identified on each genome. The degree of homology was determined by reassociation kinetics to be 25%. According to the present nomenclature, laryngeal papilloma virus therefore represents a different type of human papilloma virus and is tentatively designated as human papilloma virus type 11. Sequences homologous to laryngeal papilloma virus DNA were also found in four of nine additional laryngeal papillomas. Attempt to detect homologous DNA in 12 carcinomas of the larynx were negative.
OBJECTIVES: To determine a putative role and relation between human papilloma virus (HPV) and p53 in the etiology of sinonasal carcinomas associated with papillomas. STUDY DESIGN: The study group consists of all patients with sinonasal carcinomas associated with papillomas diagnosed in Denmark from 1980 to 1998. After reviewing our national pathological files, tumor tissues from 36 patients were collected, comprising 15% of the total cases of sinonasal carcinomas. In 35 cases a squamous cell carcinoma was demonstrated and in one case an adenocarcinoma was evident. Inverted papilloma was associated with carcinoma in 31 cases and exophytic papillomas in 5 cases. The material was investigated for HPV using polymerase chain reaction analyses with two sets of consensus primers (GP5+/GP6+ and MY09/MY11). The HPV-positive cases were submitted to dot-blot hybridization to establish the HPV type. Using immunohistochemistry, the p53 expression was determined. A p53 overexpression is defined as positive staining in 10% or more of the tumor cells. RESULTS: Among 30 examined cases of carcinomas associated with inverted papillomas, 4 cases were HPV-positive (13%). P53 overexpression was not shown among the HPV-positive cases, whereas p53 overexpression was seen in 21 of the 24 (88%) examined HPV-negative cases. Among the 5 carcinomas associated with exophytic papillomas, HPV was demonstrated together with p53 overexpression in 3 cases (60%). In addition, one case more was with p53 overexpression. CONCLUSION: An inverse relation between HPV and p53 overexpression in sinonasal carcinomas associated with inverted papillomas appears to have been demonstrated. HPV and p53 might also have an etiological role among the carcinomas associated with exophytic papillomas.
To investigate the histopathological characteristics of inverted papillomas of the urinary bladder, including the possibility of malignant transformation, we studied the indicators of cellular proliferation activity in 7 inverted papillomas of the bladder including two cases of malignant inverted papilloma of the bladder. PCNA expression rates in two cases of malignant inverted papilloma were higher than in benign inverted papillomas. Mean numbers of AgNORs per nucleus in malignant inverted papillomas were much more than in benign inverted papillomas. The c-erbB-2 oncoprotein was expressed only in malignant inverted papillomas. These results suggest that PCNA expression rate, mean number of AgNORs per nucleus and c-erB-2 oncoprotein expression may be merited as good indicators to detect the inverted papilloma with more proliferative and aggressive lesions, and with the potential of malignant transformation.
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Immunologic evaluations of women with genital neoplasia-papilloma syndrome demonstrated the presence of subclinical immunodeficiency when compared with results in 20 control women. All patients with genital neoplasia-papilloma syndrome were previously found to have human papillomavirus deoxyribonucleic acid in genital neoplasias or papillomas occurring either synchronously (in at least two genital organs at the same time) or metachronously (at different times during a period of months to years). Immunologic tests included blastogenic responses of lymphocytes to mitogens (phytohemagglutinin, concanavalin A, pokeweed mitogen, and tetanus antigen) and lymphocyte phenotyping with the use of monoclonal antibodies (OKT3, OKT4, OKT8, and OKT11). As compared with those of control subjects, the responses of the lymphocytes of patients with genital neoplasia-papilloma syndrome to mitogens were significantly decreased. The group with genital neoplasia-papilloma syndrome had a significantly higher percentage of suppressor-cytotoxic T cells (OKT8-positive cells) when compared with that of control subjects (mean 33% versus 18%) and a lower proportion of helper T cells (OKT4-positive cells) when compared with that of control subjects (35% versus 50%). The mean helper-to-suppressor/cytotoxic T-cell ratio (mean OKT4/OKT8 ratio) in the human papillomavirus-infected women was 1.72 +/- 0.29 (SE) as compared with 3.21 +/- 0.33 (SE) in the control group, demonstrating a significant reduction of the ratio in the patients with genital neoplasia-papilloma syndrome. These findings suggest that patients with genital neoplasia-papilloma syndrome have a reduced suppressor/cytotoxic T-cell ratio (mean OKT4/OKT8 ratio; that in the human papillomavirus-infected women was 1.72 +/- 0.29 (SE) as compared with 3.21 +/- 0.33 (SE) in the control group, demonstrating a significant reduction of the ratio in patients with genital neoplasia-papilloma syndrome. These findings suggest that patients with genital neoplasia-papilloma syndrome have reduced immunocompetence of unknown etiology.
