Solitary condylomatous papilloma of the bronchus

Two case reports of solitary bronchial papillomas are presented. The histologic features of the lesions are those of squamous papillomas exhibiting prominent condylomatous changes. Immunoperoxidase stains revealed the presence of human papillomavirus antigens in the koilocytotic cells. Ultrastructural studies demonstrated possible intranuclear viral-size particles. Solitary condylomatous papillomas of the bronchus should be distinguished from solitary bronchial squamous papillomas that do not have condylomatous features. The rationale for this separation is the likelihood of a viral origin for these condylomatous papillomas and their potential for malignant change.     

Human papillomavirus (HPV) genotypes associated with laryngeal papilloma.

Biopsy specimens from 14 patients treated for laryngeal papillomatosis were tested for the presence of human papillomavirus (HPV) genome by the technique of DNA-DNA hybridisation. According to the age of initial presentation, cases were subdivided into juvenile (less than 16 years) and adult onset (older than 16 years) groups. Histological investigation confirmed that it was impossible to distinguish the groups on this basis. Molecular virology using both dot blot and Southern transfer techniques showed that 10 cases carried the HPV type 6 genome, three cases HPV type 11, and in one case no HPV DNA was detected. All six adult onset cases carried HPV 6 sequences while the juvenile onset group comprised four HPV 6 and three HPV 11 cases. In the juvenile onset group more females were affected; in the adult onset group more males were affected. Two of the patients shown to have HPV type 11 sequences in their biopsy material were the most resistant to treatment. One of the adult onset cases subsequently developed a squamous cell carcinoma of the larynx in which HPV 6 DNA was detected. As far as we know this is first time that HPV-DNA has been confirmed in laryngeal papilloma undergoing malignant change.     

Solitary squamous cell papilloma of the lung in a 40-year-old woman with recurrent laryngeal papillomatosis

A rare case of recurrent respiratory papillomatosis (RRP) is reported with a review of the literature. A 40-year-old Japanese woman had suffered from RRP since 1 year of age. She developed a pulmonary squamous papilloma with a thin-walled cavity, which was suspected as being lung carcinoma. The trachea and bronchi around the tumor were intact, and no malignant transformation was present. Two types of human papillomavirus, 6 and 16, were detected, both in the laryngeal and pulmonary papillomas by in situ hybridization and the polymerase chain reaction method. To date, only 40 cases of juvenile laryngeal papilloma with pulmonary involvement have been reported in the English literature.     

Epithelial expression of HLA-DR antigens in laryngeal papillomas with a dense inflammatory reaction

Thirty six laryngeal papillomas taken from 11 children and 10 adults were investigated with an indirect immunofluorescence technique for the occurrence of T cell subsets, Langerhans cells and HLA-DR antigen using specific monoclonal antibodies. A mild local cellular immune response was preferentially associated with juvenile laryngeal papillomas, whereas a more intense inflammatory reaction with T8 cell infiltration and large amounts of Langerhans cells in the chorion and the epithelium was observed in adult lesions. Some lesions either from adults or children characterized by high densities of lymphoid and dendritic cells exhibited the expression of DR antigen by epithelial cells. This result may suggest either a role of lymphokines released by activated T cells or a direct effect of viral infection on epithelial cells inducing DR antigen in laryngeal papillomas.     

Human papillomavirus DNA in respiratory papillomatosis detected by in situ hybridization and the polymerase chain reaction.

The authors have demonstrated the presence of human papillomavirus (HPV) types 6 and 11 in 10 of 13 (77%) juvenile laryngeal papillomatosis by in situ DNA hybridization using as probes the radiolabeled DNAs of HPVs 6, 11, 16, and 18. Of six specimens from adult laryngeal papillomatosis assayed by the same technique, only 33% were positive. Immunohistochemistry to detect HPV capsid antigens performed on serial sections gave positive signals in 44% (8 of 18) of the specimens, all from juvenile lesions. These results were in agreement with in situ hybridization, except in two cases. When both series (juvenile and adult) were analysed by amplification of a 450-bp fragment corresponding to the L1 ORF of the HPV genomes directed by the polymerase chain reaction, the frequency of positive specimens rose to 100%. Our data agree with the concept that HPV is implicated in the etiology of laryngeal papillomatosis.     

Deletion in the L1 open reading frame of human papillomavirus type 6a genomes associated with recurrent laryngeal papilloma

Human papillomavirus (HPV) type 6a genomes with a large deletion in their L1 open reading frames (ORF) were found in two of five recurrent cases of laryngeal papilloma. One of these mutant HPVs had a 186 base pair (bp) deletion near the N-terminus end of the L1 ORF, which encodes a major capsid protein. The other had a 454 bp deletion at the C-terminus end of L1 at which is located a nuclear localising signal (NLS). No other large deletion or insertion was found in the remaining regions of all five HPV6a genomes. The laryngeal papillomas which harboured the mutant viruses showed typical hyperplasia and pathological changes as observed in tumours induced by the wild-type virus. The biological significance of the two large deletions in the late region of HPV6a associated with laryngeal papilloma is discussed. © Wiley-Liss, Inc.     

