A new type of human papillomavirus associated with oral focal epithelial hyperplasia.

Lesions from 10 patients suffering from focal epithelial hyperplasia (FEH) of the oral mucosa, including those of 4 Greenlandic Eskimos, were investigated for the presence of human papillomavirus (HPV) DNA sequences by blot hybridization experiments. Two distinct HPVs were detected in the DNA extracted from these lesions, and their genomes were molecularly cloned and characterized. One of these HPVs, detected in 4 patients, was found to be identical with HPV13, whose association with FEH was already known. The other one, detected in 6 patients, was only weakly related to HPV13 and to the other HPVs associated with lesions of the mucous membranes, and constituted a new HPV type, tentatively named HPV32. Lesions from other types of oral papillomas, obtained from 14 additional patients, were also analyzed. Human papillomavirus DNA sequences were detected in the DNA preparations extracted from 5 specimens: HPV6 DNA in a condyloma and in a papilloma, 2 as yet uncharacterized HPV DNAs in 2 papillomas, and HPV32 DNA in a papilloma which showed histologic similarities to FEH. Thus, it seems likely that FEH of the oral mucosa is a disease associated with 2 specific HPVs--HPV13 and HPV32.

[History of 2 cells in T cell lymphomas and leukemias: the cerebriform Lutzner cell in Sézary syndrome and the polylobulated or polypetaloid cell in acute T cell lymphoma/leukemia]. / Die Geschichte von zwei Zellen in T-Zell-Lymphomen/Leukämien: Die zerebriforme Lutzner-Zelle beim Sézary-Syndrom (SS) und die polylobulierte oder polypetaloide Zelle beim akuten T-Zell-Lymphom/Leukämie (ATLL).

In normal blood, there appears to be two similar but different subsets of T-lymphocytes present: (1) the cerebriform or convoluted Sézary-syndrome Lutzner cell, which may give rise to cutaneous T-cell lymphoma; (2) the polypetaloid or lobated acute T-cell lymphoma/leukemia (ATLL) cell, which may give rise to ATLL. Both cell types can be differentiated by their characteristic nuclear shapes.

Multiple cutaneous papillomas and carcinomas that develop spontaneously in a mouse mutant, the repeated epilation heterozygote Er/+.

After a chance observation that multiple cutaneous papillomas and squamous cell carcinomas occurred in 2 adult mice heterozygous for the repeated epilation gene Er, we surveyed a panel of 10 +/+ (wild type) and 30 Er/+ (heterozygous) mice from birth to over 2 years of age. Homozygous Er/Er mice could not be included since their defect is lethal at birth. Whereas no cutaneous tumors developed in the +/+ mice, 20 of the Er/+ mice, males and females, had developed 1-5 cutaneous papillomas and at least 1 cutaneous invasive squamous cell carcinoma by 2 years of age. No lesions were seen in mice younger than 6 months old. Although almost all Er/+ mice died with their tumor burden, no metastases have yet been proven histologically. The Er/+ mouse should serve as a useful model for the exploration of genetic factors in cutaneous squamous cell carcinomas in humans.

Molecular cloning and characterization of the genomes of nine newly recognized human papillomavirus types associated with epidermodysplasia verruciformis.

The genomes of 11 human papillomaviruses (HPVs) found in benign lesions of eight patients suffering from epidermodysplasia verruciformis were cloned in Escherichia coli after insertion into plasmid pBR322. The study of the sensitivity of the cloned HPV DNAs to 14 restriction endonucleases permitted the construction of physical maps. DNA-DNA hybridization experiments, performed under stringent conditions, showed that these viruses represent nine new types, HPVs 14 (with subtypes a and b), 15, 17 (with subtypes a and b), 19, 20, 21, 22, 23, and 24. These HPVs were divided into three groups based on an absent or very weak cross-hybridization among the genomes of the viruses belonging to different groups.

Clinical observations, virologic studies, and treatment trials in patients with epidermodysplasia verruciformis, a disease induced by specific human papillomaviruses.

