What is the approach to investigating POEM (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy) syndrome?

Investigating POEMS Syndrome

The investigation of POEMS syndrome requires serum VEGF levels, bone marrow biopsy, serum and urine immunofixation with free light chains, whole body skeletal imaging (X-rays and FDG-PET), CT abdomen/pelvis, and endocrine function tests to establish the mandatory major criteria (polyneuropathy and monoclonal plasma cell disorder) plus at least one additional major or minor criterion. 1, 2

Mandatory Diagnostic Criteria

POEMS syndrome diagnosis requires three major criteria (with polyneuropathy and monoclonal plasma cell disorder being mandatory) plus at least one minor criterion. 1

Major Criteria (2 mandatory + 1 additional):

• Polyneuropathy (present in 96% of cases, typically length-dependent and painful in 75%) 3
• Monoclonal plasma cell disorder (almost always λ-restricted) 1, 2
• Elevated serum VEGF levels 1, 2
• Sclerotic bone lesions 1, 2
• Castleman disease 1, 2

Minor Criteria (need ≥1):

• Organomegaly (hepatomegaly, splenomegaly, or lymphadenopathy) 1, 2
• Extravascular volume overload (edema, ascites, pleural effusions) 1, 2
• Endocrinopathy (thyroid, adrenal, gonadal dysfunction) 1, 2
• Skin changes (hyperpigmentation, hypertrichosis, hemangiomas) 1, 2
• Papilledema 1, 2
• Thrombocytosis or polycythemia 1, 2

Essential Laboratory Investigations

Plasma Cell Disorder Workup:

• Serum protein electrophoresis with immunofixation to detect monoclonal protein 2, 4
• 24-hour urine protein electrophoresis with immunofixation 2
• Serum free light chain assay (λ predominance expected) 2, 1
• Bone marrow aspiration and biopsy from iliac crest with flow cytometry, immunohistochemistry, and FISH cytogenetics 1, 2

Critical pitfall: Approximately 10-15% of POEMS patients have undetectable monoclonal gammopathy by standard methods but still respond to plasma cell-directed therapy—elevated VEGF and bone marrow clonal plasma cells remain diagnostic. 5

Disease Activity Marker:

• Serum VEGF levels (typically markedly elevated, median >4000 pg/mL; serves as both diagnostic marker and treatment response indicator) 1, 2, 5

Baseline Hematologic and Metabolic Panel:

• Complete blood count with differential (assess for thrombocytosis/polycythemia) 2
• Comprehensive metabolic panel including calcium and creatinine 2
• Endocrine function tests: TSH, free T4, cortisol, testosterone/estradiol, FSH/LH, prolactin, IGF-1 1, 2

Imaging Studies

Skeletal Assessment:

• Whole body X-rays to detect sclerotic bone lesions (present in majority of cases) 1, 2
• FDG-PET scan to identify metabolically active bone lesions and assess disease extent (note: optimal response may lag 6-12 months after treatment) 1, 2, 6
• MRI if spinal cord compression or plasmacytomas suspected 2

Organ Assessment:

• CT abdomen and pelvis to evaluate organomegaly (hepatomegaly, splenomegaly, lymphadenopathy) 1, 2

Functional Organ Assessment

Cardiopulmonary Evaluation:

• Pulmonary function tests (assess for restrictive defects from volume overload or pulmonary hypertension) 1, 2, 6
• Echocardiogram to evaluate cardiac function, pericardial effusion, and pulmonary hypertension 1, 2, 6

Important caveat: Pulmonary hypertension, thrombotic events, and congestive heart failure are recognized complications that may develop during disease course. 7

Diagnostic Algorithm

1. Screen with: Serum VEGF, serum/urine immunofixation, skeletal survey
2. If VEGF elevated + monoclonal protein detected: Proceed to bone marrow biopsy
3. Confirm plasma cell clone: Flow cytometry and immunohistochemistry on bone marrow
4. Stage disease extent: FDG-PET and CT abdomen/pelvis
5. Assess organ involvement: Endocrine panel, pulmonary function tests, echocardiogram
6. Establish baseline for monitoring: Document number of major/minor criteria present

Common Diagnostic Pitfalls

• Misdiagnosis as CIDP: 54% of POEMS patients are initially misdiagnosed with chronic inflammatory demyelinating polyneuropathy due to demyelinating features on nerve conduction studies. 3 The presence of organomegaly, skin changes, elevated VEGF, or sclerotic bone lesions should prompt POEMS evaluation.

• Delayed diagnosis: Mean time from symptom onset to diagnosis is 15 months, with 35% of patients wheelchair or bedbound at diagnosis. 3 Maintain high index of suspicion in any patient with progressive sensorimotor polyneuropathy plus unexplained systemic features.

• Overlooking atypical presentations: Some patients lack detectable monoclonal protein but have elevated VEGF and bone marrow clonal plasma cells—these variants still respond to plasma cell-directed therapy. 5