FA is a disease in which underlying human genome instability plays an important role. With a rare incidence of one to five cases per million persons, heterozygous carrier frequency of FA is one in 300 persons (21). In certain populations, such as Ashkenazi Jews and Spanish gypsies, the carrier frequency is believed to be as high as 1/100 (22, 23). Cases of FA are usually diagnosed through recognition of congenital and hematological abnormalities, with a median age of diagnosis at 4.8-7.5 years (24, 25); therefore, it is rarely considered for diagnosis in adults.
FA patients are at high risk for the development of hematological malignancies and various solid tumors especially HNSCC. Onset of tumors in patients with FA is as early as 16 to 31 and shows a more aggressive behavior. Interestingly, 22% of FA patients who develop solid tumors are diagnosed with FA only after discovery of their cancer (26). In this case, the diagnosis of FA was atypical, presenting in an adult, and made only after unexpected toxicity of DNA cross-linking agents in an initially assumed sporadic malignancy. Therefore, FA should be considered in early-onset malignancies, especially if a typical FA-related malignancy is diagnosed. In addition, severe hematologic abnormalities of the patient did not appear until initiation of systemic tumor therapy. In some FA patients, genomic duplication is reversed to wild-type alleles in hematopoietic tissues, which can induce spontaneous correction of hematological alterations. In non-hematopoietic tissue, the biallelic inactivation stills remains, and thus the patient harbors mosaicism for the mutated FA gene (27). This phenomenon may explain a milder haematological phenotype for this patient with FA. Notably, FA is a heterogeneous disease and 30% of FA patients can present without any congenital abnormalities (3, 28). Thus, lack of physical manifestations does not preclude a diagnosis of FA.
Chemotherapy is one treatment option of most patients presenting with recurrent/metastatic HNSCC. It also can be used as a radiation sensitizer. Cisplatin is a DNA cross-linking agent recommended to be used in patients with oral cancer. However, people with FA have a substantially increased risk of toxicity to this kind of agent. It has been reported that one patient developed high-grade mucositis, cytopenia, tracheal stenosis, radiation pneumonitis, recurrent pneumonia, persistent myelosuppression and hemorrhage after receiving radiotherapy with cisplatin, bleomycin and methotrexate (29). In the present patient, the cisplatin chemotherapeutic regime was given before the diagnosis of FA. Severe and persistent bone marrow failure was observed and the treatment plan was interrupted, which most likely resulted from the chemotherapy. Although concurrent radio-chemotherapy is recommended to treat inoperable oral cancer patients, patients with FA may experience potentially fatal bone marrow toxicity from concurrent radio-chemotherapy; therefore, cytotoxic chemotherapy is discouraged for these patients. Most importantly, timely identification of underlying FA would lead to a different therapeutic approach with a potential better outcome.
However, FA patients with HNSCC tend to have a poor prognosis, which is associated with the aggressive disease presentation and the limitations of multimodality therapy due to potential bone marrow failure (30). Given the bone marrow abnormalities and low tolerance to standard therapies, treatment is more challenging in these patients. Radiotherapy has been served as a definitive treatment in many FA patients with HNSCC given the significant but acceptable toxicity; 70 Gy was recommended for definitive initial treatment (31). However, these patients have a significantly increased complication rate compared with the general HNSCC population, sometimes patients with FA even cannot complete full course of the treatment (32). Based on the International Fanconi Anemia Registry (IFAR) series, radiation-related side effects including anemia, thrombocytopenia, myelosuppression, skin ulceration and stenosis of the trachea were observed in the 8 FA patients treated with 40-61Gy radiotherapy (15). Previous studies have reported that doses of radiotherapy ranged from 3.2 to 80 Gy and the acute hematologic toxicity was individualized. Severe radiation-related toxicity could occur in a low dose such as 8 Gy in some FA patient, while the higher dose was acceptable in others (33-35). In this case, the patient was initially treated with 24.2 Gy IMRT in 11 fractions. After 8 months interruption of treatment, standard chemotherapy agent was not considered after diagnosis of FA in the patient due to the risk of unacceptable myelosuppression and irreversible aplastic anemia. IMRT of 42Gy/21f was then treated to the progressed tumor. From the DCE-MRI evaluation, radiotherapy has successfully alleviated the symptoms of tumor invasion and progression, and the radiation-related side effects were acceptable. Combined with the above evidence, a precise dose of radiotherapy with careful toxicity assessment is needed for each patient to enhance the treatment, since other therapeutic options are not available because of the high risk.
For FA patients with HNSCC, longer duration treatment courses with lower dose per fraction of radiotherapy may maximize the therapeutic effect and reduce complications. Furthermore, in view of the adaptability of dose and target volume, application of the technique allowing the best sparing of healthy tissues, such as IMRT with image-guided radiotherapy and intensity-modulated proton therapy, may be a safer option (36). Overall, any decision on different modalities of management in such patients should be based on a balance between locoregional control and therapeutic toxicity.