An Evaluation of High-Risk HPV in Squamous Cell Carcinomas of the Lip in a South African Cohort.

BACKGROUND: To determine the prevalence of HR-HPV in a series of lip SCC from South African patients, using currently accepted HPV-testing methodologies and to define the clinical and histomorphologic features of HPV-associated lip SCC. METHODS: Fifty SCC of lip and 50 control cases were tested for HR-HPV using p16 and HR-HPV DNA PCR. p16-equivocal/positive and HPV DNA PCR-positive SCC were further evaluated for the expression of HPV-16 and HPV-18 mRNA transcripts using reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) to confirm transcriptionally active HPV. RESULTS: p16 was positive in 22% (n = 11) and equivocal in 4% (n = 2) of the SCC. One p16-positive case showed positivity for both HPV-16 DNA and HPV-16 E6/E7 mRNA transcripts (HPV prevalence rate of 2%). The HPV-positive case was non-keratinizing and occurred in an 80-year-old female. The two p16-equivocal cases were HR-HPV DNA positive and mRNA PCR negative. p16 was found to have a positive predictive value of 9%. CONCLUSION: Findings from our cohort of lip SCC suggest that HR-HPV may have an insignificant role in the pathogenesis of SCC at this site. Due to its low ppv, p16 is insufficient to establish HR-HPV infection in SCC of the lip. The combination of p16 and DNA PCR appears to correlate with the presence of transcriptionally active virus. HPV E6/E7 mRNA detection is the gold standard for identifying HR-HPV. mRNA testing is not widely available in sub-Saharan Africa due to technical and financial constraints; however, the test appears to be of great value in p16-equivocal lip SCC.

Prevalence of human papilloma virus in oropharyngeal, tongue and lip squamous cell carcinoma: an experience from the Egyptian National Cancer Institute.

Human papilloma virus (HPV) is now a well-known risk factor for head and neck cancer besides smoking and alcohol. Most studies mentioned that patients affected with high-risk HPV cancers have a better outcome, and many clinical trials are trying to prove that such group of patients can receive a different and less aggressive treatment than the HPV-negative group. Although such field has received great interest within different countries and continents, African and Egyptian populations are not yet well studied within the literature. Our aim was to detect the prevalence of HPV in oropharyngeal (OP), lip and tongue squamous cell carcinoma (SSC) and correlate the viral prevalence with different clinicopathologic parameters as well as patients' outcome. HPV detection was done on 99 cases from the lip (29), tongue (38) and oropharynx (32) diagnosed at the Pathology Department of the National Cancer Institute, Cairo University. p16 immunohistochemistry was performed on all cases, followed by HPV DNA in situ hybridization (ISH) for p16-positive cases. The prevalence of HPV in OPSSC was 28% and in lip and tongue cancers lumped together was 37%. There was more than 90% concordance between p16 and HPV DNA ISH results. HPV positivity showed a statistically significant correlation with better disease-free survival (DFS), which was also maintained for OP cases. HPV is highly prevalent in OP and common oral cavity cancers in the Egyptian population. HPV positivity correlated significantly with better DFS, especially in OP cancers.

Oral fibropapillomatosis and epidermal hyperplasia of the lip in newborn lambs associated with bovine Deltapapillomavirus.

Congenital fibropapillomatosis of the gingiva and oral mucosa and epidermal hyperplasia of the lip are described, for the first time, in two newborn lambs. Expression of the E5 oncoprotein of bovine deltapapillomavirus types 2 (BPV-2) and -13 (BPV-13) was detected in both fibropapillomas and the hyperplastic epidermal cells suggesting the BPV infection was the cause of the proliferative lesions. No DNA sequences of BPV-1 and BPV-14 were detected. Both BPV-2 and BPV-13 DNA were also amplified from peripheral blood mononuclear cells (PBMCs) of the newborn lambs' dams. The concordance between BPV genotypes detected in the blood of dam and the oral and skin pathological samples of their offspring suggests that a vertical hematogeneous transmission was most likely source of BPV infection. Immunoblotting revealed the presence of E5 dimers allowing the viral protein to be biologically active. E5 dimers bind and activate the platelet derived growth factor ß receptor (PDGFßR), a major molecular mechanism contributing to disease. The detection of E5 protein within the proliferating cells therefore adds further evidence that the BPV infection was the cause of the proliferative lesions seen in these lambs. This is the first evidence of vertical transmission of BPVs in sheep resulting in a clinical disease.

Human Papilloma Virus-Associated Lips Verrucous Carcinoma in HIV-Infected Male.

