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Keywords:

  • Fanconi anemia;
  • squamous cell carcinoma;
  • head and neck;
  • hematopoietic stem cell transplantation

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND.

Fanconi anemia (FA) is a chromosomal instability disorder with a very high risk of developing head and neck squamous cell carcinoma (HNSCC), most notably after hematopoietic stem cell transplantation (HSCT).

METHODS.

In the current study, the authors reported 13 cases of HNSCC in FA patients who underwent HSCT at the Saint Louis Hospital between 1976 and 2007.

RESULTS.

The median age of the patients at time of HSCT was 9.7 years. All patients received irradiation-based conditioning before HSCT and all developed extensive chronic graft versus host disease (GVHD). HNSCC was diagnosed at a median interval of 10 years after HSCT, mainly in numerous sites within the oral cavity (11 patients). Lymph node involvement was diagnosed in 4 patients. The TNM classification was: T1 in 6 patients, T2 in 2 patients, T3 in 2 patients, and T4 in 3 patients. Treatment was comprised of surgery in 10 patients, with clear surgical margins reported in 7 (including cervical lymph node dissection in 6 patients). Surgery was performed in addition to other treatments in only 2 patients (radiotherapy or cryotherapy). For the remaining 3 patients, treatment consisted in radiotherapy (2 patients) or chemotherapy (1 patient). Disease progression while receiving therapy was observed in 5 patients and 5 other patients developed disease recurrence between 3.5 and 23.7 months after treatment. Death occurred in 11 patients. At the time of last follow-up, only 2 patients were alive without any disease between 9 and 23 months after diagnosis.

CONCLUSIONS.

HNSCC developing in FA patients after HSCT is associated with a very poor prognosis. A systematic surveillance of the oral cavity is essential to permit early surgery, which to the authors' knowledge remains the only curative treatment for a minority of patients. It is very important to attempt to prevent this cancer by reducing chronic GVHD and using conditioning without irradiation. Cancer 2008. © 2008 American Cancer Society.

Fanconi anemia (FA) is a rare autosomal recessive disease with a birth incidence of approximately 3 per 1 million. This disease is characterized by various congenital abnormalities.1 The most significant feature of FA is progressive bone marrow failure, which leads to aplastic anemia and myelodysplastic syndrome, usually during childhood. Hematologic abnormalities develop in virtually all FA patients at a median age of 7 years,1, 2 with complications resulting in death in approximately 81% of patients by the age of 40 years.3 To our knowledge, hematopoietic stem cell transplantation (HSCT) is thus the only curative treatment with which to restore normal hematopoiesis.4

On the cellular level, FA is characterized by chromosomal instability and hypersensitivity to DNA cross-linking agents.5, 6 Defects within the FA pathway result in prolonged G2/M–phase transition in the cell cycle and defective DNA repair by homologous recombination.7 A total of 13 genes have been identified to date.8

One of the main characteristic of FA patients is the development of malignancies at an early age, particularly acute myeloid leukemia and solid tumors.9, 10 Cancers in very young children are specifically associated with FANCD1/BRCA2, FANCJ/BRIP1, and FANCN/PALB2 gene mutations. In young FA adults, squamous cell carcinoma is the most commonly reported solid neoplasm and occurs mainly within the head and neck region and in the female genital tract.11 Liver tumors are also relatively common, particularly after androgen therapy.9, 11 FA patients who survive into early adulthood are approximately 50 times more likely to develop solid tumors compared with the average population. In the International Fanconi Anemia Registry study, the hazards rate for cancer was reported to be 2% per year by the age of 24 years, with a cumulative incidence of 29% by the age of 48 years.9, 12 The cancer susceptibility noted in patients with FA is associated with a defect in the ability to maintain the genome's integrity, which leads to a high degree of chromosomal instability. As such, FA belongs to a group of hereditary disorders termed caretaker gene diseases.13

HSCT, which is the treatment of choice in FA patients who develop hematopoietic failure, may predispose to late cancer development. We previously reported a 4-fold increased risk of head and neck squamous cell carcinoma (HNSCC) in FA patients after HSCT above the already very high baseline relative risk reported in FA patients who do not undergo HSCT.14 The risk of a solid tumor may be even higher because death from FA is reduced, and because patients survive longer after HSCT. We and others have analyzed the risk factors of developing HNSCC in FA patients after HSCT: HSCT conditioning with chemotherapy and radiotherapy, prolonged immunosuppressive treatment, and chronic graft versus host disease (GVHD).15–18 Chronic GVHD appears to be a major risk factor, even in non-FA patients.14, 18–20

