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], Kamal Akbar, M.D.[4]; Grammar Reviewer: Natalie Harpenau, B.S.[5]

Overview

The ALK gene is involved in the pathogenesis of ALK positive anaplastic large cell lymphoma. The DUSP22 gene is involved in the pathogenesis of ALK negative anaplastic large cell lymphoma. On microscopic histopathological analysis, medium sized cells, abundant cytoplasm, kidney shaped nuclei, and a paranuclear eosinophilic region are characteristic findings of anaplastic large cell lymphoma.

Pathophysiology

Genetic

• ALK-positive lymphoma is associated with a translocation in the ALK gene [T(2;5)(p23;q35)], which expresses the ALK protein.
• ALK negative anaplastic large cell lymphoma is characterized by a translocation T(6;7)(p25.3;q32.3), which inactivates the DUSP22 gene and leads to a higher proliferation rate.
• In healthy people, the product of the DUSP22 gene, the DUSP22 protein (also known as the JNK pathway-associated phosphatase or JKAP), inactivates the lymphocyte-specific tyrosine kinase protein during T-cell receptor signaling.
• DUSP22 mutations are also associated with breast cancer (the UDSMP22 protein can also block estrogen receptors) and primary cutaneous anaplastic large cell lymphoma.

Molecular biology

• The majority of anaplastic large cell lymphomas, 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.
• Oncogenic potential is conferred by up regulation 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 tumor cells and is characterized 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 (FISH).
• The nucleophosmin component associated with the common 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) pathways. These molecules then control cell proliferation and survival and cytoskeletal rearrangements.
• Other gene mutations include:
  • T(1;2), encoding a tropomyosin 3 (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%)

Immunophenotype

• The hallmark cells portray immunopositivity for CD30 (also known as Ki-1)
• True positivity requires pinpointing of the signal to the cell membrane and/or paranuclear region.
• Another useful marker, which helps to decipher this lesion from Hodgkin lymphoma, is Clusterin.
• The neoplastic cells have a golgi staining pattern (hence paranuclear staining), which is tell tale indicator 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 neither T nor B cell type. These lymphomas show immunopositivity for ALK protein in 70% of cases.
• They are also typically positive for epithelial membrane antigen (EMA). In contrast to many B-cell anaplastic CD30 positive lymphomas, the neoplastic cells are negative for markers of Epstein-Barr Virus (EBV).

Microscopic Pathology

The histological 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.

Histological 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 females. 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

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