RESUMO
Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1ß secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1ß at baseline. Finally, both patients displayed elevated levels of inflammasome-induced cytokines in the serum. Six NLRP1 GOF mutations have previously been described to underlie 3 allelic Mendelian diseases with differing phenotypes and modes of inheritance. Our results demonstrate that an autosomal recessive, syndromic form of JRRP can be associated with an NLRP1 GOF mutation.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Mutação com Ganho de Função , Homozigoto , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções Respiratórias/genética , Infecções Respiratórias/patologia , Pré-Escolar , Citocinas/metabolismo , Feminino , Humanos , Lactente , Inflamassomos , Queratinócitos/citologia , Queratinócitos/imunologia , Queratinócitos/metabolismo , Masculino , Proteínas NLR , Linhagem , Irmãos , SíndromeRESUMO
Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by persistent flat warts or pityriasis versicolor-like lesions caused by betapapillomaviruses (EV-HPVs). Autosomal recessive EVER1 and EVER2 deficiencies account for EV in most patients. The mechanisms by which mutations in these partners of the Zinc transporter ZnT1 impair host defense against EV-HPVs are still poorly understood. Keratinocytes of EVER-deficient patients display an alteration of zinc homeostasis and an enhanced proliferative activity. Since EVER proteins are highly expressed in T lymphocytes, we aimed to assess the impact of EVER2 deficiency on T-cell development and function. We studied circulating lymphocyte populations in three adult EV patients sharing the same EVER2 mutation (T150fsX3). We found a normal count of CD4(+) and CD8(+) T cells and a normal proliferative capacity in response to anti-CD3 stimulation. However, we observed a significant increase of memory CD4(+) and effector memory CD8(+) T cells, a bias of the TCR Vαß and Vγδ repertoires and an increase of skin-homing CD4(+) T-cell subsets. Our findings suggest that EVER2-deficient patients display mild T-cell abnormalities. It remains unclear whether these abnormalities result from EVER deficiency, chronic EV-HPV infection, or both.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Betapapillomavirus/patogenicidade , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/virologia , Movimento Celular/genética , Movimento Celular/imunologia , Proliferação de Células , Doença Crônica , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/imunologia , Epidermodisplasia Verruciforme/patologia , Feminino , Humanos , Memória Imunológica/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Mutação/imunologiaRESUMO
Epidermodysplasia verruciformis (OMIM 226400) is a rare autosomal recessive genodermatosis associated with a high risk of skin carcinoma that results from an abnormal susceptibility to infection by specific human papillomaviruses (HPVs). We recently mapped a susceptibility locus for epidermodysplasia verruciformis (EV1) to chromosome 17q25. Here we report the identification of nonsense mutations in two adjacent novel genes, EVER1 and EVER2, that are associated with the disease. The gene products EVER1 and EVER2 have features of integral membrane proteins and are localized in the endoplasmic reticulum.
Assuntos
Códon sem Sentido , Epidermodisplasia Verruciforme/genética , Predisposição Genética para Doença , Proteínas de Membrana/genética , Motivos de Aminoácidos , Sequência de Aminoácidos , Sequência de Bases , Cromossomos Humanos Par 17 , Sequência Conservada , Análise Mutacional de DNA , Retículo Endoplasmático/genética , Éxons , Feminino , Marcadores Genéticos , Haplótipos , Homozigoto , Humanos , Masculino , Repetições de Microssatélites , Dados de Sequência Molecular , Linhagem , Estrutura Terciária de Proteína , Recombinação Genética , Alinhamento de SequênciaRESUMO
Cervical cancer screening concerns women between the ages of 25 and 65. It consists of the collection of cervical cells with a spatula by rubbing the cervix. The material was initially spread out and fixed on a glass slide. It was subsequently fixed in a liquid preservative with an automated spread on a thin-layer slide after centrifugation or filtration, a process called liquid cytology. Microscopic reading was facilitated by field selection using an automated pre-reading system. In July 2019, the French High Authority for Health (HAS) recommended to position DNA research of high-risk human papillomavirus types by PCR (HPV HR test) in first position after the age of 30. This approach is more sensitive than cytology in diagnosing a histological high-grade squamous intraepithelial lesion, and more effective in preventing invasive cancers. The HPV HR test, if positive, is followed by a cytological examination on the same sample to select patients requiring examination of the cervix by colposcopy. Vaccination against the nine most common types of HPV in girls and boys aged 11 to 14 years is the other part of the prevention of invasive cancer.
