Metastatic breast cancer and monoclonal gammopathy of undetermined significance resembling multiple myeloma

Abstract

Radiological evidence of lytic bone lesions has a wide differential diagnosis including metastatic bone disease, multiple myeloma, primary bone cancers and infection. Here, we present the case of a woman in her 80s found to have lytic bone lesions associated with an IgA paraproteinaemia who was thus presumed to have a diagnosis of multiple myeloma. However, bone marrow biopsy results were indicative of monoclonal gammopathy of undetermined significance. She was subsequently referred to the ‘carcinoma of unknown primary (CUP) team’, and ultimately diagnosed with metastatic breast cancer following a repeat trephine biopsy. A range of conditions may present with lytic bone lesions and these differentials must be suitably investigated even in the presence of paraproteinaemia. Early CUP team involvement is pivotal to ensure appropriate clinical management and patient support.

Background

In response to the National Institute for Health and Care Excellence (NICE) guidelines published in 2010 addressing the ‘Diagnosis and Management of Metastatic Malignant Disease of Unknown Primary Origin’ recommendations were made that every hospital with a cancer centre or unit should establish a ‘carcinoma of unknown primary (CUP) team’.¹ The team should consist of, at minimum, an oncologist, palliative care consultant and a specialist nurse.¹ It is the role of the CUP team to ensure that for each referral a management plan exists which includes:

• Appropriate investigations.

• Symptom control.

• Access to psychological support.

• Provision of information.

The aim of this service is to ensure these patients are investigated appropriately and promptly.

A variety of primary bone tumours including osteosarcomas, chondrosarcomas and giant cell tumours may produce lytic bone lesions in addition to infections, haematological malignancies such as multiple myeloma, leukaemia and lymphoma, and solid organ metastases particularly breast, prostate and lung cancers.^{2 3} Paraprotein, a monoclonal immunoglobulin produced following clonal B cell expansion, may be present in autoimmune, infective, pre-malignant and malignant conditions. Monoclonal gammopathy of undetermined significance (MGUS) describes a low level paraproteinaemia, typically requiring surveillance, which is associated with a 1% annual risk of progression to multiple myeloma.⁴

This case highlights the importance of investigating new lytic bone lesions as a potential CUP, even in the presence of a detectable paraprotein, to ensure a secondary diagnosis is not missed.

Case presentation

A woman in her 80s presented to primary care with intermittent lower back associated with a burning sensation radiating from her right hip to ankle. Although she had previously suffered from back pain, she described these symptoms as significantly different in that the pain was unresponsive to simple analgesia, and impacted on her quality of life by, for example, disrupting her sleep. She reported increasing fatigue and anorexia which she felt was related to the pain. She had a medical history of a subarachnoid haemorrhage treated conservatively, hypertension and atrial fibrillation. There was no significant social or family history. Clinical examination was unremarkable and she continued to maintain a good performance status.

Investigations

Her general practitioner had organised X-ray imaging of the lumbar spine which reported widespread lytic bone lesions. This was confirmed on MRI of the thoraco-lumbar spine which displayed widespread lytic bone lesions associated with diffuse neoplastic marrow infiltration (figure 1). In terms of baseline blood tests she had a normal haemoglobin 117 g/L (normal 110–150 g/L), normal creatinine 71 µmol/L (normal 49–92 µmol/L) and normal adjusted calcium 2.12 mmol/L (normal 2.20–2.60 mmol/L). Her myeloma screen was found to have a low concentration IgA lambda paraprotein, the kappa:lambda light chain ratio was 0.68 (normal 0.26–1.65) and serum lambda light chain level was 28.3 mg/L (normal 5.7–26.3 mg/L).

Figure 1.

T1-weighted thoraco-lumbar spinal MRI demonstrating extensive lytic bone neoplastic infiltration.

In view of the finding of a paraprotein with lytic bone lesions she was investigated further by the haematology team. They proceeded to carry out a bone marrow biopsy which revealed plasma cells of <5% with an inversion of the kappa/lambda ratio in keeping with a diagnosis of MGUS (figure 2A, B). Since this did not explain the radiological finding of lytic bone lesions she went on to have a positron emission tomography scan which did not demonstrate any abnormal uptake in the lytic bone lesions, axillae or breasts.

Figure 2.

Bone marrow biopsy shows cellular infiltrate (A: black arrow) of atypical cells, which display AE1/3 keratin positive staining (C). Occasional plasma cells are visualised (A: red arrow) and are highlighted by CD138 (B).

