What are the differential diagnoses for a 39-year-old healthy female with a body mass index (BMI) of 20.1, stable white blood cell (WBC) and red blood cell (RBC) counts, and a 3mm lytic lesion on the occipital bone?

Differential Diagnoses for a 3mm Lytic Lesion of the Occipital Bone in a 39-Year-Old Healthy Female

In a 39-year-old healthy woman with normal blood counts and a small 3mm lytic occipital bone lesion, the most likely diagnoses are benign bone cyst or hemangioma, followed by early multiple myeloma or solitary plasmacytoma, with metastatic disease and primary bone sarcoma being less likely but requiring exclusion. 1

Age-Stratified Differential Framework

The patient's age of 39 years places her in a critical diagnostic zone where the differential shifts significantly:

• After age 40, bone metastases and multiple myeloma statistically outnumber primary bone sarcomas 1, 2, though at 39 she sits just below this threshold
• Primary bone sarcomas (osteosarcoma, Ewing sarcoma) peak in adolescence and young adulthood 1, making them less likely at this age
• The median age for multiple myeloma diagnosis is 63-70 years 1, but 10-15% of cases occur in younger patients 1

Most Likely Diagnoses

Benign Lesions (Most Probable)

Benign bone cyst or hemangioma should be the primary consideration given the small size, asymptomatic presentation, and normal laboratory values. 1

• In patients with a single asymptomatic lytic bone lesion, benign bone cyst or bone angioma (hemangioma) must be considered first 1
• Aneurysmal bone cysts can occur in the skull, though rarely in the occipital region, and typically present with characteristic soap-bubble appearance on CT 3
• Simple (unicameral) bone cysts are fluid-filled lesions that can involve any bone 4
• CT or MRI is specifically recommended to differentiate benign cysts from malignant lesions 1

Multiple Myeloma/Plasmacytoma (Important to Exclude)

Despite normal blood counts, early multiple myeloma or solitary plasmacytoma remains in the differential and requires specific workup. 1

• Lytic bone lesions are a defining feature of symptomatic multiple myeloma (part of CRAB criteria) 1
• However, the presence of stable WBC and RBC counts argues against active myeloma, as anemia (hemoglobin <10 g/dL) is typically present in symptomatic disease 1
• A solitary plasmacytoma can present as an isolated lytic lesion without systemic findings 1
• Required workup includes: serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), immunofixation, serum free light chain assay, and quantitative immunoglobulins 1
• Bone marrow biopsy showing ≥10% clonal plasma cells would confirm myeloma 1

Metastatic Disease (Must Exclude)

Metastatic disease to bone is common in adults over 40 and must be systematically excluded. 1, 2

• Bone metastases are the most common malignant bone lesions in adults over 40 1, 2
• Common primary sources include breast, lung, kidney, thyroid, and prostate cancers 5
• Workup requires CT chest/abdomen/pelvis to identify occult primary malignancy 2

Langerhans Cell Histiocytosis

LCH predominantly affects the skull and can present as unifocal lytic lesions, though more common in children. 6, 5

• LCH can occur in adults and has predilection for skull involvement 6
• Typically presents as punched-out lytic lesions 5
• Can be associated with secondary aneurysmal bone cyst formation 6

Primary Bone Sarcomas (Less Likely)

Primary bone sarcomas are statistically unlikely at age 39 but cannot be completely excluded without biopsy. 1

• Osteosarcoma median age is much younger (peak in adolescence) 1
• Ewing sarcoma median age is 15 years, with skull involvement in 25% of cases 1
• Chondrosarcoma occurs between ages 30-60 but is rare in the skull 1

Diagnostic Algorithm

Immediate Workup Required

1. Complete myeloma screening panel 1:

• SPEP, UPEP with immunofixation
• Serum free light chain assay
• Quantitative immunoglobulins (IgG, IgA, IgM)
• Serum calcium and creatinine
• Complete skeletal survey (not just skull)

2. Advanced imaging of the lesion 1, 2:

• CT scan to visualize calcifications, periosteal bone formation, and cortical destruction 1, 2
• MRI provides superior detail for differentiating benign cysts from aggressive lesions 1, 2
• Look for fluid-fluid levels (suggests aneurysmal bone cyst) 3

3. Systemic staging if malignancy suspected 2:

• CT chest/abdomen/pelvis to exclude metastatic disease
• Consider PET-CT if myeloma or metastatic disease is suspected 1

Biopsy Considerations

If imaging cannot definitively exclude malignancy, referral to a bone sarcoma center for biopsy is mandatory BEFORE any intervention. 1, 2, 7

• All patients with suspected primary malignant bone tumors must be referred to a specialized center before biopsy 1, 2, 7
• Core needle biopsy under imaging guidance is preferred over open biopsy 1, 2, 7
• Biopsy must be performed by the surgeon who will perform definitive resection if malignancy is confirmed 2, 7
• Samples require interpretation by an experienced bone pathologist in multidisciplinary conference 2, 7

Critical Pitfalls to Avoid

• Do not assume the lesion is benign based solely on size and normal blood counts—early myeloma and metastases can present this way 1
• Do not perform biopsy at a non-specialized center—bone lesions are frequently misdiagnosed even by experienced clinicians 1, 2
• Do not skip the myeloma workup—a single lytic lesion can be the presenting feature of solitary plasmacytoma 1
• Do not order only skull imaging—complete skeletal survey is required to identify additional lesions 1
• Do not assume recent trauma rules out malignancy 1, 8

Clinical Context Considerations

The combination of young age (39), healthy status, normal BMI, and stable blood counts strongly favors a benign process, but systematic exclusion of myeloma and metastatic disease is non-negotiable. 1, 2

• Many elderly patients have concomitant diseases that mimic myeloma, but this 39-year-old healthy patient lacks these confounders 1
• The small 3mm size and asymptomatic presentation further support benign etiology 1
• However, solitary plasmacytoma can present identically and requires specific exclusion 1