However, to our knowledge, the characteristics of HNSCC developing in FA patients after HSCT have not been well described to date. Therefore, we report herein 13 cases of HNSCC in FA patients developing after HSCT. We analyzed tumor characteristics, patient age at diagnosis, clinical presentation, TNM stage, treatment, and disease evolution.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients, Donors, and Transplant Characteristics

A total of 134 consecutive FA patients underwent HSCT at the Saint Louis Hospital between 1976 and 2007. Thirteen of these patients developed HNSCC and therefore we analyzed the characteristics of these 13 patients. There were 9 males and 4 females. From a family history standpoint, 1 patient had a cousin with neuroblastoma, 3 patients had a brother or cousin with acute leukemia, and 1 patient had 3 cancers diagnosed in other family members. In all cases, the diagnosis of FA was confirmed by chromosomal fragility studies as previously described.21 None of the patients had a history of tobacco or alcohol abuse.

All patients underwent transplantation according to previously described protocols.14, 18, 22 The age of the patients at the time of transplantation ranged from 4.5 years to 19.2 years (median, 9.7 years). Twelve patients were conditioned with low-dose cyclophosphamide (at a dose of 20 to 40 mg/kg) and 1 patient received conditioning with high–dose cyclophosphamide (120 mg/kg) (the first FA patient who underwent HSCT in 1976). All patients received irradiation; 11 received thoracoabdominal irradiation at a dose of 5 grays (Gy), 1 patient received total body irradiation (TBI) at a dose of 4.5 Gy, and 1 patient received TBI at a dose of 12 Gy. Two patients received antithymocyte globulin (ATG). The source of the stem cells was the bone marrow in all patients. Ten patients received transplants from related donors and 3 patients received transplants from human leukocyte antigen (HLA)–matched unrelated donors. All related donors were tested before transplantation and were found to be unaffected by the disease. GVHD prophylaxis was comprised of cyclosporine A in 11 patients; steroids were added in 1 case because of renal failure. One patient received steroids only and 1 patient was treated with methotrexate only. All patients were treated in laminar air-flow rooms until discharge and received prophylaxis against infection.

Definitions

Acute and chronic GVHD was graded according to Seattle criteria.23–25 Premalignant lesions were defined by the existence of lichen planus-like lesions or leukoplasia before diagnosis. Paraffin blocks of surgical specimens corresponding to areas of premalignant lesions were selected for immunohistochemical staining with a monoclonal antibody directed against p53 (D07; Dakopatts, Glostrup, Denmark), as described.15, 18

The diagnosis of HNSCC was confirmed by biopsy or surgery and demonstrated well-differentiated squamous cell carcinoma. Patient delay represents the time in months between the date the first symptoms were noted and the date of treatment. The delay periods were divided into 2 categories: <1month and >3 months. Locoregional disease recurrence was defined as disease recurrence occurring at a site within the oral mucosa other than the primary tumor site.

This analysis focused on the features of HNSCC: clinical history, TNM stage according to standard criteria, management, recurrence, and outcome. Data were analyzed with a date point of June 1, 2008. The median follow-up was calculated as the time elapsed in months between the date of HSCT and the date of death or last follow-up. Estimation of overall survival was determined according to the Kaplan-Meier method using SPSS statistical software (version 11.0; SPSS Inc, Chicago, Ill).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

As of August 1, 2007, the median follow-up of these 13 patients was 11 years (range, 5.7 years–25.5 years) and the median follow-up of survivors was 17 years (range, 10.3 years–19.3 years).

Outcomes After HSCT

All patients underwent hematopoietic engraftment. Acute GVHD of ≥ grade 2 developed in 11 of 13 (84.6%) patients (6 patients with grade 2 disease, 4 patients with grade 3 disease, and 1 patient with grade 4 disease). The treatment of acute GVHD included steroids in 11 patients, cyclosporine A in 10 patients, and ATG in 4 patients. Extensive chronic GVHD with lichen planus-like lesions occurred in all patients. Localization was only mucosal in 6 patients, 3 of whom had no additional lichen planus-like lesions at the time of diagnosis of HNSCC. Two patients presented with severe chronic GVHD that did not respond to steroids and 1 patient was treated with total lymphoid irradiation at a dose of 1 Gy. One woman developed genital GVHD, with carcinoma in situ of the cervix. The median time of post-transplantation immunosuppressive therapy was approximately 18.2 months (range, 5.2 months–93.6 months). Other post-transplantation supportive care and follow-up has been described in detail elsewhere.16, 18

HNSCC

All HNSCC characteristics are described in Table 1 and Table 2 and summarized in Table 3.

