What is the diagnosis and treatment for a patient presenting with generalized weakness, weight loss, multiple skin lesions, generalized lymphadenopathy, and hepatosplenomegaly?

Diagnosis: Adult T-Cell Leukemia/Lymphoma (ATLL) or Waldenström Macroglobulinemia

The most likely diagnosis in a patient from an endemic location presenting with generalized weakness, weight loss, skin lesions, generalized lymphadenopathy, and hepatosplenomegaly is either Adult T-Cell Leukemia/Lymphoma (ATLL) if from HTLV-1 endemic areas, or a lymphoproliferative disorder such as Waldenström Macroglobulinemia (WM), and definitive diagnosis requires immediate bone marrow biopsy with comprehensive immunophenotyping, flow cytometry, and peripheral blood smear examination to guide risk-stratified treatment. 1

Immediate Diagnostic Workup

The peripheral blood smear requested is critical but insufficient alone—do not delay bone marrow biopsy waiting for peripheral blood results, as definitive diagnosis requires marrow evaluation. 1

Essential Laboratory Studies

• Complete blood count with differential to assess for cytopenias, lymphocytosis, or atypical cells 2
• Peripheral blood smear review by hematopathologist to identify abnormal lymphocytes, "flower cells" (ATLL), or lymphoplasmacytic cells 2, 1
• Serum protein electrophoresis with immunofixation to detect monoclonal IgM (WM) or other paraproteins 2
• Quantitative immunoglobulins (IgA, IgG, IgM) 2
• Serum β2-microglobulin for prognostication 2
• Lactate dehydrogenase (LDH) and serum albumin 2
• Viral serology: HBV, HCV, HIV, and HTLV-1 (critical given geographic location and clinical presentation) 2

Mandatory Tissue Diagnosis

Bone marrow aspiration and biopsy with:

• Immunohistochemistry (required for diagnosis) 2
• Flow cytometry for comprehensive immunophenotyping 2, 1
• Cytogenetics and molecular testing including MYD88L265P mutation (for WM) 2

CT chest/abdomen/pelvis to assess extent of lymphadenopathy and organomegaly 2

Skin biopsy of lesions to evaluate for lymphomatous infiltration or leukemia cutis 2

Differential Diagnosis Considerations

If Waldenström Macroglobulinemia

WM diagnosis requires bone marrow infiltration by lymphoplasmacytic cells AND detection of monoclonal IgM protein confirmed by immunofixation. 2 The presence of monoclonal IgM without histopathological LPL diagnosis does not constitute WM. 2

Treatment indications for WM include: 2

• Constitutional symptoms (fever, night sweats, weight loss, fatigue)
• Symptomatic hepatomegaly and/or splenomegaly
• Symptomatic lymphadenopathy or bulky disease (≥5 cm)
• Hemoglobin ≤10 g/dL
• Platelet count <100 × 10⁹/L

If Adult T-Cell Leukemia/Lymphoma

ATLL presents with generalized lymphadenopathy, hepatosplenomegaly, skin lesions, and constitutional symptoms in HTLV-1 endemic regions. 2 Peripheral blood smear shows characteristic "flower cells" (multilobulated lymphocytes). 2

Other Considerations

HIV-associated lymphoproliferative disorders must be excluded given the presentation—HIV testing is mandatory as these infections cause clinically indistinguishable presentations. 2, 3

Systemic lupus erythematosus can present with diffuse lymphadenopathy and constitutional symptoms, though less likely with hepatosplenomegaly. 4

Treatment Approach

Do not initiate treatment empirically without tissue diagnosis, as treatment differs dramatically between ATLL, WM, and other lymphoproliferative disorders. 1

For Waldenström Macroglobulinemia (if confirmed)

First-line therapy selection based on clinical urgency: 2, 1

• For rapid disease control or hyperviscosity: Bortezomib + dexamethasone + rituximab 2, 1
• For high tumor bulk: Bendamustine + rituximab (BR) 2
• Standard therapy: Dexamethasone + rituximab + cyclophosphamide (DRC) 2

Avoid R-CHOP as first-line therapy—no longer recommended per IWWM-7 consensus. 2

Supportive Care

If fever or infection signs present:

• Obtain blood cultures before antibiotics 1
• Start empiric broad-spectrum antibiotics immediately 1
• Add vancomycin if skin/soft tissue infection or hemodynamic instability 1

Critical Pitfalls to Avoid

• Never delay bone marrow biopsy—peripheral blood findings alone are insufficient for definitive diagnosis 1
• Do not miss HTLV-1 testing in patients from endemic areas (Japan, Caribbean, parts of Africa, South America) 2
• Avoid starting treatment before tissue diagnosis—therapeutic approaches vary dramatically by specific diagnosis 1
• Do not overlook HIV testing—can cause identical clinical presentation 2, 3
• Beware of IgM flare with rituximab-based therapy—does not necessarily indicate disease progression 2
• Evaluate CXCR4 mutational status if considering ibrutinib therapy, as mutations affect response kinetics 2