Multiple Myeloma Presenting as Breast Metastasis: Diagnostic Challenges and Case Analysis

Introduction

Multiple myeloma (MM), a proliferative disorder of plasma cells, generally affects patients with an average age of 60 years and usually shows osteomedullary infiltration [1]. Extramedullary disease (EMD) is typically observed in aggressive MM that becomes independent of the bone marrow microenvironment and infiltrates other organs [2,3]. The incidence of EMD is higher in patients with relapsed/refractory MM (6–20%) than in patients with newly diagnosed MM (7%) [4]. Relapsed MM often shows EMD, including in the pleura, pericardium, lymph nodes, liver, kidneys, brain, and breast, in contrast to newly diagnosed MM, which usually involves skin and soft tissues [2,5,6]. In relapsed/refractory MM, breast involvement, similarly to the involvement of other viscera, has a significantly worse prognosis than MM without visceral involvement, with a median overall survival of 0.5 vs 0.9 years in the absence of visceral involvement [4]. The management of MM with secondary breast involvement is no different from management of the underlying aggressive disease and usually includes polychemotherapy treatments [4–10]. Only a few cases of breast metastasis from MM have been described in the literature, and all highlight the clinical and radiological difficulties in making a differential diagnosis with primary breast cancer [7–10]. Histology and immunohistochemistry are necessary in differentiating these different entities [7–10]. We report here the case of a patient with a breast metastasis of a relapsed/refractory MM that was initially misdiagnosed as a primary breast cancer.

Case Report

In January 2023, an 83-year-old woman, non-smoker, with a diagnosis of MM was admitted to the Emergency Department for a fall with chest trauma. Her medical history consisted of glaucoma, iatrogenic hypothyroidism, gastritis, osteoporosis, and arthrosis. The patient’s history was characterized by a right nephrectomy for non-functional hypertrophic kidney, a bilateral reductive mastoplasty, and a left breast lumpectomy for removal of a fibroadenoma, a hysterectomy for vaginal prolapsus, a thyroidectomy, a resection of a skin squamous-cell carcinoma from the para-scapular region, and a Hartmann’s colectomy for perforated sigmoiditis.

The patient was treated for an immunoglobulin A (IgA) kappa MM (Figure 1A–1C), diagnosed in April 2016 in the context of diffuse bone pain and hypercalcemia. Cytogenetic testing by fluorescence in situ hybridization (FISH) found an amplification of chromosome arm 1q21 (1q21+), which is usually associated with disease progression and drug resistance [11,12]. At the diagnosis, the patient also presented a pre-sternal soft-tissue secondary localization, histologically confirmed. After discussion in the multidisciplinary tumor board, she received 5 cycles of a first-line chemotherapy (melphalan/prednisone/ bortezomib regimen) from May to October 2016. In November 2016, a whole-body computed tomography (CT) scan detected a tumor progression of the sternal lesion, infiltrating the mediastinal area and the pericardium. This tumor was treated by radiotherapy (30 Gy/10 Fr) in December 2016. From January 2017 to September 2020, second-line chemotherapy with lenalidomide/dexamethasone was administered, and this resulted in a complete response. However, this treatment was interrupted due to severe miliary pneumonia. In October 2020, the patient presented with a right pathological femoral fracture while undergoing osteosynthesis and radiotherapy in January 2021 (30 Gy in 10 fractions). In March 2021, third-line chemotherapy with isatuximab/pomalidomide/desamethasone was started, resulting in a partial response. In August 2022, a vertebral magnetic resonance image (MRI) of the right buttock confirmed a sacral tumor progression that was treated with radiotherapy in September 2022 (20 Gy in 5 fractions) followed by a fourth-line treatment with carfilzomib/dexamethasone. At the following clinical examination, 2 nodular lesions were found in the right breast. The first was 4 cm in size and located in the lower-outer quadrant; the second was 2 cm in size and located in the upper-inner quadrant, without any palpable axillary lymphadenopathy. Bilateral mammography (Figure 2A) and breast ultrasound revealed multiple, bilateral, nodular lesions, the majority of which were in the right breast, without any axillary lymph nodes nor pathological microcalcifications. All these lesions appeared heterogenous and compatible with hematomas, except for a lesion of 14 mm in diameter, located in the upper-inner quadrant, and 3 other lesions, located at the intersection of the internal quadrants of the right breast, 9, 18, and 6 mm in size, that showed a solid pattern at the elastography. A 2-deoxy-2-[fluorine-18] fluoro-D-glucose (18F-FDG) positron emission tomography (PET)-CT scan showed further, multiple, tumor progression, with metastasis to the breast (Figure 2B, 2C), lymph nodes, pericardium, lung, peritoneum, adrenal glands, rectum, colon, bone, and subcutaneous tissue. Breast MRI confirmed the presence of multiple, contiguous, nodular lesions at the union of the internal quadrants and another peripheral lesion in the lower-outer quadrant of the right breast with a heterogeneous contrast uptake (Figure 3A, 3B). In the left breast, another contrast-enhanced lesion was seen in the lower-inner quadrant (Figure 3C). The suspected lesion of the upper-inner quadrant of the right breast was biopsied. The histology documented a tumor with a solid and discreetly trabecular architecture, without calcifications or ductal/lobular in situ lesions nor peritumoral, lymphatic, or vascular invasion, consisting of non-cohesive cells with eosinophils, with poorly developed cytoplasm, and a rare eccentric nucleus without a nucleolus (Figure 4). Tumor cells were negative for hormonal receptors (Figure 5) and human epidermal growth factor receptor 2 (HER2). This histological pattern was first misdiagnosed as an infiltrating, pleomorphic, lobular-type primary breast carcinoma of grade II with a high proliferating index (Ki67 >50%). However, because of the history of a concomitant MM and the discordance between the histological diagnosis showing a tumor with a triple negative phenotype and the immunohistochemical profile of pleomorphic lobular breast cancer, which usually overexpresses hormonal receptors, a histological revision was ordered. The histology confirmed the diagnosis of a breast localization of MM, as the tumor cells expressed IgA kappa (Figure 6) and MUM-1, and were negative for the cytokeratin AE1/AE3 (Figure 7).

