Increasing Evidence for the Association of Breast Implant-Associated Anaplastic Large Cell Lymphoma and Li Fraumeni Syndrome

We report a case of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) occurring in a 53-year-old female with Li Fraumeni syndrome (LFS) with a prior history of breast cancer. We present the clinical features, investigation, and management of this patient and potential mechanisms that could explain the increasing association of BIA-ALCL and LFS.


Introduction
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare T-cell lymphoma particularly associated with textured breast implants [1]. In 2016, the World Health Organization classification of lymphoid neoplasms included BIA-ALCL as a separate entity from other ALCLs, with features of CD30-positivity and ALK-negativity [2]. Assessing the incidence in women with textured implants has proved challenging, with estimates varying from 1 in 300,000 to 1 in 1000-10,000, with more recent reports suggesting the higher range [3]. National Comprehensive Cancer Network (NCCN) consensus guidelines have been published on diagnosis and treatment [4]. BIA-ALCL is generally associated with a good prognosis. However, concern regarding the association has led to the French National Agency for Safety of Medicines and Health Products (ANSM) recently withdrawing certain textured implant products from the market [5].
Li Fraumeni syndrome is an autosomal dominantly inherited multiple cancer predisposition syndrome due to germline pathogenic mutations in the TP53 gene [6]. Typical malignancies associated with the syndrome include breast cancer, sarcomas, adrenocortical carcinoma, and primary brain tumours. The population prevalence has been estimated historically at around 1 in 20,000, although underascertainment and existence of lower-penetrance variants mean that the true penetrance is likely to be higher. A study including genomic datasets estimated a conservative prevalence of 1 in 3555-5476 and potentially as high as 1 in 400-865, if variants with less clear evidence for pathogenicity were included [7]. Screening and management protocols have been proposed for pathogenic mutation carriers, including whole body magnetic resonance imaging [8]. Imaging involving ionizing radiation and treatment with radiotherapy is advised to be minimised, or avoided unless essential, in view of the potential for inducing subsequent malignancies. Women with Li Fraumeni syndrome may consider riskreducing bilateral mastectomies.
We report a case of BIA-ACLC occurring in a patient subsequently confirmed to have Li Fraumeni syndrome.

Case Report
The patient is a 53-year-old female. At the age of 33, she was diagnosed with grade 3, ER and PR negative, axillary node negative, ductal adenocarcinoma of the right breast cancer in the 2 o' clock position. HER2 status was not available, as testing was not routinely available at that time. This cancer was treated with wide local excision, axillary node clearance, adjuvant cyclophosphamide, methotrexate and one. The largest lymph node was excised. Histopathological examination ( Figure 3) demonstrated both the breast capsule and lymph node to be infiltrated with CD30 positive, ALKnegative BIA-ALCL. This was somewhat unusual in showing lymph node involvement and also expression of CD15. The patient was reviewed in the Clinical Genetics service. The pedigree is shown in Figure 4. The patient (A on the pedigree) also had a past history of hysterectomy, with ovaries preserved, at the age of 31 for grade 3 cervical intraepithelial neoplasia, nonmelanomatous skin cancer, and lower limb squamous cell carcinoma in-situ (Bowen's disease). She reported that her late mother (B) had radiotherapy treatment for a cancer affecting a finger at the age of 10 years in the early 1950s, subsequently developed breast cancer at the age of 58, and died at the age of 67. The patient's maternal grandmother died at the age of 62 without cancer, but the brother (C) of that lady was reported to have died from a cancer affecting his leg, considered possibly a sarcoma. The patient's paternal grandmother (D) died of a cancer of unknown primary site aged 42. TP53 gene screening was performed for the patient, identifying a heterozygous pathogenic mutation c.524G>A; p.(Arg175His), consistent with a diagnosis of Li Fraumeni syndrome. From the family history, inheritance was considered more likely to be from the proband's mother than father, although unconfirmed at present.
The patient was treated with three cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP), followed by a further three cycles with the doxorubicin replaced with gemcitabine in view of previous anthracycline-exposure during her adjuvant breast cancer treatment. A post-treatment PET CT scan showed no remaining abnormal lesion or metabolic activity. Radiotherapy was not given.

Discussion
To our knowledge, this is the fifth case of BIA-ALCL in association with Li Fraumeni syndrome reported in the literature to date. This strengthens the evidence that this is 4 Case Reports in Genetics a true, rather than chance, association. There have been two single case reports [9,10]. In another series of BIA-ALCLs, germline TP53 mutations were detected in 2 of 11 cases; both patients had previous personal and family history of breast cancer; in one of the two cases, a somatic "second hit" mutation was detected in the tumour, which is the same mutation that we detected in germline in our patient [11].
The mechanism of development of BIA-ALCL is unclear. It has been postulated that chronic inflammation due to a bacterial biofilm, more prevalent on textured implants, leads to T-cell hyperplasia and subsequent malignant transformation [12]. Somatic mutations leading to increased activation JAK/STAT signalling, particularly STAT3 gene mutations, are common, suggesting that this is the main driver pathway in BIA-ALCL [11].
TP53 mutations have been identified in some BIA-ALCL tumours [11,13]. However, TP53 mutations are not identified in the majority of BIA-ALCL, with either single or biallelic "hits". Therefore, Li Fraumeni syndrome/germline TP53 mutation may be a risk factor, rather than a driver for BIA-ALCL development. BIA-ALCL-derived cell line studies have shown evidence of dysregulation of p53 signalling pathways in response to DNA damage [14]. A high incidence of thymic lymphoma development was noted in a study of biallelic TP53-knockout mice [15]. There is also evidence that TP53 can show haploinsufficiency in the heterozygous state [16]. Therefore, it is possible that BIA-ALCL develops due to inadequate tumour-suppressor activity in Li Fraumeni patients, allowing greater likelihood of clonal survival of lymphoma cells that have developed due to the implantassociated biofilm and cytokine environment.
In around 80% of cases, BIA-ALCL presents as effusionlimited disease, with nodal involvement being less common. In our patient, the presence of lymph node involvement at presentation may suggest more aggressive behaviour, possibly in the context of Li Fraumeni syndrome. However, pathological lymph node involvement was not reported in two other single detailed case reports [9,10], so it is not possible to draw firm conclusions.
CHOP is a standard first-line chemotherapy for the management of T-cell lymphoma, but with ongoing investigation of use of etoposide (in CHOEP) and gemcitabine amongst other agents [17]. Our patient had some adjustment of standard treatment (second half of treatment using gemcitabine rather than doxorubicin) in view of previous anthracyclineexposure, still achieving complete response on functional imaging.
The interval between initial breast implant surgery and diagnosis with the BIA-ALCL was 14 years in this case, which is longer than described in other single detailed case reports in which there were intervals of 3 years [9] and 7 years [10]. It could be hypothesized that LFS-associated lymphomas would develop after a shorter median interval than non-LFSassociated. However, the interval range in general series is wide from 2 years to 32 years [1]. The number of reported cases in the literature confirmed as being associated with LFS is currently too small to draw firm conclusions.
The absolute risk of BIA-ALCL in Li Fraumeni patients is unknown. However, avoidance of textured implants in known or suspected TP53 mutation carriers is prudent. Our patient is planned to have removal of the contralateral implant (on the previously radiotherapy-treated side).
It is important to assess personal and family history to identify potential Li Fraumeni cases amongst those affected with BIA-ALCL.

Consent
Written consent was obtained from the patient for publication of her clinical case, including photographs.

Conflicts of Interest
The authors declare that they have no conflicts of interest.