Title: La prévention du cancer du col utérin. Abstract: Le dépistage du cancer du col de l'utérus concerne les femmes âgées de 25 à 65 ans. Il consiste à recueillir des cellules en frottant le col utérin avec une spatule. Le matériel biologique prélevé est ensuite déposé directement sur lame ou après l'avoir dilué dans un conservateur et cytocentrifugé (cytologie en milieu liquide). Il est ensuite analysé au microscope. En juillet 2019, la Haute autorité de santé a recommandé de rechercher l'ADN des types de papillomavirus humains (human papillomavirus, HPV) à haut risque ou potentiellement oncogènes, par PCR (test HPV HR), comme première étape du dépistage après l'âge de 30 ans. Ce test est plus sensible que la cytologie pour diagnostiquer une lésion histologique malpighienne intraépithéliale de haut grade, et plus efficace pour prévenir les cancers invasifs. Lorsque ce test est positif, une analyse cytologique sur le même prélèvement est réalisée afin de sélectionner les patientes nécessitant une colposcopie. Le deuxième volet de la prévention du cancer du col utérin repose sur la vaccination. Nous discutons, dans cette revue, l'importance de la détection des lésions du col utérin et le rôle des HPV.
Assuntos
Infecções por Papillomavirus , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Gravidez , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/patologia , Displasia do Colo do Útero/diagnóstico , Displasia do Colo do Útero/patologia , Detecção Precoce de Câncer , ColposcopiaRESUMO
Pasteur's work on fermentations has variously influenced the conception that veterinarians had of the origin of virulent diseases. Jean-Baptiste Chauveau asserted as early as 1866 the specificity of contagious diseases and their exogenous origin. Henri Bouley was initially a supporter of the spontaneity of these diseases. He became an advocate of the germ theory when Pasteur unambiguously demonstrated the causal role of anthrax bacteridia in 1877. Pasteur then had a fruitful collaboration with veterinarians during his work on chicken cholera, swine erysipelas, contagious pleuropneumonia and rabies. After Pasteur's experience at Pouilly-le-Fort, Henri Bouley and Edmond Nocard, a disciple of Pasteur, were strong advocates for the adoption of vaccinations by veterinarians and farmers. Nocard's work on various contagious animal diseases greatly contributed to the foundation of veterinary microbiology.
Les travaux de Pasteur sur les fermentations ont diversement influencé la conception qu'avaient les vétérinaires de l'origine des maladies virulentes. Jean-Baptiste Chauveau a affirmé dès 1866 la spécificité des maladies contagieuses et leur origine exogène. Henri Bouley a d'abord été un partisan de la spontanéité de ces maladies. Il est devenu un défenseur de la théorie des germes quand Pasteur a démontré sans ambiguïté, en 1877, le rôle causal de la bactéridie charbonneuse. Pasteur a ensuite eu une fructueuse collaboration avec des vétérinaires lors de ses travaux sur le choléra des poules, le rouget du porc et la péripneumonie contagieuse. Après l'expérience de Pasteur à Pouilly-le-Fort, Henri Bouley et Edmond Nocard, un élève de Pasteur, ont été les fervents avocats de l'adoption des vaccinations par les vétérinaires et les agriculteurs. Les travaux de Nocard sur diverses maladies animales contagieuses ont grandement contribué à fonder la microbiologie vétérinaire.
