Characteristics of histiocytic neoplasms presenting as breast masses

To the Editor, Histiocytic disorders encompass a rare and diverse group of pathogenic entities that are characterized by proliferation of the mononuclear phagocyte system. Discovery of activating mutations or kinase gene fusions implicating the canonical mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3-kinase (PI3K) signalling cascades are detected in a substantial percentage of histiocytoses, rendering these clonal neoplasms amenable to targeted therapy.1, 2 Histiocytoses are classified under dendritic cell and histiocytic neoplasms in the fifth edition of the World Health Organization Classification of Tumours.3 Langerhans cell histiocytosis (LCH) is categorized independently, while Erdheim–Chester disease (ECD) and Rosai–Dorfman disease (RDD) are included under histiocytic neoplasms. B-Raf proto-oncogene, serine/threonine kinase (BRAF) p.V600E mutations are common in LCH and ECD, yet are vanishingly rare in RDD. Activating mutations in MAP2K1 or RAS isoforms (e.g. KRAS, NRAS) constitute the next most common alterations.4-6 Nonetheless, a substantial number of cases lack detectable driver alterations despite whole-exome sequencing.7 Histiocytosis presenting initially as a breast mass is exceptionally uncommon and may pose significant diagnostic difficulty. Infiltration into breast tissue can manifest as a palpable mass in females8-11 or gynecomastia in males,12 often appearing as a malignant process on imaging. Given the nonspecific radiological findings, histopathological evaluation of biopsy material is essential for establishing a definitive diagnosis. In the current study, we sought to interrogate the clinical, radiological and histopathological features of histiocytic neoplasms involving the breast, with a particular focus on cases presenting with a breast mass as the initial sign of disease. To this end, we retrospectively queried our database from the Departments of Neurology and Pathology at Memorial Sloan Kettering Cancer Center to identify patients with biopsy-proven histiocytosis afflicting breast parenchyma. Breast involvement was identified through imaging studies, either via routine mammography or in patients presenting with a palpable mass. A total of 447 patients with histiocytosis were screened (ECD, n = 130; LCH, n = 182; RDD, n = 98; overlap histiocytosis, n = 37), with breast involvement observed in 2.9% (n = 13). The collective patient characteristics are displayed in Table 1. KRAS p.K117N (c.351A>C), VAF: 3% KRAS p.A146P (c.436G>C), VAF: 7% First line: Cobimetinib Second line: Fostamatinib NRAS p.G12D (c.35G>A), VAF: 2% KRAS p.A146T (c.436G>A), VAF: 4% The median age at initial diagnosis was 52 years (range, 29–77), with 12 of 13 patients being female. Eight patients presented with a breast mass as their initial clinical concern, either as an overt palpable lesion (n = 5) or detected subclinically on routine mammogram (n = 3). Among all, RDD (n = 9) was the predominant histiocytosis involving breast parenchyma. Notably, two patients presented with bilateral breast masses (i.e. ECD and mixed histiocytosis [ECD/LCH]), while one patient with multisystem non-LCH involving the breast was initially misdiagnosed with sarcoidosis. Additionally, a patient with multisystem LCH developed a breast rash and discomfort following diagnosis from a cutaneous neck lesion and bilateral pulmonary nodules. Among patients with available clinical information (n = 12), other sites of involvement included the skin or subcutaneous tissue (66.7%), bone (50%), lymph nodes (41.7%) and nervous system (25%). Breast involvement by histiocytosis typically appeared as an ill-defined mass with indistinct margins on mammography and ultrasound (Figure 1A,B; Figure S1), and as hypermetabolic lesions on 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) (Figure 1C). Presentations varied, including solitary, multifocal or bilateral lesions distributed throughout the breast, sometimes with dermal extension. Calcifications were generally absent. Overall, the imaging characteristics were nonspecific and radiologically indistinguishable from primary breast cancer (Figure S2). Core needle biopsy specimens disclosing RDD revealed an exuberant histiocytic and lymphoplasmacytic infiltrate (Figure 1D), with large atypical histiocytes frequently