The patient started fifth-line chemotherapy with a melphalan/ cyclofosfamide/prednisone regimen that was discontinued early, after just 1 cycle, as the patient’s clinical conditions quickly worsened, leading to her death in June 2023.

Discussion

MM is a monoclonal malignant neoplasm of plasma cells that primarily involves the bone marrow [1]. EMD represents an aggressive form of MM, characterized by the ability of a tumor subclone to proliferate and grow independently of the bone marrow microenvironment [2–10]. EMD is usually associated with resistance to treatment and an extremely poor prognosis [2–10], and should be distinguished from paraskeletal MM, solitary plasmacytoma, and plasma cell leukemia [4]. Genetic mechanisms are important for the biological evolution from MM to high-risk EMD [11]. Primary immunoglobulin heavy chain (IgH) translocations with 5 recurrent chromosomal partners (4p16, 6p21, 11q13, 16q23, and 20q11) and hyperdiploidy (typically with trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19, and 21) are critical in the progression from a precursor state to active MM [11]. The acquisition of secondary chromosomal anomalies (amplification of 1q21 to >4 copies or loss of 17p) or terminal events (secondary chromosomal translocations and mutations involving single genes) are instead fundamental for the progression towards aggressive forms of MM, such as EMD involving skin, soft tissues, pleura, pericardium, lymph nodes, liver, kidneys, brain, and breast or plasma cell leukemia [12]. Generally, their frequency is higher in extramedullary lesions than in bone marrow lesions [13,14]. However, Liu et al found that del(1p32) and gain(1q21) were common events both in bone marrow plasma cells and in extramedullary sites, suggesting that the anomalies of chromosome 1 could play a role in the initiation and progression of high-risk EMD involving the breast and other viscera [15]. The gain(1q21) genetic alteration was found in our patient at the time of diagnosis of MM. The 1q21+ can upregulate the activity of cyclin D by driving the oncogene CDC28 protein kinase regulatory subunit 1B (CKS1B), to further drive the proliferation of downstream cells and promote the circulation of plasma cells, which can also reach the mammary glands, bilaterally [15].

