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HPV-associated head and neck squamous cell carcinoma

Monday 26 March 2012

HPV-positive oropharyngeal cancer; HPV-related head and neck squamous cell carcinoma; HPV-associated HNSCC

WP

Human papilloma virus (HPV)-related squamous cell carcinoma is a distinct variant of head and neck squamous cell carcinoma (HNSCC).

Human papilloma virus (HPV)-related oropharyngeal carcinoma represents a clinically distinct form of head and neck squamous cell carcinoma (HNSCC) that results from oral HPV infection.

These tumors are associated with an improved overall survival, progression-free survival, and disease-specific survival in comparison to their HPV-negative counterparts.

In contrast to HPV-negative HNSCC, which has been gradually decreasing in incidence in the United States due to a decline in tobacco exposure, HPV-related HNSCC has seen a dramatic increase in overall incidence (225% from 1998 to 2004 / 6 years).

HPV-related HNSCC is typically seen in younger patients ( < 60 years) whose sexual behavior increases risk factors for HPV infection including early age of sexual contact, high number of lifetime sexual partners, oral–genital and oral–anal sex, and lack of barrier protection during sexual contact.

HPV-related HNSCC has a strong association with oral high-risk HPV (HR-HPV) infection, most frequently HPV type 16 (85–90% of cases).

These tumors are more frequently encountered in men than in women who are often non-smokers and without a history of alcohol abuse.

They most commonly involve the oropharynx, with particular predilection for the tonsil and base of the tongue.

HPV-related HNSCC is driven by the production of viral oncoproteins E6 and E7, which interfere with the p53 and retinoblastoma (Rb) tumor suppressor pathways.

Inactivation of Rb by E7 leads to upregulation and overexpression of p16. Immunohistochemical (IHC) detection of p16 in tumor cells is thus often used as a surrogate for HR-HPV infection.

HPV-related HNSCC forms a distinct clinicopathologic entity primarily because of its much improved prognosis and clinical outcomes when compared with non-HPV associated HNSCC.

The option of treating these patients with less intense chemo/radiotherapy than conventional treatment for non-HPV HNSCC is currently being addressed in clinical trials.

The most common histomorphology seen in HPV-related HNSCC is a non-keratinizing basaloid form of squamous cell carcinoma (SCC). This tumor typically infiltrates in sheets, cords, and lobules with associated central necrosis often leading to cystic degeneration.

Strong stromal desmoplastic response is uncommon, but hyalinization is usual, and the tumor is often surrounded by lymphoid tissue which may infiltrate as tumor-infiltrating lymphocytes (TILs) thereby imparting a lymphoepithelial-like appearance.

Cytologically, malignant cells display high nuclear–cytoplasmic ratios giving a classic basaloid appearance. Cytoplasmic keratinization and intercellular bridges are absent.

The distinction of HPV-related HNSCC with basaloid cytomorphology from clinically aggressive non-HPV-related basaloid variant of HNSCC is important.

Other morphologic variants of HPV-related HNSCCs reported in the literature include papillary, adenosquamous, and rare reports of small cell transformation which is associated with a more aggressive behavior and poor prognosis.

HPV-related HNSCCs frequently undergo necrosis and cystic degeneration, especially when they metastasize to cervical lymph nodes resulting in cystic degeneration.

The cystic change in an enlarged cervical node with a metastatic deposit is so characteristic of HPV-related HNSCC that in the absence of a known primary, an occult oropharyngeal HPV-related HNSCC should always be suspected.

Oropharyngeal HNSCCs frequently present with small, often occult tumors, and low tumor (T) stage disease but with higher nodal (N) stage and enlarged metastatic cervical lymph nodes.

Cytology

The role of cytology for the diagnosis of HPV-related HNSCC at the primary site is very limited.

The small size of the tumors, together with the most prevalent sites of occurrence in the base of tongue and tonsillar crypts, makes cytological sampling techniques such as oral brushing/rinsing relatively ineffective for detection of these tumors.

Therefore, an oral Papanicolaou (Pap) screening test similar to the hugely successful cervical cytology screening has not been considered for early diagnosis of HPV-related HNSCC.

In contrast to the limited role of traditional cytology for the diagnosis of HPV-related HNSCC in the oropharynx, fine-needle aspiration (FNA) biopsy of enlarged metastatic neck lymph nodes very often plays a significant role in the initial diagnosis of HPV-related HNSCC.

The role of neck lymph node FNA in the recognition of occult HPV-related HNSCC in patients who present with metastatic carcinoma of unknown primary is now well accepted clinically.

Therefore, evaluating HPV status in any patient with a newly diagnosed metastatic SCC to a neck node without a known primary is highly recommended in determining a primary site of origin. Having a positive HPV result is a strong indicator of oropharyngeal origin and facilitates clinical management.

FNA biopsy results in these patients lead to targeted endoscopic examination of the oropharynx, particularly the tongue base and tonsils, to identify the primary tumor site.

In the rare event of an unidentified primary site despite exhaustive clinical/radiological evaluation, positive HPV status can be used to direct localized radiation therapy to the oropharynx instead of irradiating the entire upper respiratory mucosa, thereby sparing the patient significant morbidity and associated complications.

The possibility of metastatic HPV-related squamous cell carcinoma (SCC) from distant sites such as lung and cervix needs to be excluded in such patients because of the significant morphologic and immunophenotypic overlap in SCCs arising from different sites.

References

- http://www.semdiagpath.com/article/S0740-2570(14)00113-0/fulltext

Epidemiology

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- Chaturvedi, A.K., Engels, E.A., Pfeiffer, R.M. et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011; 29: 4294–4301.

- Chaturvedi, A.K., Graubard, B.I., Pickard, R.K. et al. High-risk oral human papillomavirus load in the US population, National Health and Nutrition Examination Survey 2009–2010. J Infect Dis. 2014; 210: 441–447. 24625808

- Smith, E.M., Ritchie, J.M., Summersgill, K.F. et al. Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. Int J Cancer. 2004; 108: 766–772

- Summersgill, K.F., Smith, E.M., Levy, B.T. et al. Human papillomavirus in the oral cavities of children and adolescents. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001; 91: 62–69

- Kreimer, A.R., Alberg, A.J., Daniel, R. et al. Oral human papillomavirus infection in adults is associated with sexual behavior and HIV serostatus. J Infect Dis. 2004; 189: 686–698

- Kreimer, A.R., Alberg, A.J., Viscidi, R. et al. Gender differences in sexual biomarkers and behaviors associated with human papillomavirus-16, -18, and -33 seroprevalence. Sex Transm Dis. 2004; 31: 247–256

- Marur, S., D’Souza, G., Westra, W.H. et al. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol. 2010; 11: 781–789

HPV analysis

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