gemcitabine, dexamethasone, and cisplatin), DHAP, and ICE.Drugs that inhibit ALK activity such as crizotinib and alectinib have been successful in establishing complete and partial remissions in a limited number of patients with advanced, refractory ALK-positive ALCL. These and other drugs are undergoing clinical trials to determine there safety and effectiveness in treating ALK-positive ALCL. (Also see clinical trials that use ALK inhibitors in ALK-positive ALCL and clinical trials that use ALK inhibitors in ALK-positive cancers.) ALK-negative anaplastic large cell lymphoma
Signs and symptoms
Unlike ALK-positive ALCL, ALK-negative ALCL tends to occur in older adults (median age at diagnosis: 55–60 years) and presents primarily with lymph node involvement; only 20% of patients with ALK-ALCL present with extra-nodal disease in sites such as the skin, bone, and soft tissues. Nonetheless, most individuals (~67%) present with advanced stage grade III or IV disease in which neoplastic infiltrates occur in multiple lymph node locations and/or extra-nodal sites. ALK autoantibodies are not found in this type of ALCL. The prognosis of ALK-negative ALCL is often quoted as being worse than that for ALK-positive ALCL but this may reflect the older age and advanced stage at which ALK-negative disease presents: studies comparing age- and grade-matched ALK-positive to ALK-negative ALCL patients show little differences in prognoses. Diagnosis
The histology of ALK-negative ALCL, similar to ALK-positive ALCL, consist of "hallmark" cells that strongly express CD30. Unlike ALK-positive ALCL, however, ALK-negative ALC does not fall into different morphological patterns.
The histology of palpable masses exhibit a different pathological picture: the tumor masses have multinodular areas that consist of necrosis or fibrous tissue interspaced with areas that consist of large neoplastic cells that have abundant cytoplasm and abnormally shaped nuclei within a fibrotic and chronic inflammatory cell background. Again, typical ALCL-defining "hallmark" cells may be difficult to find in these masses. The effusions show abundant, uniform-appearing, non-cohesive large cells with irregularly-shaped nuclei, prominent nucleoli and abundant cytoplasm. The histology and pathological features of diseased lymph nodes and tissues outside of the breast implant are indistinguishable from those seen in ALK-negative ALCL. The neoplastic cells in the capsules, effusions, and tissues strongly and uniformly express CD30, CD4 (75–84% of cases), EMA (48–90%), CD43 (86-95%), CD45 (44-74%), and in a far fewer percentage of cases various other marker proteins. These cells do not express ALK and often lack the characteristic surface marker proteins of T-cells. Identification of the status of these markers helps diagnose the disease. Gene and molecular abnormalities
No chromosome translocations, chimeric genes, or fusion proteins have been described in BIA-ALCL although the neoplastic cells in the disease have been described to have gene copy number variations involving gains in gene copies on the p arm of chromosome 19 and losses of gene copies in the p arms of chromosome 10 and 1. The neoplastic cells in BIA-ALCL show mutations of the STAT3 gene in 64% of cases and reports of mutations in JAK1, JAK3, DNMT3A, and TP53 genes.