Assuntos
Médicos Veterinários , Animais , Masculino , Suínos , Humanos , Galinhas , FrutasRESUMO
The outcomes of infection by human papillomaviruses (HPV), both oncogenic and non oncogenic, show major interindividual variability The underlying genetic factors and mechanisms are poorly known, but their complexity is illustrated by epidermodysplasia verruciformis (EV), a rare autosomal recessive genodermatosis associated with a high risk of non melanoma skin cancer. This model disease is characterized by abnormal susceptibility to widespread betapapillomaviruses, including HPV-5, a virus associated with EV cancers. Most cases of EV are caused by a mutation that inactivates either of two related genes, EVER1 and EVER2. This inactivation likely compensates for the absence of a viral gene (E5 or E8) essential for HPV pathogenicity. Proteins E5 and E8 interfere with the interaction between EVER proteins and ZnT1, a zinc transporter EV is thus likely to represent a primary defect of intrinsic (constitutive) immunity or innate immunity to betapapillomaviruses, involving modulation of zinc homeostasis upon keratinocyte infection. It remains to be established which cellular genes are involved in intrinsic, innate or acquired immune responses to other human papillomaviruses, including oncogenic genital types.
Assuntos
Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/virologia , Predisposição Genética para Doença , Infecções por Papillomavirus/genética , HumanosRESUMO
Epidermodysplasia verruciformis (EV) is an autosomal recessive skin disorder with a phenotype conditional on human beta-papillomavirus (beta-HPV) infection. Such infections are common and asymptomatic in the general population, but in individuals with EV, they lead to the development of plane wart-like and red or brownish papules or pityriasis versicolor-like skin lesions, from childhood onwards. Most patients develop non-melanoma skin cancer (NMSC), mostly on areas of UV-exposed skin, from the twenties or thirties onwards. At least half of the cases of typical EV are caused by biallelic loss-of-function mutations of TMC6/EVER1 or TMC8/EVER2. The cellular and molecular basis of disease in TMC/EVER-deficient patients is unknown, but a defect of keratinocyte-intrinsic immunity to beta-HPV is suspected. Indeed, these patients are not susceptible to other infectious diseases and have apparently normal leukocyte development. In contrast, patients with an atypical form of EV due to inborn errors of T-cell immunity invariably develop clinical symptoms of EV in the context of other infectious diseases. The features of the typical and atypical forms of EV thus suggest that the control of beta-HPV infections requires both EVER1/EVER2-dependent keratinocyte-intrinsic immunity and T cell-dependent adaptive immunity.
RESUMO
Patients with epidermodysplasia verruciformis (EV) and biallelic null mutations of TMC6 (encoding EVER1) or TMC8 (EVER2) are selectively prone to disseminated skin lesions due to keratinocyte-tropic human ß-papillomaviruses (ß-HPVs), which lack E5 and E8. We describe EV patients homozygous for null mutations of the CIB1 gene encoding calcium- and integrin-binding protein-1 (CIB1). CIB1 is strongly expressed in the skin and cultured keratinocytes of controls but not in those of patients. CIB1 forms a complex with EVER1 and EVER2, and CIB1 proteins are not expressed in EVER1- or EVER2-deficient cells. The known functions of EVER1 and EVER2 in human keratinocytes are not dependent on CIB1, and CIB1 deficiency does not impair keratinocyte adhesion or migration. In keratinocytes, the CIB1 protein interacts with the HPV E5 and E8 proteins encoded by α-HPV16 and γ-HPV4, respectively, suggesting that this protein acts as a restriction factor against HPVs. Collectively, these findings suggest that the disruption of CIB1-EVER1-EVER2-dependent keratinocyte-intrinsic immunity underlies the selective susceptibility to ß-HPVs of EV patients.