Table 1. Characteristics of HNSCC
Patient No.Symptoms at DiagnosisClinical LymphadenopathiesSite of HNSCCPatient DelayTNM StageTreatmentEvolutionLast Follow-up
  • HNSCC indicates head and neck squamous cell carcinoma; ND, neck dissection; Rx, radiotherapy; Gy, grays; NA, none available; LN, lymph node; LR, locoregional recurrence.

  • *

    Patients received transplants from unrelated donors.

1*UlcerationNoTongue, palate<1 moT1NOMOSurgery (clear margins)+ ipsilateral NDDisease remissionAlive, 9 mo
2UlcerationYesTongue<1 moT2N+MoSurgery (incomplete) + Rx, 22 GyPartial response, disease progression at the end of RxDied, 5.5 mo
3Dysphagia, dyspneaNoHypopharynx>3 moT4N2cMxChemotherapyNo response, disease progressionDied, 6 mo
4*UlcerationNATongue<1 moT1NXMXSurgeryDisease progressionDied, 6 mo
5NoNoPelvilingual<1 moT1N0MOSurgery (clear margins) + bilateral NDDisease remissionAlive, 23 mo
6Mass, trismusYesOropharynx>3 moT4N2cMxRx, 70 GyPartial response, disease progression at the end of RxDied, 4.5 mo
7Painful swellingNoPelvilingual>3 moT3NOMxSurgery (clear margins) + ipsilateral NDLocal recurrence at 6 mo, chemotherapy and Rx, (60 Gy); LN recurrence at 11 moDied, 16 mo
8Swelling, trismusNoTongue<1 moT3NOMxRx, 25 GyNo response, disease progressionDied, 2.5 mo
9NoNoJugal, pelvilingual<1 moT1NxMXSurgery (clear margins) + cryotherapyLR at 24 mo, cryotherapy; LR at 31 mo, cryotherapy; LR + LN recurrence at 35 moDied, 46.5 mo
10UlcerationNoPalate, jugal>3 moT1NXMXSurgery (incomplete)Local + LN recurrence at 3 mo, surgery and ND; LR recurrence at 6 moDied, 11 mo
11NAYesGingival>3 moT4N1M0Surgery (clear margins) + bilateral NDLocal +LN recurrence at 12 mo, palliative chemotherapyDied, 15 mo
12Painful swellingNoGingival>3 moT2NOMXSurgery (clear margins) + ipsilateral NDLR + LN recurrence at 4 mo, surgery + ND;Immediate disease progressionDied, 6.5 mo
13*UlcerationNoTongue<1 moT1NOMOSurgery (clear margins) + ipsilateral NDLR + LN recurrence at 39 mo, palliative treatmentDied, 41 mo
Table 2. Characteristics of the 13 Patients
Patient No.SexAge at Transplantation, YearsConditioning RegimenAcute GVHD*Treatment for Acute GVHDChronic GVHD LocalizationDuration of Immunosuppressive Treatment, MonthsPremalignant LesionOral SurveillanceAge at Diagnosis of HNSCC, YearsTime Elapsed From BMT to HNSCC, YearsTNM StageLast Follow-up
  • HNSCC indicates head and neck squamous cell carcinoma; GVHD, graft versus host disease; BMT, bone marrow transplantation; Cy LD, low-dose cyclophosphamide; TBI, total body irradiation; ATG, antithymocyte globulin; TAI, thoracoabdominal irradiation (5 grays [Gy]); S, steroids; CSA, cyclosporine A; Cy HD, high-dose cyclophosphamide.

  • *

    Acute GVHD was graded according to Seattle criteria.

  • Patients received transplants from unrelated donors: Patient 1, unrelated 10/10; Patient 4, unrelated 6/6; and Patient 13, unrelated 6/6.

  • p53 indicates the result of immunohistocheminal staining on a premalignant lesion. In Patient 1, p53 was examined 1 year before cancer, in Patient 5 it was examined 3 years before cancer, and in Patient 12 it was examined 1 year before cancer.

  • §

    Patient received total lymphoid irradiation at a dose of 1 Gy.

