Anaplastic Large Cell Lymphoma

Epidemiology and Etiology:

• ALK+: 
• Children and young adults more common (first 3 decades of life)
• 10-20 % of childhood lymphomas
• ALK-:
• Adults (40-65 years peak)

Common sites:

• Lymph nodes
• Peripheral
• Abdominal
• (Mediastinum less common than HL)
• Extranodal sites common
• Skin
• Bone
• Soft tissues
• Lung
• Liver
• (gut and CNS rare)
• Bone Marrow (10% by H&E, 30% by IHC)
• Peripheral blood (small cell variant)

Gross features:

Histologic features:

• Broad morphologic spectrum
• All cases contain a variable proportion of hallmark cells:
• Eccentric, horseshoe, or kidney-shaped nuclei
• pleomorphic
• Pseudoinclusions (ex. doughnut cells)
• Eosinophilic region near the nucleus often
• typically large cells
• smaller cells with similar morphology can be seen
• in ALK- cells tend to be larger and more pleomorphic than in ALK+
• may have higher n:c ratio
• abundant cytoplasm
• common pattern (60 %):
• multiple wreath-like nuclei
• finely clumped chromatin or dispersed with multiple small basophilic nucleoli
• (eosinophilic, inclusion-like nucleoli are arely seen)
• cells resembling Reed-Sternberg cells maybe
• sinus pattern of growth for lymph nodes only partially effaced
• lymphohistiocytic pattern (10%):
• reactive histiocytes admixed (large number)
• erythrophagocytosis occasionally
• malignant cells often smaller than in common pattern
• neoplastic cells often clustered around blood vessels
• small cell pattern (5-10 %) (not recognized in ALK-)
• predominant population of small to medium-sized neoplastic cells
• irregular nuclei
• “fried egg cells” in some cases
• Pale cytoplasm
• Centrally located nucleus
• Signet ring cells (rarely)
• Hallmark cells always present
• Around blood vessels often
• Often diagnosed as PTCL, NOS
• Flower-like cells in PB on smear preparations (often)
• ALK staining usually restricted to the nucleus
• Hodgkin-like pattern (3%)
• Mimics NSCHL
• Others:
• Monomorphic, rounded nuclei, either predominant or mixed with more pleomorphic cells
• Multinucleated neoplastic giant cells
• sarcomatoid
• Hypocellular in a myxoid or edematous background
• Cases with
• Composite pattern (15%)
• More than one of the above patterns
• Relapses may change patterns

Immunophenotype:

Marker:	Sensitivity:	Specificity:
CD30 strong (especially strongest in cell membrane and golgi), homogeneous;	Smaller tumour cells may be only weakly positive or even negative, but larger tumour cells even in small cell variant, particularly around vessels show the strongest staining	Negative in all postnatal tissues except rare cells in the brain. Polyclonal Ab may give false positivity Other PTCL may express CD30 in at least a proportion of cells, usually with variable intensity
EMA	Commonly in ALK+ Substantial minority in ALK-	Only occasionally in PTCL, NOS
ALK-1 location varies depending on translocation (see below)	Negative in ALK- by definition	ALK+ DLBCL shows granular cytoplasmic staining
TdT (neg)
Pan T	-/+ (overall more than half express 1 or more, but some cases may have an apparent “null cell” phenotype but with evidence of T cell lineage at the genetic level)
CD2	70%
CD5	70% in ALK+ less often in ALK-
CD4	70%
CD43	66% in ALK+, almost always in ALK-
CD3	25% in ALK+ more in ALK-
TIA1	Most
Granzyme B	Most
Perforin	Most
BCL6		Not useful
CD45	+/-
CD45RO	+/-
CD25 (strong)
Clusterin	Common	Rarely in PTCL, NOS, and negative in cHL so far
CD15 (neg)	(rarely positive)	CD15 may be expressed in some cases of PTCL, NOS
CD68 (neg)
Lysozyme (neg)
CD8 (neg)	Usually
BCL2 (neg)	Negative in ALK+
EBV (EBER and LMP1) (neg)	consistently	Expression should strongly raise suspicion of cHL
PAX5 (neg)	All cases	cHL shows weak expression in the majority of cases
BNH9	+/-

Molecular features:

• TCR gene rearrangement (90%)
• Remainder show no rearrangement of TCR or IG genes
• ALK translocation (ALK+) (good prognosis)
• t(2;5) translocation (50-80%)
• fusion of NPM (5q35) with ALK (2q23)
• ALK staining of cytoplasm and nucleus
• Variant translocations
• Other partner genes on chromosomes 1, 2, 3, 17, 19, 22, and X (see table in WHO book)
• ALK staining restricted to the nucleus generally
• may be membranous or cytoplasmic
• no difference in survival
• frequent secondary chromosomal imbalances:
• losses:
• 4
• 11q
• 13q
• Gains:
• 7
• 17p
• 17q

Other features:

• advanced stage often (70% stage III-IV) 
• B symptoms often (75%)

References:

•  WHO Classification of Tumours of Haematopoietic and Lymphoid Organs (2008)