Benign Tumors and Non-Melanoma Skin Cancers in Patients with Fanconi Anemia

Abstract


Introduction
Fanconi anemia (FA) is a rare genetic disorder that is a predominant contributor to inherited bone marrow failure (BMF).Beyond its impact on blood cell production, this condition gives rise to congenital abnormalities and increases the likelihood of cancer development (1).
FA is characterized by pathogenic variants in the genes making up the FA DNA repair pathway, which consists of 22 proteins, organized into complementation groups based on their position in the FA pathway (2).Inheritance patterns for most FA genes are biallelic, autosomal recessive, except FANCB which is X-linked and FANCR (RAD51), which is autosomal dominant (3,4).
Patients with FA exhibit a diverse range of clinical presentations, typically diagnosed around the age of 7 years (5,6).These individuals often display congenital malformations, skin abnormalities, BMF, and an increased susceptibility to malignancies (5,7).
Patients with FA face a heightened risk of developing cancer, particularly hematological disorders such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), with cumulative incidence rates of 40% and 10% respectively by the age of 50 (6, 8).The cumulative incidence of solid tumors reaches 20-30% by age 50 (6, 8).Among the solid tumors observed in patients with FA, head and neck squamous cell carcinoma (SCC), esophageal, brain, and anogenital cancers are the most common (9,10).
We earlier reported cases of skin SCC and basal cell carcinoma (BCC) in patients with FA (9,10).Our current objective was to thoroughly characterize patients with FA who are enrolled in the National Cancer Institute (NCI) inherited bone marrow failure syndrome (IBMFS) cohort who have experienced nonmelanoma skin cancers (NMSC), either SCC or BCC, and/or benign tumors (BT).There have been no previous reports on benign tumors (BT) in patients with FA.This case series aims to shed light on the occurrence and clinical features of these tumors in the context of FA We investigated various factors, such as the age at the rst adverse event, HCT status, biological sex, FA complementation group, cumulative incidence, and survival probability.

Methods
Individuals diagnosed with FA enrolled in the Etiologic Investigation of Cancer Susceptibility in Inherited Bone Marrow Failure Syndromes: A Natural History Study, which was approved by the NCI Institutional Review Board (NCT00027274).Patients were followed from time of enrollment (earliest January 2002) through October 2023.A total of 200 patients with FA were enrolled.Participants or their proxies provided written consent and authorized the release of their medical records.Data were gathered from individual questionnaires, biennial follow-up forms, medical records, and evaluations conducted at the National Institutes of Health Clinical Center (for a subset of patients).The diagnosis of FA was made based on an abnormal chromosomal breakage test and was further con rmed through genetic testing when possible.
Retrospective review of medical records identi ed thirty patients within this study having at least one adverse event of interest: NMSC (SCC, BCC), or benign tumors (BT).The diagnoses of SCC, BCC, or BT were reported through various methods, such as biopsy, pathology reports, surgery/operation reports, physician/consultation reports, self-reports, and personal relations reports.The control group consisted of the remaining 170 FA patients with available data.HCT status, sex distribution, and survival probability were compared between FA patients with an adverse event and the control group.Kaplan-Meier method was used to estimate survival probabilities and cumulative incidence.If a patient had more than one NMSC or BT, data for only the rst event of NMSC and BT were used to calculate cumulative incidence.
The time to the event of interest was measured from the individual's date of birth to the occurrence of the rst NMSC, BT or their last follow-up date, with censoring applied to those who did not experience an adverse event at their respective last follow-up point.For comparisons between groups, the log-rank test was utilized.P-values less than 0.05 were considered statistically signi cant.Events with available data were used for age range, median age, HCT status before an adverse event, cumulative incidence, and survival probability analysis.
One patient with a single event of BT was excluded from age range, median age, HCT status before an adverse event, and cumulative incidence, as information on the age at tumor diagnosis was not provided.
Last follow-up age for two patients in the control group was less than one year old, and data for these patients was omitted in survival probability and cumulative incidence analysis.Patients reported alive in October 2023, were assumed alive, and their last follow-up date according was utilized for age calculation.We completed data analysis using GraphPad Prism 8, Venny 2.1, and Microsoft Excel.