Recently, despite the arrival of new anti-myeloma therapies, the incidence of EMD appears to be increasing and it is higher in patients with relapsed/refractory MM than in patients with newly diagnosed disease [4]. Only a few cases of breast secondary localization of MM have been reported in the literature to date [7–10]. Similarly to these cases, the breast lesions of our patient appeared during the treatment of an aggressive MM, were accompanied by other extra-osseous localizations, and were bilateral, multifocal, and not associated with any clinical skin involvement nor with pathological axillary lymph nodes. The appearance of breast lesions in patients with MM makes mandatory a differential diagnosis between a breast localization of MM and primary breast cancer. This aspect is even more important in our case as the patient presented with a relapsed/ refractory MM with unfavorable cytogenetics and also a family of breast cancer that suggested the development of a new primary breast cancer. In addition, our patient received radiotherapy treatment for the sternal metastasis of the MM, which could increase the risk for development of a primary breast cancer [16]. On mammography, breast localizations of MM generally present as 1 or more high-density, bilateral, oval or round lesions with well-defined margins and rare microcalcifications [9]. Consisted with this radiological pattern, our patient presented multiple, bilateral, nodular lesions without parenchymal distortion or microcalcifications. In addition, they show a homogeneous density without necrosis on CT scan, a low T2 signal on MRI due to high cellularity, and an increased uptake on 18F FDGPET scan [17]. Even if MRI is the best imaging approach for spinal and brain involvement, the International Myeloma Working Group (IMWG) specifically recommends 18F-FDG-PET/CT for the EMD diagnosis, particularly for all patients with a suspicion of EMD, such as those with high lactate dehydrogenase serum levels or revised stage III cancer [18]. However, these radiological aspects are not specific to a breast localization of MM, as they overlap with those of primary breast carcinoma, particularly of the pleomorphic lobular subtype. This subtype is also multifocal and bilateral, rarely shows microcalcifications [19,20], and often presents a high incidence of distant metastases [21]. Based on these considerations, the biopsy is the only tool for making a correct, differential diagnosis [10]. However, the histological differentiation of a breast localization of MM from a primary breast cancer, including the lobular pleomorphic subtype, may be challenging in the absence of close cooperation between clinicians and pathologists. The difficulty encountered by our pathologists can be understood by looking at the histological pattern of the tumor cells. These cells displayed nuclear atypia and the absence of cellular cohesiveness, which is related to the loss of expression of E-cadherin [21,22] and is a constitutional characteristic of MM and breast pleomorphic lobular carcinoma. The tumor cell expression of light chains, CD138, Ig, and MUM1, which are specific to the plasma cells, is essential to confirm the diagnosis [1–4].

Although the comparison between the pathologic and the control breast tissue was ideal for the differential diagnosis, it was impossible to obtain a control breast sample because of the patient’s progressive clinical impairment. However, the immunochemical expression of light chains CD138, kappa, and MUM1, in accordance with the patient’s clinical history of MM, led the pathologist to the correct diagnosis.

The management of breast localization from MM is not different from that of the underlying disease, which usually includes chemotherapy such as vincristine, adriamycin, and dexamethasone (VAD) or melphalan and 6-methylprednisolone (MP) regimens. Often the results are disappointing, as the prognosis is very poor, reflecting the clinical aggressiveness of this entity [7–10]. Recently, new regimens and new agents, including carfilzomib, selinexor, isatuximab, CAR-T cells, BiTE, and melflufen, have showed promising results [22]. However, to propose a personalized treatment to these patients and improve their prognosis, it could be useful to better understand the mechanisms of resistance and the physiopathology of the MM breast localization.

Conclusions

Despite the low frequency of breast localization of MM, it is important, in patients with new multiple breast lesions and a diagnosis of relapsed/refractory MM with unfavorable cytogenetics, to consider the breast as a possible site of MM extra-medullary involvement vs a primary breast cancer. However, it is a challenge to make a correct, differential diagnosis between MM breast localization and primary breast cancer in the absence of specific radiological and histological characteristics clearly distinguishing these 2 entities, which require completely different management. Thus, immunohistochemical analysis is fundamental but it should be conducted in the context of strict cooperation between clinicians and pathologists in a multidisciplinary, collegial discussion of the medical records.