1Male11.7Cy LD, TBI, ATGNo Mucosal, Skin11YesYes p53 score of 021.710T1NOMOAlive, 9 mo
2Male11.2Cy LD, TAIGrade 3S, CSA, ATGMucosal24NoNo16.95.7T2N+MoDied, 5.5 mo
3Male9.7Cy LD, TAIGrade 3S, CSA, ATGMucosal21NoNo17.57.8T4N2cMxDied, 6 mo
4Female8.9Cy LD, TAI, ATGGrade 2S, CSAMucosal24YesNo17.28.3T1NXMXDied, 6 mo
5Male5.2Cy LD, TAIGrade 3S, CSAMucosal, Skin10YesYes p53 score of low20.515.3T1N0MOAlive, 23 mo
6Male7.3Cy LD, TAIGrade 2S, CSAMucosal, Eye32YesYes19.712.4T4N2cMxDied, 4.5 mo
7Male11.2Cy LD, TAIGrade 2S, CSAMucosal11YesNo18.27T3NOMxDied, 16 mo
8Male4.6Cy LD, TAIGrade 4S, CSA, ATGMucosal, Skin, Eye Hepatic65§YesNo10.15.5T3NOMxDied, 2.5 mo
9Female6.5Cy HD, TBI 12Grade 3S, ATGMucosal, Eye6YesYes28.121.6T1NxMXDied, 46.5 mo
10Male10.3Cy LD, TAIGrade 2S, CSAMucosal18NoNo24.314T1NXMXDied, 11 mo
11Male19.2Cy LD, TAINo Mucosal14NoNo32.613.4T4N1M0Died, 15 mo
12Female14.3Cy LD, TAIGrade 2S, CSAMucosal, Skin, Eye93YesYes p53 score of 90%23.79.4T2NOMXDied, 6.5 mo
13Female7.5Cy LD, TAIGrade 2S, CSAMucosal, Eye16YesYes26.719.2T1NOMODied, 41 mo
Table 3. Main Characteristics of 13 Fanconi Anemia Patients Diagnosed With HNSCC After HSCT
No. of MalesMedian Age at Time of HSCT, Years*Median Age at Time of Diagnosis of HNSCC, YearsMedian Interval Between HSCT and HNSCC Diagnosis, YearsTumor Location and TNM ClassificationSurgeryFollow-up After HNSCC
  • HNSCC indicates head and neck squamous cell carcinoma; HSCT, hematopoietic stem cell transplantation.

  • *

    All 13 patients received radiation-based conditioning with the bone marrow as the source of stem cells. Ten patients received transplants from related donors. All patients developed chronic graft versus host disease.

99.72010Oral cavity (n=11; 85%) T1 (n=6; 46%)10 (clear margins in 7)2 patients alive between 9 and 23 mo after HNSCC
Premalignant lesions

Nine patients (69.2%) had premalignant dyskeratotic lesions before the diagnosis of HNSCC was made. Of these 9 patients, 6 were treated with surveillance of the oral cavity once or twice yearly with regular biopsies performed. These biopsies revealed keratinized squamous cell epithelium and chronic inflammatory infiltration in the chorion, which was compatible with chronic GVHD. Immunohistochemical studies using the p53 antibody were also analyzed in 3 biopsy specimens and only 1 was found to be positive at 90%, 1 year before the diagnosis of HNSCC was made.

Diagnosis

The median age of the patients at the time of diagnosis of HNSCC was 20.6 years (range, 10 years–32.6 years) and the diagnosis occurred a median of 10 years (range, 5.5 years–21.6 years) after HSCT. Biopsy of the lesions confirmed the diagnosis and demonstrated well-differentiated squamous cell carcinoma.

Clinical presentation

At the time of diagnosis, 3 (23%) patients had no symptoms, and the diagnosis was discovered during systematic consultation. Six (46%) patients had moderate symptoms such as painful ulceration or swelling and 3 (23%) had significant and severe clinical symptoms (trismus in 2 patients and dysphagia and dyspnea in 1 patient). Patient delay was <1 month in 7 patients and >3months in 6 patients. At the time of diagnosis, 3 patients underwent regional lymphadenopathies at the time of clinical examination. The site of the tumor was the oral cavity in 11 patients, the hypopharynx in 1 patient, and the oropharynx in 1 patient. The tongue was the most frequently affected site, being involved in 8 of 13 (62%) patients. Three patients had 2 tumor sites.

TNM classification

The clinical T classification was T1 in 6 patients (46%), T2 in 2 patients (15%), T3 in 2 patients (15%), and T4 in 3 patients (23%). Six patients were classified as having N0 disease, 4 patients were found to have positive lymph nodes, and 3 patients were not evaluated for N classification. Five patients had no metastases and 6 patients were not evaluated. When classifying patients with a delay of <1 month, T1 disease was diagnosed in 4 patients, T2 disease in 2 patients, and T3 disease in 1 patient. All patients with T4 disease were diagnosed after a delay of >3 months.

