What are the differential diagnoses for a patient presenting with clinical and histologic features of anaplastic large‑cell lymphoma (ALCL)?

Differential Diagnosis of Anaplastic Large-Cell Lymphoma (ALCL)

When evaluating a patient with clinical and histologic features of ALCL, the differential diagnosis must systematically distinguish between primary cutaneous ALCL (PCALCL), systemic ALCL with cutaneous involvement, lymphomatoid papulosis (LYP), and several non-lymphomatous conditions that can mimic ALCL.

Primary Lymphoproliferative Differentials

Lymphomatoid Papulosis (LYP) vs. Primary Cutaneous ALCL

The most critical distinction is between LYP and PCALCL, as both are CD30+ lymphoproliferative disorders with overlapping histology 1. The key differentiating feature is clinical behavior: LYP presents with recurrent self-healing papulonodular lesions that spontaneously regress within weeks to months, whereas PCALCL presents with persistent solitary, grouped, or multifocal nodular lesions without spontaneous regression 1.

However, this distinction can be challenging because:

• Multifocal PCALCL can occasionally show spontaneous regression 1
• Short disease duration may not allow adequate observation of clinical behavior
• Both conditions may coexist in the same patient

In borderline cases where clinicopathologic correlation cannot establish a definitive diagnosis initially, follow-up observation of clinical behavior becomes essential for final diagnosis 1.

Systemic ALCL with Secondary Cutaneous Involvement

This is a critical differential with major prognostic implications. The presence of ALK-1 (p80) expression and t(2;5) translocation strongly suggests systemic ALCL with cutaneous manifestations rather than PCALCL 1. Additional distinguishing features include:

• PCALCL: ALK-negative, lacks epithelial membrane antigen, expresses cutaneous lymphocyte antigen (HECA-452) 1
• Systemic ALCL: Often ALK-positive (especially in younger patients), expresses epithelial membrane antigen, presents with disseminated disease and B-symptoms 2, 3

Systemic ALCL subtypes include ALK-positive (better prognosis, 5-year OS 70-90%), ALK-negative (poorer prognosis), and molecular variants with DUSP22 rearrangement (favorable, 5-year OS 80-90%) or TP63 rearrangement (poor, 5-year OS 17%) 2.

Other Cutaneous T-Cell Lymphomas

Mycosis fungoides (MF) with transformation must be excluded, particularly when patches or plaques are present alongside nodular lesions 1. Transformed MF can express CD30 in large tumor cells, creating diagnostic confusion. Look for:

• History of preceding patches/plaques characteristic of MF
• Epidermotropism in earlier lesions
• LYP type B shows epidermotropic infiltrate resembling MF but with CD30+ cells 1

Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma can mimic LYP type D, which shows epidermotropic infiltrate of CD8+ and CD30+ lymphoid cells 1.

Non-Lymphomatous Differentials

Hodgkin Lymphoma

Classical Hodgkin lymphoma with secondary cutaneous involvement is an important consideration, as Reed-Sternberg cells are CD30-positive 1. Careful clinicopathologic correlation and staging are essential, with particular attention to:

• History of nodal Hodgkin lymphoma 1
• Presence of characteristic Reed-Sternberg cells
• CD15 expression (can occur in ALCL, creating diagnostic confusion) 4

Solid Tumors and Other Malignancies

The anaplastic morphology of ALCL necessitates consideration of 3, 4:

• Carcinoma: Particularly metastatic carcinoma with anaplastic features
• Melanoma: Especially amelanotic variants
• Myeloid sarcoma: Can present with cutaneous involvement

Cytokeratin expression can occur in ALCL, potentially leading to misdiagnosis as carcinoma 4. CD30 immunostaining is pivotal in establishing the correct diagnosis.

Infectious and Inflammatory Conditions

The presence of CD30+ large atypical lymphoid cells is not specific to lymphoproliferative disorders and can occur in various inflammatory and infectious processes 1. The guideline explicitly notes this broad differential, though specific infectious etiologies are not detailed. One case report describes ALCL mimicking noduloulcerative tertiary syphilis 5.

Diagnostic Algorithm

1. Establish CD30 expression: At least 75% of tumor cells must be CD30+ for PCALCL diagnosis 1

2. Assess clinical presentation:

   • Self-healing papulonodular lesions → LYP
   • Persistent nodular lesions without regression → PCALCL
   • Patches/plaques present → Consider MF with transformation
   • B-symptoms, disseminated disease → Systemic ALCL

3. Perform ALK-1 immunostaining:

   • ALK-positive → Highly suspicious for systemic ALCL 1
   • ALK-negative → Consistent with PCALCL but requires staging to exclude systemic disease

4. Complete staging workup 1:

   • History: Previous lymphoid neoplasms (Hodgkin lymphoma, nodal ALCL, MF), immunosuppression, B-symptoms
   • Physical exam: Lymphadenopathy, hepatosplenomegaly
   • Labs: CBC, LDH, HTLV-1/2 serology (in endemic areas) 1, 2
   • Imaging: CT chest/abdomen/pelvis with contrast ± PET for PCALCL 1
   • Lymph node biopsy if nodes >1.5 cm 1

5. Additional immunophenotyping:

   • Epithelial membrane antigen (positive in systemic ALCL, negative in PCALCL)
   • HECA-452/cutaneous lymphocyte antigen (positive in PCALCL)
   • Pan-T-cell antigens (variable loss in both)
   • CD4/CD8 expression
   • Consider CD15 (can be positive in ALCL) 4

Critical Pitfalls

• Do not diagnose PCALCL without excluding systemic disease through proper staging 1
• ALK-positivity should trigger high suspicion for systemic ALCL, not PCALCL 1
• Cytokeratin expression in ALCL can lead to misdiagnosis as carcinoma 4
• Spontaneous regression is not absolutely specific for LYP; multifocal PCALCL can occasionally regress 1
• CD30 expression alone is insufficient for diagnosis; inflammatory and infectious conditions can show CD30+ cells 1
• Borderline cases between LYP and PCALCL may require clinical follow-up for definitive diagnosis 1