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ORIGINAL ARTICLE
Year : 2021  |  Volume : 23  |  Issue : 3  |  Page : 107-111

Bone marrow failure disease and head-and-neck squamous cell carcinoma in king faisal specialist hospital and research center in Riyadh


1 Otorhinolaryngology Head and Neck Surgery Consultant at King Faisal Specialist Hospital and Research in Riyadh; Otorhinolaryngology Head and Neck Surgery Residency Training Program Director at King Faisal Specialist Hospital and Research in Riyadh, Riyadh, Saudi Arabia
2 Senior Resident in Otorhinolaryngology Head and Neck Surgery Residency Training Program, King Faisal Specialist Hospital and Research in Riyadh, Riyadh, Saudi Arabia
3 Medical Students, Alfaisal University, Riyadh, Saudi Arabia

Date of Submission14-Apr-2021
Date of Acceptance30-May-2021
Date of Web Publication05-Oct-2021

Correspondence Address:
Dr. Rawan Salem Alayed
14215, Riyadh
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjoh.sjoh_20_21

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  Abstract 


Objective: This study aims to look at bone marrow failure disease patients who presented to our center, as to analyze the presentation and possible ways to improve the survival outcome in these cases. Methods: This was a retrospective chart review study. Results: In our series, most of the head-and-neck squamous cell carcinomas (HNSCCs) were found in Fanconi anemia (FA) patients, and most are located within the oral cavity, most frequently at the tongue margins and the gingival areas. These tumors arise in both male and female bone marrow failure disease patients without a prior history of excessive tobacco and alcohol use. Even if a patient presents at an early stage, there are frequent relapses. The highly aggressive nature of the tumors is reflected by poor survival, amounting to <2 years. FA is a rare but well-studied inherited disorder that is clinically characterized by progressive bone marrow failure, congenital malformations, and increased incidence of malignancies, especially acute myeloid leukemia and squamous cell carcinomas (SSCs) of the head and neck. Greatly improved protocols for stem cell transplantation increasingly save the lives of these young patients. However, in both transplanted and not transplanted patients, the emergence of aggressive SSC represents a major medical challenge. Noninvasive screening options, including frequent self-examination and inspection by a medical team, should lead to early detection and treatment. Standard platinum-based chemotherapy in combination with radiotherapy cannot be used in FA patients due to therapy-associated toxicities and mortalities even with reduced dosing. Therefore, surgery is the most important treatment option for HNSCC in bone marrow failure disease patients and requires an early and efficient detection of malignant lesions. Conclusion: So far, no uniform treatment protocol for the management of HNSCCs in FA patients exists. Therefore, we propose that the information on affected FA patients should be collected worldwide, practical therapeutic guidelines developed and national treatment centers established.

Keywords: Bone marrow failure, DNA hypersensitivity, Fanconi anemia, head-and-neck squamous cell carcinomas


How to cite this article:
Jebreel A, Alayed RS, Al-Soufi RM, Farahat RH. Bone marrow failure disease and head-and-neck squamous cell carcinoma in king faisal specialist hospital and research center in Riyadh. Saudi J Otorhinolaryngol Head Neck Surg 2021;23:107-11

How to cite this URL:
Jebreel A, Alayed RS, Al-Soufi RM, Farahat RH. Bone marrow failure disease and head-and-neck squamous cell carcinoma in king faisal specialist hospital and research center in Riyadh. Saudi J Otorhinolaryngol Head Neck Surg [serial online] 2021 [cited 2021 Dec 2];23:107-11. Available from: https://www.sjohns.org/text.asp?2021/23/3/107/327565




  Introduction Top


Fanconi anemia (FA) was initially described by the Swiss pediatrician Guido Fanconi in 1927. After three brothers presented to him with congenital developmental disabilities and died of a condition resembling pernicious anemia, he soon realized that the disease affected all blood lineages and involved cancer predisposition.[1],[2] FA is a rare autosomal recessive genetic disease and is X-linked in the case of Fanconi Anemia Complementation Group B (FANCB). It is characterized by congenital abnormalities, severe bone marrow failure, and an increased risk of developing acute myeloid leukemia (SSCs).[3] Recessive mutations that occur in one of the 19 FA genes, is playing a role in the fundamental DNA repair mechanisms for the maintenance of genome stability. Array-based comparative genome hybridization of 21 sporadic oral SSCs showed deregulation of many FA and FA-associated genes, including BRCA1, BRCA2 (FANCD1), FANCG, and FANCD2.[4] Genome integrity is ensured through the participation of FA genes in a common pathway that controls a myriad of chromatin processing and DNA damage response pathways. A mutation of any of the FA genes leads to FA's clinical presentation.[5],[6],[7],[8]

