Although the risk of developing OSCC in patients with GVHD is well established, no studies report on the unique concerns regarding the population of patients who have been transplanted as children. Therefore, the purpose of the present paper was to review scientific literature to extrapolate all the published data on HSCT pediatric patients, affected by oral GVHD, who have been developed OSCC.
2. Materials and MethodsMEDLINE/PubMed and Web of Science literature searches were performed, using the following keywords in different combinations: “graft versus host disease” (GVHD), “oropharyngeal cancer”, “children”, “head and neck cancer”, “pediatric”, “oral squamous cell carcinoma” (OSCC), “hematopoietic stem cell transplantation” (HSCT), “oral cancer”. Studies were included if fulfilled the following eligibility requirement: to report data on patients with oral GVHD, affected by OSCC, who were of pediatric age at the time of the hematopoietic stem cell transplantation. Studies were excluded if reporting data on patients with oral GVHD, affected by OSCC, who were not of pediatric age at the time of the HSCT and when it was not specified if GVHD in patients submitted to HSCT in pediatric age involved oral cavity.
The following data were provided, when available, for each patient: type of disease requiring HSCT; age at transplantation; gender; stem cell source; HLA compatibility; type of conditioning regimen; GVHD prophylaxis; aGVHD/cGVHD (time lapse between HSCT and aGVHD/cGVHD, sites involved, aGVHD/cGVHD grading/severity, therapy); time lapse between HSCT and OSCC; SCC site; OSCC staging; OSCC treatment; histology; outcome.
4. DiscussionOSCC is a significant cause of public health concern worldwide, representing one of the ten most common cancers in the world with an overall 5-year survival rate equal to 65% [6,28]. It mainly affects elderly males who have a long history of smoking tobacco and drinking alcohol. Other risk factors include: oral human papilloma virus (HPV) infection, ultraviolet radiation, and immune deficiency. Despite OSCC being rare among children, recent research showed that several cases of oral SCC in children and young adults were secondary cancers associated with HSCT [23].A very recent systematic review and meta-analysis proved that patients with GVHD undergoing HSCT had a higher risk of developing OSCC compared to patients not exposed to this condition, even for a very long time after HSCT [7]. While the frequency of GVHD is usually lower in pediatric patients than in adult populations, the oral cavity can be affected by both acute and chronic forms of the disease [29]. So, young HSCT patients with GVHD, supposed to be long-term survivors, may be at high risk of developing OSCC [24].Therefore, the present review aimed at extracting from the scientific literature all the published data on patients with oral GVHD, affected by OSCC, who were of pediatric age at the time of the transplant. Thus, the analysis of the collected data provided relevant considerations.
Gender distribution supported the observation by Gervazio et al. that OSCC in patients with GVHD had a predilection for the male gender [7], though males were only slightly more likely than females to undergo HSCT [6].Among the selected studies, data on HLA compatibility were available for 24 patients out of 33, of which only one male patient received bone marrow from a sex-mismatched donor. This condition is well known to be associated with a higher incidence of GVHD and inferior survival as a result of allogeneic immune responses against minor histocompatibility antigens encoded on the Y-chromosome of a male recipient (H-Y antigens) [30].In relation to the conditioning regimen, the pre-treatment was specified in 30 out of 33 patients, of those 10 were myeloablative conditioning and 20 were reduced-intensity conditioning. The myeloablative conditioning regimens, such as total-body irradiation and/or chemotherapy, can influence the risk of secondary solid malignancies in HSCT patients [7].Regarding chronic immunosuppressive therapy, it has been speculated that long-term immune suppression may compromise immune surveillance and exert a cocarcinogenic effect on the genetic damage caused by chemoradiation [19]. In particular, the immunosuppressive treatment with cyclosporine and azathioprine was considered a significant risk factor for secondary malignant tumors [31]. In the selected studies the type of drugs utilized for immunosuppressive therapy was specified for about one-third of patients; thus, any hypothesis concerning the correlation between specific immunosuppressive treatments and cancer onset was not possible due to lack of data.In relation to the indication for HSCT, among the selected studies, 12 patients out of 33 were affected by Fanconi Anemia (FA), a genetically and phenotypically heterogeneous autosomal recessive, dominant or X-linked disorder, characterized by congenital abnormalities, bone marrow failure, and increased risk for cancer [32]. HSCT is considered the treatment of choice in FA patients who develop hematopoietic failure, but it may predispose to late cancer development by adding risk factors; among these, a strong association between GVHD and late malignancies has been demonstrated [20,27].From the analysis of the reported studies emerged that none of the patients developed only aGVHD, 20 patients developed both acute and chronic forms, and 13 patients presented with cGVHD exclusively. This was in line with the study of Curtis et al., who found that, compared