Detection of the human papillomavirus 6b E2 gene product in genital condyloma and laryngeal papilloma tissues

We have previously reported that the E2 open reading frame of human papillomavirus type 6b (HPV6b) was expressed in Bombyx mori cell line Bm-N as a fusion protein with baculovirus polyhedrin. Here we show that antibody against this E2-polyhedrin fusion protein recognized a putative gene product as a 49-kDa protein in some genital condyloma and laryngeal papilloma tissues, which were associated with HPV6 and HPV11, by immunoblotting analysis. The antibody reacted also with antigens in the nucleus of cells in the middle and upper layers of these papilloma tissues.     

The predictive value of human papilloma virus (HPV) typing in the prognosis of bronchial squamous cell papillomas

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.     

Frequency and distribution of papillomavirus structural antigens in verrucae, multiple papillomas, and condylomata of the oral cavity

Sixty-seven proliferous squamous epithelial lesions of the oral cavity were examined for the presence of human papillomavirus whole (structural) virion antigens by a peroxidase-antiperoxidase technique having immunospecificity against genus-specific (common) antigens of the papillomaviruses. A positive reaction for papillomavirus genus specific antigens was found in 18 of 29 verrucae, 2 of 5 multiple papillomas, and 3 of 5 condylomata; common antigens were not detected in 28 keratoacanthomas. The positive reaction was invariably intranuclear in cells having a focal or diffuse distribution in the superficial epithelium. This study shows that a variety of squamous epithelial lesions of the mucosa are associated with human papillomaviruses and suggests that these viruses may play an important role in the etiology of some cases of squamous hyperplasia of the oral cavity.     

Pleomorphic (spindle and squamous cell) carcinoma arising in a peripheral mixed squamous and glandular papilloma in a 70-year-old man

Solitary papillomas of the bronchial tree are rare, particularly in the distal airways. When encountered, solitary papillomas are not frequently found to undergo malignant transformation. When this does happen, it is usually a squamous cell carcinoma arising in a human papillomavirus-associated squamous papilloma (usually in a central airway). Here we report a unique case of pleomorphic (spindle and squamous cell) carcinoma arising in a mixed glandular and squamous papilloma without human papillomavirus association.     

Laryngeal papillomatosis: molecular,histopathological, and clinical evaluation

Molecular, histopathological, and clinical studies were carried out on a series of 79 laryngeal papillomas (LP) from 36 patients in order to investigate the hypothesis that juvenile and adult LP may represent a biological entity causally related to Human papilloma virus (HPV) infection. Using in situ hybridization with biotin-labelled probes and polymerase chain reaction, we detected human papilloma virus (HPV) 6/11 in 28 of 29 juvenile LP, in 26 of 30 adult multiple, and in 17 of 20 adult solitary LP. None of LP was found to harbour HPV types 16, 18, 31, 33, and 51. There were no clear-cut histological differences between juvenile and adult LP, the presence of koilocytosis was equally observed in both, and there was no prevalent type of epithelial hyperplasia in either form, except that all three cases of atypical hyperplasias (precancerous lesions) were found among adult patients. During a 14 year follow-up, no carcinomatous transformation of LP was observed. All juvenile LP in our study had frequent recurrences of the disease, however, numerous surgical procedures were also required in 16 of 27 adult patients. Our study supports Lindeberg's hypothesis of a similar pathogenesis for all forms of LP caused by the HPV types 6/11.     

Virus expression EGF and transferrin receptors in human papillomas

Summary Thirty five non regressing cutaneous and mucosal human papillomas were studied for the expression of EGF and transferrin receptors by indirect immunofluorescence on frozen sections. The lesions were also examined for the presence of human papillomavirus (HPV) DNA by in situ-hybridization with biotinylated probes and viral capsid antigen. The mapping of EGF and transferrin receptors was modified in cutaneous lesions with drastic viral cytopathic effects and was enhanced in mucosal lesions mainly in laryngeal papillomas, which are poor virus producers. The greatest increase in EGF and transferrin receptor reactivity was observed in the group of mucosal lesions in which viral DNA was more frequently detected than viral antigen. This suggests that viral DNA may play a role in basal cell stimulation. Moreover some of these lesions with dense inflammatory reactions showed DR antigen expression by epithelial cells. Our findings indicate that epithelial cell activation in papillomas might be modulated by other factors than HPV such as mediators of the local immune response.This work was supported by grants from Féderátion Nationale des Centres de Lutte Centre le Cancer, 1985 and Fondation Mérieux, Lyon, France     