The induction of mouse skin papillomas in two stages by initiation-promotion protocols has been studied extensively. On the basis of kinetics of induction and morphological observations of apparent progression to carcinomas, it has been argued that the papillomas sequentially advance to carcinomas through promoter-dependent and promoter-independent premalignant stages. Although this hypothesis has been widely accepted, the step-wise development of the same cell population from papilloma to carcinoma has not been established at the cellular level. We show here that some carcinomas which morphologically appear to result from progression of promoter-dependent papillomas do not develop from sequential progression of the same cell population as was found in the original papillomas. Other initiated cells also participate during the growth of these tumors and may replace the original papilloma cells. We also present evidence that some tumors develop directly as promoter-independent papillomas without going through an apparent promoter-dependent papilloma stage.
In this study we analyzed the mutations in c-Ha-ras from skin papillomas initiated with benzo[a]pyrene (B[a]P), 7-methylbenz[a]anthracene (7-MBA), and 10-fluoro-7-methylbenz[a]anthracene (10-F-7-MBA) and from papillomas induced by treatment with tumor promoter alone. Among the papillomas induced by treatment with tumor promoter alone, 56% (nine of 16) had mutations in c-Ha-ras. These mutations were found primarily in codon 61 and included both A182-->T and A182-->G mutations. In addition, one promoter-induced tumor had a G35-->A mutation in codon 12, and one had a G37-->C mutation in codon 13. The other promoter-induced papillomas did not have detectable mutations in codons 12, 13, or 61. Most of the B[a]P-initiated papillomas (77%; 10 of 13) did not have detectable mutations in c-Ha-ras codons 12, 13, or 61. However, three of these B[a]P-initiated papillomas had c-Ha-ras codon 13 mutations; one had a G37-->C transversion and two had G38-->T transversions. Most of the 7-MBA-initiated tumors and all of the 10-F-7-MBA-initiated tumors had an activated c-Ha-ras gene [nine of 10 (90%) and 11 of 11 (100%), respectively]. These mutations were almost exclusively A182-->T transversions in codon 61 except for two 7-MBA-initiated papillomas that had G37-->C transversions in codon 13. The results suggest that more than one mechanism may contribute to activation of c-Ha-ras by polycyclic aromatic hydrocarbons (PAHs) in mouse skin. Furthermore, the absence of c-Ha-ras mutations in most B[a]P-initiated papillomas, as well as in a significant fraction of those induced by tumor promoter alone, suggests that there may be other molecular targets involved in tumor initiation by PAHs in mouse skin.
A series of 19 paraffin-embedded sinonasal papillomas (four squamous papillomas, three fungiform papillomas, nine inverted papillomas, and three cylindrical cell papillomas) were investigated for evidence of human papillomavirus (HPV) infection using immunohistochemistry (polyclonal antibody to HPV capsid antigen), in situ hybridization (DNA probes for HPV 6/11, 16/18, and 31/33/35), and the polymerase chain reaction (primers and probes for HPV 6, 11, 16, 18, and 33). All three fungiform papillomas were positive by all three techniques: immunohistochemistry, in situ hybridization for HPV 6/11, and the polymerase chain reaction for HPV 11. None of the other lesions contained detectable HPV using the specific probes included in this study. These results support the continued classification of fungiform papilloma as a distinctive variant of schneiderian papilloma characterized by a predominantly exophytic growth pattern and an association with HPV 11.
OBJECTIVE: To determine the association of p53 protein in malignant cases of inverted papilloma compared with cases of benign inverted papilloma of the sinonasal tract. DESIGN: Case-control study of archived pathologic material. SETTING: Tertiary care hospital. METHODS: Archived pathologic material of cases of malignancy associated with inverted papilloma and controls of benign inverted papilloma were obtained from Mount Sinai Hospital. These were subjected to immunohistochemistry for p53. Clinical correlation was obtained by retrospective chart review. MAIN OUTCOME MEASURES: Staining of pathologic specimens for p53 and survival or recurrence. RESULTS: Four of the five cases of malignancy associated with inverted papilloma demonstrated overexpression of p53. None of the benign cases of inverted papilloma demonstrated overexpression. Only two of the five patients with malignancy associated with inverted papilloma were alive at 2 years. CONCLUSIONS: Overexpression of p53 may serve as a marker for malignant transformation of inverted papilloma.
Carcinomas arising in pre-existing sinonasal papillomas of the nasal septum are rare. To our knowledge only one case has been reported. We report two cases of carcinomas occurring in septal papillomas. In the first case a carcinoma developed in an exophytic papilloma 16 years after the first operation for a papilloma. In the second case a carcinoma was present at the first presentation within an inverted papilloma, and a metastasis had also developed. In the first case HPV type 6/11 was demonstrated by in-situ hybridisation and PCR in the original papilloma as well as in the recurrent papilloma and in the carcinoma. In the second case HPV type 18 was found in the nasal lesion as well as in the metastasis. All samples were examined for Epstein-Barr virus (EBV) by PCR, but with negative results. We believe that case one is the first reported case of carcinomatous transformation within an exophytic septal papilloma.
