The results of HPV analysis are summarized in and . A total of sixty-eight patients were identified who had a primary HNSqCC and went on to develop a SqCC in their lungs. We were able to obtain tissue blocks on fifty-four cases, which were included in the study. Two patients had two primary HNSqCCs. In 32 cases, the lung carcinoma presented as a solitary mass, while in 21 cases there were multiple (>2) lung nodules; in 1 case, radiographic information was not available. There were a total of 166 primary lung SqCCs from patients without a prior HNSqCC. Overall, high-risk HPV was detected by in situ hybridization in 11 of the 220 (5%) carcinomas involving the lung. HPV was not detected in any of the 166 primary lung carcinomas from patients without a prior HNSqCC, but it was detected in 11 of 54 (20%) lung SqCCs from patients with a prior HNSqCC. In these patients, HPV was detected in 11 of 28 patients with an oropharyngeal primary, but in none of the 26 patients with HNSqCC arising only from a non-oropharyngeal site (39% vs. 0%, p =0.0003, Fisher exact, 2-sided). In 7 cases (64%), the HPV-positive lung cancer presented as a solitary mass, while the remaining four cases presented with multiple nodules. All 11 HPV-positive tumors demonstrated prominent basaloid features including a lobular pattern of growth, nuclear hyperchromasia, a high nuclear to cytoplasmic ratio, and absent to minimal keratinization.
P16 expression and HPV status of lung carcinomas including squamous cell carcinomas in patients with prior squamous cell carcinomas of the head and neck
HPV detection in carcinomas involving the lungs of patients with and without prior squamous cell carcinomas of the head and neck. HPV detection is strictly limited to those patients with a prior squamous cell carcinoma arising from the oropharynx.
The HPV status and histopathologic features of the tumor pairs were compared for those patients with oropharyngeal SqCC who developed a SqCC in their lung. Tissue blocks were available for 22 of the 28 oropharyngeal carcinomas. HPV status was concordant in 21 (95%) cases. In 10 cases the tumor pairs were HPV positive; and in 11 cases the tumor pairs were HPV negative. In these concordant HPV-positive cases, the basaloid phenotype was well developed in both the oropharyngeal carcinomas and the paired lung carcinomas (). The single discordant case involved a patient with an HPV positive oropharyngeal SqCC who developed an HPV negative SqCC in the lung 14 months after treatment of the primary tumor. In the HPV positive concordant cases, the time intervals from treatment of the oropharyngeal primary to detection of carcinoma in the lung were 1, 8, 11, 14, 15, 31, 32, 53, 96 and 97 months (range 1 to 97 months, mean36 months, median 23 months).
Figure 2 Squamous cell carcinomas of the base of tongue (A-C) and lung (D-F) from the same patient. The carcinomas are morphologically very similar (A and D, routine hematoxylin and eosin staining), and they exhibit concordant patterns of p16 expression (B and (more ...)
Notably, 2 HPV-positive carcinomas were detected in the lung 8 years after treatment of the oropharyngeal primary. To address whether these tumor pairs were clonally related, we sequenced E6 to determine whether the specific HPV-16 variant in the oropharynx and lung was the same or different. For one of the patients, E6 sequencing confirmed that the tumor pair harbored the identical 131/2GG HPV-16 variant.(40
) E6 sequencing could not be performed in the other tumor pair due to insufficient tissue in the lung biopsy.
P16 overexpression as visualized by immunohistochemical staining is commonly used as a surrogate marker for the presence of high risk HPV. Overall, p16 overexpression was observed in 54 of 220 (24.5%) carcinomas involving the lung. In contrast to HPV detection by in situ hybridization, p16 overexpression in carcinomas involving the lung was not restricted to patients with prior oropharyngeal HNSqCCs. P16 overexpression was detected in 37 of 166 (22%) lung carcinomas from patients without any prior HNSqCC including 3 of 3 (100%) small cell carcinomas, 4 of 11 (25%) large cell/pleomorphic carcinomas, 15 of 74 (20%) adenocarcinomas, 14 of 66 (21%) squamous cell carcinomas, and 1 of 12 (8%) non-small cell carcinomas not otherwise specified. Among the squamous cell carcinomas, strong p16 staining was present in 8 of 20 (40%) tumors demonstrating the basaloid phenotype. For patients with a prior HNSqCC, p16 overexpression in the lung carcinoma was more common in patients with prior oropharyngeal carcinomas than those without oropharyngeal carcinomas (54% vs. 8%, p = 0.0003, Fisher exact, 2-sided).