Psittacid herpesviruses associated with mucosal papillomas in neotropical parrots

Mucosal papillomas are relatively common lesions in several species of captive neotropical parrots. They cause considerable morbidity and in some cases, result in mortality. Previous efforts to identify papillomavirus DNA and proteins in these lesions have been largely unsuccessful. In contrast, increasing evidence suggests that mucosal papillomas may contain psittacid herpesviruses (PsHVs). In this study, 41 papillomas from 30 neotropical parrots were examined by PCR with PsHV-specific primers. All 41 papillomas were found to contain PsHV DNA. This 100% prevalence of PsHV infection in the papilloma population was found to be significantly higher than PsHV infection prevalence observed in other surveys of captive parrots. PsHV genotypes 1, 2, and 3, but not 4 were found in these lesions. Psittacus erithacus papillomavirus DNA and finch papillomavirus DNA were not found in the papillomas. A papilloma from a hyacinth macaw (Anodorhynchus hyacinthinus) was found to contain cells that had immunoreactivity to antiserum made to the common antigenic region of human papillomavirus (HPV) L1 major capsid protein. However, four other mucosal papillomas were negative for this immunoreactivity, and negative control tissues from a parrot embryo showed a similar staining pattern to that seen in the cloaca papilloma of the hyacinth macaw, strongly suggesting that the staining seen in hyacinth macaw papilloma was nonspecific. Based on these findings, it was concluded that specific genotypes of PsHV play a direct role in the development of mucosal papillomas of neotropical parrots and there is no evidence to suggest the concurrent presence of a papillomavirus in these lesions.     

儿童喉乳头状瘤组织中Survivin及Caspase-3蛋白表达及相关性研究

目的:研究儿童喉乳头状瘤中survivin及caspase-3蛋白的表达及其相互关系.方法:应用免疫组化方法对儿童喉乳头状瘤组织、儿童声带小结组织及正常的喉黏膜组织中survivin及caspase-3的表达进行检测并进行相关性分析.结果:42例儿童喉乳头状瘤组织中survivin阳性表达率为57.14%, 明显高于儿童声带小结组(P<0.01)和正常黏膜组(P<0.01);42例喉乳头状瘤组织中caspase-3阳性表达率为26.19%, 显著高于儿童声带小结组和正常喉黏膜组 (P<0.01);Spearman相关性分析显示, 儿童喉乳头状瘤中survivin与caspase-3的表达呈显著负相关(r=-0.682, P<0.01).结论:Survivin的高表达和caspase-3的低表达可能在儿童喉乳头状瘤发生发展过程中起着重要作用.     

Impact of genetic changes to the CRPV genome and their application to the study of pathogenesis in vivo

The cottontail rabbit papillomavirus (CRPV)/rabbit model has been used to study oncogenicity and immunogenicity of different antigens from the papillomavirus genome and has therefore served as a preclinical model for the development of preventive and therapeutic vaccines against papillomavirus infections. One unique property of the CRPV model is that infection can be initiated using viral DNA. This property allows for the functional testing of viral mutants in vivo. We have introduced point mutations, insertions and deletions into all of the different coding and non-coding regions of the CRPV genome and have tested their infectivity in this model. We found that the majority of the mutant genomes retained viability and could induce papillomas in domestic rabbits. These data indicated that the CRPV genome is tolerant of many modifications without compromising its ability to initiate skin papillomas. In combination with our recently established HLA-A2.1 transgenic rabbit model, this plasticity allows us to extend the utility of the CRPV/rabbit model to the screening of HLA-A2.1 restricted epitopes from other human viral and tumor antigens.     

Chronic cavitary respiratory papillomatosis

A 19-year-old white man with multiple recurrences of respiratory papillomatosis was admitted for recurrent left lower lobe pneumonia and lung abscesses. He was found to have a single large laryngeal papilloma, widespread bronchial papillomatosis, and large cavitary lesions of the left lower lobe. A lobectomy was performed. The smooth-walled, squamous-lined cavities contained large numbers of papillomas, which were strongly positive for human papillomavirus type 11 by in situ DNA hybridization. Findings of evaluation of the patient's humoral and cell-mediated immunity were within normal limits. Cavitation appears to have resulted from bronchial obstruction, postobstructive pneumonia, and liquefactive necrosis. We speculate that squamous metaplasia allowed the continued proliferation of papillomavirus within the cavities.     

