Breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) is a rare T-cell lymphoproliferative disorder occurring in patients with breast implants. Despite histologically aggressive features, the outcome of patients diagnosed with BIA-ALCL is generally favorable.1 Recently, through next generation sequencing (NGS)-based genomic characterization, the molecular basis of BIA-ALCL and its oncogenic drivers are beginning to be understood. However, despite some initial insights, we are still only at the beginning of our understanding of this rare lymphoma subtype. This review aims to describe the current understanding of the molecular drivers and genomic abnormalities identified in BIA-ALCL to date and to compare these to its more extensively characterized and clinically aggressive counterpart, systemic anaplastic large cell lymphoma (sALCL).
SYSTEMIC ANAPLASTIC LARGE CELL LYMPHOMA
Clinicogenomic Classification of sALCL
sALCL is an aggressive T-cell lymphoproliferative disorder characterized by presentation at advanced disease stage, frequent extranodal involvement, aggressive clinical course, and generally poor outcomes with current treatment strategies.2 sALCL can be divided into 4 groups based on the presence of recurrent large-scale genomic structural variations which correlate closely with both molecular pathogenesis and clinical outcomes:
- (i) sALCL with anaplastic lymphoma kinase (ALK) rearrangement: This group of sALCL is characterized by ALK expression by immunohistochemistry (IHC) as a result of chromosomal translocations involving the ALK gene and is typically known as ALK-positive ALCL. Overall, the proportion of cases of sALCL classified as ALK-positive and ALK-negative is approximately equal; however, this proportion varies with age, with ALK-positive sALCL being more common in children and young adults.3 The most common structural variant in ALK-positive sALCL involving the ALK gene is a chromosomal translocation resulting in the fusion of ALK with Nucleophosmin 1 NPM1 [t(2;5)(p23;q35)]; however, other translocation partners are possible.4 ALK-positive ALCL has a relatively favorable outcome with a 5-year progression-free survival of approximately 60%–80% with current treatment strategies.5,6
- (ii) sALCL with Dual Specificity Phosphatase 22 (DUSP22) rearrangement: Structural variants involving the DUSP22 gene occur in approximately 30% of cases of non-ALK rearranged tumors (ie, ALK-negative ALCL) and are mutually exclusive with ALK rearrangements.7,8 Disruption of the DUSP22 gene with this recurrent structural variant results in decreased DUSP22 expression but preserved expression of the adjacent gene, Interferon Regulatory Factor 4 (IRF4).7 This subgroup of ALK-negative sALCL appears to have relatively unique molecular characteristics when compared with other ALK-negative sALCL (detailed below).9 Importantly, cases of ALK-negative sALCL with a DUSP22 rearrangement are associated with more favorable outcomes and as a group, have similar outcomes to ALK-positive sALCL.8,10
- (iii) sALCL with tumor protein p63 (TP63) rearrangement: Disruption of the tumor protein p53 (TP53) homolog TP63 occurs through large-scale genomic aberrations in approximately 10% of ALK-negative ALCL.8 In contrast to both ALK-positive and DUSP22-rearranged ALK-negative sALCL, patients with TP63-rearranged ALCL have markedly inferior outcome with a 5-year overall survival of <20% with current therapies.8
- (iv) “Triple negative” sALCL: Cases of sALCL that do not harbor any of the above 3 rearrangements are sometimes referred to as “triple negative” sALCL, likely representing a relatively molecularly heterogenous subgroup. Patients with triple-negative disease have outcomes that are intermediate between TP63-rearranged and DUSP22-rearranged disease.8,10
Two other separate but related entities are recognized: primary cutaneous ALCL (pcALCL) and BIA-ALCL. Despite having aggressive-appearing histologic features, pcALCL typically responds well to localized therapy alone and has a favorable prognosis. ALK rearrangements are not observed in pcALCL, and the presence of an ALK rearrangement in what is otherwise thought to be pcALCL typically signifies cutaneous involvement by ALK-rearranged sALCL. However, pcALCL has DUSP22 rearrangements at approximately the same frequency as sALCL (approximately 30%).11,12DUSP22 and TP63 rearrangements have recently been studied in 22 cases of BIA-ALCL without detection of either rearrangement in any cases (Table 1).13 Therefore, although the total number of cases evaluated is still relatively few, BIA-ALCL appears to fall into the “triple-negative” group in terms of the presence of canonical sALCL genomic rearrangements.
