A 68-year-old man presents to his physician with a 3-month history of a persistent rough patch on the side of his tongue and an unintentional 15-lb weight loss. Past medical history is significant for hypertension which is controlled with lisinopril. He has a 50-pack-year smoking history and drinks 3–4 alcoholic beverages daily. Vital signs are within normal limits, and his weight loss is confirmed by chart review. On physical examination, there is a 2-cm, indurated, ulcerated lesion on the left lateral border of the tongue that bleeds easily on contact. A firm, 2-cm, non-tender, fixed lymph node is palpable in the left submandibular region. Biopsy of the tongue lesion confirms invasive squamous cell carcinoma. Immunohistochemical staining for p16 is negative.
Which of the following molecular findings is most likely present in this patient's tumor cells?
The correct answer is:
B) Inactivation of the TP53 gene by somatic mutation
This patient has non-HPV-related head and neck squamous cell carcinoma (HNSCC). For the USMLE Step 2, the distinction between HPV-positive and HPV-negative HNSCC is a high-yield concept based on risk factors, location, and molecular pathology. This patient’s presentation, including older age, heavy tobacco and alcohol use, an ulcerated lesion on the oral tongue (rather than the tonsils), and p16-negative status, is classic for traditional HNSCC. In these cases, malignancy is driven by direct genomic damage from carcinogens, leading to somatic mutations in tumor suppressor genes, most notably TP53.
Answer choice A: Amplification of the HER2/neu proto-oncogene, is incorrect. HER2/neu amplification is associated with certain breast and gastric adenocarcinomas, not HNSCC.
Answer choice C: Integration of high-risk viral DNA into the host genome, is incorrect. Integration of viral DNA is the mechanism for HPV-related cancers, typically HPV-16. These usually occur in the oropharynx (tonsils/base of tongue) of younger, non-smoking patients.
Answer choice D: Overexpression of p16 protein due to Rb inactivation, is incorrect. Overexpression of p16 occurs in HPV-positive tumors. In those cases, the viral E7 protein inactivates the retinoblastoma (Rb) protein, which leads to a compensatory increase in p16 expression. Since this patient’s tumor is p16-negative, this mechanism is incorrect.
Answer choice E: Translocation of chromosomes 9 and 22, is incorrect. The Philadelphia chromosome t(9;22) is associated with chronic myeloid leukemia (CML).
Key Learning Point
Head and neck squamous cell carcinoma (HNSCC) can be divided into two distinct molecular pathways:
Non-HPV HNSCC: Driven by tobacco and alcohol. Associated with p53 mutations and p16-negative status. Most common in the oral cavity and larynx.
HPV-related HNSCC: Driven by HPV-16. Characterized by viral E6/E7 oncogenes that bypass p53/Rb. Associated with p16-positive status. Most common in the oropharynx (tonsils or base of the tongue).
