Expression of p16, Rb, and p53 Proteins in Squamous Cell Carcinomas of the Anorectal Region Harboring Human Papillomavirus DNA

Lu, Danielle W.; El‐Mofty, Samir K.; Wang, Hanlin L.

doi:10.1097/01.mp.0000077417.08371.ce

Cited by 100 publications

(83 citation statements)

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“…An association with human papillomavirus has been previously assessed in 25 cases, all of which were found to harbor high-risk human papillomavirus DNA, mostly type 16. 29 Clinical follow-up data were available in 18 cases. All of these patients were treated with synchronous chemoradiation therapies, with the chemotherapeutic regimens consisting of fluorouracil plus mitomycin or cisplatin.…”

Section: Clinicopathologic Features Of Squamous Cell Carcinomas Of Thmentioning

confidence: 99%

“…27,28 Population-based case-control studies have linked this increase to changes in sexual behavior, 27 with a strong etiopathogenetic association with human papillomavirus infection. 29,30 As the patients with squamous cell carcinoma of the anal canal are traditionally managed with combined chemoradiation therapy, rather than by surgical means alone, 31 we investigated EGFR expression in these tumors to determine whether the patients might rationally benefit from targeted therapies, such as cetuximab.…”

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confidence: 99%

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Expression of epidermal growth factor receptor in squamous cell carcinomas of the anal canal is independent of gene amplification

et al. 2006

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Immunohistochemical detection of expression of the epidermal growth factor receptor (EGFR) has been utilized to identify eligible patients with solid malignant tumors, including colorectal adenocarcinoma, for monoclonal antibody therapy (eg, cetuximab). The EGFR status in squamous cell carcinoma of the anal canal, an uncommon malignancy traditionally treated with chemoradiation, has not been well investigated. In this study, 38 primary squamous cell carcinomas of the anal canal were immunohistochemically examined for EGFR expression and analyzed by fluorescence in situ hybridization (FISH) for EGFR gene copy numbers. The results showed a variable degree of EGFR expression in 21 (55%) tumors, among which 13 (62%) cases exhibited a 2 þ to 3 þ staining pattern according to the Dako EGFR phamDx interpretation guide. There were no significant differences among tumors stratified by stage, degree of keratinization, or tissue block storage times. FISH analysis showed that none of the 34 cases with interpretable results had EGFR gene amplification. Increased gene copy numbers due to polysomy 7 were seen in seven of 18 (39%) cases that expressed EGFR protein and four of 16 (25%) cases that did not (P ¼ 0.3876). Ten (56%) tumors with positive EGFR staining showed a balanced disomy 7 pattern and one case with monosomy 7 exhibited strong EGFR expression (3 þ ). These results demonstrate that EGFR is overexpressed in more than one-half of the squamous cell carcinomas of the anal canal through mechanisms other than gene amplification. These observations may have important therapeutic implications since EGFR-based targeted therapies have shown promise for other malignant neoplasms.

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Section: Clinicopathologic Features Of Squamous Cell Carcinomas Of Thmentioning

confidence: 99%

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confidence: 99%

Expression of epidermal growth factor receptor in squamous cell carcinomas of the anal canal is independent of gene amplification

et al. 2006

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“…The same patterns of expression for p16 and pRb have been identified in HPV-16 positive anorectal cancers. 35 It has been suggested that loss of pRb through the activities of HPV E7 overcomes the need for cyclin D1 in G1 and leads to upregulation of p16 through a feedback loop. The scenario in cervical cancer is not as well defined.…”

Section: Discussionmentioning

confidence: 99%

“…There is evidence for a similar scenario in HPV 16-positive anorectal cancers. 16 The processes in cervical cancer seem more complex. Strong diffuse p16 staining with concomitant loss of cyclin D1 have been widely associated with cervical dysplasia and cancer and/or the presence of highrisk HPVs, 6,17,18 but there is no consensus on the expression of pRb in relation to the presence of HPV; some studies have reported loss of pRb, 19 but in others, pRb has either been conserved 20 or overexpressed.…”

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confidence: 99%

The site of infection and ethnicity of the patient influence the biological pathways to HPV-induced mucosal cancer