We have studied 11 patients with the papillomavirus-induced disease epidermodysplasia verruciformis (EV). Clinical diagnostic features are widespread, long-lasting, pityriasis versicolor-like macules and flat, wart-like papules, both usually occurring in early childhood, with the subsequent development in the third decade of multiple skin cancers of the Bowenoid in situ and squamous cell types, primarily in sun-exposed skin. Virologic studies using the methods of immunofluorescence microscopy, restriction endonuclease analysis, and DNA blot hybridization have shown benign lesions to be associated with one or several types of the human papillomaviruses (HPVs) specifically associated with EV (at least 15 types recognized on the basis of sequence homology studies of molecularly cloned genomes). Skin cancers in these patients were associated with the genomes of either HPV-5, HPV-8 or HPV-14, suggesting that these three viruses are potentially oncogenic. A genetic factor appears to play a role in the pathogenesis of EV, since 5 of our patients were children of consanguineous parents and 2 had siblings also suffering with EV, suggesting a recessive inheritance pattern. Treatment of 4 EV patients with an oral retinoid resulted in partial temporary improvement of benign lesions, and the treatment of 2 patients with intralesional interferon injections into multiple Bowenoid cancers in situ has resulted in the disappearance of these lesions. Finally, EV serves as a model for studying the interplay of oncogenic viruses, genetic and immunologic factors, and sunlight in the production of skin cancer in humans.

Papillomaviruses and skin cancer in Africa.

Although it was suggested long ago that certain epithelial cancers preceded by papillomas might be caused by viruses, the first proof that papillomaviruses were associated with cancer dates from the work on rabbits in 1934 by Shope and Rose. In the 1970s, the introduction of the blot hybridization technique enabled Orth and his co-workers at the Institut Pasteur, Paris, to demonstrate the presence in man of the DNA of human papillomavirus type 5 (HPV-5) in cancers following Lutz-Lewandovsky epidermodysplasia verruciformis. Some years later, it was possible to demonstrate the presence of the same HPV-5 DNA in the skin cancer of an immunosuppressed recipient of a renal transplant. The number of potentially oncogenic papillomaviruses has recently been increased by the demonstration at the Institut Pasteur of the presence of the DNAs of HPV-8 and HPV-14 in the skin cancers of patients with epidermodysplasia verruciformis. In recent years, an association has been demonstrated between HPV-6, -10, -11, -16, and -18 with verrucous cancers of the skin and mucous membranes, Bowenoid papules, Bowenoid skin diseases and cervical cancer. Such cancers of the skin and mucous membranes are usually treated by surgery, but it has been shown that oral administration of retinoids (synthetic derivatives of vitamin A) or the use of leucocyte interferon intralesionally are effective in cancers in situ following epidermodysplasia verruciformis.

Detection of human papillomavirus type 5 DNA in skin cancers of an immunosuppressed renal allograft recipient.

A renal allograft recipient with an epidermodysplasia-verruciformis-like syndrome was found to have human papillomavirus type 5 (HPV-5) in his benign warty lesions and HPV-5 DNA in two of his skin cancers. This finding points to a role for HPV-5 in skin oncogenesis in renal allograft recipients.

Different papillomaviruses as the causes of oral warts.

We have observed four patients with oral papillomas. Two children had oral mucosal lesions characteristic of focal epithelial hyperplasia, a young man had common, wart-like lesions on his hard palate, and a male immunosuppressed renal allograft recipient had condyloma-like lesions on his gingivae. Papillomavirus-like particles were seen by electron microscopy in lesions from both patients with focal epithelial hyperplasia. No structural antigens for human papillomavirus (HPV) 1, 2, 3, or 5 were found by immunofluorescent microscopy, but further evidence of the presence of a papillomavirus was found by immunoperoxidase microscopy using a cross-reacting sodium lauryl sulfate-disrupted bovine papillomavirus 1 anti-rabbit serum sample. The distinct histologic pattern seen in focal epithelial hyperplasia suggests that a yet undescribed HPV type might be associated with this disease. Histologic, ultrastructural, and immunofluorescent microscopy and restriction endonuclease analysis all gave evidence of HPV 2 in the palatal lesions in patient 3. Evidence of papillomavirus antigen was found by immunoperoxidase microscopy in the oral condylomas from our immunosuppressed patient.

An unusual wart-like skin lesion found in a renal allograft recipient.

Immunosuppressed renal allograft recipients have an increased tendency to acquire warts. While studying such patients, we found a virus-induced, wart-like lesion that had an unusual histologic picture. Light microscopic studies showed bizarre keratinocytes with cytoplasmic, juxtanuclear, giant, crescentic bodies and round, nuclear inclusions, By electron microscopy, the giant cytoplasmic bodies were found to be composed of tonofilaments, and the nuclear inclusions were found to be composed of papillomavirus-like particles in a filamentous matrix. Typical papillomavirus particles were observed in a wart extract by the negative-staining method. Although virus was abundant in infected cells, no structural viral antigens of the human papillomavirus (HPV) types 1, 2, 3, or 5 could be detected by immunofluorescence microscopy, indicating infection by HPV 4 or some other, as yet undescribed, HPV type.