Anaplastic Large Cell Lymphoma

General: Anaplastic large cell lymphoma (ALCL) represents approximately 3% of all NHL in adults, but 10-30% of NHL in childhood.85 Typically, the disease presents in systemic fashion with involvement of lymph nodes and possibly extranodal sites, including skin, bone, soft tissue, and other sites. This systemic form of disease must be distinguished from cases that present with disease limited to the skin (see section on CD30+ lymphoprolif-erative disorders of the skin below). Most patients will present at advanced stage (stage 3 or 4). Detection of ALK rearrangements (see below) are of importance due to the superior outcome of ALK+ ALCL compared to ALK -ALCL.86

Pathology: Although the morphologic features of ALCL are variable, essentially all cases will contain varying numbers of large cells with eccentrically placed, band- or horseshoe-shaped nuclei, often with a punctate area of eosinophilic cytoplasm located adjacent to the nucleus.85 These large cells are known as "hallmark cells," because their morphology is characteristic of ALCL (Figure 52.16). Variants of ALCL, termed "lymphohistiocytic variant ALCL" and "small cell variant ALCL," have also been described.

Figure 52.16 Anaplastic large cell lymphoma. Sheets of large, pleomorphic cells are present. The inset shows a characteristic "hallmark cell" with a band-shaped nucleus and central, punctate eosinophilic cytoplasm

Figure 52.17 Anaplastic large cell lymphoma. Immunostains of the case shown in Figure 52.16 demonstrate the large cells to be positive for CD30 (left panel) and ALK (right panel)

Figure 52.16 Anaplastic large cell lymphoma. Sheets of large, pleomorphic cells are present. The inset shows a characteristic "hallmark cell" with a band-shaped nucleus and central, punctate eosinophilic cytoplasm

Figure 52.17 Anaplastic large cell lymphoma. Immunostains of the case shown in Figure 52.16 demonstrate the large cells to be positive for CD30 (left panel) and ALK (right panel)

The marked nuclear pleomorphism seen in routine histologic sections of ALCL leads to a wide differential diagnosis. In some cases, the malignant cells resemble the Reed-Sternberg cells of Hodgkin's lymphoma. In other cases, the cells resemble metastatic carcinoma, especially in cases with only partial effacement, where the malignant cells may be confined to the lymph node sinuses.

Immunophenotype: The large cells will be strongly positive for CD30 and recent studies have indicated the vast majority of cases will express clusterin.8788 Most cases will also express cytotoxic proteins such as granzyme B or TIA1. The expression of other T-cell antigens is quite variable, although most cases will express at least one T-cell antigen. In some cases, no detectable T-cell antigens will be identified, leading to the designation "null cell." The T-cell origin of these latter cases is only revealed by the presence of monoclonal T-cell receptor rearrangements. In the majority of cases, ALK protein can be detected by immunohis-tochemistry as a result of a balanced translocation involving the ALK gene at 2p23 (Figure 52.17) The ALK-positive cases are also typically positive for EMA.

Molecular genetics: In approximately 60-80% of cases overall, and in an even greater percentage of cases arising in childhood, a balanced translocation is present involving the ALK gene at 2p23.85'89 In roughly 75% of such cases, the translocation is t(2;5)(p23;q35) involving ALK and NPM. In the remaining 25% of translocations, one of a large number of other translocation partner genes is involved instead of NPM, such as TPM3 (1q25), TFG (3q35), ATIC (2q25), or CLTC (17q23). Other translocation partner genes have also been described.

Translocations involving the ALK gene generally lead to aberrant expression of the ALK protein, which can be detected by immunohistochemistry. ALK translocations are best detected at the molecular level

FISH probes, which are capable of detecting rearrangement of the ALK gene, regardless of the partner gene present.90

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