Molecular Drivers of sALCL
One of the central molecular hallmarks of sALCL is aberrant activation of signal transducer and activator of transcription (STAT3).14 When the STAT3 transcription factor becomes activated by phosphorylation, it forms homodimers and heterodimers with other STAT transcription factors and translocates from the cytoplasm to the nucleus where it results in the transcription of important oncogenes and antiapoptotic genes such as BCL2L1 (B-cell lymphoma [BCLXL]), tumor necrosis factor receptor superfamily (TNFRSF8) (CD30), and Interleukin 2 Receptor Subunit Alpha (IL2RA).15,16 Through the suite of target genes controlled by STAT3, aberrant activation of STAT3 results in cell proliferation and malignant behavior of the ALCL cell. There are multiple established genomic mechanisms leading to STAT3 activation in sALCL:
- (i) The NPM1-ALK rearrangement results in aberrant STAT3 activation through either direct activation by the ALK fusion protein or indirectly through other mechanisms such as enhanced expression of protein phosphatase 2A (PP2A).17,18
- (ii) Activating mutations of STAT3 itself occurring predominantly in the SH2 domain or in the gene encoding the upstream activating protein tyrosine kinase, janus kinase (JAK1).
- (iii) Gene fusions, particularly of NFKB2 with tyrosine kinases such as ROS Proto-Oncogene (ROS1), Tyrosine Kinase 2 (TYK2) in ALK-negative sALCL14
Interestingly, and emphasizing the importance of the JAK/STAT pathway in sALCL, NGS performed on a cohort of ALK-negative sALCL demonstrated multiple mechanisms of activation of STAT3 in the same case, particularly comutation of JAK1 and STAT3.14
Importantly, DUSP22-rearranged ALK-negative sALCL appears to have relatively distinct molecular drivers with these cases generally not showing the same degree of activation of STAT3 as cases without this rearrangement.9 In addition to lack of STAT3 activation, DUSP22-rearranged sALCL is characterized by global hypomethylation, expression of immune costimulatory molecules (such as CD58), and the overexpression of immunogenic cancer–testis antigen genes.9
Other important general molecular drivers in sALCL include:
- (i) MYC dysregulation: Overexpression of the master proliferation transcription factor MYC is critical to lymphomagenesis in sALCL. Indeed MYC overexpression can be detected by IHC in the majority of cases of sALCL regardless of the presence of ALK rearrangement.19 Although the mechanism of MYC dysregulation is not known in all cases, one important contributor appears to be overexpression of IRF4.19
- (ii) TP53 dysfunction: Approximately one-quarter of sALCL has a copy number loss of TP5320 and approximately 10% of cases have TP53 mutations.21 Importantly, despite the minority of cases having specifically identifiable genomic abnormalities in TP53, the majority of cases show abnormal TP53 IHC staining consistent with the presence of abnormalities in the TP53 DNA damage pathway outside of direct loss or deleterious mutations of TP53. Such abnormalities of the TP53 pathway in hematological malignancy are typically associated with genomic instability and chemotherapy insensitivity.
- (iii) Abnormal T-cell receptor (TCR) signaling: Signaling from the microenvironment through the TCR provides one of the most important growth signals for T-cells under normal physiologic conditions. Despite having clonally rearranged TCR loci, the vast majority of cases of ALCL do not express a TCR on their surface22 and there are emerging experimental data that TCR signaling may instead be provided by certain canonical genomic structural variations such as the NPM1-ALK fusion.23
BREAST IMPLANT–ASSOCIATED ANAPLASTIC LARGE CELL LYMPHOMA
Apart from the unique compartment and associated anatomical structures, BIA-ALCL shares much of its cytomorphologic features with sALCL. Initial insights into the potential pathogenesis and molecular drivers of BIA-ALCL came from the description of the immunophenotype of individual cases by IHC/flow cytometry and functional experiments performed on cell lines derived from patient tumors. BIA-ALCL cells show positive staining for CD30 which, in the presence of anaplastic cytomorphology and appropriate clinicopathologic context, should be considered the hallmark feature of BIA-ALCL. The expression of other T-cell antigens in the malignant cells is variable with a proportion of cases showing aberrant loss of T-cell antigens such as CD3, CD4/8, CD5, and CD7.24 In the majority of cases, BIA-ALCL tumor cells also stain positively for Multiple Myeloma 1 (MUM1) (IRF4) and activated pSTAT3 by IHC suggesting the potential of importance of both MYC (through IRF4) and STAT3 dysregulation as observed in sALCL.1
The first BIA-ALCL cell line (TBLR-1) was derived from a 42-year-old woman patient and showed many of the typical immunophenotypic features of BIA-ALCL including CD30 expression and loss of typical pan T-cell antigens.25 This cell line also showed significant aneuploidy including partial trisomy 2 and monosomy of 16 and 20. Chromosomal aneuploidy was again observed in 2 subsequent cell lines (TBLR-2 and TBLR-3).26STAT3 overexpression and activation were noted in all 3 cell lines, and importantly, dose-dependent cell death was observed in the presence of STAT3 inhibitors in vitro.26 BIA-ALCL cell lines also demonstrate abnormal TP53 activation in response DNA damage by radiation and cytotoxic agents without detectable mutation or copy number loss, again analogous to its systemic counterpart.27