Treatment

Ten patients (77%) underwent surgery. The tumors were surgically removed with clear surgical margins in 7 patients. Two patients had microscopically positive surgical margins. There was no data available regarding the quality of surgery for 1 patient. Cervical lymph node dissection was performed in 6 patients (ipsilateral in 4 patients and bilateral in 2 patients). One patient received radiotherapy after incomplete surgery and 1 patient underwent cryotherapy for a second lesion that was considered to be carcinoma in situ.

Three patients were considered inoperable and palliative treatment was initiated with local radiotherapy for 2 patients and low-dose chemotherapy for 1 patient. One patient received 70 Gy of local and cervical irradiation. A transitional improvement was observed, but it was complicated by mucositis (grade 3, determined according to the Common Toxicity Criteria grading system) and dehydration (requiring placement of a feeding gastrostomy). Another patient should have received local irradiation at a dose of 65 Gy but after 4 weeks, the disease progressed and severe mucositis was observed. It was then decided to withdraw irradiation at a dose of 25 Gy. The patient who was treated with very low-dose chemotherapy, because of the severe toxicity observed in FA patients, received cisplatin at a dose of 8 mg and 5-fluorouracil at a dose of 60 mg; no response was observed.

Evolution

After the first treatment, 5 patients (39%) developed disease progression without any remission. Eight patients (62%) achieved a clinical response but 5 of them developed disease recurrence at a median of 5.6 months (range, 3.4 months–23.7 months) after the first treatment.

Three patients developed local disease recurrence and 2 developed locoregional disease recurrence. Lymph node recurrence was reported in 3 patients. A second surgery with cervical lymph node dissection was performed in 2 patients with lymph node recurrences, but their disease progressed after treatment. One patient who received low-dose chemotherapy developed severe toxicity and treatment was withdrawn; the patient then received radiotherapy and achieved a partial response, but developed disease progression immediately afterward.

One patient was treated with cryotherapy but developed disease recurrence 6 months later. All patients who developed disease recurrence ultimately died, with survival times after first recurrence of 2.5 months, 3 months, 8 months, 10 months, 23 months, and 41 months, respectively.

A total of 11 patients died at a median of 6.4 months (range, 2.5 months–46 months). As of June 1, 2008, only 2 patients (15%) were still alive without any evidence of disease recurrence or metastasis at a median time after the diagnosis of HNSCC of 9 months and 23 months, respectively. At the time of last follow–up, these patients continued to undergo regular surveillance of the oral cavity with biopsy. The median survival after HSCT was 10.3 years (range, 5.7 years–25.5 years) and that after the diagnosis of HNSCC was 6 months (range, 2 months–46 months).

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

It was previously reported that HNSCC is the most significant long-term complication after HSCT in patients with FA.14, 16, 18 In particular, we previously evaluated the risks of SCC and death in 145 patients with FA in the North American Survey (NAS) cohort who did not undergo transplantation, and in 117 patients with FA in the Saint Louis Hospital cohort who did undergo transplantation. The age-specific hazard of SCC was 4.4-fold higher in patients who underwent transplantation compared with those who did not (P = .003), and SCC was found to occur at significantly younger ages in the former group (respective median ages of 18 years and 33 years, respectively; P = .004). Survival after SCC was similarly poor in both cohorts (P = 35; median, 13 months). The hazards rate of SCC increased at a greater than linear rate, to 4.4% per year by age 40 years in the NAS cohort and 4.7% per year by 10 years after transplantation in the patients at Saint Louis Hospital. In the Saint Louis Hospital cohort, the hazards rate of death from a non-SCC was biphasic, declining significantly (P = .004) from 7.1% per month during the first 6 months after transplantation to 0.13% per month (1.6% per year) after the first year. Acute and chronic GVHD was found to be a significant risk factor for SCC.

Conversely, to our knowledge, the natural history and best treatment of these tumors have not been yet documented thoroughly. Therefore, in the current study, we attempted to report the clinical course of HNSCC in 13 patients with FA after HSCT, representing what to our knowledge is the largest clinical cohort reported to date. Our patients developed HNSCC at a young age (median of 20.6 years) and at a median of 10 years after HSCT (range, 5.5 years–21.6 years). There were numerous tumor sites throughout the oral cavity, but these were localized mainly to the tongue. This is similar to the findings of the review by Millen et al, who reported a 54% incidence of carcinoma of the tongue26 after allogeneic transplantation in FA patients, whereas in non-FA patients, the incidence was reported to vary by 10% to 16%.