FA is a chromosomal instability disorder. It can target and affect multiple organ systems with variable severity. Its damage occurs through the mechanism of cellular hypersensitivity to DNA damaging agents, which leads to DNA interstrand cross-link (ICL) that impairs DNA strand separation and unwinding, ultimately interfering with DNA replication and transcription. Cells cultured from FA patients exhibit accumulation in the G2 phase of the cell cycle. Exposure to cross-linker agents such as mitomycin C (MMC) or diepoxybutane was found to have pronounced chromosomal breakage. The formation of radial chromosomes in lymphocytes from FA patients was utilized as a screening test for FA. Many forms of genotoxic stress, such as ultraviolet, ionizing radiation, and oxidative stress, activate the FA pathway.[9],[10],[11],[12],[13] Symptoms frequently occur early in life and include a combination of congenital disabilities, hematological abnormalities, and cellular and organismal hypersensitivities to agents that lead to DNA ICLs. These agents include melphalan, cisplatin, and MMC. It is recommended to screen leukemia patients who have poor recovery from chemotherapy, particularly those who develop severe toxicities from chemotherapy and/or radiation. Young patients who present with SSCs are also recommended to be screened.[14],[15] The International FA Registry has shown that FA patients are highly susceptible to nonhematologic neoplasms.[16] The most commonly diagnosed solid tumors in FA patients are SCCs of the anogenital region and head-and-neck region, with a 1400-fold risk over the average population. Extreme risk of head-and-neck, vulvar, and esophageal SCCs was reported in the German FA Registry.[17] FA patients who undergo successful bone marrow transplants as management of severe bone marrow failure are still likely to develop head-and-neck, esophageal, gastrointestinal, anal, and vulvar cancers at a higher incidence by 50 folds from the average population.[18]

During our practice in the head-and-neck department, we found that head-and-neck squamous cell carcinomas (HNSCCs) are a growing problem in the clinical care of bone marrow failure disease patients, in particular FA patients. Most of these patients present with locally advanced disease at the time of diagnosis, which usually requires a multimodality approach. What is also challenging for FA patients is that they have limited therapeutic options. The management for HNSCC in non-FA patients is combined surgery, chemotherapy, and radiation. Primary surgical resection of cancers with clear margins followed by local radiotherapy and concurrent delivery of high-dose chemotherapy has improved the survival rate in the majority of HNSCC patients significantly.[19],[20] As the percentage of patients reaching older ages is increasing, the prevention and therapy of HNSCC in bone marrow failure patients in recent years has become more critical. Since cisplatin-based chemotherapy in combination with radiotherapy is an essential part in the standard treatment of sporadic HNSCCs, and they are not suitable to be used in the treatment of HNSCCs i n bone marrow failure patients, especially FA. Surgery is considered the most important treatment option for HNSCCs in bone marrow failure patients and requires an early and efficient detection of malignant lesions, which can be done by early screening performed by a specialist.[21] So far, no uniform treatment protocol for the management of HNSCCs in FA patients exists. Therefore, a unified guideline should be established for screening and management purposes worldwide. We help our study design a plan that includes standardized preventive, diagnostic, and therapeutic measurements for all FA patients and create a multidisciplinary team that includes otolaryngology, oncology, and genetic departments.


  Methods Top


Our research is a retrospective chart review study of HNSCC development in bone marrow failure disease patients. The patients presented to our head-and-neck clinic in King Faisal Specialist Hospital and Research Center between 2009 and 2018. We have collected the data of 14 patients with bone marrow failure. The patients were of adult age and involved both genders.

Ethical consideration/consent documents

We conducted our study following the ethical principles in the Declaration of Helsinki (2000). The ICH harmonized tripartite good clinical practice guidelines and the policies and guidelines of the Research Advisory Council KFSH and RC. The privacy of research participants, and adequate level of confidentiality of the research data, are protected as collected data stored in a database. The access is granted only to the authorized parties, i.e., the principal and co-investigators. This study is a retrospective study since only the patients' charts will be reviewed, and a waiver of consent is attached along with the manuscript. We ensured the anonymity of individuals participating in the research. The aims and objectives of the study are clear of any deception and exaggeration. We will declare affiliations in any form, sources of funding, as well as any possible conflicts of interests. Any communication concerning the research will be done with honesty and transparency. Primary data will be free of any misleading information or bias.

