What are the epidemiology, pathogenesis, clinical manifestations, and laboratory findings of Anaplastic Large Cell Lymphoma (ALCL)?

Anaplastic Large Cell Lymphoma (ALCL): Epidemiology, Pathogenesis, Clinical Manifestations, and Laboratory Findings

Epidemiology

ALCL accounts for fewer than 5% of all non-Hodgkin lymphomas and represents approximately 15% of peripheral T-cell lymphomas. 1, 2

• ALK-positive ALCL is most common in children and young adults with a median age of approximately 30 years 1, 3
• ALK-negative ALCL predominantly affects older patients with a median age of 52-61 years 3
• Geographic variation exists, with ALK-positive ALCL diagnosed more frequently in North America than Europe, and both subtypes are uncommon in Hispanic and Asian populations 4
• Four distinct subtypes are recognized: systemic ALK-positive ALCL, systemic ALK-negative ALCL, primary cutaneous ALCL (pcALCL), and breast implant-associated ALCL (BIA-ALCL) 1

Pathogenesis

The pathogenesis of ALCL centers on chromosomal translocations and molecular alterations that drive T-cell transformation.

ALK-Positive ALCL

• Characterized by overexpression of ALK-1 protein resulting from chromosomal translocation t(2;5) in 40-60% of patients, producing the NPM-ALK fusion protein 1, 3
• This translocation leads to constitutive activation of ALK kinase activity, driving oncogenic signaling 4

ALK-Negative ALCL

• DUSP22 rearrangement occurs in approximately 30% of cases and is associated with intermediate prognosis 1, 5
• TP63 rearrangement is identified in approximately 8% of cases and confers very poor prognosis with 5-year overall survival of 17% 1, 3
• Triple-negative ALCL (lacking ALK, DUSP22, and TP63 rearrangements) has poor prognosis with 5-year progression-free survival and overall survival rates of 19% and 28% respectively 1, 3
• JAK1 and/or STAT3 mutations activate the JAK/STAT signaling pathway in systemic ALK-negative ALCL (except DUSP22-rearranged cases) 5

Primary Cutaneous ALCL

• Biologically distinct from systemic ALCL despite similar CD30 expression 1
• Distribution of DUSP22 and TP63 rearrangements similar to systemic ALK-negative ALCL 1
• Does not harbor JAK1/STAT3 mutations unlike systemic forms 5

Breast Implant-Associated ALCL

• Develops after prolonged exposure to textured-surface breast implants, with median time to diagnosis of 8 years after implant placement 1
• Risk significantly higher with Allergan's BIOCELL textured implants compared to other textured implants 1
• JAK1/3 and STAT3 mutations identified but no DUSP22 or TP63 rearrangements detected 1, 5

Clinical Manifestations

Most patients with systemic ALCL present with advanced stage III or IV disease (65% for ALK-positive and 58% for ALK-negative) frequently associated with systemic symptoms. 1, 3

Systemic ALCL (ALK-Positive and ALK-Negative)

• B symptoms (fever, night sweats, weight loss) occur in 70% of patients at presentation 3
• Extranodal involvement occurs in approximately 95% of cases, commonly affecting liver, bone marrow, gastrointestinal tract, and skin 3
• Generalized lymphadenopathy is typical 1
• Hepatomegaly or splenomegaly may be present 1

Primary Cutaneous ALCL

• Solitary tumors, grouped tumors, or thick plaques of disease are characteristic presentations 1
• Rarely presents with generalized multifocal lesions 1
• Partial spontaneous regression may occur but is rarely complete 1
• Prognosis is excellent with 5-year survival rates of 96% 1

Breast Implant-Associated ALCL

• Most common presentation is seroma (fluid collection around the implant) 1
• Other presentations include mass or hardening adjacent to the implant without seroma 1
• Relatively indolent clinical course when disease is limited to effusion fluid and capsule invasion has not occurred 1
• Deaths have been reported with disease progression, emphasizing need for prompt diagnosis 1

Laboratory Findings

The diagnosis requires integration of morphology, immunohistochemistry, flow cytometry, cytogenetics, and molecular biology. 1

Morphology

• Dense nodular dermal infiltrate composed of large pleomorphic, anaplastic, or immunoblastic cells 1
• Large, irregularly shaped nuclei with abundant pale or eosinophilic cytoplasm 1
• Horseshoe-shaped or reniform nuclei (hallmark cells) are characteristic 2
• Clusters of small reactive lymphocytes and eosinophils may surround tumor cells 1

Immunohistochemistry

• CD30 expression by at least 75% of tumor cells is mandatory for diagnosis 1
• ALK-1 protein expression distinguishes ALK-positive from ALK-negative subtypes 1
• CD4 or CD8 expressed in most cases with variable loss of pan-T-cell antigens (CD2, CD3, CD5) 1
• EMA (epithelial membrane antigen) frequently positive 1
• CD25 typically positive 1
• Cytotoxic granules (TIA-1, granzyme B, perforin) often positive 1
• CD45 may be negative in one-third of cases 1
• PAX5 systematically negative, helping distinguish from Hodgkin lymphoma 1

Flow Cytometry

• Neoplastic cells typically distribute in lymphocyte and monocyte regions on CD45 versus side scatter plots 1
• CD30+ cells identified with CD3 negativity or aberrant expression 1
• CD45+, CD30+, CD3-/+ pattern characteristic 1

Molecular Studies

• T-cell receptor (TCR) gene rearrangements demonstrate clonality (predominantly αβ, rarely γδ) 1
• DUSP22 rearrangement testing recommended if ALCL is ALK-negative 1
• TP63 rearrangement analysis considered if immunohistochemistry is positive for TP63 1
• FISH and cytogenetic analysis to detect t(2;5) translocation in ALK-positive cases 1

Additional Laboratory Tests

• Complete blood count may show cytopenias or elevated white blood cell count 1
• Elevated lactate dehydrogenase (LDH) common 1
• Bone marrow aspirate and biopsy required for staging 1
• Assessment of HTLV-1/2 by serology encouraged as results can impact therapy 1
• HIV, hepatitis B and C testing recommended 1
• Quantitative EBV PCR may be considered 1

Imaging

• PET/CT preferred over CT alone as extranodal disease may be inadequately imaged by CT 1
• Contrast-enhanced CT scan of chest, abdomen, and pelvis for staging 1