Assuntos
Betapapillomavirus/imunologia , Proteínas de Ligação ao Cálcio/imunologia , Epidermodisplasia Verruciforme/imunologia , Imunidade Inata , Queratinócitos/imunologia , Proteínas de Membrana/imunologia , Complexos Multiproteicos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Adesão Celular/imunologia , Movimento Celular/imunologia , Epidermodisplasia Verruciforme/patologia , Feminino , Papillomavirus Humano 16/imunologia , Humanos , Queratinócitos/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Oncogênicas Virais/imunologiaRESUMO
Integration of the human papillomavirus (HPV) genome into the host genome is associated with the disruption of the HPV E2 gene and with amplification and rearrangement of the viral and flanking cellular sequences. Molecular characterization of the genomic structures of coamplified HPV sequences and oncogenes provides essential information concerning the mechanisms of amplification and their roles in carcinogenesis. Using fluorescent hybridization on stretched DNA molecules in two cervical cancer-derived cell lines, we have elucidated the genomic structures of amplified regions containing HPV/myc genes over several hundreds of kilobases. Direct visualization of hybridization signals on individual DNA molecules suggests that overreplication and breakage-fusion-bridge-type mechanisms are involved in the genomic instability associated with HPV cervical cancers. Further analysis from two other genital cancer-derived cell lines reveals a recurrent motif of amplification, probably generated by a common mechanism involving overreplication upon viral integration. Interestingly, different amplification patterns seem to be correlated with the disease outcome, thus providing new insights into HPV-related cancer development and tumor progression.
Assuntos
Genes myc/genética , Genoma Humano , Papillomaviridae/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Feminino , Amplificação de Genes , Humanos , Família Multigênica , Proteínas Oncogênicas Virais/genética , Integração Viral/genéticaRESUMO
Haemopoietic stem-cell transplantation is a life-saving treatment for severe combined immune deficiency. However, there has been little long-term follow-up of this treatment. There is evidence for the persistance of partial immunodeficiency associated with significant infections, including severe human papillomavirus (HPV) disease. We did a retrospective analysis of severe HPV disease in a group of 41 patients with severe combined immune deficiency from one centre who were alive 10 years or longer after haemopoietic stem-cell transplantation. Nine of the 41 patients had extensive chronic HPV disease limited to the skin, with a median onset at 8 years after transplantation. Four had lesions typical of epidermodysplasia verruciformis, a rare genodermatosis. Transplant characteristics, immune status, and chimerism of these nine patients did not differ significantly from those of the other patients. The nine patients with HPV disease had severe combined immune deficiency associated with either common gammac receptor cytokine subunit or Janus kinase-3 (JAK-3) deficiency. By contrast, patients with other forms of severe combined immune deficiency did not have any signs of HPV disease. That genetic causes are the only predisposing factor to be identified for severe combined immune deficiency, suggests that natural-killer cells or gammac/JAK-3-dependent signalling in keratinocytes could have a role in anti-HPV immunity.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções por Papillomavirus/etiologia , Proteínas Tirosina Quinases/deficiência , Receptores de Interleucina-7/deficiência , Imunodeficiência Combinada Severa/terapia , Dermatopatias Virais/etiologia , Criança , Pré-Escolar , Epidermodisplasia Verruciforme/etiologia , Feminino , Seguimentos , Genótipo , Humanos , Subunidade gama Comum de Receptores de Interleucina , Janus Quinase 3 , Masculino , Papillomaviridae/genética , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/patologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Dermatopatias Virais/imunologia , Dermatopatias Virais/patologia , Quimeras de TransplanteRESUMO
OBJECTIVE: This study was undertaken to investigate the impact of highly active antiretroviral therapy (HAART) on the regression of cervical intraepithelial neoplasia (CIN) in HIV-infected women. DESIGN: Prospective study of 168 HIV-infected women with evidence of CIN until regression to a lower grade or to normality (end-point) or until surgical treatment or last visit. Ninety-six patients received HAART. METHODS: Women were examined every 6 months by Papanicolaou smears, colposcopy, and biopsy if required. The probability of CIN regression was calculated using survival analysis. HAART was entered as a time-dependent covariate according to the date of first prescription. RESULTS: Regression of CIN was observed in 67 (39.9%) women. The probability of regression at 12 months was significantly higher for high-grade CIN [23.8%; 95% confidence interval (CI), 14.2-33.5] than for low-grade lesions (14.8%; 95% CI, 7.0-22.6) (P = 0.04). The risk of regression of CIN was twice as high in women receiving HAART as compared with women not receiving HAART (relative hazard of regression, 1.93; 95% CI, 1.14-3.29). There was a trend for a larger increase in CD4 cell counts among those women taking HAART and who showed regression as compared with those who did not regress. CONCLUSION: The positive impact of HAART on CIN regression may be associated with some restoration of specific immune reactivity. This is not sufficient enough, however, to modify the gynecological follow-up of HIV-infected women.