Statistical consideration

We are studying the modality of treatment, screening, and diagnosis to improve the survival rate and the quality of life of FA patients. We are analyzing the data using statistical Package for the social Sciences SPSS version 20 software. Continuous data were summarized as the mean and standard deviation, whereas categorical data were summarized as absolute values and percentages. Continuous data compared using a t-test. At the same time, we utilized the Chi-square test for comparison of categorical data.


  Results Top


We did a retrospective chart review of patients who presented to the head-and-neck tumor board clinic from 2009 to 2018. We analyzed data of 14 patients who had bone marrow failure disease, 12 of which were diagnosed with FA (85.7%), while of the remaining two, one was diagnosed with AML (7.15%) and the other with beta-thalassemia major (7.15%). The male-to-female ratio was 1:2. When looking at the patients' distribution, we found that seven were from the southern region (50%) [Figure 1]. All patients were having negative habituate histories, including alcohol, smoking, and shamma using. Only four patients were having a positive family history of FA in their siblings (28%). Most of the patients underwent stem cell transplants for their bone marrow failure at 10 years of age or younger.
Figure 1: Distribution of patients among Saudi Arabia Regions

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The mean age of head-and-neck cancer diagnosis was 27.69, and the median age was 22. We found that the most common site for HNSCC was the oral cavity, which was the case in 13 patients (92.9%), while only one patient had a nasopharyngeal tumor. The most common subsite was the lateral tongue, as found in five patients (35.7%). Three out of these 14 patients developed non-head-and-neck cancer later in their life. Two of them developed cervical cancer and one SCC of the skin (21.4%). Sixty-four percent of the patients presented with Stage IV disease at their first clinic visit. Six out of the 14 patients (43%) developed recurrence or second primary or metastasis with a median period of 1 year. Most of the patients underwent multimodality treatments. Surgery was the main treatment. Ten of them (71.4%) underwent surgery for tumor resection. Surgery as a single modality was used for three patients diagnosed with Stage I and II HNSCCs. Those patients are still alive and attending their clinic follow-up. Three patients required more than one surgery (21.4%) for recurrence or second primary. Two patients who presented with Stage IV disease received palliative chemotherapy, and both passed away due to their advanced disease [Table 1].
Table 1: Charactristics of the study sample

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  Discussion Top


Fanconi anemia happens due to a defect in the FA genes. FA genes are responsible for multiple cellular processes but, most notably, the DNA damage repair. It maintains the DNA replication and gene transcription by removing the DNA ICLs.[22] This DNA hypersensitivity limits the benefit of radio and chemotherapy in FA patients. Agata Smogorzewska study has reported that 16 patients with FA have received radiotherapy. Among them, mucositis was the most common complication developed in 9 out of 16 patients. They were followed by hematological abnormalities and dysphagia present in 8 patients each. Overall, 11 patients have completed the planned therapy, while the other 5 radiations had to be stopped or interrupted due to the complications. For chemotherapy, one out of three patients developed pancytopenia, dysphagia, and folliculitis.

The risk of oral cancer is higher in Fanconi anemia patients; thus, early detection is of great benefit in those patients. However, the method of screening should be determined carefully. A study of 45 Fanconi patients taught to do mouth self-examination either by themselves or by the children's caregiver. They reported that the results of the oral surveillance were inaccurate.[23] Jrodi Surrallés found that buccal multinucleated frequency was significantly increased in Fanconi patients, suggesting that multinucleated assay could be used to detect oral cancer in FA patients.[24] Martin Schramm et al. examined 713 FA patients by general mouth inspection and brushed cytology over 12 years. They have found that around 63% of the SCCs at noninvasive or early stages. Early detection by brush cytology is beneficial for the detection of oral cancer in FA patients.[25] Many studies have highlighted the propensity of FA developing cancer of different types at different ages and sites. Our study is the first one in KSA to follow up on Fanconi patients and bone marrow failure. In a study that included 145 patients diagnosed with Fanconi anemia, 9 patients developed leukemia while 14 developed 18 different solid tumor types. The results were significant for liver, head-and-neck, and esophageal cancers among the solid tumors.[26] Our study found that FA patients have a high propensity for developing carcinomas in the oral cavity with 92.9%, with the lateral tongue representing the most common subsite for the oral cavity, which was similar to the findings of Agata, who found supraglottic to be the most common subsite for the larynx.[27]

