Hypercalcemia and Osteolytic Lesions in Chronic Lymphocytic Leukemia: A Diagnostic Challenge

A 79-year-old female with past medical history of chronic lymphocytic leukemia (CLL), hypothyroidism, and hypertension presented to the hospital for hypercalcemia and a lytic lesion of the left distal femur. She initially presented to her outpatient hematology appointment for follow-up of her known CLL and was found to have severe hypercalcemia and an acute kidney injury. Her laboratory results are listed below.

A few years prior to this presentation, the patient was found to have bulky bilateral supraclavicular lymphadenopathy. A supraclavicular lymph node biopsy revealed atypical lymphoid infiltrates positive for CD19, CD20, CD25, CD79b, CD23, CD5, CD43, CD38, CD200, PAX-5, and LEF1 and negative for cyclin D-1. The flow cytometry was consistent with a CLL diagnosis, and she was treated initially with ibrutinib and subsequently switched to pirtobrutinib after having progression of disease and testing positive for a mutation conferring Bruton tyrosine kinase (BTK) resistance.

Upon arrival, the patient endorsed left lower extremity pain for several weeks. Physical examination revealed swelling of her left knee as well as tenderness to palpation of the medial and lateral femoral condyles, medial and lateral joint lines, and tibial plateau. An MRI of the left femur demonstrated a destructive lytic lesion at the medial femoral condyle, intercondylar notch, and distal femoral metaphysis with soft tissue extension.

Laboratory studies demonstrated a new M-protein spike of 0.7 g/dL on serum protein electrophoresis, which localized to immunoglobulin M (IgM) on immunofixation. Given this, there was high concern for an underlying plasma cell disorder or lymphoplasmacytic lymphoma rather than isolated CLL progression.

The patient’s hypercalcemia improved after treatment with IV fluids, pamidronate, zoledronic acid, corticosteroids, and denosumab. During her hospitalization, she underwent bone marrow biopsy and biopsy of the left femur for further workup. Her bone marrow biopsy revealed a monoclonal B-cell population with expression of CD45, CD19, CD20, CD5, CD23, CD43, and CD200, consistent with her prior CLL diagnosis. A subpopulation of the monoclonal lambda-restricted B cells also showed expression of CD38 and CD138, consistent with plasma cell differentiation of the CLL clone and 5% plasma cells. The left femur biopsy revealed lymphoid tissue with atypical lymphocytes and atypical plasmacytoid cells that were positive for CD20, CD79a, and CD5. LEF1 staining was positive, and testing for MYD88 L265P mutation was negative. This pathology ultimately demonstrated findings consistent with CLL, with no evidence of a plasma cell dyscrasia or Richter’s transformation.

Discussion

This case represents an abnormal presentation of CLL with IgM monoclonal gammopathy of undetermined significance (MGUS). Often, patients with CLL are asymptomatic, but if present, symptoms include fatigue, lymphadenopathy, fever, night sweats, weight loss, and anemia.¹ While common in other types of malignancies, hypercalcemia and lytic bone lesions in patients with CLL are rare, occurring in less than 5% of cases. When present, these lesions are indicative of advanced and aggressive disease with poor prognosis.^2-4 In this case, the presence of a lytic lesion of the femur, coupled with laboratory testing significant for hypercalcemia, anemia, renal dysfunction, and monoclonal gammopathy, raised concern for a separate plasma cell dyscrasia such as Waldenström macroglobulinemia or multiple myeloma.

Ultimately, bone marrow biopsy and biopsy of the lytic lesion were necessary to differentiate between an atypical presentation of CLL and a separate plasma cell dyscrasia. The dominant B-cell population on bone marrow biopsy was consistent with the patient’s prior diagnosis of CLL, with a subset of cells showing plasma cell differentiation. LEF1 staining was also positive, which supported the diagnosis of CLL, and MYD88 L265P mutation was negative, making lymphoplasmacytic lymphoma less likely.

Takeaway Points:

• While PTH-independent hypercalcemia, renal dysfunction, anemia, and lytic lesions are hallmark findings in multiple myeloma, they are not pathognomonic of this disease. These findings can rarely be due to other lymphoproliferative disorders such as CLL, even in the absence of large cell transformation.
• Biopsy is the gold standard in the diagnosis of bony lesions of unknown etiology. The positivity of LEF1 is useful in distinguishing CLL from other neoplasms.

1. Shadman M. Diagnosis and treatment of chronic lymphocytic leukemia: a review. JAMA. 2023;329(11):918-932.
2. Bacchiarri F, Gozzetti A, Mondanelli N, Lazzi S, Bocchia M. A case of bone lesion in a patient with relapsed chronic lymphocytic leukemia and review of the literature. Clin Case Rep. 2022;10(4):e05379.
3. Katz H, Sagun S, Griswold D, Alsharedi M. Solitary lytic bone metastasis: a rare presentation of small lymphocytic leukemia. Case Rep Hematol. 2018;2018:6154709.
4. Hua J, Ide S, Ohara S, et al. Hypercalcemia and osteolytic bone lesions as the major symptoms in a chronic lymphocytic leukemia/small lymphocytic lymphoma patient: a rare case. J Clin Exp Hematop. 2018;58(4):171-174.

Disclosure Statement: The authors indicated no relevant conflicts of interest.

Acknowledgement: This article was edited by Carolina Velez-Mejia, MD, and Urshila Durani, MD, MPH.