Anaplastic large-cell lymphoma
|Anaplastic large-cell lymphoma|
|Classification and external resources|
Signs and symptoms
It occurs in both nodal and extranodal locations. It typically presents at a late stage and is often associated with systemic symptoms ("B symptoms").
To make this diagnosis under its present system of classification, the WHO the presence of "hallmark" cells and immunopositivity for CD30.
The classification acknowledges as typical, but does not require, immunopositivity for ALK (anaplastic lymphoma kinase) protein. It specifically excludes primary cutaneous T-cell lymphomas and 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)
- Signet ring
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 (cytoplasmic 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).
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 NPM–ALK interacting molecules which ultimately lead to the activation of key pathways including RAS/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. It has been demonstrated that NPM-ALK oncogenic effects is sustained by STAT3 activation. Activation of STAT3 is associated with a specific signature, which includes several transcription factors (i.e., CEBP/β), cell cycle (i.e., Cyclin D, c-myc etc.), survival/apoptosis molecules (Bcl-A2, Bcl-XL, Survivin, MCL-1) and cell adhesion, and mobility proteins.
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.
- Managed under "Aggressive Lymphoma" guidelines.
- Localized primary cutaneous ALCL
- Radiation therapy alone
- Surgical excision alone
- Surgically excision with adjuvant radiation.
During treatment, relapses may occur but these typically remain sensitive to chemotherapy.
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. Whereas ALK-positive ALCLs are molecularly characterized and can be readily diagnosed, specific immunophenotypic or genetic features to define ALK-negative ALCL are missing and their distinction from other T-cell non-Hodgkin lymphomas (T-NHLs) remains controversial, although promising diagnostic tools for their recognition have been developed and might be helpful to drive appropriate therapeutic protocols.
Systemic ALK+ ALCL 5-year survival: 70-80%. Systemic ALK- ALCL 5-year survival: 15-45%. Primary Cutaneous ALCL: Prognosis is good if there is not extensive involvement regardless of whether or not ALK is positive with an approximately 90% 5-year survival rate.
The lymphoma is more common in the young and in males.
A 2008 study found an increased risk of ALCL of the breast in women with silicone breast implants, although the overall risk remained exceedingly low due to the rare occurrence of the tumor.
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- Liu, Delong. "Anaplastic Large Cell Lymphoma". Medscape.
- Agnelli L, Mereu E, Pellegrino E, Limongi T, et al. (2012). "Identification of a 3-gene model as a powerful diagnostic tool for the recognition of ALK-negative anaplastic large-cell lymphoma". Blood 120 (6): 1274–81. doi:10.1182/blood-2012-01-405555. PMID 22740451.
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- Information on Anaplastic Large Cell (Ki-1 / CD-30) Lymphomas from Lymphoma Information Network