Prevaccination genomic diversity of human papillomavirus genotype 6 (HPV 6)

Prevaccination genomic diversity of human papillomavirus genotype 6 (HPV 6) was established by sequencing 3798 bp of 77 clinically important HPV 6 isolates obtained from 45 and 32 patients with genital warts and laryngeal papillomas, respectively. By analyzing pooled L1, LCR, E6, E2, and E5 nucleotide data of an individual isolate, a total of 36 different genomic variants were identified, of which six (12 isolates), one (one isolate) and 29 (64 isolates) corresponded to HPV 6b, HPV 6a, and HPV 6vc genetic lineages, respectively. Several novel, potentially important mutations were identified. Non-prototypic HPV 6vc genomic variants were found in the majority of genital warts and laryngeal papillomas included in the study. The presence of serious HPV 6 genome sequence errors was confirmed and novel sequence errors were identified in sequence repositories.     

Intra- and extrathymic B cells in physiologic and pathologic conditions

Summary Normal thymuses and thymuses with lymphofollicular hyperplasia have been examined immunohistologically using immunoenzymatic single and double labelling methods and a panel of monoclonal antibodies against B lymphocyte differentiation antigens (CD19-, CD20-, CD21-, CD22-, CD23- and CD37ag) and human immunoglobulins (IgM, IgD) for the presence and localisation of B lymphocytes and cells expressing B cell differentiation antigens. The numerous hyperplastic lymph follicles which occur in the pathological condition of lymphofollicular hyperplasia of the thymus were found to originate in the extrathymic compartment of the interlobular septal space. This area was found to be blown up by the growing lymph follicles with exactly the same cellular composition as their counterparts in the peripheral lymphatic tissue. Some of the B lymphocytes expressing the immunophenotype of follicular mantle zone lymphocytes which were detected in the thymic medulla probably infiltrated through discontinuities of the border between the perivascular space and the thymic medulla. Apart from this primarily extrathymic B cell compartment, B lymphocytes and cells expressing B cell antigens were found within the thymus medulla of normal control thymuses of different ages from fetal to adult life. These cells were detected as a small subpopulation in normal fetal, juvenile and adult thymuses. Morphologically they could be subdivided into small, round lymphoid cells accounting for less than 1% of medullary lymphoid cells, and into a larger variant, asteroidally shaped because of short cytoplasmic processes. These asteroid cells were even more infrequent than the lymphoid variant. Immunophenotype (CD19ag+, CD20ag+, CD22ag+, CD37ag+, IgM+, IgD+) and morphology of the first cell type led to the conclusion that the lymphoid cells were in fact B lymphocytes. They were scattered throughout the medulla of fetal and juvenile and adult thymuses alike. The second, the asteroid cell type, constantly expressed CD20ag and inconstantly IgM, CD22ag and CD37ag; furthermore, CD23ag was detected in a subset of the asteroid cells either restricted to the perinuclear zone or expressed in the entire cytoplasma and on the plasma membrane. The asteroid cells were located in the corticomedullary region of the fetal thymuses but were randomly distributed with a tendency to Hassall's corpuscles in juvenile and adult thymuses. They often formed rosettes with non-B lymphocytes. It can be concluded that a small number of B cells and asteroid cells of still uncertain origin, but expressing B cell antigens, are constitutive elements of the fetal and adult thymic medulla. It can be assumed that the asteroid cell might represent a novel type of thymic accessory cell and that the rosetting of non-B lymphocytes around this asteroid cell might simulate or in fact be the earliest B cell interaction of maturing T cells.Abbreviation mAb(s) monoclonal antibody(-ies) - CDxxag antigen defined by the mAb cluster xx - CDxx(mAb) mAb of the cluster xx This study was supported by the Land Baden-Württemberg (Förderung der AIDS Forschung)Dedicated to Prof. Dr. V. Becker on the occasion of his 65th birthday     

Electron microscopy of intraductal papilloma of the breast. Ultrastructural comparison of papillary carcinoma with normal mammary large duct

Intaductal papillomas, papillary carcinomas, and normal mammary large ducts were studied by electron microscopy. The intraductal papillomas were divided into two subtypes: fibrous and glandular. Comparative ultrastructural analysis of these two subtypes revealed definitive differences in the nucleus, chromatin, and presence of myoepithelial cells. An irregularly shaped nucleus, aggregated heterochromatin, and prominent myoepithelial cells were the conspicuous features of the fibrous type which appeared to be almost absent in the glandular type. Moreover, the fibrous type possessed intact basal laminae, various differentiations of the cell surface, desmosomes, terminal bar, intrastromal projections of crab-finger-like appearance of the myoepithelial cells, and a two cell layer arrangement of epithelial cells. In these features, the ultrastructural appearance of the fibrous type closely resembled that of the cells of the normal mammary large duct. The glandular type, on the other hand, more or less lacked myoepithelial cells, well-developed organelles and showed a euchromatin pattern in the nucleus. This type resembled the papillary carcinoma in its histological characters. An absence of basal laminae (infiltrating carcinoma only) and the presence of intracytoplasmic lumina were characteristic of papillary carcinomas, and these two features were not found in the intraductal papillomas.