Assuntos
Terapia Antirretroviral de Alta Atividade , Soropositividade para HIV/complicações , Displasia do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Feminino , Soropositividade para HIV/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Neoplasias do Colo do Útero/complicações , Displasia do Colo do Útero/complicaçõesAssuntos
DNA/genética , Epidermodisplasia Verruciforme/genética , Proteínas de Membrana/genética , Mutação , Adolescente , Adulto , Criança , Códon sem Sentido , Análise Mutacional de DNA , Epidermodisplasia Verruciforme/metabolismo , Feminino , Heterogeneidade Genética , Humanos , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Linhagem , Adulto JovemRESUMO
Epidermodysplasia verruciformis (EV) is characterized by persistent cutaneous lesions caused by a specific group of related human papillomavirus genotypes (EV-HPVs) in otherwise healthy individuals. Autosomal recessive (AR) EVER1 and EVER2 deficiencies account for two thirds of known cases of EV. AR RHOH deficiency has recently been described in two siblings with EV-HPV infections as well as other infectious and tumoral manifestations. We report here the whole-exome based discovery of AR MST1 deficiency in a 19-year-old patient with a T-cell deficiency associated with EV-HPV, bacterial and fungal infections. MST1 deficiency has recently been described in seven patients from three unrelated kindreds with profound T-cell deficiency and various viral and bacterial infections. The patient was also homozygous for a rare ERCC3 variation. Our findings broaden the clinical range of infections seen in MST1 deficiency and provide a new genetic etiology of susceptibility to EV-HPV infections. Together with the recent discovery of RHOH deficiency, they suggest that T cells are involved in the control of EV-HPVs, at least in some individuals.
Assuntos
Predisposição Genética para Doença , Fator de Crescimento de Hepatócito/deficiência , Fator de Crescimento de Hepatócito/genética , Padrões de Herança/genética , Papillomaviridae/fisiologia , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Adolescente , Sequência de Aminoácidos , Antígenos Virais/imunologia , Sequência de Bases , Proliferação de Células/efeitos dos fármacos , Criança , Códon sem Sentido/genética , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/imunologia , Epidermodisplasia Verruciforme/microbiologia , Epidermodisplasia Verruciforme/virologia , Exoma/genética , Fator de Crescimento de Hepatócito/química , Homozigoto , Humanos , Imunofenotipagem , Lactente , Masculino , Mitógenos/farmacologia , Dados de Sequência Molecular , Papillomaviridae/efeitos dos fármacos , Proteínas Proto-Oncogênicas/química , Linfócitos T/efeitos dos fármacos , Linfócitos T/patologia , Adulto JovemRESUMO
Epidermodysplasia verruciformis (EV) is a rare genetic disorder characterized by increased susceptibility to specific human papillomaviruses, the betapapillomaviruses. These EV-HPVs cause warts and increase the risk of skin carcinomas in otherwise healthy individuals. Inactivating mutations in epidermodysplasia verruciformis 1 (EVER1) or EVER2 have been identified in most, but not all, patients with autosomal recessive EV. We found that 2 young adult siblings presenting with T cell deficiency and various infectious diseases, including persistent EV-HPV infections, were homozygous for a mutation creating a stop codon in the ras homolog gene family member H (RHOH) gene. RHOH encodes an atypical Rho GTPase expressed predominantly in hematopoietic cells. Patients' circulating T cells contained predominantly effector memory T cells, which displayed impaired TCR signaling. Additionally, very few circulating T cells expressed the ß7 integrin subunit, which homes T cells to specific tissues. Similarly, Rhoh-null mice exhibited a severe overall T cell defect and abnormally small numbers of circulating ß7-positive cells. Expression of the WT, but not of the mutated RHOH, allele in Rhoh-/- hematopoietic stem cells corrected the T cell lymphopenia in mice after bone marrow transplantation. We conclude that RHOH deficiency leads to T cell defects and persistent EV-HPV infections, suggesting that T cells play a role in the pathogenesis of chronic EV-HPV infections.