displaying emperipolesis (Figure 1E). Background breast tissue was only focally present. Immunohistochemical analysis demonstrated the lesional histiocytes to be positive for PU.1, S100 and OCT2 (Figure 1F–H), while negative for CD1a and langerin. In the patient with ECD, histology revealed large foamy histiocytes and touton-type multinucleated giant cells in a background of reactive fibrosis (Figure 1I). Immunohistochemical studies demonstrated the histiocytes to be positive for BRAF V600E (VE1) (Figure 1J). Notably, in a patient who underwent bilateral implant removal years after augmentation mammoplasty, histopathological evaluation showed mixed inflammatory infiltrates with multinucleated giant cells and xanthomatous changes. This patient subsequently experienced recurrent episodes of breast engorgement over several years, with PET-CT revealing bulky, irregular, expansive formations diffusely infiltrating both breasts. Bilateral segmental breast resection of grey spongy lesional tissue demonstrated mixed histiocytosis, predominantly ECD with a minor LCH component (Figure S3). Oncogenic driver alterations were identified in seven tumours. Molecular analyses were performed on lesional breast tissue in nine patients, peripheral blood in two and on samples from the septum and flank in one patient each. DNA next-generation sequencing (NGS) was performed using Memorial Sloan Kettering – Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)13 or Memorial Sloan Kettering - Analysis of Circulating cfDNA to Evaluate Somatic Status (MSK-ACCESS)14 platforms, with RNA-based NGS via MSK-Fusion15 applied in select cases. Cases of ECD, LCH and mixed histiocytosis (ECD/LCH) harboured BRAF codon 600 hotspot mutations detected either by DNA NGS, real-time polymerase chain reaction or immunohistochemistry. MSK-ACCESS was performed on peripheral blood from two patients, one of whom had no identifiable mutation. By contrast, only in three cases of RDD (33.3%), a driver alteration was detected by DNA NGS (Table 1). In cases where no mutation was detected by DNA NGS, or for confirmation of a fusion detected by MSK-IMPACT, reflex testing was performed with MSK-Fusion (n = 4). One case of non-LCH was confirmed to harbour an in-frame ETV6::SYK t(9;12)(q22.2;p13.2) fusion transcript that has been reported to result in aberrant activation of the Janus kinase-signal transducer and activator of transcription, PI3K or MAPK signalling pathways (16). In our series, eight of 13 patients received targeted therapy. Seven patients were treated with an MEK inhibitor (i.e. cobimetinib) at some time point and one with dual BRAF/MEK inhibition (i.e. dabrafenib and trametinib). The patient with ETV6::SYK-driven non-LCH initially responded to an MEK inhibitor, however, ultimately progressed and was switched to a spleen tyrosine kinase inhibitor (i.e. fostamatinib) with poor tolerance and without clinical response. Partial or complete metabolic response was observed with cobimetinib in our series in all but one patient. Three patients were managed with observation alone, with subsequently stable disease, whereas another patient with nasal sinus involvement received steroids and indomethacin for pain management with overall stable disease. No current treatment information was available for one patient. Dramatic response was seen in the patient with ECD harbouring a BRAF p.V600E mutation, who exhibited multisystem involvement, including bilateral breast masses, bone lesions and central nervous system infiltration. Whole-body PET-CT scan demonstrated extensive 18F-FDG avid bilateral breast masses associated with diffuse oedema of the breast parenchyma and areas of skin thickening (Figure 1K). Extensive hypermetabolic disease was also present in the bones, kidneys and retroperitoneum. Magnetic resonance imaging of the brain was further performed and showed dural-based nodular lesions along the frontoparietal convexity with associated enhancement (Figure S4). Treatment with dabrafenib and trametinib, as per ECD guidelines, led to remarkable clinical and radiological improvement after 4 months (Figure 1L,M). In our series, clinical and radiological responses were seen in RDD patients with no detectable driver alteration by NGS (n = 4) who received cobimetinib (Figure S5). Overall, robust clinical and durable therapeutic responses have been observed with