Results
Out of 200 patients with available data, 30 patients had at least one NMSC and/or BT.Of these 30 patients, 19 (63.3%) were female, and 14 (46.6%) were alive at last follow up (Table 1).The majority were self-identi ed as white.The association between HCT and early malignancy onset in FA patients has been previously documented (10).To evaluate whether this association exists in our patient cohort, we compared the HCT status of FA patients with NMSC/BT to that of the control group.Fifteen (50%) of the 30 patients with NMSC/BT had undergone HCT.Among these, seven were female and eight were male.The median age at the time of HCT was 10.8 years, (range 1 to 46 years).Similarly, in the control group, 85 (50.3%) of FA patients had an HCT, with a median age of 9.1 years (range 4 to 43 years).Out of 25 patients with a BT, 11 (44%) received HCT.Six patients underwent transplant prior to their rst BT occurrence, and four patients underwent transplant after their rst BT occurrence (Table 2).The median age at transplant for this group was 9. Transplant date information was unavailable for one patient.Of the 11 patients with BT who received transplant, seven (63%) were alive at last follow up while four were deceased.In contrast, of the 12 patients with NMSC, six (50%) underwent transplant, and the median age at transplant for this group was 30.5 years (Table 3).Three patients received transplant prior to their rst skin cancer while the other three underwent transplant after their rst skin cancer.Five patients were deceased at last follow up while one patient in this group was alive.HCT prior to rst NMSC 3 Among the 12 patients identi ed with NMSC, 8 patients had a diagnosis of SCC, and 7 had a diagnostic of BCC, and three patients had both SCC and BCC (Supplemental Fig. 1).The median age for the rst occurrence of NMSC was approximately 31.3 years.The median age at rst diagnosis were 35.9 years (range 11-64) for SCC and 31.0 years for BCC (range 11-41).Six patients (50.0%) had one NMSC occurrence, two patients (16.7%) had two, two patients (16.7%) had three, and two patients (16.7%) had more than three occurrences.The range of events per patient extended from 1 to 26.One patient had 11 events of SCC and 15 events of BCC (Table 3).
Within the NMSC patient group we found that eight (66.7%) were female cases and four (33.3%) were male cases (Supplemental Fig. 2).In the SCC subgroup, six (75.0%) were female cases and two (25%) were male patients.BCC was identi ed in four (57.1%) female patients and three (42.9%)male patients.Furthermore, eight (42%) out of 19 females experienced at least one event of SCC or BCC, while four (33%) out of 12 males had such events.
Twenty-ve individuals developed at least one event of a BT.The median age at rst diagnosis of BT in the cohort was 17.5 years (range 0-56).Seventeen (68.0%) patients experienced one, ve (20%) patients had two, two (8%) patients encountered three, and one (4%) patient had more than three instances of BT (Table 2).Three benign tumors were endocrine in origin, six within the central nervous system (CNS), seven were associated with solid organs, eight involved the reproductive system and breast tissue, seven were categorized as cutaneous lesions, and six were grouped as other (Table 4).
CNS lipoma Tumor, NOS Benign tumors occurred across various anatomical regions.In the endocrine system, we identi ed an instance of a thyroid cyst and two adenomas in the pituitary gland.In the CNS, two cases of lipoma were identi ed, with one located in the third ventricle, and the other reported as a spinal lipoma.Additionally, we identi ed two cases of a parietal lobe mass (histopathology unknown), one case of cerebellum angioma, and one case of a pineal region cyst.Occurrences involving the gallbladder, liver, kidney, and lung were classi ed as solid organ benign tumors.In the reproductive system and breast tissue, BT instances included cysts of the testis, ovaries, uterus, as well as breast tubular adenoma and uterine broids.The cutaneous lesions category included anal warts, hemangiomas, dysplastic nevi, and dermato bromas.
The cumulative incidence of adverse events in our FA patient cohort, at age 30, was 4.5% for NMSC (SCC ± BCC) and 18.5% for BT.At age 50, the incidence of NMSC and BT increased to 28.0% and 33.0%respectively (Fig. 1).To investigate the impact of NMSC and BT on survival probability of FA patients, we compared survival probability of FA patients with an adverse event (NMSC or BT) to the survival probability of FA patients without an adverse event.Our analysis revealed no statistically signi cant difference in survival probability between the two groups (Log rank test, p = 0.0930).Interestingly, the survival probabilities of FA patients with NMSC and BT at age 30 were both 91.5%, a notable contrast to the lower survival probability of 58.5% observed in our control group at the same age (Fig. 1).

Discussion
Within the cohort of 200 patients with FA, 12 individuals presented with at least one NMSC (SCC or BCC), while 25 patients had at least one BT.Though BT were detected at an earlier age than NMSCs (median 17.5 vs 31.3,respectively), patients with FA with skin cancers had them at a younger age compared with the general population.NMSC is known as the most common type of cancer in the general population, but usually does not occur until later in life.For individuals of European ancestry, incidence of NMSC peaks at around 70 years of age and is highly unusual in the teenage years, but were observed at these ages in patients with FA (11).In a recent study that analyzed statistical associations between clinical parameters in NMSC occurrences, researchers found that the mean diagnostic age was 70.1 years for BCC and 74.2 years for SCC (12).Patients with FA may be at increased risk of developing an NMSC due to their FA diagnosis (a DNA repair disorder).Additionally, patients with FA may be exposed to radiation or long periods of immunosuppression, which could further increase their likelihood of developing an NMSC.Further investigation is necessary to reach this conclusion within the FA population, and proactive monitoring through routine consultations with dermatologists could prove bene cial.Among the cohort of 30 patients diagnosed with at least one BT or NMSC, 63.3% were female, which is greater compared to the control group, which consisted of 55% females.A greater proportion of female patients had at least one NMSC or benign tumor event compared to male counterparts.In the general population, several studies found a higher incidence of NMSC in males than in females (13)(14)(15).However, when Evans et al strati ed their analysis based on patient age, they found that in the 10 to 49 years cohort, the majority of BCC patients were females, constituting 60.4% of the cases.Conversely, among individuals 50 to 99 years, females accounted for only 36.0% of the BCC cases (13).Taking in consideration the lower survival probability of FA patients compared to the general population, the Evans et al study could explain the sex distribution found in our NMSC cohort.To further elucidate the potential factors in uencing this unusual sex distribution of NMSC in our FA patient group, it is essential to consider unique aspects related to FA, speci cally factors that affect sun exposure and lifestyle choices.
In this case series, one patient demonstrated 26 occurrences of NMSC.Most of these instances occurred post HCT, which was performed at the age of 33, following their diagnosis of FA at 32.This patient also presented with an unspeci ed immunode ciency, potentially contributing to the heightened susceptibility to multiple skin cancers.Collins et al conducted an investigation on malignancies post organ transplant which highlighted the increased aggressiveness of NMSC in recipients due to immunosuppression (16).Although this patient did not undergo organ transplantation speci cally, it is possible that a long period of immunosuppression played a role in their many occurrences of NMSC.
One patient experienced all three events studied: SCC, BCC, and benign tumors.The patient had the FANCA genotype, and like the patient with 26 NMSC occurrences, received her diagnosis and underwent transplant later in life, at 38 years of age.Prior to the transplant, she was diagnosed with BT and BCC, and subsequently experienced both BCC and SCC post-transplant.
Among the 12 patients diagnosed with SCC or BCC, the majority belonged to the FANCA group (9), with one patient in the FANCC category and two patients with unknown genotypes (Supplemental Fig. 3).Conversely, in the cohort of 25 patients with BT, FANCA remained the predominant genotype, accompanied by two FANCC cases.However, this group displayed a more diverse genotype distribution, encompassing FANCI, FANCJ (BRIP1), FANCG, FANCD1 (BRCA2), and FANCR (RAD51).
Notably, two patients with the rare FANCI genotype presented with BT-one with a colloid cyst of the thyroid and the other with a pineal brain cyst.Additionally, a patient with the rare FANCR genotype manifested a BT in the central nervous system, a spinal lipoma.None of these patients underwent hematopoietic cell transplantation, and none experienced SCC or BCC occurrences.All three patients were diagnosed with FA before the age of 6 months.