Assuntos
Epidermodisplasia Verruciforme/genética , Linfócitos T/patologia , Fatores de Transcrição/deficiência , Proteínas rho de Ligação ao GTP/deficiência , Adulto , Animais , Sequência de Bases , Betapapillomavirus , Estudos de Casos e Controles , Códon sem Sentido , Consanguinidade , Suscetibilidade a Doenças , Epidermodisplasia Verruciforme/imunologia , Epidermodisplasia Verruciforme/patologia , Epidermodisplasia Verruciforme/virologia , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Integrinas/metabolismo , Contagem de Linfócitos , Camundongos , Camundongos Knockout , Linhagem , Polimorfismo de Nucleotídeo Único , Receptores de Antígenos de Linfócitos T/metabolismo , Análise de Sequência de DNA , Transdução de Sinais , Fatores de Transcrição/genética , Proteínas rho de Ligação ao GTP/genéticaAssuntos
Carcinoma Basocelular/virologia , Carcinoma de Células Escamosas/virologia , Epidermodisplasia Verruciforme/virologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/complicações , Neoplasias Cutâneas/virologia , DNA Viral/isolamento & purificação , Humanos , Reação em Cadeia da Polimerase , Carga ViralRESUMO
PURPOSE: Epithelial tumours of the lacrimal sac are rare but important entities that may carry grave prognoses. In this study the prevalence and possible role of human papillomavirus (HPV) infection in epithelial tumours of the lacrimal sac were evaluated. METHODS: Five papillomas and six carcinomas of the lacrimal sac were investigated for the presence of HPV using the polymerase chain reaction (PCR) technique. Fifteen specimens of dacryocystitis were included in the PCR reactions as controls. Furthermore, DNA in situ hybridization (ISH) and RNA ISH were performed. RESULTS: Low-risk HPV types 6 or 11 were identified in all four lacrimal sac papillomas suitable for PCR analysis and in situ hybridization. Four of six lacrimal sac carcinomas harboured HPV. One carcinoma was positive for HPV 11 only, two carcinomas had concomitant infection with HPV 6 or 11 and high-risk HPV 16, and the remaining carcinoma was positive for HPV 16. All specimens of dacryocystitis were betaglobin-positive and HPV-negative. Using DNA ISH, two papillomas and a single carcinoma showed evidence for vegetative HPV 11 DNA replication, whereas no HPV 16 DNA replication was found in the five carcinomas tested. HPV 11 RNA was demonstrated in two papillomas. CONCLUSIONS: By analysing 11 epithelial lacrimal sac papillomas and carcinomas using PCR, DNA ISH and RNA ISH, we found HPV DNA in all investigated transitional epithelium tumours of the lacrimal sac. HPV RNA was present in two of eight epithelial lacrimal sac tumours positive for HPV DNA. As RNA degrades fast in paraffin-embedded tissue, only a small fraction of DNA-positive tumours can be expected to be RNA-positive. We therefore suggest that HPV infection is associated with the development of lacrimal sac papillomas and carcinomas.