DNA from one biopsy sample of invasive cancer of the cervix contained sequences hybridizing with human papillomavirus (HPV) type 11 DNA only under nonstringent conditions. This DNA was molecularly cloned in lambda phage. Under stringent conditions of hybridization it cross-hybridized to a minor extent (less than 0.1%) with HPV types 10, 14, and 15 and showed no homology with DNA of other human HPV types. We therefore propose to designate it tentatively as HPV 16. HPV 16 DNA was used as a probe to test additional cancer biopsy samples from cervical, vulval, and penile cancer, as well as benign genital warts (condylomata acuminata) and cervical dysplasias for the presence of homologous sequences. In 61.1% (11/18) of cervical cancer samples from German patients sequences were found hybridizing with HPV 16 DNA under conditions of high stringency. In contrast, only 34.8% (8/23) of cancer biopsy samples from Kenya and Brazil revealed this DNA. Vulval and penile cancer biopsy samples hybridized to 28.6% (2/7) or 25% (1/4), respectively. Only 2 out of 33 condylomata acuminata contained HPV 16 DNA. Both positive tumors harbored in addition HPV 6 or HPV 11 DNA. The data thus indicate that HPV 16 DNA prevails in malignant tumors, rendering an accidental contamination with papillomavirus DNA from adjacent papillomas rather unlikely. The rare presence in benign genital papillomas in addition to common genital papillomaviruses suggests a dependence of HPV 16 replication on helper virus.

https://www.pnas.org/content/pnas/80/12/3812.full.pdf

A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions.

We reviewed all studies since 1940 on the prognosis of squamous cell carcinoma (SCC) of the skin and lip. The following variables are correlated with local recurrence and metastatic rates: (1) treatment modality, (2) prior treatment, (3) location, (4) size, (5) depth, (6) histologic differentiation, (7) histologic evidence of perineural involvement, (8) precipitating factors other than ultraviolet light, and (9) host immunosuppression. Local recurrences occur less frequently when SCC is treated by Mohs micrographic surgery. This local recurrence rate differential in favor of Mohs micrographic surgery holds true for primary SCC of the skin and lip (3.1% vs 10.9%), for ear SCC (5.3% vs 18.7%), for locally recurrent (previously treated) SCC (10% vs 23.3%), for SCC with perineural involvement (0% Ys 47%), for SCC of size greater than 2 cm (25.2% vs 41.7%), and for SCC that is poorly differentiated (32.6% vs 53.6%).

Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip : implications for treatment modality selection

Papillomaviruses in the causation of human cancers — a brief historical account

DNA of a new papillomavirus type was cloned from a cervical carcinoma biopsy. Two EcoRI clones of 7.8 and 6.9 kb in length were obtained, the latter contained a 900-bp deletion. The BamHI fragments of both clones were used to characterize the DNA. It represents a distinct type of papillomavirus as determined by its size, its cross-hybridization with DNA of other papillomavirus types under conditions of low stringency only, the co-linear alignment of its genome with HPV 6 and HPV 16 prototypes and its occasional occurrence as oligomeric episomes. We tentatively propose to designate it as HPV 18. DNA hybridizing with HPV 18 under stringent conditions was detected in 9/36 cervical carcinomas from Africa and Brazil, in 2/13 cervical tumors from Germany and 1/10 penile carcinomas. Benign tumors (17 cervical dysplasias, 29 genital warts), eight carcinomata in situ and 15 biopsies of normal cervical tissue were devoid of detectable HPV 18 DNA. HPV 18-related DNA was found, however, in cells of the HeLa, KB and C4-1 lines all derived from cervical cancer. The state of the viral DNA was investigated in four cervical cancer biopsies. The data reveal that the DNA might be integrated into the host cell genome. One tumor provided evidence for head to tail tandem repeats some of which persisted as circular episomes.

/pdf/a-new-type-of-papillomavirus-dna-its-presence-in-genital-36984ac3l8.pdf

A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer.

ISSUES Cervical squamous cell carcinomas, adenocarcinomas and their precursors are caused by the human papillomavirus (HPV). Although HPV appears to be essential to the transformation of these epithelial cells, it is not sufficient, and a variety of cofactors and molecular events must take place between when an HPV infection occurs and a cervical cancer or its precursor develops. This review examines the data supporting these contentions, briefly outlines the molecular events that occur, considers the epidemiology and natural history of the disease, and details the implications of using HPV detection and typing in both clinical management and population-based screening programs. CONSENSUS POSITION 1. Based on the available molecular, clinical and epidemiologic data, a subset of HPVs are unequivocally the etiologic agents for cervical cancers and their precursors. 2. Different mucosotropic HPVs have varying neoplastic potential. However, the great majority of cervical HPVs have oncogenic potential. Since oncogenic HPV-induced epithelial transformation to a high grade lesion or cancer is rare relative to the rate of infection, the term high risk is discouraged. 3. HPV's interaction with host cells has two principal biologic consequences: a) All anogenital HPVs induce low grade squamous lesions, which are the morphologic correlate of a productive infection. b) Rarely, HPVs induce a proliferative epithelial phenotype that pathologists recognize as a high grade lesion and that is the proximate cytohistologic precursor of invasive cervical carcinoma. 4. HPV biology and issues of practical clinical management should be reflected in the classification systems used for cytologic and histologic diagnosis. ONGOING ISSUES The molecular identification of HPVs (HPV testing) potentially may be very useful for primary screening or secondary triage of patients with certain lesions. However, the technology available to the practicing clinician is still evolving. Optimization of type spectrum, sensitivity, specificity and ease of use is under development. Data regarding these factors as well as a clear cost benefit analysis are sparse or pending in several large trials. Until such data are available, caution in clinical implementation of HPV testing is warranted.