The history of this tumor in FA patients appears to be different compared with the general population. Sporadic HNSCC occurs mainly in men aged ≥60 years who abuse both tobacco and alcohol, and is treated with a combination of radiotherapy, chemotherapy, and surgery.27 In the average population, the survival rate is principally determined by the extent of lymph node metastases and ranges from 75% in patients with early–stage, lymph node–negative disease to 30% in patients with advanced lesions.28 The management of these tumors is much more difficult in FA patients because of their hypersensitivity to DNA cross-linking agents29 and radiation.30 Therefore, radiotherapy and chemotherapy appear to have no place in the curative treatment of these patients.11, 31 Surgery is the only curative treatment. Early surgical intervention with clear surgical margins is recommended. Cervical lymph node dissection should always be performed because of the high propensity of this disease for the lymph nodes. Elective cervical lymph node dissection provides pathologic information regarding the status of the cervical lymph nodes. Positron emission tomography may be useful in this setting, but was not evaluated in the current study. However, even with aggressive surgery and cervical lymph node dissection being performed in patients with T1 tumors, their prognosis remains particularly grim.

In the case of inoperable patients, irradiation may be useful, at least as a palliative treatment. In the current study, we observed improvement in the tumor in 3 patients during radiotherapy. Two of these 3 patients developed disease progression at the end of radiotherapy and the third patient presented with severe radiotherapy–related toxicity. This treatment, which is associated with increased toxicity, has to be carefully discussed between physicians. With regard to chemotherapy, despite a significant decrease in dosages, we reported high rates of toxicity without any response being noted in 2 patients.

Unfortunately, this cancer is not always symptomatic, and it is very aggressive with a rapid course of evolution. In the current study, 23% of patients presented with no symptoms at the time of diagnosis and patient delay appeared to be associated with an advanced stage of disease at the time of presentation. Regular monitoring every 6 months is required for all patients and is needed more frequently (every 3 months) if patients present with lichen planus-like lesions, leukoplasia, or chronic GVHD and a history of previous irradiation, which are known to be major risk factors in this population.14, 16, 18 It is therefore not surprising that in the current study all patients received irradiation as a conditioning regimen and all developed extensive chronic GVHD. Oral surveillance must be performed by surgeons who have expertise in head and neck cancers. All suspicious oral lesions must be biopsied and systematic biopsies are recommended in this particularly high–risk population to allow for early diagnosis. To our knowledge, the role of p53 immunohistochemical staining as a predictive factor of the development of HNSCC remains unclear.32

Despite careful surveillance of the oral cavity and appropriate treatment, this tumor is particularly aggressive, with a high rate of recurrence. The survival rate for these patients is very poor. We report here a Kaplan–Meier median survival time of 6 months after diagnosis. Therefore, it is necessary to also prevent potential associated risk factors. It is essential to avoid exposure to carcinogens such as tobacco and alcohol. The role of the human papillomavirus (HPV), which has been strongly implicated in the pathogenesis of vulvar SCC,33 remains unclear in the development of HNSCC in patients with FA.34 However, the prevention of HPV infection with vaccination in these patients is an interesting approach to consider.

New preparative regimens before HSCT might be useful in improving long-term results. In addition, a fludarabine-based protocol may be an approach with which to reduce these risk factors. Such a protocol completely excludes irradiation and uses fludarabine in combination with low-dose cyclophosphamide and ATG as a conditioning regimen. It has demonstrated low toxicity, prompt engraftment, and a low risk of GVHD.35 Since 2000 at the Saint Louis Hospital, FA patients undergoing HLA genotypically identical transplantation have received this irradiation-free preparative regimen, and to our knowledge none has been reported to have developed HNSCC. However, longer follow-up is necessary to determine whether this protocol will be associated with a lower risk of secondary malignancies and we cannot exclude the possibility that HNSCC may develop.

Systematic surveillance of the oral cavity in patients with FA is fundamental after HSCT and even more so for patients with lichen planus-like lesions or premalignant lesions. It is very important to detect these tumors early to allow surgery. Very thorough monitoring is mandatory after treatment because of the high rate of disease recurrence in these patients: twice yearly for FA patients without GVHD at a minimum and every 3 months for FA patients with GVHD.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES