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Orbit The International Journal of Orbital Diaceder, Oculoplastic and Litrimal Surgery
Orbit
The International Journal on Orbital Disorders, Oculoplastic and Lacrimal Surgery
ISSN: 0167-6830 (Print) 1744-5108 (Online) Journal homepage: www.tandfonline.com/journals/iorb20
Ocular adnexal sebaceous carcinoma in a patient with Li-Fraumeni syndrome
Chia W. Hsu, Cornelia W. Peterson, Charles G. Eberhart, Christian F. Meyer, Deborah K. Armstrong, Katie Fiallos & Ashley A. Campbell
To cite this article: Chia W. Hsu, Cornelia W. Peterson, Charles G. Eberhart, Christian F. Meyer, Deborah K. Armstrong, Katie Fiallos & Ashley A. Campbell (2025) Ocular adnexal sebaceous carcinoma in a patient with Li-Fraumeni syndrome, Orbit, 44:3, 321-325, DOI: 10.1080/01676830.2024.2382268
To link to this article: https://doi.org/10.1080/01676830.2024.2382268
Published online: 29 Jul 2024.
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CASE REPORT
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Ocular adnexal sebaceous carcinoma in a patient with Li-Fraumeni syndrome
Chia W. Hsuª*, Cornelia W. Peterson @Db,c*, Charles G. Eberhartd, Christian F. Meyere, Deborah K. Armstronge, Katie Fiallose, and Ashley A. Campbell (Da
aWilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; bDepartment of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; “Department of Comparative Pathobiology, Tufts University Cummings School of Veterinary Medicine, North Grafton, Massachusetts, USA; dDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; eDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
ABSTRACT
Li-Fraumeni syndrome (LFS) is caused by a pathogenic germline variant at the TP53 locus and is associated with an increased predisposition to a variety of cancers. The neoplasms most frequently associated with LFS are sarcomas, breast cancer, brain tumors, and adrenocortical carcinomas. In this case report, we present a 43-year-old male diagnosed with an ocular adnexal sebaceous carcinoma of the right upper eyelid who was confirmed to have LFS with subsequent genetic testing. The mutational profile of both the patient’s genetic screen and tumor sequencing were congruent, demonstrating the same pathogenic loss-of-function TP53 variant. This case report highlights the importance of pursuing genetic testing in patients with a history of multiple tumor types, particularly those with uncommon diagnoses. In this case, confirmation of LFS had impor- tant implications for personalized patient care, including identification of contraindicated treat- ment interventions and the imaging modalities necessary for vigilant follow-up screening.
ARTICLE HISTORY Received 28 April 2024 Accepted 14 July 2024
KEYWORDS
Li-Fraumeni syndrome; sebaceous carcinoma; TP53; genetic screening; next generation sequencing
Li-Fraumeni syndrome (LFS) is a rare autosomal domi- nant genetic disorder caused by a pathogenic germline TP53 variant which results in an increased cancer predisposition.1 Patients with LFS demonstrate early onset of multiple primary cancers at different anatomic sites, most commonly including sarcomas, breast can- cer, brain tumors, and adrenocortical carcinomas.1-5
Ocular adnexal (OA) sebaceous carcinomas (SebCAs) arise from the sebaceous glands of the perio- cular region, most commonly the Meibomian glands, and account for approximately 5% of all epithelial eyelid malignancies.6-9 Interestingly, OA SebCAs demonstrate more aggressive clinical and histopathological charac- teristics, resulting in increased rates of tumor recur- rence, metastasis, and mortality, when compared to extraocular SebCAs.7,9-11 These tumors have been pre- viously classified into two distinct molecular subgroups, with approximately two-thirds harboring pathogenic variants at the TP53 or RB1 loci and the remaining one- third retaining wildtype tumor suppressor alleles.12 Molecular studies have further validated these genomic data by demonstrating dysregulation of p53 or RB expression in OA SebCAs.
Due to the overlapping significance of pathogenic TP53 variants to both LFS and OA SebCAs, we present a unique case of OA SebCA arising from the right superior eyelid in a patient with LFS. Our patient has an extensive clinical history of multiple cancers prior to presenting to our clinic with a nodular mass of right upper eyelid margin which was subsequently histologi- cally diagnosed as an OA SebCA. To our knowledge, this is the first reported case in the English literature of a patient with diagnoses of both an OA SebCA and LFS with the same pathogenic TP53 variant identified by concurrent tumor sequencing and germline genetic screening. The collection and evaluation of protected patient health information included in this report were HIPAA compliant and adhered to the tenets of the Declaration of Helsinki.
Case presentation
A 43-year-old white male presented to the clinic with a nodular mass of right upper eyelid. His past medical history was significant for rectal cancer diagnosed at age 22 with a recurrence versus second primary colon
acampb23@jhmi.edu @ Wilmer Eye Institute, Johns Hopkins
cancer at age 34. He underwent chemotherapy, surgery, and radiation for both instances of colon cancer. He subsequently developed a radiation-associated sarcoma of the left gluteal muscles at age 42, which was surgically resected. Additionally, the patient reported an estimate of greater than 20 colonic polyps over several years.
On presentation, the patient was noted to have a well-circumscribed, pale, firm, nodular mass involving the central one-third of the right upper eyelid margin (Figure 1A). He reported that the lesion had been pre- sent for one year but had recently started increasing in size. A biopsy was performed, and the histopathology (Figure 1B) was consistent with OA SebCA (T1MONO; AJCC Cancer Staging System, 8th ed). Conjunctival map biopsies were performed and were negative for malig- nancy. The tumor was subsequently completely surgi- cally excised using frozen sections to confirm that the margins were clear intraoperatively. Margins measuring 5 mm were attempted. The superior, lateral, and medial margins were clear in one, two, and three passes, respec- tively. The final defect size was 12 x 8 mm. Of note, the final pathology report indicated the eyelid margin to be clear, and no intraepithelial involvement by the tumor was identified in the excisional biopsy. Adjuvant cryotherapy using a double freeze-thaw technique was performed followed by reconstruction, yielding good cosmetic and functional outcomes. Given the patient’s extensive cancer history, the possibilities for either Muir-Torre syndrome, a condition due to a pathogenic germline variant of genes encoding mis- match repair proteins, or a pathogenic variant at the MUTYH locus, which have also been documented in association with SebCAs, were considered, and the patient was referred for genetic counseling.17
During his consultation with genetics at our institu- tion, a complete multi-generational pedigree was obtained (Figure 1C), including a maternal aunt with breast cancer at age 60 and cervical cancer in her seven- ties, and several maternal relatives with cutaneous squa- mous cell carcinomas. The patient underwent Invitae genetic screening, which demonstrated a pathogenic variant at the TP53 locus (c.586C>T, a.Arg196*). A sample of the tumor was also submitted for next- generation sequencing (NGS). While the DNA isolated from the tissue sections was not sufficient for the com- prehensive Solid Tumor Panel, a smaller NGS panel demonstrated the same pathogenic TP53 variant with a variant allele frequency (VAF) of 56%. The only other alteration identified in this smaller clinical panel of 27 genes was a p.F384L change at the FGFR3 locus, which was suspected to represent a benign germline variant.
Immunohistochemical staining of the tumor was further supportive of the initial findings, as a subset of
tumor cells strongly expressed adipophilin, a marker of sebaceous differentiation (Figure 1D) and the majority of the neoplasm strongly expressed p16, which can be useful in highlighting intraepithelial tumor cells.15,16 Immunolabeling for Ki67 further demonstrated the pro- liferative capacity of the atypical cells. Neoplastic cells largely failed to express p53 (1E), consistent with the expected attenuation of p53 translation which results from the variant sequence producing a premature stop codon. Conversely, expression of the mismatch repair proteins MLH1, MSH2, MSH6, and PMS2 was retained, diminishing the concern for Muir-Torre syndrome.
Discussion
Li-Fraumeni syndrome (LFS), first described by Frederick Pei Li and Joseph F. Fraumeni Jr., in 1969, results from pathogenic germline variants at the TP53 locus.3 While LFS exhibits a pattern of autosomal domi- nant inheritance, the de novo (spontaneous) mutation rate of LFS has been estimated to range from 7% to 20%.4,5,18 To our knowledge, this is the first report of a patient with LFS presenting with OA SebCA and with the same pathogenic TP53 variant demonstrated in the tumor and in the germline. To our knowledge, there have been two other previously published cases of OA SebCA in patients with LFS; however, genetic sequen- cing of the tumor for confirmation of the same variant was not reported.19,20
TP53 is a tumor suppressor gene which encodes the transcription factor p53, a major effector in cell cycle progression with primary roles in preventing genomic mutation.21 The pathogenic variant observed in our patient and tumor, TP53 Exon 6 c.586C>T p.Arg196*, is a cytosine to thymine nonsense mutation at codon 586 (c.586C>T) on exon 6. This substitution creates a premature translational stop signal at amino acid position 196 (p.Arg196*) of the TP53 locus, resulting in absent or disrupted p53 translation. Loss-of-function variants such as this in TP53 are pathogenic and have been well documented in other tumors.22,23 The patho- genic variant demonstrated in this tumor is highly sug- gestive of loss of p53 heterozygosity due to an estimated tumor cellularity of the histologic sections submitted for NGS of 60-80%, and the variant allele frequency of 56%.
This case report highlights the importance of prompt histopathologic and genomic evaluation of primary and recurrent tumors in patients with LFS, even those arising from anatomic sites not previously associated with LFS. Since OA SebCA can exhibit more aggressive phenotypes, and the initial clinical presenta- tions can mimic benign ocular conditions, physicians managing patients with LFS should have a low
A
B
C
☒
☒
Squamous Cell Carcinoma (80’s)
☐
Squamous Cell Carcinoma (70’s) Normal colonoscopy
Breast Cancer (60) Uterine Cancer (70’s)
☒
Normal colonoscopy
Colon Cancer (22, 34) Sarcoma (42) SBC (43) Tubular adenomas (43)
Squamous Cell Carcinoma (30’s)
D
E
threshold to refer their patients to an ophthalmologist or oculoplastic surgeon if there is any suspicion for the development of ocular adnexal tumors. Additionally, it is critical to suspect an underlying cancer predisposing syndrome in patients presenting with a history of multiple different cancer types, and a referral to a genetic counselor should be recommended. In this case, the diagnosis of LFS permitted the patient’s care team to tailor recommendations regarding treatment and screening. Oncologists determined that radiation, a DNA damaging therapy, should be avoided in the future if possible, and MRI and ultrasound, rather than CT imaging, would be preferable for ongoing screen- ing. Having access to genetic screening for germline variants and tumor sequencing allows physicians to treat patients with more precise care, which may have future applications for more targeted OA SebCA therapies. Finally, a complete family history is neces- sary to identify other potentially at-risk relatives for genetic testing, which can lead to a determination of de novo inheritance.
Disclosure statement
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.
ORCID
Cornelia W. Peterson (D http://orcid.org/0000-0001-6550- 1883
Ashley A. Campbell (D http://orcid.org/0009-0006-5420-3411
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