Human papillomavirus (HPV) infection, widely known as the necessary cause of cervical cancer, has been established as a major etiologic factor for head and neck cancer (HNC). HIV-infected individuals are at higher risk of HPV-associated cancers than the general population. We describe a 45-year-old man with HIV and HPV coinfection, who presented progressively enlarging verrucous neoformations of the lips. The final diagnosis of verrucous carcinoma was delayed. Early detection of HPV lesions in oral mucosa and HPV screening activities could be important in improving the diagnostic sensitivity for the HIV-infected patients with oral cancer.

A rare case of undifferentiated nonkeratinizing carcinoma of the lip mucosa.

Undifferentiated nonkeratinizing carcinoma (UNC) is a poorly differentiated squamous cell carcinoma accompanied by a prominent reactive lymphoplasmacytic infiltrate that can occur in many anatomic sites. It shares morphologic features with undifferentiated nonkeratinizing nasopharyngeal carcinoma, in which a strong association with Epstein-Barr virus (EBV) has been noted. Among UNCs arising outside the nasopharynx, the linkage with EBV is variable; in particular, the few cases of UNC of the lip described thus far have been negative for EBV. This report describes a rare case of primary UNC of the lower lip mucosa in a 73-year-old man in whom molecular analysis for EBV showed some amount of viral DNA within the tumor. Surgical excision without adjuvant treatment was performed and the patient was alive without recurrence after 42 months of follow-up. This report presents a rare localization of UNC possibly related to EBV infection and with a good clinical outcome.

[The analysis of human papillomavirus infection in lip squamous cell carcinoma patients].

OBJECTIVE: To analyze the infection of human papillomavirus in lip squamous cell carcinoma patients. METHODS: The pathological samples of 9 clinical diagnosed lip cancer patients were collected. Lunimex and PCR techniques were used to detect the HPV gene infection and immunohistochemistry method was used to analyze the HPV protein expression in the samples. RESULTS: In the 9 cases, 1 was positive for HPV16 gene and 7 were positive for HPV16/18 E6 protein expression. The total positive rate was about 8/9. CONCLUSION: The high HPV infection rate in lip cancer patients in the study indicated indirectly that the importance of the direct contact to the infection of HPV what was the basis for pathogenesis of the lip squamous cell carcinoma.

Low prevalence of high risk genotypes of human papilloma virus in normal oral mucosa, oral leukoplakia and verrucous carcinoma.

OBJECTIVE: Squamous Cell Carcinoma (SCC) is the most common malignancy of the oral cavity and Verrucous Carcinoma (VC) is its least invasive form with no metastasis potential. Leukoplakia (clinical term for hyperkeratosis and acanthosis with and without dysplasia) is the most common pre-malignant lesion of the oral cavity. Human Papilloma Virus (HPV) has been recognized as an etiologic factor for mentioned lesions. In this study the relationship between high risk types of this virus (HPV(HR)) with VC and Leukoplakia is investigated. MATERIALS AND METHOD: Forty-one paraffin-embedded blocks including 21 VC, 20 leukoplakias in addition to 18 normal oral mucosal tissues as the control group were studied by Polymerase Chain Reaction (PCR) to detect HPV 16, 18, 31 and 33. RESULTS: In three specimens of VCs (14.3%) HPV(HR) was detected. Each of these contained both HPV 16 and 18. All three positive specimens belonged to women older than 65 and were obtained from the vestibule of the mandible. Neither Leukoplakia nor normal mucosa showed HPV presence. No significant relationship between HPV and VC was found compared with the control group (p = 0.23). CONCLUSION: This study did not show relationship between HPV and leukoplakia. Although no statistically significant relationship was found between HPV and VC, but considering sample size limitation for such uncommon cases, its presence in three cases of 14 makes more investigations to overcome the controversies necessary.

HPV 6-positive giant keratoacanthoma in an immunocompetent patient.

