Adenosquamous carcinoma of the head and neck is a rare variant of squamous cell carcinoma. Little is known about its etiopathogenesis, mainly due to its rarity and lack of larger, controlled studies. However, there is nearly unanimous agreement among authors about its aggressive behavior and propensity for locoregional and distant metastases. A strong male predilection (M:F > 6:1) is observed, and the tumors occur over a broad age range (21–87 years). The larynx is the most common site (48.4%), followed by the oral cavity (30%). Most tumors are high stage at the time of presentation. In our series of 18 cases, 10 patients (55.6%) had local recurrence or nodal metastases and 4 (22.2%) developed distant metastases. In our combined review, 49 patients (52.7%) developed local recurrence or nodal metastases and 19 (20.4%) developed distant metastases [4
]. Also, in a previous review of 58 cases of head and neck ADSC, Keelawat et al. reported 65% regional metastases, 23% distant metastases, and 43% of patients dying of disease [26
]. The lung is the most common site for distant metastases. Thus, our current data and the overall literature support the notion that ADSC is more clinically aggressive than typical head and neck SCC, for which only 10–15% of patients develop distant metastases [42
], and which has a 5 years relative overall survival of approximately 50% [44
Recent studies have demonstrated that head and neck SCC patients, particularly of the oropharynx, have a much better prognosis when their tumors are associated with transcriptionally-active HPV than when they are not [13
]. High risk HPV types, particularly type 16, have been detected in as many as 80% of oropharyngeal SCC [11
]. The virus contributes to carcinogenesis by expressing E6 and E7 oncoproteins, which bind to p53 and retinoblastoma (Rb), respectively. These latter proteins are critical for apoptosis and cell cycle regulation and, when disrupted, cause cells to proliferate and fail to undergo apoptosis appropriately. Inactivation of Rb, in particular, leads to marked overexpression of the tumor suppressor protein p16, for which transcription is normally repressed by Rb. This marked overexpression, which is very uncommon in non-HPV-related SCC, makes p16 a good surrogate marker of HPV, but more importantly, a good marker of transcriptionally-active HPV [18
], because while HPV DNA can be found in a relatively high numbers of head and neck SCC of all anatomic subsites, the ones with better clinical outcomes have only been those where HPV is present in the tumor and in transcriptionally active form [12
]. It is generally accepted that if one finds evidence of high risk HPV in a tumor that coexistent overexpression of p16 and/or significant expression of HPV E6 and E7 transcripts, this indicates biologically and clinically significant role of HPV in the tumor. Occasionally, p16 is overexpressed but no HPV can be detected. These tumors, in the oropharynx, still appear to have the same good prognosis, but their biology is still unknown. It is possible that in most such tumors, HPV is present but the tests don’t detect it. But one can also speculate that tumors can truly overexpress p16 in the absence of HPV. This is something yet to be clearly defined. For non-oropharyngeal SCC, the significance of p16 overexpression is not clear. It does not seem to be a good marker of prognosis or necessarily a good surrogate for HPV. We had a few non-oropharyngeal, p16 overexpressing ADSC cases and these did not harbor HPV. Although they appeared to do well clinically, the number of cases is too small to make any meaningful conclusions.
Several histologic variants of SCC, including nonkeratinizing SCC, basaloid SCC, papillary SCC, and undifferentiated carcinoma [7
], have been shown to harbor high risk HPV when arising in the oropharynx. Papillary SCC, in particular, can have transcriptionally-active HPV in non-oropharyngeal locations such as the larynx [9
]. Where clinical outcomes have been investigated in these variants, HPV-positive patients have had better survival. The relationship of head and neck ADSC to HPV has not been previously investigated. In the uterine cervix [24
], as many as 75% of cases harbor HPV [45
], and in the single series of lung cases, most harbored HPV as well [46
In our series of 18 ADSC cases, we utilized a novel, slide-based high risk HPV RNA ISH assay along with the traditional p16 IHC and Ventana DNA ISH assays. This new RNA-based assay for transcriptionally-active HPV allows evaluation for viral E6 and E7 directly in tissue sections. This is considered by many to be the “gold standard” for biologically relevant tumor HPV. Only a small minority of ADSC harbored HPV (2 oropharynx, 1 nasal cavity, 2 larynx) with fewer still (2 oropharynx, 1 nasal cavity) harboring transcriptionally active HPV and showing overexpression of p16. As mentioned earlier, the oropharynx and the nasal cavity are sites with known high-prevalence of HPV-related carcinomas. We have added 18 cases of ADSC to the existing literature. Our cases had a similar prognosis to those in the literature review, supporting the notion that ADSC of the head and neck is more aggressive than typical squamous cell carcinoma. ADSC may be relatively even more aggressive if one excludes good prognosis, HPV-related oropharyngeal cases and evaluates the remaining group.
Two of the five HPV DNA ISH positive cases lacked both p16 overexpression and high risk HPV RNA expression. These are likely false positives due to high, nonspecific background blue staining on the DNA ISH masquerading as true staining. Or, alternatively, this may represent the presence of high risk HPV DNA which does not have enough transcriptional activity to demonstrate E6 and E7 expression above background. As is well known, high risk HPV DNA can be found in a large percentage of non-oropharyngeal SCC from PCR assays, but we know from functional assays that there isn’t evidence of transcriptional activity in most non-oropharyngeal SCC. These ADSC cases could simply represent this phenomenon.
It is generally accepted that the majority of HPV-related tumors harbor an unmutated wild type p53 protein. In contrast, we observed a high rate of p53 protein overexpression as evidenced by p53 immunostaining in the majority of our cases, including the HPV-related ones. Similar findings were also reported by Alos et al. in their series of 12 patients [30
]. This observation suggests that p53 mutations may play an important role in tumorigenesis of ADSC. The four patients in our series with p53 negative tumors were alive without disease with follow up ranging from 3.5 to 123 months (cases 7, 8, 9, 13). Interestingly, however, all six patients with p16 and HPV negative tumors also showing overexpression of p53 suffered disease recurrence, with most dying with disease.
In conclusion, ADSC of the head and neck are relatively heterogeneous with regard to localization and HPV status. Most of the cases show p53 protein overexpression/mutation, as documented by immunostaining. Only a small minority of cases are HPV-related, and these occur in the oropharynx and nasal cavity, sites with a known high prevalence of HPV-related tumors. The HPV-related oropharyngeal cases, in particular, appear to do very well clinically, akin to other SCC variants in the oropharynx that are HPV-related. The remaining cohort of ADSC patients do quite poorly. While the numbers are small, our study suggests that ADSC of the head and neck may be a mixed variant that may not be uniformly associated with poor clinical outcome.