Definition/General
Introduction:
Anaplastic large cell lymphoma (ALCL) is a T-cell non-Hodgkin lymphoma characterized by large pleomorphic cells with strong and uniform CD30 expression
It represents 2-3% of all non-Hodgkin lymphomas
The disease is divided into ALK-positive and ALK-negative variants based on ALK protein expression
Hallmark cells with eccentric, kidney-shaped nuclei are characteristic
Shows predilection for young males especially in ALK-positive cases.
Origin:
Originates from activated T-lymphocytes with aberrant expression of CD30
ALK-positive cases result from chromosomal translocations involving ALK gene
Most common is t(2;5)(p23;q35) creating NPM1-ALK fusion
ALK-negative cases lack ALK rearrangements but show similar morphology
Clonal T-cell receptor gene rearrangements present
Shows post-thymic T-cell origin with loss of some T-cell antigens.
Classification:
WHO classification recognizes systemic ALCL with two main variants: ALK-positive ALCL (better prognosis)
ALK-negative ALCL (worse prognosis than ALK-positive)
Primary cutaneous ALCL (separate entity with excellent prognosis)
Breast implant-associated ALCL (rare variant)
Grade not applicable as morphologically anaplastic
Staging follows Ann Arbor system.
Epidemiology:
Bimodal age distribution
ALK-positive: peak in children and young adults (<30 years)
ALK-negative: peak in older adults (>50 years)
Male predominance (M:F = 1.5-3:1)
Higher incidence in developed countries
Asian populations may show different ALK translocation patterns
Indian subcontinent data limited but shows similar patterns.
Clinical Features
Presentation:
Lymphadenopathy (60-70% of cases)
Extranodal involvement common (60%)
B-symptoms frequent (50-80%)
Mediastinal involvement rare (unlike classical Hodgkin lymphoma)
Skin involvement (25% of systemic cases)
Bone involvement (15-20%)
GI involvement less common
Liver and spleen involvement in advanced cases.
Symptoms:
Fever (most common B-symptom)
Night sweats
Weight loss >10% body weight
Fatigue and malaise
Skin lesions (nodules, ulcers)
Bone pain if skeletal involvement
Abdominal pain with hepatosplenomegaly
Performance status often preserved in ALK-positive cases.
Risk Factors:
Age (young adults for ALK-positive, older adults for ALK-negative)
Male gender
Geographic factors (higher in developed countries)
Genetic predisposition possible
Immunodeficiency states (controversial association)
Previous malignancy rare association
Environmental factors not well established.
Screening:
No specific screening recommendations
Complete blood count and peripheral smear
Comprehensive metabolic panel
LDH elevation common
ESR often elevated
Imaging studies for staging (CT, PET-CT)
Bone marrow biopsy for staging
CSF examination if CNS symptoms.
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Gross Description
Appearance:
Enlarged lymph nodes with effaced architecture
Firm to hard consistency
Gray-white cut surface with fish-flesh appearance
Necrosis may be prominent
Hemorrhage occasionally present
Capsular involvement and extension common
Matting of adjacent nodes may occur.
Characteristics:
Fish-flesh appearance typical of high-grade lymphomas
Homogeneous gray-white color
Firm consistency due to cellular infiltrate
Areas of necrosis more common than in other lymphomas
Well-demarcated from surrounding tissue when encapsulated
Infiltrative borders in aggressive cases.
Size Location:
Node size typically 3-15 cm
Peripheral lymph nodes commonly involved
Cervical and axillary nodes frequent sites
Mediastinal involvement uncommon
Abdominal nodes in advanced disease
Extranodal masses vary in size
Skin lesions range from small nodules to large tumors.
Multifocality:
Multifocal nodal involvement at presentation
Extranodal spread characteristic
Skin involvement often multifocal
Bone lesions may be multiple
Systemic dissemination common
Stage III-IV disease frequent
Contiguous spread less predictable than Hodgkin lymphoma.
Microscopic Description
Histological Features:
Anaplastic large cells with pleomorphic nuclei
Hallmark cells with eccentric, kidney-shaped nuclei
Abundant eosinophilic cytoplasm
Prominent nucleoli
High mitotic activity
Cohesive growth pattern in many cases
Sinusoidal infiltration pattern common
Reed-Sternberg-like cells may be present.
Cellular Characteristics:
Large pleomorphic cells (>15 times small lymphocyte)
Hallmark cells pathognomonic (eccentric kidney-shaped nuclei)
Abundant cytoplasm with eosinophilic quality
Vesicular chromatin
Large prominent nucleoli
Multinucleated giant cells common
Wreath-like nuclei in some cells
Frequent mitoses and apoptotic figures.
Architectural Patterns:
Diffuse growth pattern most common
Sinusoidal infiltration characteristic pattern
Paracortical expansion in lymph nodes
Cohesive growth distinguishes from other T-cell lymphomas
Sheet-like arrangement of tumor cells
Perivascular distribution may be seen
Interfollicular pattern with sparing of follicles
Necrosis often present.
Grading Criteria:
No grading system as morphologically anaplastic by definition
ALK status most important prognostic factor
Proliferation index (Ki-67) typically high (>50%)
Degree of pleomorphism noted
Mitotic rate invariably high
Presence of hallmark cells important diagnostic feature
Necrosis extent may correlate with aggressiveness.
Immunohistochemistry
Positive Markers:
CD30 (uniformly positive, defining feature)
ALK (positive in ALK-positive variant)
CD3 (variable, often lost)
CD2 (often positive)
CD4 (positive in most cases)
CD8 (rarely positive)
CD25 (activation marker)
Granzyme B (cytotoxic marker)
Perforin (cytotoxic marker)
EMA (epithelial membrane antigen, often positive).