Human papillomavirus. International Academy of Cytology Task Force summary. Diagnostic Cytology Towards the 21st Century: An International Expert Conference and Tutorial.

DNA extracted from squamous cell carcinomas from patients with the chronic wart disease syndrome, epidermodysplasia verruciformis, was analyzed for the presence of human papillomavirus (HPV)-specific DNA sequences by Southern blot hybridization analysis. Employing an HPV probe obtained by molecular cloning of viral DNA purified from benign warts from these patients, we have unequivocally identified HPV-specific nucleotide sequences in squamous cell carcinomas from these patients. Restriction endonuclease mapping indicated that the DNA present in the carcinomas was of the same type (type 5) as that found in the benign tumors from these patients and was present as unintegrated, free viral DNA. Moreover, we have demonstrated the presence of HPV-5 DNA in a subcutaneous metastatic tumor from one of these patients. This latter observation essentially eliminates the possibility that the HPV-5 DNA present in the malignant tumors in these patients resulted from cross-contamination from an adjacent benign warty lesion. In addition to wild-type HPV-5 DNA, both the primary and metastatic carcinomas analyzed also contained an HPV-5 DNA species lacking approximately 20% of the HPV-5 DNA genome. These subgenomic forms of HPV-5 DNA could not be detected in benign papillomas from these patients.

Human papillomavirus DNA in cutaneous primary and metastasized squamous cell carcinomas from patients with epidermodysplasia verruciformis

The presence of papillomaviruses in epithelial-derived cancers from several animal species1–3 has led to the speculation that these viruses may also have a pathogenic role in the development of certain human carcinomas, particularly those associated with the anogenital tract4. Recently, human papillomavirus (HPV) DNA has been detected in epithelial-derived cancers, both cutaneous1,5 and metastatic5, from patients exhibiting the rare, chronic flat wart disease, epidermodysplasia verruciformis (EV). Except for patients exhibiting this chronic wart syndrome, the association of HPV genomes with human epithelial cancers has not been demonstrated6. In an attempt to delineate the association and possible involvement of papillomaviruses with human anogenital carcinomas, we have begun an analysis of these cancers for the presence of HPV-specific nucleotide sequences by using highly sensitive hybridization procedures capable of detecting distantly related papillomaviruses at low copy number. Here we demonstrate the presence of HPV DNA in several types of anogenital tumours: Bowenoid papulosis, carcinoma in situ, and verrucous carcinoma. These data indicate that HPV can be detected in several types of premalignant and malignant tumours, supporting the contention that this group of viruses may be involved in the development of certain types of human epithelial-derived cancers.

Detection of human papillomavirus DNA in anogenital neoplasias.

• Immunosuppressed patients such as renal transplant recipients are prone to increased incidence of wart disease. We examined 48 tissue specimens from 36 renal transplant recipients using human papillomaviruses (HPVs) 1, 2, 3, 4, 5, and 6 in filter hybridization under stringent conditions. The results showed that 90% of the samples contained HPV DNA. Of these 43 positive samples, we found HPV-1 in 2%, HPV-2 in 56%, HPV-3 in 19%, HPV-4 in 47%, HPV-5 in 9%, and HPV-6 in 5%. In several cases, more than one type of HPV DNA was observed. In a few of these cases, the clinical appearance of the lesions differed from what might have been expected, such as those lesions containing HPV-3— or HPV-5—related DNAs. ( Arch Dermatol 1987;123:354-357)

https://jamanetwork.com/journals/derm/articlepdf/548060/archderm_123_3_022.pdf

Human papillomavirus heterogeneity in 36 renal transplant recipients.

Human papillomavirus DNA has been detected in the semen of three patients, two of whom have severe chronic wart disease. These data support the contention that sexual transmission of human papillomavirus DNA could occur via semen, a possibility suggested by epidemiological data on the sexual transmission of human papillomavirus.

https://science.sciencemag.org/content/sci/231/4739/731.full.pdf

Detection of papillomavirus DNA in human semen

• A middle-aged man with a 20-year history of a warty lesion on his finger was diagnosed histologically as having an invasive carcinoma at that location. Molecular analysis of the lesion showed that human papillomavirus (HPV) DNA was present in this tumor. Under stringent hybridization conditions, only HPV-16 DNA, which is commonly associated with genital neoplasia or cutaneous bowenoid lesions, was detected. Two-dimensional gel electrophoresis revealed that various sections of the tumor contained mostly episomal viral DNA; but in one case, low levels of integrated HPV-16 DNA were detected as well. (Arch Dermatol1989;125:666-669)

Mitchell Bender

Papers

Human papillomavirus DNA in cutaneous primary and metastasized squamous cell carcinomas from patients with epidermodysplasia verruciformis

Detection of human papillomavirus DNA in anogenital neoplasias.

Human papillomavirus heterogeneity in 36 renal transplant recipients.

Detection of papillomavirus DNA in human semen

Human Papillomavirus-16 DNA in a Cutaneous Invasive Cancer