Discussion
Hypopharyngeal SCCs account for <10% of HNSCCs and are
difficult to visualize at early stages.1 Patients
diagnosed with hypopharyngeal SCCs are predominantly males in their
early 60s with a history of smoking and heavy alcohol use. These risk
factors are a key determinant of clinical suspicion since tumors are
associated with non-specific early symptoms.
BRCA2 mutations in HNSCC have been reported in the context of
genetic variants in some patients with Fanconi Anemia, which is
associated with hypopharyngeal SCC. These patients are typically young
adult females with history of hematologic malignancies who develop
HNSCCs in their third and fourth decade.2 One other
truncating BRCA2 mutation has been linked to hypopharyngeal SCC,
however, lung SCC is the most common with this mutation and breast
cancer is rare.3 In some studies of families with aBRCA2 mutation, a significant increased risk of laryngeal and
pharyngeal cancer has been identified.3
BRCA2 mutations can result in many cancer phenotypes due to the
vital role of the BRCA2 protein in DNA homologous recombination repair.
The BRCA2 gene is involved in the Fanconi Anemia (FA)/BRCA
pathway for double-strand DNA break repair, which has been implicated in
tumor development for both sporadic and Fanconi Anemia-related
HNSCC.3-4 In this pathway, BRCA2 and other FA/BRCA
proteins form a complex for DNA cross-link repair through homologous
recombination (HR). Mutations at genes involved in the HR complex can
impair DNA repair and potentiate cancer formation.
BRCA2 mutations may have management implications by enhancing
platinum-based chemotherapy response in cancer cells from deficient DNA
repair leading to increased platinum-DNA adducts.4This interaction could explain the excellent chemoradiation response
observed in our patient and has been supported for HNSCCs previouslyin vitro .4 In other malignancies including
ovarian, prostate and pancreatic cancers, germline BRCA2mutations have been associated with clinically distinct tumor phenotypes
that respond better to agents targeting the FA/BRCA HR
pathway.5 Genetic screening to direct use of
platinum-based therapies, immunotherapy and PARP inhibitors is currently
underway for these malignancies suggesting similar targeted therapy
potential in HNSCC.