to patients without GVHD, the risk of solid malignancies was not elevated for patients with aGVHD; however, a previous history of aGVHD further increased the risk of solid malignancies among patients with cGVHD [33]. In relation to the GVHD characteristics, most of the papers included in the present review failed to report significant information both on clinical phenotype and exact intraoral site. Only three authors clearly described how GVHD diagnosis was made [6,22,27]. Data on histological analysis were rarely reported. Only three studies reported cGVHD clinical features, mainly described as lichenoid lesions [18,20,24]. Only in seven cases, the description of the cGVHD severity was available. The lack of this information prevents to formulate any hypothesis on the possible correlation between specific anatomical sites and a higher risk of malignant transformation; furthermore, it was also not possible to correlate cGVHD severity with an increased risk of OSCC onset. The time lapse between HSCT and OSCC, among the selected studies, was about 10 years. This was in accordance with other researchers, who found that the risk of solid malignancies may increase with the duration of follow-up after HSCT because of the long latency of such malignancies [2,34]. Furthermore, patients developed OSCC at a younger age if compared to that of the general population.One of the largest international studies on this matter demonstrated that the risk of solid malignancies increased from 1.6-fold higher than the general population in the first 5 years after HSCT to 4.5-fold higher among survivors of 10 or more years [9]. According to Danylesko and Shimoni, there is no evidence for any plateau in the incidence rate; instead, the slope of the curve continues to show a steadily increased incidence with increased follow-up [35].The pathogenesis of secondary solid malignancies after HSCT is multifactorial [2]. Therapeutic agents, such as chemotherapy and radiation, can cause breaks in double-strand DNA, resulting in gene mutations, deletions and translocations, and genomic instability conferred by loss of DNA repair [2,35]. Genomic alterations in the mucosal epithelium, as shown by microsatellite instability, have been frequently reported after HSCT, particularly in tissues affected by GVHD, and may contribute to the onset of secondary solid malignancies; immunologic alterations may also be involved in the pathogenesis [2,35]. In the context of prolonged immune suppression, pre-existing or new infections with oncogenic viruses, such as HPV and EBV, could play an etiologic role in many post-transplant solid cancers [21]. Moreover, somatic mutations in the tumor suppressor gene TP53 are frequently reported in these tumors [34]. As highlighted by Adhikari et al., these factors may cooperatively predispose HSCT recipients to an improved risk of solid malignancies [2].Regarding HPV status, two p16/HPV-positive OSCC cases were reported [21,25].Although HPV infection is well-recognized to be associated with head and neck squamous cell carcinoma (HNSCC), being involved in about one-quarter of the cases in the general population, the role of HPV in the development of HNSCC in post-HSCT patients has not yet been clarified [21,25]. The reports about HPV involvement in HNSCC after HSCT are quite scarce, suggesting the need for routine HPV screening in HSCT patients [21,25].In the present review, the development of two synchronous OSCCs was described by two authors, respectively [16,24]. Montebugnoli et al. reported the development of two synchronous carcinomatous lesions on the tongue and the floor of the mouth in a young female patient 17 years after HSCT [24]. Somers et al. described the development of two synchronous carcinomatous lesions on the tongue in a female teenage patient 8 years after HSCT [16].As stated by Abdelsayed et al., the presence of synchronous carcinomas indicated that OSCC in HSCT patients with GVHD may have an aggressive biologic potential with an increased tendency for recurrence and the development of new lesions [14].Furthermore, secondary tumors were reported to respond less well to standard therapy compared with de novo OSCC [29]. In fact, as it is possible to deduce from the reported data, the prognosis for HSCT pediatric patients, affected by oral cGVHD, who have been developed OSCC, remained poor, despite therapeutic advances. Therefore, a strict surveillance, such as allowing an early diagnosis, continues to be the key element to increase the survival rate [31]. Patients, who are at high-risk for SCC of the oral cavity such as those with oral chronic GVHD and Fanconi’s anemia, should undergo oral evaluations every 6 months. Avoidance of smoking and alcohol may also reduce the risk of oral cancer [2].The present review had certain limitations that should be addressed. First, from the literature search it was not always possible to quantify how many patients with oral GVHD, who underwent HSCT as children, developed OSCC, because, in some large surveys, data on age at HSCT were reported exclusively as median age. Furthermore, other studies failed to specify if GVHD in patients submitted to HSCT in pediatric age involved oral cavities. Another limitation concerned possible under-reporting by transplant centers to the registry as transplant centers may not have information on long-term HSCT survivors, which is important when considering secondary cancer screening in patients who underwent HSCT as children.
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