Rund H. Brakenhoff, in his study, reported that SSC in FA patients is genetically similar to the sporadic SCC. Furthermore, that HPV does not have a role in carcinogenesis in FA. In our study, the only risk factor that were observed to have, is the bone marrow failure.[28] In a review of 121 cases of oral cancer in FA, Cassius Torres found that 69 patients (57%) were female and 52 patients (43%) were male, with a median age of 26.5 years.[29] Our study's median age of onset is 22 years, with a 2:1 male-to-female ratio. which is consider an earlier age of onset for developing SCC in comparison with the general population. In a study of 754 patients, the incidence of developing HNSCC reached 3%, which is significantly higher than the general population.[30] A 10-year follow-up study with Fanconi patients found that the median age of developing a solid tumor in FA was around 28.9 years, which was significantly higher than leukemia with the age of 11.3 years. Another study which included 35 FA patients, 5 of them (14%) cancer preceded the diagnosis of FA.[27]Hematopoietic stem cell transplant was associated with an increased risk of developing solid tumors, especially in the head-and-neck region. It is considered as one of the long-term challenges that face Hematopoietic stem cell transplantation (HSCT). The major factor that increased the risk of solid cancers was the history of chronic graft versus host disease after receiving the transplant. Other factors were chemotherapy and radiation for HSCT conditioning. We found that nine of our study patients had a successful bone marrow transplant. Most of them received it below the age of 10 years. Two patients who had their transplants at 45 and 50 years developed HNSCC cancer 1 year after.[31],[32]

According to the literature, the DNA hypersensitivity found in FA patients, depending on surgery alone for treatment without the use of chemotherapy and radiation of HNSCC, appears to be the best approach. In one case series, nine cases of FA who developed HNSCC got reviewed. Seven of the patients were found to have oral cavity tumors. Five of them underwent annual head-and-neck cancer surveillance. This surveillance led to early detection in two cases with T1-stage disease. The other three patients were found to have more advanced diseases. Of all nine patients, the only two who were still alive were those who underwent annual surveillance and were treated with surgery alone as they were diagnosed at an early stage. This proves that even though screening might not pick up all tumors at an early stage, it is still beneficial for many patients who can, with the help of screening, have their disease managed at an early stage with surgery alone.[32] Nine of our 12 patients are still alive. Eight of them had surgeries to resect the head-and-neck tumors they presented with. Seven of these patients presented at an early stage between T1 and T2, while one patient presented with an advanced tumor. He was also managed with adjuvant chemotherapy and radiation. Moreover, patients with milder disease do better than patients with advanced disease, highlighting the importance of early detection. Furthermore, four of the nine patients had both adjuvant chemotherapy and radiation, while one had adjuvant radiation therapy only.

Two of our patients, who were siblings, were diagnosed with FA after being sent to the genetics clinic for FA workup due to a family history of FA in their older sibling, who unfortunately died of complications. They started to get screened for head-and-neck tumors and were diagnosed with early-stage tumors that were treated with surgery alone successfully. On the other hand, one of our study patients who were not diagnosed with FA was managed with cisplatin chemotherapy. The patient developed cisplatin toxicity which led to the multiorgan failure that was fatal. Moreover, a 33-year-old Turkish male developed fatal myelotoxicity after being managed for Stage IV cholangiocarcinoma with cisplatin and gemcitabine as palliative therapy. Similar to our patient, he was not diagnosed with FA previously. The patient was diagnosed postmortem using a buccal swab that was acquired for whole-exome sequencing. The patient did not have the usual hematologic presentation of FA that is usually displayed by the first decade of life, although he had a few physical features of FA.[33] Clinicians must have a high suspicion of a hereditary abnormality when a patient presents with solid tumors at a young age, which will prevent toxicity cases in the case of FA and DNA hypersensitivity and help in choosing the right management for the patient.


  Conclusion Top


FA is an inherited disorder, which is characterized by bone marrow failure and cancer predisposition. Patients with bone marrow failure disease, in particular FA, have a high propensity for developing HNSCC in the absence of common risk factors. Due to the cellular hypersensitivity to agents that cause DNA damage, the surgery-alone approach with early detection represents the best opportunity for cure. During our practice, we found that HNSCCs are a growing problem in the clinical care of FA patients, and no uniform treatment protocol for the management of HNSCCs in FA patients exists. We recommend that the information on affected FA patients be collected, practical therapeutic guidelines should develop, and national treatment centers must be established.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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