What is the diagnostic workup and treatment approach for a patient with atypical lymphoid proliferation, Kimura disease, angiolymphoid hyperplasia with eosinophilia (AE), or pseudolymphoma cutis?

Diagnostic Workup and Treatment for Atypical Lymphoid Proliferations

For patients presenting with atypical lymphoid proliferation including Kimura disease, angiolymphoid hyperplasia with eosinophilia (ALHE), or pseudolymphoma cutis, the primary diagnostic imperative is to exclude cutaneous lymphoma through comprehensive clinicopathologic correlation, as these benign entities can histologically mimic malignant lymphoproliferative disorders. 1, 2

Critical Diagnostic Distinction

The fundamental challenge with these entities is their histologic overlap with malignant lymphomas, particularly CD30+ lymphoproliferative disorders and Hodgkin lymphoma. The final diagnosis must always be based on careful clinicopathologic correlation, not histology alone. 1

Kimura Disease vs. Malignancy

• Kimura disease characteristically presents with subcutaneous masses, regional lymphadenopathy, and elevated IgE levels in young Asian men (20-30 years old). 2, 3
• Key histologic features include intact lymph node architecture, florid germinal center hyperplasia, extensive eosinophilic infiltrates, and postcapillary venule proliferation. 2, 4
• Critical pitfall: These exact features can also occur in Hodgkin disease and T-cell lymphoma, making initial diagnosis unreliable. 2
• Immunohistochemical staining for CD15 and CD30 is mandatory to exclude Reed-Sternberg cells, though initial testing may be falsely negative. 2

Angiolymphoid Hyperplasia with Eosinophilia (ALHE)

• ALHE is distinguished from Kimura disease by absence of lymphatic follicle formation, lack of fibrosis in the infiltrate, and epithelioid/histiocytoid appearance of proliferating endothelia forming small vascular lumina. 5
• ALHE occurs predominantly in white populations, whereas Kimura disease is rare in non-Asians. 5
• However, these entities overlap significantly in practice, and strict division may not be possible with absolute certainty. 5

Pseudolymphoma Cutis (Cutaneous Lymphoid Hyperplasia)

• Pseudolymphoma represents exaggerated reactions to external antigens (insect bites, tattoos, zoster, trauma) and can be B-cell or T-cell predominant. 6
• Molecular analysis reveals occult B- or T-cell clones in a significant proportion of cases (clonal CLH), with minority progression to overt lymphoma. 6

Essential Diagnostic Workup

History and Physical Examination

• Document waxing and waning of lesions (spontaneous regression within weeks suggests lymphomatoid papulosis rather than malignancy). 1
• Inquire about previous lymphoid neoplasms, particularly Hodgkin lymphoma, nodal anaplastic large cell lymphoma, and mycosis fungoides. 1
• Assess for B-symptoms (fever, night sweats, weight loss >10% over 6 months). 1, 7
• Examine for hepatosplenomegaly and enlarged lymph nodes (>1.5 cm in greatest diameter or firm, irregular, clustered, or fixed nodes require biopsy). 1

Laboratory Investigations

• Complete blood count with manual differential to assess for eosinophilia, lymphocytosis, and circulating atypical cells. 1, 8, 9
• Serum IgE levels (elevated in Kimura disease). 2, 3
• Comprehensive metabolic panel and LDH. 1
• Peripheral blood flow cytometry if lymphocytosis is present or Sézary syndrome is suspected. 1, 9

Tissue Diagnosis

• Excisional biopsy is preferred over fine needle aspiration, as FNA has limited diagnostic utility for these entities. 3
• Histopathology must include routine H&E, immunophenotyping, and assessment for clonality via T-cell receptor or immunoglobulin gene rearrangement. 1
• Immunohistochemistry panel must include CD30 (expressed by ≥75% of tumor cells in primary cutaneous anaplastic large cell lymphoma), CD15, CD4, CD8, and pan-T-cell markers (CD2, CD3, CD5). 1
• Assess for ALK-1 (p80) and t(2;5) translocation—if present, suspect systemic ALCL with cutaneous involvement rather than primary cutaneous disease. 1

Radiologic Staging

• For suspected Kimura disease or ALHE: Contrast-enhanced CT chest/abdomen/pelvis to exclude systemic involvement. 1
• For pseudolymphoma cutis with typical clinical features and no concerning physical exam findings: Radiologic staging is optional. 1
• For atypical presentations or CD30+ infiltrates: PET-CT is recommended to exclude nodal or extracutaneous disease. 1

Lymph Node Biopsy

• Excisional biopsy is mandatory for any lymph node >1.5 cm or with concerning features (firm, irregular, clustered, fixed). 1
• Include routine histology, immunohistochemistry, and TCR gene rearrangement analysis. 1

Bone Marrow Examination

• Not indicated for typical pseudolymphoma cutis or lymphomatoid papulosis. 1
• Required if clinical behavior suggests aggressive lymphoma or if radiologic staging reveals systemic involvement. 1

Critical Diagnostic Pitfalls

• Never rely on a single biopsy for definitive diagnosis—clinical progression may reveal malignancy initially masked by reactive features. 2
• Repeat biopsy is mandatory if clinical course is atypical or progressive, as the second case in the literature demonstrated initial KD-like features that evolved into CD30+ Hodgkin disease. 2
• Patients with clonal B- or T-cell populations and persistent lesions require close surveillance for emergence of lymphoma, even if initial diagnosis is benign. 6
• Do not attribute extensive eosinophilia solely to allergic disease—myeloid/lymphoid neoplasms with tyrosine kinase fusions (PDGFRA, PDGFRB) can present with eosinophilia and require molecular testing. 8, 9

Treatment Approach

Kimura Disease

• Observation with antihistamines (cetirizine) is appropriate for stable disease. 2
• Surgical excision for symptomatic masses, though recurrence is frequent. 3
• Intralesional or systemic corticosteroids for progressive disease. 6

Angiolymphoid Hyperplasia with Eosinophilia

• Surgical excision is the primary treatment. 3, 6
• Radiotherapy for recurrent or unresectable lesions. 6

Pseudolymphoma Cutis

• Remove inciting antigen if identifiable (discontinue offending drug, treat infection). 6
• Intralesional corticosteroids for localized disease. 6
• Excision or radiotherapy for persistent lesions. 6
• Systemic immunosuppressants for refractory cases. 6

If Malignancy is Confirmed

• For CD30+ lymphoproliferative disorders: Treatment depends on extent of disease, ranging from observation (lymphomatoid papulosis) to radiotherapy or systemic therapy (primary cutaneous anaplastic large cell lymphoma). 1
• For Hodgkin lymphoma: Refer immediately to hematology/oncology for combination chemotherapy. 2

Surveillance Strategy

All patients with atypical lymphoid proliferations require longitudinal follow-up, as the natural history and clinical behavior over time are essential for accurate diagnosis. 1, 2 Patients with molecular evidence of clonality require particularly vigilant monitoring for transformation to overt lymphoma. 6