Genomic Characterization of BIA-ALCL
The availability of NGS has allowed comprehensive genomic characterization of mutations, copy number changes, and structural variants to be performed in BIA-ALCL (and indeed most malignancies) which has subsequently given further insight into candidate molecular drivers (Table 2). The initial application of NGS to patients with BIA-ALCL was through whole exome sequencing (WES) on 2 patients with localized disease.28 The WES analysis on these 2 patients detected an activating STAT3 mutation in 1 case and an activating JAK1 mutation in the other.28 This finding provided initial supporting evidence that the phenotypic similarity of BIA-ALCL to sALCL (ie, STAT3 activation) was mediated by similar genomic events (at least in these initial 2 cases). Including this initial description, the JAK/STAT3 pathway has now been analyzed in 23 cases in the literature to date. Of these cases, JAK1 and/or STAT3 activating mutations have been detected in approximately one-third of patients.13,29,30 In addition, deleterious mutations in the JAK/STAT pathway regulator Suppressor Of Cytokine Signaling 1 (SOCS1) have also been detected.30 Together, these findings support the finding of STAT3 dysregulation by IHC in patients and cell lines and provide a genomic basis for this in at least a proportion of cases. A summary of the genomic findings from patients with BIA-ALCL to date is presented in Table 1.
The interrogation of BIA-ALCL cases to date with regard to copy number abnormalities and the presence of structural variants has been more limited when compared with sALCL. However, the recurrent structural variants seen in sALCL (DUSP22 and TP63) have been negative in all BIA-ALCL cases tested by fluorescence in situ hybridization to date.1,13
With respect to TCR abnormalities in BIA-ALCL, like systemic ALCL, it has been observed that although the majority of cases of BIA-ALCL have clonally rearranged TCR loci, there is a failure of expression of surface TCR (as assessed by IHC).1 Although more studies are required, this preliminary observation supports that there are other key proliferative and survival signals that are driving the growth of BIA-ALCL cells other than through an intact TCR pathway.
Genomic Predispositions to Developing BIA-ALCL
The relative contribution of genetic and environmental factors to the development of BIA-ALCL is currently unknown and an area of active research. One hypothesis is the development of an implant-associated bacterial biofilm which results in inflammation, and chronic activation of lymphocytes potentially resulting in transformation.31,32 In terms of genetic contributors to disease development, it is notable that there have been now 2 descriptions of cases of BIA-ALCL occurring in patients with germline TP53 mutations.33,34 Patients with germline TP53 mutations are at risk of multiple malignancies including breast carcinoma.35 Although it is unknown whether patients with germline TP53 mutations are at specifically at increased risk of developing BIA-ALCL, the high prevalence of dysregulation of the TP53 pathway in this disease and the presence of constitutive genomic instability suggests that this area warrants further study and monitoring.
In one of the initial cases to undergo WES, a germline JAK3 polymorphism (JAK3 Val722Ile) was detected.28 Although this is a relatively common germline polymorphism (present in approximately 0.5%–1% of the healthy population), this variant is also observed as a recurrent mutation in T-cell lymphoma associated with in vitro activation of the JAK/STAT pathway in lymphoma cells.36 Given the observation of cooperating multiple JAK/STAT mutations in sALCL, 1 speculation is that this germline polymorphism may have contributed to oncogenic STAT3 activation in this patient.
CONCLUSIONS AND FUTURE DIRECTIONS
In summary, genomic characterization of BIA-ALCL has found this entity to harbor similar genomic abnormalities to those observed in sALCL with the notable absence of canonical (ALK, DUSP22, TP63) rearrangements in the relatively small number of cases analyzed to date. The molecular and genomic similarity with sALCL and “triple-negative” status of BIA-ALCL seems paradoxical given the markedly different clinical behavior and outcomes of the 2 conditions. It remains to be determined what the relevant modifiers of the disease phenotype are and whether these modifiers are undetected novel genomic changes in BIA-ALCL or whether it is another feature such as the anatomical limitation and localization within the seroma fluid. Moreover, identification of germline genomic factors that may predispose to disease development and identification of predictive genomic biomarkers will be important areas of study of this rare lymphoma subtype.
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