HPV-Related Squamous Cell

Carcinoma Conventional Squamous Cell Carcinoma

Age

Adults with peak in fifth and sixth decades

Adults with peak in sixth and seventh decades

Location

Vast majority arise in the oropharynx (tonsil and base of the tongue), where they constitute up to 80% of squamous cell carcinomas

Arise from all mucosal head and neck sites, including the oropharynx

Symptoms

Often present with neck mass representing lymph node metastasis, may have oral mass associated with pain or difficulty swallowing

White and/or red patch, ulcer, or mass, sometimes with associated pain

Signs

Often present with a cystic cervical neck mass. Although an oropharyngeal mass may be seen, these tumors are often not apparent because they arise deep within tonsillar crypts

White and/or red patch, ulcer, or mass, sometimes with associated cervical lymphadenopathy

Etiology

High-risk types of human papillomavirus (especially type 16). Correlated with histories of high-risk sexual practices and not strongly associated with smoking or ethanol consumption

Correlated with smoking or ethanol consumption

Histology

1. 
   

   Arise from tonsillar crypt epithelium (Fig. 6.1.1)

   
   
2. 
   

   Surface epithelium does not demonstrate dysplasia or squamous carcinoma in situ. When carcinoma does involve the surface epithelium, it is abrupt, by secondary extension (Fig. 6.1.2)

   
   
3. 
   

   Invades as sheets and lobules (Fig. 6.1.3)

   
   
4. 
   

   Has a “blue” appearance due to minimal keratinization and high nuclear:cytoplasmic ratios with minimal cytoplasm (Fig. 6.1.4)

   
   
5. 
   

   Does not typically induce a desmoplastic stromal reaction (Figs. 6.1.3 and 6.1.4)

   
   
6. 
   

   Accompanied by a lymphoplasmacytic inflammatory cell infiltrate (Figs. 6.1.3 and 6.1.4)

   
   
7. 
   

   Mitotic rates are typically high, and necrosis is common

1. 
   

   Arise from surface epithelium (Fig. 6.1.7)

   
   
2. 
   

   Surface epithelium usually demonstrates varying degrees of dysplasia or squamous carcinoma in situ (Fig. 6.1.7)

   
   
3. 
   

   Invades as nests and cords (Figs. 6.1.7 and 6.1.8)

   
   
4. 
   

   Has a “pink” appearance due to keratinization and low nuclear:cytoplasmic ratios with abundant glassy cytoplasm (Figs. 6.1.7 and 6.1.8)

   
   
5. 
   

   Typically induces a desmoplastic stromal reaction (Fig. 6.1.8)

   
   
6. 
   

   Usually not accompanied by a lymphoplasmacytic inflammatory cell infiltrate

   
   
7. 
   

   Mitotic rates are typically high, and necrosis is common

Special studies

• 
  

  Positive for squamous immunohistochemical markers p40, p63, and CK5/6

  
  
• 
  

  HPV studies show positive immunostaining by p16 (at least 70%) and signals by in situ hybridization for HPV DNA or RNA (Figs. 6.1.5 and 6.1.6)

• 
  

  Positive for squamous immunohistochemical markers p40, p63, and CK5/6

  
  
• 
  

  Usually negative for p16 by immunohistochemistry, always negative by in situ hybridization for HPV DNA or RNA

Treatment

Surgery with or without postoperative chemotherapy and/or radiation. May be treated with chemoradiation without surgery. Currently no standard treatment difference based on HPV status

Surgery with or without postoperative chemotherapy and/or radiation. May be treated with chemoradiation without surgery. Currently no standard treatment difference based on HPV status

Prognosis

Good, with 5-year survival rates of 70%-80%

Fair, with 5-year survival rates of 40%-50%

HPV-Related Squamous Cell Carcinoma

HPV-Related Small Cell Carcinoma

Age

Adults with peak in fifth and sixth decades

Adults, mean age approximately 60 years

Location

Vast majority arise in the oropharynx (tonsil and base of the tongue), where they constitute up to 80% of squamous cell carcinomas

Almost all cases have arisen in the oropharynx

Symptoms

Often present with neck mass, may have oral mass associated with pain or difficulty swallowing

Present with oral and/or neck masses

Signs

Often present with a cystic cervical neck mass. Although an oropharyngeal mass may be seen, these tumors are often not apparent because they arise deep within tonsillar crypts

Often present with neck cervical neck mass or lung metastases on imaging

Etiology

High-risk types of human papillomavirus (especially type 16). Correlated with histories of high-risk sexual practices and not strongly associated with smoking or ethanol consumption

High-risk types of human papillomavirus (especially type 16). Etiology of small cell transformation is unknown

Histology

1. 
   

   Invades as sheets and lobules

   
   
2. 
   

   Nonkeratinizing or partially keratinizing, with tumor cells that have minimal cytoplasm (Fig. 6.2.1)

   
   
3. 
   

   Tumor cells with round to oval nuclei, open chromatin, and variably prominent nucleoli (Fig. 6.2.1)

   
   
4. 
   

   No nuclear molding or prominent crush artifact

   
   
5. 
   

   Mitotic rates are typically high, and necrosis is common (Fig. 6.2.1)

1. 
   

   Invades as sheets, lobules, and trabeculae (Fig. 6.2.5)

   
   
2. 
   

   No keratinization with tumor cells that have virtually no cytoplasm (Fig. 6.2.6)

   
   
3. 
   

   Tumor cells with dark, hyperchromatic nuclei with indistinct nucleoli (Fig. 6.2.6)

   
   
4. 
   

   Nuclear molding and crush artifact are commonly identified (Fig. 6.2.6)

   
   
5. 
   

   Mitotic rates are high, numerous apoptotic bodies and necrosis present (Figs. 6.2.5 and 6.2.6)

   
   
6. 
   

   A subset has a component of squamous cell carcinoma within the tumor (Fig. 6.2.6)

Special studies

• 
  

  Positive for squamous immunohistochemical markers p40, p63, and CK5/6 (Fig. 6.2.2)

  
  
• 
  

  Negative for neuroendocrine markers synaptophysin, chromogranin and CD56 and negative for TTF-1 (Figs. 6.2.3 and 6.2.4)

  
  
• 
  

  HPV studies show positive immunostaining by p16 (at least 70%) and signals by in situ hybridization for HPV DNA or RNA

• 
  

  Positive for at least one neuroendocrine marker (synaptophysin, chromogranin, and CD56) and sometimes positive for TTF-1 (Figs. 6.2.3 and 6.2.4)

  
  
• 
  

  Negative for squamous immunohistochemical markers p40, p63, and CK5/6 (Fig. 6.2.2)

  
  
• 
  

  HPV studies show positive immunostaining by p16 (at least 70%) and signals by in situ hybridization for HPV DNA or RNA

Treatment

Surgery with or without postoperative chemotherapy and/or radiation. May be treated with chemoradiation without surgery. Currently no standard treatment difference based on HPV status

Optimal treatment is unclear due to the rarity of the variant, but small cell carcinoma chemotherapy protocols may be employed

Prognosis

Good, with 5-year survival rates of 70%-80%

Poor. Majority of patients experience recurrences, distant metastases (especially to lung), and death due to disease