Negative Markers:
CD20 (B-cell marker, negative)
PAX5 (B-cell marker, negative)
CD79a (B-cell marker, negative)
CD15 (usually negative, unlike Hodgkin lymphoma)
CD5 (often lost)
CD7 (often lost)
TdT (negative in mature T-cell lymphoma)
CD10 (negative).
Diagnostic Utility:
CD30 positivity is diagnostic requirement (strong, uniform)
ALK expression defines prognostic subgroups
Loss of T-cell antigens (CD5, CD7) supports neoplasia
Cytotoxic markers often positive
EMA positivity helps distinguish from Hodgkin lymphoma
Ki-67 shows high proliferation (>50%)
ALK patterns indicate different translocations.
Molecular Subtypes:
ALK-positive ALCL (better prognosis)
ALK-negative ALCL (worse prognosis)
Different ALK staining patterns: cytoplasmic and nuclear (NPM1-ALK)
Cytoplasmic only (other ALK partners)
Primary cutaneous ALCL (CD30+, ALK-, excellent prognosis)
Breast implant-associated ALCL (ALK-, indolent course).
Molecular/Genetic
Genetic Mutations:
ALK gene rearrangements in ALK-positive cases
t(2;5)(p23;q35) most common (80% of ALK+ cases)
NPM1-ALK fusion from t(2;5)
Other ALK partners: TPM3, TFG, ATIC, CLTC
TP53 mutations in some ALK-negative cases
DUSP22 rearrangements in subset of ALK-negative cases
TP63 rearrangements in ALK-negative subset.
Molecular Markers:
NPM1-ALK fusion protein in most ALK-positive cases
Constitutive ALK kinase activity
JAK/STAT pathway activation
Clonal TCR gene rearrangements
JUNB overexpression
IRF4/MUM1 expression
STAT3 activation
Different ALK fusion proteins with various partners.
Prognostic Significance:
ALK-positive ALCL: 5-year OS 70-80%
ALK-negative ALCL: 5-year OS 40-50%
Age important prognostic factor
Stage at presentation
IPI score correlates with outcome
Primary cutaneous ALCL: excellent prognosis (>95% cure)
DUSP22 rearrangements better prognosis in ALK-negative cases
TP63 rearrangements worse prognosis.
Therapeutic Targets:
ALK inhibitors (crizotinib) for ALK-positive relapsed cases
Anti-CD30 therapy (brentuximab vedotin)
Standard chemotherapy (CHOP-like regimens)
Autologous stem cell transplant for relapsed cases
JAK/STAT inhibitors under investigation
Immunotherapy approaches being studied
Targeted combination therapies.
Differential Diagnosis
Similar Entities:
Classical Hodgkin lymphoma (Reed-Sternberg cells, CD15+)
Primary mediastinal large B-cell lymphoma (CD20+, mediastinal mass)
Diffuse large B-cell lymphoma (CD20+, CD30 variable)
Embryonal carcinoma (germ cell marker positive)
Poorly differentiated carcinoma (cytokeratin positive)
Malignant melanoma (S-100, melanoma markers).
Distinguishing Features:
ALCL: CD30+, ALK+/-, T-cell markers, hallmark cells
Classical Hodgkin: CD15+, CD30+, mixed inflammatory background
PMLBCL: CD20+, mediastinal location, young females
DLBCL: CD20+, B-cell markers
Carcinoma: cytokeratin+, CD30 variable
Melanoma: S-100+, melanoma markers
Immunohistochemistry panel crucial for diagnosis.
Diagnostic Challenges:
CD30-positive carcinomas can mimic ALCL
Loss of T-cell markers may obscure lineage
Hodgkin lymphoma distinction in some cases
Primary cutaneous vs systemic ALCL distinction
ALK-negative cases more challenging diagnosis
Reactive immunoblasts with CD30 expression
Limited tissue may prevent full evaluation.
Rare Variants:
Small cell variant (rare, diagnostic challenge)
Lymphohistiocytic variant
Neutrophil-rich variant
Composite lymphomas (rare)
Leukemic phase (extremely rare)
CNS involvement (rare)
Breast implant-associated variant
Primary cutaneous variant.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
[Biopsy type] from [anatomical site], measuring [size] cm
Primary Diagnosis
Anaplastic large cell lymphoma, [ALK-positive/ALK-negative]
WHO Classification
Anaplastic large cell lymphoma, [ALK-positive/ALK-negative] (WHO 2016)
Histological Features
Shows sheets of anaplastic large cells with characteristic hallmark cells having eccentric kidney-shaped nuclei
Cellular Morphology
Large pleomorphic cells with abundant cytoplasm, vesicular chromatin, and prominent nucleoli; hallmark cells present
Growth Pattern
Growth pattern: [diffuse/sinusoidal/cohesive]; Architecture: [effaced/partially preserved]
Immunohistochemistry
CD30: strongly positive (uniform); ALK: [positive/negative]; CD3: [positive/negative/variable]; EMA: [positive/negative]
Molecular Studies
T-cell receptor rearrangement: clonal; ALK rearrangement: [positive/negative/not tested]
Staging Information
Clinical stage: [I/II/III/IV]; Extranodal involvement: [present/absent]
Prognostic Factors
ALK status: [positive - better prognosis/negative - intermediate prognosis]; Age: [years]; IPI: [score]
Final Diagnosis
Anaplastic large cell lymphoma, [ALK-positive/ALK-negative], WHO 2016