BRAF kinase inhibition in patients with BRAF p.V600E-driven ECD (17). Furthermore, MEK inhibition has been implemented for histiocytic neoplasms both with and without the presence of BRAF p.V600E, and single-agent cobimetinib is Food and Drug Administration-approved in adults with histiocytic neoplasms regardless of somatic driver mutation. Within the entire cohort (n = 13), one patient died of multisystemic disease progression. Histiocytoses represent a diagnostic challenge, with delayed diagnosis after initial presentation being common, especially for RDD (18) and ECD (19, 20). On imaging, the differential diagnosis is broad, with the main concern being a primary breast malignancy. Benign lesions such as fat necrosis and pseudoangiomatous stromal hyperplasia can present similarly. Infection should also be considered, particularly when the mass is more diffuse and infiltrative, as well as when there is dermal involvement. Prior literature indicates that RDD predominantly presents unilaterally, with bilateral involvement being rare (21). This observation was consistent with the findings in our series, in which all breast RDD cases were unilateral. Conversely, a more recent systematic review of breast involvement in ECD reported bilateral breast involvement in six of 16 patients, all of whom presented with this as the initial manifestation of disease.12 Our series was aligned with this observation. Breast involvement by histiocytosis is an overall rare occurrence, particularly those that present with a breast mass.8-11 Histologically, fat necrosis, panniculitis, xanthogranuloma or the histiocytoid variant of invasive lobular carcinoma can mimic histiocytosis. Accurate subtyping of histiocytic neoplasms necessitates a panel of immunohistochemical stains. In instances with limited tissue material precluding molecular testing, immunohistochemistry for BRAF V600E (VE1) or phosphorylated extracellular signal-regulated kinase protein expression may serve as a surrogate marker for MAPK pathway activation (Figure S6). Prompt diagnosis and detection of mutational status is paramount for therapeutic management. In conclusion, our study raises vigilance to a very unusual site of potential involvement by histiocytic neoplasms, and the need for a multidisciplinary assessment approach to avoid potential misclassification or diagnostic delays. RDD was the most common subtype involving breast parenchyma in our series, with more than half of the cases lacking detectable mutations on completed NGS. Given its frequency, RDD warrants primary consideration in the differential diagnosis of breast histiocytosis. This work was supported by the National Institutes of Health/National Cancer Institute grant P30CA008748 and National Cancer Institute grant R37CA259260 (E.L.D.). This work was also supported by the Frame Family Fund (E.L.D.), the Joy Family West Foundation (E.L.D.), the Applebaum Foundation (E.L.D.) and the Erdheim-Chester Disease Global Alliance (E.L.D.). T.V., H.Y.W. and E.L.D. conceptualized the manuscript. T.V. wrote the original draft of the manuscript. H.Y.W. and E.L.D. supervised the manuscript. M.K.R., M.C., K.F., A.E.R., F.W., S.M., E.B., M.E.A., H.Y.W. and E.L.D. contributed to data acquisition, analysis/interpretation, reviewed and edited the final manuscript. E.L.D. discloses unpaid editorial support from Pfizer Inc. and paid advisory board activities with Day One Biopharmaceuticals and Opna Bio (outside of the submitted work). This is a single-centre, IRB/ethics board-approved, retrospective study (IRB #16-1604) for which informed consent was waived. Table S1. Safety: summary of most common adverse events. Table S2. PRO: EORTC QLQ-C30 physical functioning and fatigue in the overall patient population, patients with CR and patients without CR/PR. Table S3. PRO: FACT-Lyma in the overall patient population, patients with CR and patients without CR/PR. Table S4. PFS and OS estimates by various age cut-offs in patients with R/R FL. Figure S1. PFS by age as cut-off of (A) 60 and (B) 70 years and OS by age as cut-off of (C) 60 and (D) 70 years. Figure S2. (A) T-cell activation by flow cytometry in cycles 12, (B) cytokine kinetics of IL-6 shown as Log2 fold change from baseline. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Publication details of references [16-21] are available in the supporting information.