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

Diagnosis and Management of a Patient with Generalized Weakness, Weight Loss, Skin Lesions, Lymphadenopathy, and Hepatosplenomegaly

This clinical presentation most likely represents a hematologic malignancy requiring immediate bone marrow biopsy with comprehensive immunophenotyping, cytogenetics, and molecular testing to establish a definitive diagnosis, followed by risk-stratified treatment based on the specific diagnosis. 1

Differential Diagnosis Priority

The constellation of generalized lymphadenopathy, hepatosplenomegaly, skin lesions, weight loss, and weakness in a patient in their late 40s strongly suggests several hematologic malignancies:

Most Likely Diagnoses

Adult T-cell Leukemia/Lymphoma (ATLL) should be considered first given the characteristic tetrad of lymphadenopathy, hepatosplenomegaly, frequent skin lesions, and rapidly progressive course. 2 This diagnosis is particularly relevant if the patient has risk factors for HTLV-1 infection based on geographic location.

Waldenström Macroglobulinemia (WM) presents with constitutional symptoms (weight loss, fatigue), symptomatic hepatomegaly/splenomegaly, and lymphadenopathy—all present in this patient. 3 The median age of presentation aligns with this patient's late 40s demographic.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) commonly presents with generalized lymphadenopathy, hepatosplenomegaly, and constitutional symptoms. 3

Systemic Mastocytosis can present with skin lesions, hepatosplenomegaly, weight loss, and fatigue, though this is less common. 4

Essential Diagnostic Workup

Immediate Laboratory Studies

• Complete blood count with differential and peripheral blood smear review to evaluate for circulating abnormal cells, cytopenias, and lymphocytosis 1, 3
• Serum chemistry panel including LDH and albumin to assess disease burden and prognosis 3
• Serum protein electrophoresis with immunofixation and quantitative immunoglobulins (IgA, IgG, IgM) to detect monoclonal proteins, particularly IgM for WM 3, 1
• Beta-2 microglobulin level for prognostic stratification 3
• Viral serology (HBV, HCV, HIV, and HTLV-1/2) given the geographic location and clinical presentation 3

Critical Tissue Diagnosis

Bone marrow aspiration and biopsy with immunohistochemistry is required for definitive diagnosis. 3, 1 This must include:

• Flow cytometry for immunophenotyping 3
• Testing for MYD88L265P gene mutation (found in >90% of WM cases) 3
• Comprehensive cytogenetic analysis 1

Lymph node biopsy should be performed if nodes are >1.5 cm to distinguish between lymphoma subtypes and exclude other diagnoses. 3, 5

Skin biopsy of lesions is essential to determine if they represent direct infiltration by malignant cells (as in ATLL or mastocytosis) or are reactive. 4, 2

Imaging Studies

CT scan of chest, abdomen, and pelvis with contrast is indicated in all patients being considered for therapy to assess extent of lymphadenopathy and organomegaly. 3

Treatment Approach Based on Diagnosis

If Waldenström Macroglobulinemia is Confirmed

Treatment should be initiated if any of the following are present (all of which this patient has): 3

• Weight loss, fatigue (constitutional symptoms)
• Symptomatic hepatomegaly and/or splenomegaly
• Symptomatic lymphadenopathy or bulky disease (≥5 cm)
• Hemoglobin ≤10 g/dL or platelet count <100 × 10⁹/L

First-line therapy options include: 3, 1

• Bendamustine-rituximab (BR) is now a primary treatment option, especially for patients with high tumor bulk 3
• Dexamethasone, rituximab, and cyclophosphamide (DRC) remains a primary choice 3
• Bortezomib-rituximab combinations may be considered for patients with hyperviscosity or younger patients avoiding alkylator therapy 3

If Adult T-cell Leukemia/Lymphoma is Confirmed

This diagnosis carries a rapidly fatal course and requires aggressive combination chemotherapy, though current regimens remain largely ineffective. 2 The presence of HTLV-1 infection must be confirmed. 2

If CLL/SLL is Confirmed

Treatment is indicated if hemoglobin is ≤11 g/dL, platelets <100 × 10⁹/L, constitutional symptoms are present, or there is symptomatic lymphadenopathy/organomegaly. 3

Critical Pitfalls to Avoid

Do not delay bone marrow biopsy waiting for peripheral blood results alone, as definitive diagnosis requires marrow evaluation. 1

Do not initiate treatment empirically without tissue diagnosis, as treatment differs dramatically between WM, ATLL, CLL, and other hematologic malignancies. 1

Do not mistake this presentation for reactive lymphadenopathy or infection and treat with antibiotics alone—the combination of constitutional symptoms, organomegaly, and skin lesions demands malignancy workup. 5

Avoid corticosteroids before biopsy as they can mask the histologic diagnosis of lymphoma or other malignancy. 5

Infection Risk Management

Given the immunosuppression from underlying hematologic malignancy, obtain blood cultures before initiating antibiotics if fever or signs of infection are present. 1 Start empiric broad-spectrum antibiotics if infection is suspected, adding vancomycin if skin/soft tissue infection or hemodynamic instability develops. 1