The single patient with the FANCD1 genotype presented with both a benign kidney tumor and a parietal lobe tumor in the central nervous system.Additionally, this patient was diagnosed and treated for medulloblastoma at approximately 3 years of age.These occurrences align with existing literature, which indicates that patients with the FANCD1 genotype tend to develop solid tumors at early ages and have a predisposition to developing brain tumors before 6 years of age (17).
Seventeen of the 30 individuals with a BT or NMSC reported oral leukoplakia, which can be potentially malignant and associated with the development of oral squamous cell carcinoma (18).The prevalence of this condition, in combination with the signi cant early age of skin cancer diagnoses compared to the general population, is another indication of an increased need for surveillance in this patient population.Individuals with either BT or NMSC exhibited a noteworthy increase in survival probability at age 30 compared to the control group, (ns, p = 0.0930) (Fig. 1).While the median age at transplant for patients with NMSC was higher than that of patients with BT and controls (30.5, 9.0, 9.1 years, respectively), the median age for patients who developed NMSCs was also greater compared to benign tumor and control groups (33, 17.5, and 15.4 years).Considering these observations, we hypothesize that individuals with FA who develop NMSCs, or BT may have a modifying factor that improved their survival estimates up to age 30, which possibly allowed for the acquisition of DNA damage and subsequent NMSCs.Further investigations into the underlying mechanisms and contributing factors to these tumors and potential modifying factors will be instrumental in determining the nature of these and re ning prognostic assessments for individuals with FA.
In 2014, a research study characterized the incidence of NMSC in patients enrolled in commercial or Medicare health insurance plans.They found that in United States, NMSC incidence was less than 1% in patients aged 0 to 24, 1% in patients aged 25 to 34, 6% in patients aged 35 to 44 and 17% in patients aged 45 to 54 (13).For the patients with FA described here, the cumulative incidence of NMSC had a large increase from 4.5% at 30 years to 28% at 50 years (Fig. 1).This jump in incidence emphasizes that age is an important factor in the development of NMSC, and potentially re ects the interplay of genetic and environmental factors in patients with FA.
The ndings presented in this case study are limited by the relatively small size of the patient cohort, which consisted of 30 individuals with FA and either NMSC or BT.The sample size may impact the generalizability of the results; however, this cohort of 200 patients with FA is relatively large for this rare disorder.Conducting small case series studies, like the one presented here, becomes imperative to highlight diverse patient pro les and abnormalities within this limited population, even though the results may not be readily generalizable.Another notable limitation is the absence of pathology records for a considerable number of tumors.The lack of these records hinders the comprehensive characterization of the tumors, potentially limiting the depth of insights into their speci c nature and behavior.The unavailability of detailed information from pathology reports, including histological subtypes and molecular characteristics, makes it di cult for us to identify patterns in the etiology and progression of the tumors.In summary, this case study provides a detailed exploration of non-melanoma skin cancers and benign tumors in patients with FA, shedding light on clinical and genetic factors associated with these events.
The ndings, consistent with existing literature, underscore the signi cance of early detection and surveillance of patients with FA, even in cases with milder disease presentations, and highlight the necessity for tailored screening and management strategies for this patient population.

Declarations Author Contribution
A. Enache and B. Sajjad contributed equally to this manuscript as rst authors.All authors reviewed the manuscript.

Supplementary Files
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Figures
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Table 2
Characteristics of patients with benign tumors.