Case Presentation: An 80-year-old gentleman with a past medical history of type 2 diabetes mellitus and stage III chronic kidney disease (baseline creatinine 1.2-1.4 mg/dL) presented to the emergency department with generalized weakness, falls, unintentional weight loss, and constipation. Labs were significant for hypercalcemia (13.2 mg/dL), elevated creatinine (1.96 mg/dL), suppressed intact PTH (10 pg/mL), and normal PTHrP (2 pmol/L), 25-hydroxyvitamin D (49.6 ng/mL) and 1, 25-dihydroxyvitamin D (51.3 pg/mL). CBC demonstrated thrombocytopenia (112 k/uL) and anemia (Hb 9.8 g/dL). Beta-2 microglobulin was elevated (11.7 mg/L), though serum and urine electrophoresis were unremarkable for M protein and monoclonal immunoglobulin light chains. CT chest and kidney ultrasound were unremarkable. Medication history was negative for those associated with hypercalcemia. The patient required treatment with normal saline, IV Lasix, pamidronate, and calcitonin, resulting in improvement of calcium (10.5 mg/dL) and creatinine (1.72 mg/dL). He was discharged without a definitive underlying diagnosis.Subsequent outpatient work-up included a whole-body PET/CT, which did not reveal FDG-avid lesions. Repeat outpatient labs showed worsening hypercalcemia (12.3 mg/dL) and creatinine (3.18 mg/dL). He was started on outpatient zoledronic acid without improvement, requiring re-hospitalization. Upon admission, labs demonstrated mildly elevated 1,25-dihydroxyvitamin D (67.8 pg/mL) and persistent bicytopenia. Given these labs, there was concern for a hematological malignancy, and a subsequent bone marrow biopsy demonstrated non-necrotizing epithelioid granulomas. Further workup showed normal serum ACE levels but elevated IL-2R levels (3542.7 pg/mL). Based on the biopsy results, hypercalcemia, and IL-2R levels, a diagnosis of sarcoidosis isolated to the bone marrow was made. The patient was started on prednisone 40mg with a taper and was discharged after improvement of calcium and creatinine. He has been clinically stable on daily 10 mg prednisone since then.
Discussion: An uncommon cause of hypercalcemia, sarcoidosis is characterized by non-caseating epithelioid granulomas. Extrapulmonary sarcoidosis presents in up to 50% of sarcoidosis cases and can be associated with significant morbidity (1,2). Sarcoidosis without pulmonary involvement, however, is only seen in 5% to 9% of patients, and only a few case reports of isolated bone marrow sarcoidosis have been published thus far (3–6). Sarcoidosis is difficult to diagnose without a biopsy, and serum markers such as ACE have poor sensitivity and specificity (7). However, IL-2R has been suggested to be a marker for extrapulmonary involvement, as in our patient (8). Imaging modalities have also been investigated. In one study, more than one-third of patients with a positive PET/CT scan had bone or bone marrow involvement. However, 94% of lesions were unable to be detected on low-dose CT (9). Prednisone is the mainstay of treatment, although other medications such as adalimumab and methotrexate have been reported to be effective (5,10,11).
Conclusions: Isolated bone marrow sarcoidosis, such as in this case, is rare and requires a high index of suspicion. Unfortunately, our patient required four prolonged hospitalizations before a biopsy was obtained to make a final diagnosis. This demonstrates a need for increased awareness and ongoing research into improved detection of extrapulmonary sarcoidosis.