HPV-related nonkeratinizing squamous cell carcinoma of the oropharynx: utility of microscopic features in predicting patient outcome

Abstract

Human papilloma virus (HPV) is an etiologic agent in a subset of oropharyngeal squamous cell carcinomas (SCCs). The aim of this study was to sub-classify SCC of the oropharynx based upon histologic features into nonkeratinizing (NK) SCC, keratinizing (K) SCC, and hybrid SCC, and determine the frequency of HPV and patient survival in each group. Patients with oropharyngeal SCC with a minimum of 2 years of clinical follow-up were identified from radiation oncology databases from 1997 to 2004. All patients received either up front surgery with postoperative radiation or definitive radiation based therapy. In situ hybridization (ISH) for high-risk HPV subtypes and immunohistochemistry for p16, a protein frequently up-regulated in HPV-associated carcinomas, were performed. Overall and disease-specific survival were assessed. Of 118 cases, 46.6% were NK SCC, 24.6% K SCC and 28.8% hybrid SCC. NK SCC occurred in slightly younger patients that were more often male. It more frequently presented with lymph node metastases and was surgically resected compared to K SCC. NK SCC was significantly more likely to be HPV and p16 positive than KSCC (P < 0.001) and to have better overall and disease-specific survival (P = 0.0002; P = 0.0142, respectively). Hybrid SCC was also more likely than K SCC to be HPV and p16 positive (P = 0.003; P = 0.002, respectively) and to have better overall survival (P = 0.0105). Sub-classification of oropharyngeal SCC by histologic type provides useful clinical information. NK SCC histology strongly predicts HPV-association and better patient survival compared to K SCC. Hybrid SCC appears to have an intermediate frequency of HPV-association and patient survival.

Keywords: Head and neck; Human papillomavirus; Hybrid squamous cell carcinoma; Immunohistochemistry; In situ hybridization; Intensity-modulated radiation therapy; Keratinizing squamous cell carcinoma; Nonkeratinizing squamous cell carcinoma; Oropharynx; p16.

Fig. 1

Histologic features of NK SCC (H&E stained sections). a Low-power image (×100) showing nest of tumor cells with pushing borders and comedo-type necrosis. In addition, there is a lack of stromal desmoplasia around the tumor nests. b High-power image (×600) showing oval to spindled, hyperchromatic tumor cells that lack prominent nucleoli and have indistinct cell borders

Fig. 2

Histologic features of K SCC (H&E stained sections). a Low-power image (×100) showing sheets of tumor cells with keratin pearl formation. b Low-power image (×200) showing infiltrative nests of polygonal-shaped tumor cells with abundant, eosinophilic (“mature”) cytoplasm and distinct cell borders. c Low-power image (×200) showing desmoplastic stroma surrounding tumor nests. d High-power image (×600) highlighting intercellular bridges

Fig. 3

Histologic features of hybrid SCC (H&E stained sections). a Low-power image (×200) showing keratinizing SCC on the left and adjacent nonkeratinizing SCC on the right. b High-power image (×400) showing predominately ovoid to spindled, hyperchromatic cells. Focally, the cells have eosinophilic (“mature”) cytoplasm and distinct cell borders

Fig. 4

Examples of HR HPV-ISH and p16 immunohistochemistry results. a HR HPV positive (blue nuclear dots) tumor by ISH (×600). b HR HPV negative tumor by ISH (×600). c p16 positive tumor by immunohistochemistry showing strong nuclear and cytoplasmic staining (×400). d p16 negative tumor by immunohistochemistry (×400)

Fig. 5

Kaplan–Meier curve of overall survival in patients by histologic type (Cox-proportional hazards regression analysis). P values are adjusted for age and surgical versus nonsurgical management

Fig. 6

Kaplan–Meier curve of disease-specific survival in patients by histologic type (log-rank tests for the equality of survivor functions). P values are unadjusted