Anaplastic large cell lymphoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Shivali Marketkar, M.B.B.S. [2]Sowminya Arikapudi, M.B,B.S. [3]

Overview

Cytology Findings

According to the World Health Organization (WHO), the most important factor to diagnose a ALK negative ALCL is morphology and immunophenotype:

Immunophenotype criteria

• CD30 expression
• Nuclear negativity for the PAX5 transcription factor (usually expressed in Hodgkin’s lymphoma classic variant)
• Negativity for the EBV markers EBER and LMP1 (which may be expressed in Hodgkin’s lymphoma classic variant)
• Presence of clonal T-cell receptor rearrangements (usually absent in Hodgkin’s lymphoma classic variant).

Genetics

ALK positive anaplastic large cell lymphoma is associated with a rearrangement in the anaplastic lymphoma kinase (ALK) gene. The most frequent gene translocation is T(2;5)(p23;q35). This translocation leads to a chimeric protein between the nucleolar phosphoprotein (NPM) gene (5q35) and ALK gene (2p23), which has structural similarity to the insulin growth factor receptor. Normal T-cells require IL-2 as a growth factor; T-cells of patients with ALK positive anaplastic large cell lymphoma have a constitutive activation of IL-2 receptor caused by the new NMP-ALK chimeric protein. Other gene mutations include:

• T(1;2), encoding a tropomyosin3 (TPM3)/ALK fusion protein (10 to 20%)
• T(2;3), encoding a TRK fusion gene (TFP)/ALK fusion protein (2 to 5%)
• Inv(2), encoding a ATIC (Pur H gene)/ALK fusion protein (2 to 5%)
• T(2;17), encoding a clathrin heavy (CLTC)/ALK fusion protein (2 to 5%)
• T(2;17), encoding a ALO17/ALK fusion protein (2 to 5 percent of cases)
• T(2;19), encoding a tropomyosin 4 (TPM4)/ALK fusion protein (<1%)
• T(2;22), encoding a non-muscle myosin (MYH9)/ALK fusion protein (<1%)

Molecular biology

The majority of cases, greater than 90%, contain a clonal rearrangement of the T-cell receptor. This may be identified using PCR techniques, such as T-gamma multiplex PCR. Oncogeneic potential is conferred by upregulation of a tyrosine kinase gene on chromosome 2. Several different translocations involving this gene have been identified in different cases of this lymphoma. The most common is a chromosomal translocation involving the nucleophosmin gene on chromosome 5. The translocation may be identified by analysis of giemsa-banded metaphase spreads of tumour cells and is characterised by t(2;5)(p23;q35). The product of this fusion gene may be identified by immunohistochemistry using antiserum to ALK protein. Probes are available to identify the translocation by fluorescent in situ hybridization. The nucleophosmin component associated with the commonest translocation results in nuclear positivity as well as cytoplasmic positivity. Positivity with the other translocations may be confined to the cytoplasm. Mutagenesis and functional studies have identified a plethora of NPM1–ALK interacting molecules which ultimately lead to the activation of key pathways including Erk, PLC-γ, PI3K, and Jak/signal transducers and activators of transcription (STAT) path- ways, which in turn control cell proliferation and survival and cytoskeletal rearrangements.

Immunophenotype

The hallmark cells (and variants) show immunopositivity for CD30 (also known as Ki-1). True positivity requires localisation of signal to the cell membrane and/or paranuclear region (cyptolasmic positivity is considered non-specific and non-informative). Another useful marker which helps to differentiate this lesion from Hodgkin lymphoma is Clusterin. The neoplastic cells have a golgi staining pattern (hence paranuclear staining), which is characteristic of this lymphoma. The cells are also typically positive for a subset of markers of T-cell lineage. However, as with other T-cell lymphomas, they are usually negative for the pan T-cell marker CD3. Occasional examples are of null (neither T nor B) cell type. These lymphomas show immunopositivity for ALK protein in 70% of cases. They are also typically positive for EMA. In contrast to many B-cell anaplastic CD30 positive lymphomas, they are negative for markers of Epstein-Barr Virus (EBV).

Microscopic Pathology

The histologic features of Anaplastic large cell lymphoma are variable. The hallmark cells are of medium size and feature abundant cytoplasm (which may be clear, amphophilic or eosinophilic), kidney shaped nuclei, and a paranuclear eosinophilic region. Occasional cells may be identified in which the plane of section passes through the nucleus in such a way that it appears to enclose a region of cytoplasm within a ring; such cells are called "doughnut" cells.

Histologic Classification

Name	Description
Classical Variants
Common pattern	ALK positive anaplastic large cell lymphoma Most common morphological variant (75%). In large cells, nucleoli tend to be more prominent The cytoplasm may be either basophilic or eosinophilic and the cell might have many nuclei with dispersed or clumped chromatin Given that the lymphomatous cells grow in the lymph node's sinuses, this variant may resemble a metastatic tumor
Atypical Variants
Small cell	ALK positive anaplastic large cell lymphoma Cells have nuclear irregularity and perivascular/intravascular distribution Occasionally, lymphomatous cells have a pale cytoplasm with a central nucleus, described as "fried egg cell"
Lymphohistiocytic	ALK positive anaplastic large cell lymphoma Histiocytes have an acidophilic cytoplasm and a perinuclear clear area, with an eccentric nuclei and condensed chromatin Lymphomatous cells cluster around the perivascular area as demonstrated by immunostaining with CD30 and ALK antibodies
Giant cell	ALK positive anaplastic large cell lymphoma
Hodgkin's like	The morphological characteristics of this pattern are similar to the nodular sclerosis variant of Hodgkin's lymphoma This pattern is predominately more common among female There are two immunophenotype: Positive: CD30, ALK, epithelial membrane antigen (EMA), CD43 (only 66% of the times), and perforin Negative: CD15, CD20, Pax5/BSAP, and EBV
Rare Variants
Sarcomatoid	ALK positive anaplastic large cell lymphoma

High magnification micrograph of an anaplastic large cell lymphoma. (H&E stain)

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