Oral cavity & oropharynx
Malignant neoplasms
HPV related oropharyngeal squamous cell carcinoma

Editor-in-Chief: Debra Zynger, M.D.
Zahra Maleki, M.D.

Topic Completed: 20 November 2019

Revised: 25 November 2019

Copyright: 2019, PathologyOutlines.com, Inc.

PubMed Search: HPV related[title] oropharyngeal squamous cell carcinoma

Zahra Maleki, M.D.
Page views in 2019 to date: 719
Cite this page: Maleki Z. HPV related oropharyngeal squamous cell carcinoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/oralcavityHPVrelatedoropharyngeal.html. Accessed December 11th, 2019.
Definition / general
Essential features
  • Oropharyngeal squamous cell carcinoma caused by high risk HPV
  • Mostly present as a cystic or solid neck mass, enlarged cervical lymph node, or rarely enlarged tonsil
  • Variable squamous differentiation characterized by orangeophilic keratinized squamous cells in Papanicolaou stain
  • p16 immunostain, a surrogate marker for high risk HPV, is considered positive when expressed in ≥ 70% of tumor cells with both nuclear and cytoplasmic staining; occasionally p16 is focal / patchy positive or negative
  • High risk HPV can be detected by different methods such as RNA in situ hybridization
  • High risk HPV testing can be performed on both primary or metastatic tumor
  • No tumor grading
  • Overall favorable prognosis despite early local lymph node metastasis (Cancer Epidemiol Biomarkers Prev 2019;28:1660)
  • Rare cases associated with distant metastasis and poor prognosis
  • HPV+ squamous cell carcinoma is associated with better prognosis than HPV- squamous cell carcinoma
Terminology
Epidemiology
  • Affects both males and females, more common in white males, mostly younger than 65
  • Incidence is growing rapidly (J Clin Oncol 2011;29:4294)
  • U.S. incidence of oropharyngeal HPV+ squamous cell carcinoma is higher than the incidence of HPV- cases, 4.62 versus 1.82 per 100,000 (Cancer Epidemiol Biomarkers Prev 2019;28:1660)
  • Patients are younger, predominantly Caucasians and higher socioeconomic status compered to HPV- squamous cell carcinoma
Sites
  • Most common in oropharynx (tonsils, base of tongue and adenoids) and posterior pharyngeal wall
  • Arise from the tonsillar crypts
Pathophysiology
  • Etiologic agent is high risk HPV
  • Arises from the tonsillar crypts
  • Initial step is infection of the epithelial basal layer by HPV through microabrasions or trauma
  • HPV double stranded DNA genome encodes oncoproteins such as Early genes E1, E2, E6 and E7 after integration into the host cell nucleus (J Dent Res 2015;94:1532)
  • E1 and E2 genes activate viral replication
  • E6 binds to p53 and inactivates tumor suppressor protein p53 and E7 binds to pRB and inactivates tumor suppressor protein pRB
  • E6 and E7 expression promotes cellular proliferation and increases chance of malignancy (J Am Soc Cytopathol 2016;5:203)
Etiology
  • Caused by high risk HPV, mostly commonly associated with HPV16 and HPV18 strains
  • Also includes high risk HPV strains 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 82, as well as others (Cancer Epidemiol Biomarkers Prev 1996;5:567)
  • Oral sexual contact is a major risk factor, but not alcohol or tobacco (smoking or chewing)
Clinical features
  • Initial presentation in most cases is a neck mass or cervical lymphadenopathy
  • Occasionally presents with a unilateral enlarged tonsil
  • May have distant metastases to the lungs, mediastinal lymph nodes, brain, liver, bone, skin, duodenum (J Am Soc Cytopathol 2016;5:203)
Diagnosis
  • Tissue findings in which morphology, along with nuclear and cytoplasmic expression of p16 in ≥ 70% of tumor cells or detection of high risk HPV in tumor cells, is required for the diagnosis
Radiology description
  • Imaging findings, including ultrasound, such as enlargement, loss of the central fatty hilum, irregular cortical thickening, increased vascularity and loss of elongated shape are suspicious characteristics for metastatic HPV related squamous cell carcinoma; however, they are nonspecific
  • Central necrosis appears as a cystic area within the node, demonstrating an anechoic, or completely black, echo texture enhanced through transmission (AJR Am J Roentgenol 2005;184:1691)
Radiology images

Contributed by Zahra Maleki, M.D.
Missing Image

Ultrasound

Prognostic factors
  • Distant metastasis, although rare, is associated with poor prognosis
Case reports
Treatment
  • Resection of primary tumor with or without ipsilateral or bilateral neck dissection
  • Radiation therapy or systemic therapy in cases with extranodal extension, positive margins or other high risk associated features such as pT3 or pT4 primary, one positive node > 3 cm or multiple positive nodes, nodal metastasis in levels IV or V, perineural invasion, vascular invasion and lymphatic invasion (National Comprehensive Cancer Network, J Am Soc Cytopathol 2016;5:203)
Microscopic (histologic) description
Microscopic (histologic) images

Contributed by Zahra Maleki, M.D.
Missing Image

Infiltrating tumor

Missing Image

Basaloid cells

Cytology description
  • Non / minimally keratinized squamous cell carcinoma, fragments of basaloid cells with high N/C ratio and hyperchromatic nuclei
  • Fragments of cohesive malignant squamous cells with dense cytoplasm
  • Variable squamous differentiation, tadpole, snake cells and squamous cells with orangeophilic cytoplasm in Papanicolaou stain and blue in Romanowsky stain, respectively
  • Individual keratinized cells with marked pleomorphism
  • Necrosis, cystic degeneration and macrophages, common
Cytology images

Contributed by Zahra Maleki, M.D.
Missing Image

Atypical squamous cells

Missing Image

Pleomorphism

Missing Image

Focal keratinization

Missing Image

Cohesive fragments

Missing Image

Basaloid features

Missing Image

Cyst aspiration


Missing Image

Cell block

Missing Image

p63

Missing Image

p16

Positive stains
Molecular / cytogenetics description
Molecular / cytogenetics images

Contributed by Zahra Maleki, M.D.
Missing Image

High risk HPV DNA ISH

Missing Image

HPV16 DNA ISH

Missing Image Missing Image

HPV RNA ISH

Sample pathology report
  • Lymph node, right level II, ultrasound guided fine needle aspiration:
    • Metastatic HPV related squamous cell carcinoma (see comment)
    • Comment: An immunostain for p16 is positive in 80% of the tumor cells. In situ hybridization for high risk HPV RNA is positive.
Differential diagnosis
Additional references
Board review question #1

    An HPV related oropharyngeal squamous cell carcinoma is shown. To corroborate this diagnosis, p16 must be positive in at least which percentage and location of tumor cells?

  1. 10% nuclear and cytoplasmic
  2. 40% nuclear and cytoplasmic
  3. 50% nuclear
  4. 60% cytoplasmic
  5. 70% nuclear and cytoplasmic
Board review answer #1
E. 70% nuclear and cytoplasmic

Comment Here

Reference: HPV related oropharyngeal squamous cell carcinoma
Board review question #2
    Which one of the following statements is true about HPV related oropharyngeal carcinoma?

  1. Extranodal extension has no impact on treatment
  2. Distant metastasis is very common
  3. High risk HPV testing can be performed on primary or metastatic tumor
  4. The prognosis is poor in most cases
  5. Tumor differentiation must be reported for all cases
Board review answer #2
C. High risk HPV testing can be performed on primary or metastatic tumor

Comment Here

Reference: HPV related oropharyngeal squamous cell carcinoma

Back to top