Keratoacanthoma (KA) is a clinically distinct, rapidly growing lesion that generally presents as a solitary crateriform nodule in sun-exposed areas in elderly, fair-skinned individuals. A KA larger than 20-30 mm is referred to as giant keratoacanthoma, a relatively rare lesion especially in young patients. Such lesions grow rapidly with possible destruction of underlying tissues. In addition to ultraviolet exposure, KAs have also been associated with chemical carcinogens, chemical peels, genetic factors, chronic skin conditions that produce scarring, trauma and thermal burns. Immunosuppressed patients, especially after transplantation, also develop KAs. A viral etiology has been suggested but not confirmed. We encountered a case of giant keratoacanthoma (greater than 50 mm in diameter) with induration of underlying structures on the upper lip of a 39-year-old male sailor. The patient reported sudden appearance and rapid enlargement of the lesion in only three weeks. Biopsy of the cutaneous lesion and the characteristic clinical history suggested the diagnosis of keratoacanthoma. Total excision with primary closure of the defect by a nasolabial advancement flap was performed. Histological examination of the tumor mass confirmed the diagnosis of KA with infiltrative growth and perineural invasion. Immunosuppression was excluded by blood analyses, as were HIV, syphilis and hepatitis infections. Only low-risk genital HPV type 6 was detected in the lesion, suggesting a possible cocarcinogenic effect of HPV and UV light in a chronically sun-exposed patient.

Prevalence of human papillomavirus DNA sequences in verrucous carcinoma of the lip: genomic and therapeutic approaches.

We examined the presence of human papillomavirus (HPV) DNA sequences in tissues of verrucous carcinoma (VC) of the lip. Detection and typing of HPV DNA was performed using polymerase chain reaction with sequence analysis and restriction fragment length polymorphism analysis. All tissues of VC contained HPV DNA and one of recurrent case was infected with four different HPV DNAs including high risk types. Seven different HPV types were detected in VC, of which (accession no. in EMBL/GeneBank/DDBJ databases) has been described as a partial sequences from an unknown HPV type. Sequence analysis showed that HPVX is related to HPV-20 (74.8% sequence homology). These results indicate that various mucosal and cutaneous HPVs of high risk types are associated with the one of pathogenesis of VC of the lip. In addition, the relationship between VC of the lip and HPV infection is discussed, as is therapy against VC.

Primary cutaneous plasmacytoma: a role for a triggering stimulus?

Primary cutaneous plasmacytoma is a rare type of cutaneous B-cell lymphoma, characterized by clonal proliferation of plasma cells, that primarily develops in the skin. Five cases have been described to date in which a local triggering stimulus may be involved in development of this skin tumour. We describe the case of a primary cutaneous plasmacytoma localized to the lower lip. This site had been affected for 15 years with recurrent herpes simplex virus-1 infection. Neoplastic plasma cells were found to be bcl-2-positive. We hypothesize that chronic stimulation of keratinocytes by herpes simplex virus-1, possibly through toll-like receptors, may have favoured the release of cytokines (e.g. interleukin-6) able to induce plasma cell proliferation, transformation and survival.

Detection of various types of human papillomavirus DNA, mainly belonging to the cutaneous-group, more frequently in normal tissue than in squamous cell carcinomas of the lip.

BACKGROUND: Mucosal high-risk human papillomaviruses (HPVs), such as type 16, are detectable in oral cancers, especially of the oropharynx and tonsils, and there is evidence that they play a pathogenetic role in some cases. However, information is limited about their significance for cancers of the vermilion of the lip. OBJECTIVE: To determine the detection rate, types and localization of HPVs in squamous cell carcinomas (SCCs) of the lip. METHODS: Nested PCR for cutaneous HPVs, including epidermodysplasia verruciformis-related HPV (EV-HPV), and single PCR for mucosal HPVs, were conducted for a total of 27 SCCs and normal samples from 30 individuals. Tyramide-based in situ hybridization (ISH) was also applied. RESULTS: Various types of HPVs were detected, particularly from normal individuals. Among the kinds of the HPV types detected in this study, half were found by PCR using a primer pair, which we newly designed. The prevalence of HPV was 5 out of 27 SCCs (ca. 18%) and 10 out of 30 normal individuals (ca. 33%). They were the entire cutaneous-group except for two, from one SCC and one normal individual. CONCLUSION: On the surface of the normal lip various types of mainly cutaneous-group HPVs may be present, but there does not appear to be any obvious association with SCCs developing in this site.

The therapy of virus-associated epithelial tumors of the face and the lips in organ transplant recipients.

The risk of developing malignant cutaneous neoplasms is increased after organ transplantation. We report three patients with malignant tumors of the epithelium of the facial skin and the lips after kidney and heart transplantation, respectively. They showed an aggressive course of the disease with more than five synchronous or metachronous basal cell and squamous cell carcinomas. Tissue samples were Epstein-Barr virus (EBV) positive by PCR. Using an in situ hybridization technique EBV-encoded RNA (EBER) was detected in tumor-infiltrating lymphocytes. The aggressive course was not alone controllable by surgical or radiological therapy. The systemic and topical application of cidofovir (Vistide) led to remarkable remissions, to a better confinement and operability of the tumors, and to a cessation of tumor pain. The photodynamic therapy represents another opportunity for managing superficial local recurrences and multiple tumors. In conclusion, the results of these case reports demonstrate that combined antiviral, photodynamic and surgical therapy may be used successfully to treat aggressive cutaneous malignancies in patients after organ transplantation.

