Anaplastic large cell lymphoma

Anaplastic large cell lymphoma (ALCL) is a type of non-Hodgkin lymphoma that features in the World Health Organisation (WHO) classification of lymphomas.

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Diagnosis

To make this diagnosis under its present system of classification, the WHO:

Requires

• The presence of "hallmark" cells
• Immunopositivity for CD30

Acknowledges as typical, but does not require

• Immunopositivity for ALK (anaplastic lymphoma kinase) protein

Specifically excludes

• Primary cutaneous T-cell lymphomas
• Other specific types of anaplastic lymphoma (particularly those of B-cell lineage) with CD30 positivity

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.

By definition, on histological examination, hallmark cells are always present. Where they are not present in large numbers, they are usually located around blood vessels. Morphologic variants include the following types:

• Common (featuring a predominance of hallmark cells)
• Small cell (featuring smaller cells with the same immunophenotype as the hallmark cells)
• Lymphohistiocytic
• Sarcomatoid
• Signet ring

Clinical features

The lymphoma is more common in the young and in males. It occurs in both nodal and extranodal locations. It typically presents at a late stage and is often associated with systemic symptoms ("B symptoms"). During treatment, relapses may occur but these typically remain sensitive to chemotherapy.

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).

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. Oncogenetic 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.

Differential diagnosis and diagnostic pitfalls

As the appearance of the hallmark cells, pattern of growth (nesting within lymph nodes) and positivity for EMA may mimic metastatic carcinoma, it is important to include markers for cytokeratin in any diagnostic panel (these will be negative in the case of anaplastic lymphoma). Other mimics include CD30 positive B-cell lymphomas with anaplastic cells (including Hodgkin lymphomas). These are identified by their positivity for markers of B-cell lineage and frequent presence of markers of EBV. Primary cutaneous T-cell lymphomas may also be positive for CD30; these are excluded by their anatomic distribution. ALK positivity may also be seen in some large cell B-cell lymphomas and occasionally in rhabdomyosarcomas.

Prognostic factors

Those with ALK positivity have a better prognosis. It is possible that ALK-negative anaplastic large cell lymphomas represent other T-cell lymphomas that are morphologic mimics of ALCL in a final common pathway of disease progression. It is possible that existing systems of classification will be revised in the future to exclude such lymphomas from this specific diagnosis.

Treatment Overview

• Managed under "Aggressive Lymphoma" guidelines
  • CHOP is first line of treatment, CHOP-Rituxan in the unlikely scenario that CD20 is positive, given that CD20 is a B-cell marker.
  • Radiation therapy as per institutional preference (based on ECOG, SWOG, and GELA trials), but usually added for bulky disease
• Overall better prognosis than other "Aggressive Lymphomas"
  • ALK+ 5-year survival 70-80%
  • ALK- 5-year survival 30-40%