Thompson

Cossart

et al. 2004

Modern Pathology

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High-risk human papillomaviruses are the causative agents of cervical cancer and are also believed to be aetiologically involved in a subset of squamous cell carcinomas of the head and neck region, especially the tonsil. Cervical cancers arise through disruption of the pathways of p53 and the product of the retinoblastoma gene by the human papillomavirus oncoproteins E6 and E7. It is generally assumed that the same pathways are involved in human papillomavirus-induced carcinogenesis at other mucosal surfaces. However, the patterns of expression of cell cycle proteins targeted by human papillomavirus E6 and E7 in cancers from different anatomic sites have been inconsistent, due to either biologic or technological factors. In this study, 73 human papillomavirus, 16-positive cervical squamous cell carcinomas (35 from Australian and 38 from Chinese women) were analysed for the expression of p53, pRb, p16 INK4A , p21 CIP1/WAF1 , p27 KIP1 and cyclin D1 by semiquantitative immunohistochemistry. Cervical cancers from Chinese women were found to be significantly more likely to overexpress p53, pRb, p21 and p27 than their Australian counterparts. These findings were compared with those from 31 human papillomavirus 16-positive tonsillar squamous cell carcinomas, all of Australian origin, tested using the same methodology. Comparisons of the tonsillar and combined cervical data showed that tonsillar cancers were significantly more likely to be p53-positive, whereas cervical cancers were significantly more likely to overexpress pRb, p16 and p27. When the tonsillar data were compared with cervical data from Australian women, the associations for p53 and pRb remained. These findings represent new evidence that the molecular pathways to human papillomavirus-induced mucosal cancer may be influenced by anatomic location and ethnicity.

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“…[16][17][18] Infection with high-risk HPV has been associated with malignant transformation, and causally related to cervical cancer 19,20 and a subset of squamous cell carcinomas in the head and neck and anogenital region different from the cervix. [21][22][23] Verrucous carcinoma has been associated with both low-risk (types 6 and 11) and high-risk (types 16 and 18) types of HPV. 18,24,25 However, a causal relationship between HPV and verrucous carcinoma remains to be proven, specifically in those cases in which a low-risk HPV has been suggested to be involved in the genesis of the tumours.…”

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confidence: 99%

Comprehensive analysis of human papillomavirus prevalence and the potential role of low-risk types in verrucous carcinoma

et al. 2012

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The role of human papillomavirus (HPV) infections in the development of verrucous carcinoma, a welldifferentiated variant of squamous cell carcinoma with difficult differential diagnosis, is controversial in the literature. In this study, we analysed verrucous carcinoma from different origins for the presence and activity of a broad spectrum of HPV types, and carefully reviewed the histopathological features. A random series of 27 formalin-fixed, paraffin-embedded specimens of verrucous carcinoma was taken, representing the head and neck region (n ¼ 6), anogenital area (n ¼ 16) and extragenital skin region (n ¼ 5). After review of the histological slides, all samples were subjected to different polymerase chain reaction-based HPV detection techniques, together detecting a total of 83 HPV types, including both mucosal and cutaneous types. Histological revision was carefully performed. Lesions with keratinised papillae, blunt stromal invaginations and minimal cytological atypia were considered verrucous carcinoma. Condylomatous lesions with viral changes were defined as giant condyloma. Verrucous lesions that did not meet those criteria were classified as verrucous hyperplasia. Tumours with stromal infiltration were considered as invasive squamous cell carcinoma. Histological revision revealed that 13 out of 27 cases were verrucous carcinoma (one showing a double infection with HPV 35 and 45), 5 invasive squamous cell carcinomas, 5 verrucous hyperplasia (one with a double infection with HPV 4 and 8), 1 pseudoepitheliomatous hyperplasia and 3 giant condylomas. All three giant condylomas were low-risk HPV positive (HPV 6 and 11) and showed active mRNA transcription. None of the HPV-positive samples tested positive for diffuse p16 INK4A staining. In conclusion, our results do not support a causal role of HPV in the development of verrucous carcinoma. Testing for LR-HPV, particularly HPV 6 and 11, may help in the differential diagnosis of lesions suspicious of verrucous carcinoma as those testing positive for LR-HPV most likely represent giant condylomas.

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Expression of p16, Rb, and p53 Proteins in Squamous Cell Carcinomas of the Anorectal Region Harboring Human Papillomavirus DNA

Cited by 100 publications

References 51 publications

Expression of epidermal growth factor receptor in squamous cell carcinomas of the anal canal is independent of gene amplification

Expression of epidermal growth factor receptor in squamous cell carcinomas of the anal canal is independent of gene amplification

The site of infection and ethnicity of the patient influence the biological pathways to HPV-induced mucosal cancer

Comprehensive analysis of human papillomavirus prevalence and the potential role of low-risk types in verrucous carcinoma

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