Detection of Epstein-Barr virus DNA in a patient with Kimura's disease.

An 80-year-old man, with a past medical history of senile dementia, presented with a 6-month history of a solitary, gradually enlarging tumor, located on his chin. A squamous cell carcinoma had been surgically excised 30 years previously in the same location. Physical examination revealed an erythematous, well-defined plaque of 3 cm in diameter, located on the chin (Fig. 1). The submandibular lymph nodes were enlarged. Squamous cell carcinoma and primary cutaneous lymphoma were considered. Relevant laboratory findings were as follows: white blood cell count, 5.600/microL; eosinophils, 1000/microL; gammaglobulin, 2.4 g/dL; lactate dehydrogenase, 343 IU/L; and immunoglobulin G (IgG) antibodies to Epstein-Barr virus (EBV) positive (at 1 : 128 serum dilution), with negative IgM. Skin and lymph node biopsies were performed. Histopathologic study of the cutaneous specimen revealed a heavy lymphoid infiltrate with numerous lymphoid follicles, with prominent germinal centers involving the subcutaneous fat as well as the deep dermis and muscular fascia. Some germinal centers showed folliculolysis. The lymphoid follicles were surrounded by fibrous tissue. The interfollicular infiltrate was rich in plasma cells and eosinophils that formed scattered eosinophilic microabscesses. Thin-walled vessels were numerous and prominent, but with no epithelioid or vacuolated endothelial cells (Fig. 2). Histopathology of a lymph node biopsy specimen showed reactive lymphoid follicle hyperplasia, with prominent eosinophilic infiltrates in both follicular and interfollicular areas. Eosinophilic deposits and polykaryocytes of Warthin-Finkeldey type were seen in the germinal centers. The paracortical area showed vascular proliferation. Polymerase chain reaction (PCR) for the detection of specific sequences of EBV from routinely processed paraffin-embedded material was carried out under the conditions and with the same set of primers as described previously in detail (Tenorio A, Echevarría JE, Casas E et al. J Virol Methods 1993; 44: 261-269). DNA samples were confirmed to be amplifiable with PCR primers specific for a conserved region of the human beta-globin gene. Every sample was tested at least twice for EBV DNA and beta-globin gene. One sample from one skin lesion of the patient, with confirmed diagnosis of Kimura's disease, and 10 samples from normal skin biopsies retrospectively collected from other patients in archival files of our department were tested. Only the patient's specimen tested positive to EBV. The amplified product of EBV was analyzed using DNA sequencing and confirmed the results obtained. The patient received radiotherapy at doses of 35 Gy. Nevertheless, the tumor enlarged to reach twofold its original size 1 month later. Due to the physical status of the patient, no further treatments were considered, but the disease remained stable over the following 3 years.

Absence of latent Epstein-Barr virus in cutaneous squamoproliferative lesions after solid organ transplantation.

Recent studies implicate Epstein-Barr virus (EBV) in the pathogenesis of an increasing number of lymphoid and epithelial tumors. EBV-related disorders are particularly prevalent in immunosuppressed patients. The most common neoplasms arising in persons receiving long-term immunosuppressive agents after organ transplantation include non-Hodgkin's lymphomas and skin and lip carcinomas. Because EBV plays a major role in the evolution of post-transplantation lymphoproliferative disorders and was recently identified in a squamous cell carcinoma of the lip in a renal transplant recipient, we examined squamoproliferative lesions of the skin and lips for the presence of latent EBV. Twenty-six paraffin-embedded specimens from 23 different squamoproliferative lesions occurring in 9 solid organ transplant recipients were examined for the presence of latent EBV by in situ hybridization for EBV-encoded small RNA (EBER-1). The squamoproliferative lesions included 16 squamous cell carcinomas, 3 re-excisions of squamous cell carcinomas, 5 basal cell carcinomas, and 2 actinic keratoses. Two lesions from a single patient exhibited clusters of positive dermal lymphocytes after in situ hybridization with the EBER-1 probe. This patient is currently without clinical evidence of a lymphoproliferative disorder 2 years after the first biopsy showing this phenomenon. The squamoproliferative lesions were all uniformly negative. EBV does not seem to play a role in the initiation or progression of the majority of cutaneous squamoproliferative lesions arising in immunosuppressed patients who received solid organ transplants.