Retinoic acid (RA) was topically applied to the skin of Sencar mice during the promotion phase of specific tumor induction protocols that produce papillomas at low (12-O-tetradecanoylphorbol-13-acetate promoted, TPA) or high (mezerein-promoted) risk for premalignant progression and malignant conversion. RA consistently reduced the yield of papillomas and carcinomas in both protocols, but the frequency of malignant conversion in papillomas that emerged during RA treatment was not reduced. When TPA was reapplied after cessation of RA treatment, the number of papillomas increased 2-fold, suggesting that RA had not eliminated initiated cells. In vitro, RA prevented the emergence of transformed keratinocytes in an assay that mimics malignant conversion, suggesting that RA can suppress conversion if applied during the stage of premalignant progression. Examination of tumor markers at weeks 14 and 22 of the tumor-induction experiments in vivo indicated that papillomas evolving during RA treatment exhibited a phenotype of high progression risk, even in the TPA-promoted groups. In the majority of these tumors, the alpha6beta4 integrin and retinoid X receptor alpha transcripts were detected suprabasally, indicating an advanced state of premalignant progression. RA-treated tumors also expressed higher levels of transcripts for transforming growth factor (TGF)-beta1 and localized TGF-beta1 peptide in the basal portions of the tumor fronds. Because up-regulated expression of TGF-beta1 suppresses papilloma formation, these studies suggest a mechanism whereby RA can prevent papilloma eruption via a TGF-beta intermediate, but papillomas resistant to RA may have altered TGF-beta signaling and progress to carcinomas at an increased frequency.
Juvenile laryngeal papillomas, solitary laryngeal papillomas of the adult, and cylindric cell papillomas of the nose and sinuses were examined for the presence of papillomavirus antigens by means of immunocytochemistry. By using an antiserum capable of recognizing a common group antigen that reacts with papillomavirus antigens of different species, it was found that half of the juvenile laryngeal papillomas studied contained cells staining for papillomavirus antigens. No positive cells were found in adult solitary papillomas or cylindric cell papillomas. These results strongly implicate a human papillomavirus as the causative agent of juvenile multiple laryngeal papillomas.
The results obtained by a fluorescent antibody study of the Shope papilloma virus in papillomas of the wild and domestic rabbit are presented. In the wild rabbit papillomas the viral antigens occurred exclusively in the nucleus and were present in the differentiating cells of the keratohyaline layers and in the keratinized layers. The antigens were not present in the deeper proliferating epithelial cells of the papillomas. The Shope viral antigens were present in very minute amounts in papillomas of the domestic rabbit, as compared with papillomas of the wild rabbit, and were only detected in the superficial keratinized layers. It is postulated that virus is present in the nuclei of the proliferating cells of the papillomas of the wild and domestic rabbit but exists there in an early stage of development, consisting mainly of nucleic acid and deficient in protein, therefore non-antigenic and not demonstrable by fluorescent antibody. The nucleic acid moiety of the virus may be infective, and the protein component may provide immunologic specificity and serve to preserve transmissibility. The protein-deficient virus can be referred to as masked virus.
Three cell lines from adult domestic rabbit are infected with SV40: LP 17 and LP 45 derived from normal skin and LP 42 PS derived from skin infected for 24 h with Shope papilloma virus. The fibroblastic morphology of the cultures is not changed. SV40 is not recovered and T antigen is only detected in LP 42 PS cell line after 29 passages. To know if Shope papilloma virus facilitates penetration of SV40, cultures of LP 45 are first infected with Shope papilloma virus for 2 h and for 24 h, then superinfected with SV40. There is no cellular alteration, and T antigen induced by SV40 is only detected in cells pretreated for 24 h with Shope papilloma virus, after 20 passages. When cultures LP 45 are infected with Shope papilloma virus neutralized with a high titer antiserum and superinfected with SV40, T antigen is not detected. Superinfected cells containing specific SV40 T antigen do not induce tumors either in new born hamsters or in rabbits but they are able to grow in colonies in soft agar. LP 42 PS cell line and LP 45 cells infected with Shope papilloma virus for 24 h containe Shope papilloma virus genome which is able to modify the permissivity of rabbit cells to SV40.
Nineteen clinically diagnosed, and histologically confirmed oral squamous cell papillomas were analyzed for the presence of human papilloma virus DNA sequence by the highly sensitive polymerase chain reaction technique, followed by dot blot hybridization of the polymerase chain reaction product with digoxigenin-labeled, type-specific oligonucleotide probes for human papilloma virus DNA types 6, 11, 16, and 18. Human papilloma virus DNA types 6 and 11 were identified in 68% of these oral lesions, which raises the possibility of an etiologic role for human papilloma virus in the pathogenesis of oral squamous cell papillomas.