At this stage she was referred to the CUP team. Although the possibility of the bone changes representing benign disease was raised, for completeness, the consensus was to repeat the biopsy but of the contralateral iliac crest. This second biopsy demonstrated evidence of a hypercellular marrow, kappa/lambda inversion as well as infiltration by a metastatic adenocarcinoma strongly positive for cytokeratins AE1/AE3 and GATA3. The bone marrow trephine was reported as in keeping with metastatic lobular carcinoma of the breast. Although clinical assessment did not detect a breast lump, a breast ultrasound identified a left sided poorly defined mass like area measuring 26×8 mm. This was biopsied and confirmed the diagnosis of metastatic breast cancer (figure 2A, C).

Differential diagnosis

Differentials of lytic bone lesions include primary bone cancers, haematological malignancy, metastatic bone disease, benign and infective processes with examples described below^{2 3}:

• Primary bone cancers: osteosarcomas, chondrosarcomas.

• Infection and benign conditions: tuberculosis, bone pseudocysts.

• Haematological malignancies: multiple myeloma, lymphoma, leukaemia.

• Solid organ cancers: commonly from prostate, breast, lung, renal cancer.

Paraprotein presence may indicate differentials including⁴:

• Malignancy: multiple myeloma, Waldenstroem’s macroglobulinaemia, chronic lymphocytic leukaemia, non-Hodgkin’s lymphoma.

• MGUS.

• Infection and non-malignant disease processes: rheumatoid arthritis, hepatitis, tuberculosis.

Multiple myeloma was therefore initially a unifying diagnosis explaining both the presence of paraprotein and lytic bone lesions. However, following a diagnosis of MGUS, a second biopsy to determine the cause of the lytic bone lesions was performed which revealed a diagnosis of metastatic breast cancer.

Treatment

Following the results of the second bone marrow biopsy and subsequent breast biopsy a referral was made to the breast oncology team. In view of the fact that the cancer was hormone-receptor positive (oestrogen receptor (7/8) she commenced treatment with letrozole (an aromatase inhibitor) and monthly zoledronic acid (bisphosphonate).

Discussion

Lytic bone lesions on imaging may indicate a range of disease processes and a diagnosis of multiple myeloma may appear likely when paraproteinaemia is present. We present this case to highlight that lytic bone lesions can represent malignancy and that even in the context of paraproteinaemia, an alternative diagnosis must be considered. Although previous case reports and cohort studies have found an association between MGUS and prostate cancer, this case report to our knowledge is the first to discuss a diagnosis of metastatic breast cancer and MGUS initially resembling multiple myeloma.⁵

This case emphasises the importance of investigating a range of differential diagnoses and identifying an alternative diagnosis following a finding of lytic bone lesions. In this case, a diagnosis of multiple myeloma appeared likely; however, following the identification of MGUS on bone marrow biopsy consideration of a separate diagnosis and CUP team referral were indicated. As no primary site apart was evident, further appropriate investigations including repeat bone marrow biopsy and a targeted bone biopsy.^{6 7} The importance of the CUP service in guiding investigations to form an accurate diagnosis, thus allowing appropriate treatment initiation, in all patients with evidence of possible metastatic disease to ultimately prevent disease progression, clinical deterioration and limit patient morbidity is highlighted.

Approximately 5%–8% of breast cancer patients display metastatic disease at diagnosis, and prognosis for survival from first bony metastasis is estimated to average 20 months.^{6 7} Bone metastasis may additionally cause significant patient morbidity, in this case resulting in pain, and can precipitate permanent disability.⁶ Although generally perceived as incurable, early therapeutic oncological interventions aim to preserve quality of life, adequately manage symptoms, prevent complications and improve overall survival.^{6 7} This case emphasises the importance of the CUP service in guiding investigations to form an accurate diagnosis, thus allowing appropriate treatment initiation, in all patients with evidence of possible metastatic disease to ultimately prevent disease progression, clinical deterioration, and limit patient morbidity.

Outcome and follow-up

Following her diagnosis of metastatic breast cancer and hormone and bisphosphonate treatment initiation, her pain was controlled and breast cancer stabilised. She remained under haematological surveillance of her MGUS with no evidence of progression to myeloma, surviving for approximately 5 years until passing away aged from non-cancer related causes.

Learning points.

• Lytic bone lesions may be present in an array of disease processes and may represent metastatic disease.

• An alternative differential must be considered and investigated when an initially presumed diagnosis is not able to explain the clinical presentation to ensure a pertinent diagnosis is not missed and treatment is not delayed.

• Paraproteinaemia in the context of lytic bones lesions is not synonymous with a diagnosis of multiple myeloma and may mimic metastatic bone disease and monoclonal gammopathy of undetermined significance.

• Bone metastasis are a common site of disseminated disease in breast cancer and may cause patient morbidity. Early diagnosis and treatment initiation may improve quality of life and influence overall survival.

• Carcinoma of unknown primary services are essential in coordinating appropriate investigations and follow-up in all patients presenting with signs of possible metastatic disease.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).