Anaplastic large-cell lymphoma

Anaplastic large-cell lymphoma (ALCL) refers to a group of non-Hodgkin lymphomas in which aberrant T cells proliferate uncontrollably. Considered as a single entity, ALCL is the most common type of peripheral lymphoma and represents ~10% of all peripheral lymphomas in children. The incidence of ALCL is estimated to be 0.25 cases per 100,000 people in the United States of America. There are four distinct types of anaplastic large-cell lymphomas that on microscopic examination share certain key histopathological features and tumor marker proteins. However, the four types have very different clinical presentations, gene abnormalities, prognoses, and/or treatments. In 2016, the World Health Organization (WHO) separated ALCL into four types: ALK-positive ALCL (also termed ALK⁺ ALCL), ALK-negative ALCL (ALK⁻ ALCL), primary cutaneous ALCL (pcALCL), and breast implant-associated ALCL (BIA-ALCL). WHO defined BIA-ALCL as an ALCL type provisionally, i.e. subject to redefinition if future studies should support such a change.

ALK-positive and ALK-negative ALCL are aggressive systemic lymphomas. They are differentiated based on their expression of an abnormal ALK protein made by a somatic recombination in the ALK gene. ALK, i.e. anaplastic lymphoma kinase, is a protein product of the ALK gene located on chromosome 2. In ALK-positive ALCL, a portion of the ALK gene has merged with another site on the same or different chromosome to form a chimeric gene consisting of part of the new site and part of the ALK gene coding for ALK's activity. ALK-negative ALCL, while not involving ALK translocations, has, in a variable percentage of cases, various translocations, rearrangements, and mutations that may contribute to its development. BPI-ALCL is associated with occasional mutations in one or two genes but has not been reported to be associated with products of gene translocations or rearrangements. Most patients, including up to 90% of young children and adolescents, have circulating autoantibodies directed against the ALK fusion protein expressed by their tumor cells.

Diagnosis

thumb|Immunohistochemistry for CD30 ALK-positive ALCL is diagnosed by histological and immunological examinations of involved tissues, typically lymph nodes. These tissues have lymphoma-like infiltrates that have variable numbers of ALCL "hallmark" cells, i.e. cells with kidney- or horseshoe-shaped nuclei that strongly express CD30 as detected by immunohistochemistry and an ALK fusion protein as detected by fluorescence in situ hybridization. These cells are scattered throughout the infiltrates. WHO classifies these infiltrates into 5 patterns: a common pattern consisting of large variably shaped cells with large nuclei that typically contain multiple nucleoli (60–70% of cases); a small-cell pattern consisting of small to medium-sized neoplastic cells with clear cytoplasm and "hallmark" cells that are concentrated around small blood vessels (5–10% of cases); a lymphohistiocytic pattern consisting of small neoplastic cells along with abundant histiocytes (10% of cases); a Hodgkin's-like pattern in which the architecture resembles the nodular sclerosis pattern of Hodgkin lymphoma (3% of cases); and a composite pattern consisting of two or more of the just described patterns (15% of cases). with the ALK gene located on the short or "p" arm of chromosome 2 at position 23 (notated as 2p23) to form a chimeric gene notated as (2;5)(p23;q35). In 13% of cases ALK fuses with the TPM3 gene or in <1% of cases for each of the following genes: TFG, ATIC, CLTC, TPM4, MSN, RNF213 (also termed ALO17), MYH9, or TRAF1.

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. in 15% of cases, and the NOTCH1 gene in 15% of cases. About 24% of cases have a truncated ERBB4 gene.

Primary cutaneous anaplastic large-cell lymphoma

Signs and symptoms

pcALCL is the second most common lymphoma that includes lymphomatoid papulosis, various borderline CD30-positive cutaneous T cell lymphomas,-ALK, or TPM3-ALK chimeric genes. All 6 patients shared exactly the same breakpoint site in the ALK at exon 20 on the ALK gene. Typically leg involvement portends a worse prognosis: it has a five-year disease-specific survival rate of 76 percent compared with 96 percent for disease in other locations. Involvement of local nodes alone in patients with skin lesions does not seem to portend an adverse prognosis. to 10 it is estimated that the prevalence of BIA-ACLC in individuals with implants that have a textured surface is 1 in 30,000, with the highest risk being associated with polyurethane-coated implants, while the risk of it is 70-fold lower in individuals who have a smooth surface implant or have no implant at all (i.e. in patients that have another type of ALCL). These relations strongly suggest that BIA-ACLC develops primarily if not exclusively in patients with textured implants. In all cases, however, many researchers suspect that BIA-ALCL is an under-recognized, misdiagnosed, and under-reported complication of breast implants.

Treatment and prognosis

The treatment regimens for BIA-ALCL recommended by 1) a multidisciplinary expert review panel, 2) the National Comprehensive Cancer Network, and 3) the French National Cancer Institute (Agence Nationale de Sécurité du Médicament [ANSM]) are very similar, commonly used, and summarized here. BIA-ALCL staging is done to identify patients with BIA-ALCL confined to the implant, capsule, and effusion from more disseminated disease. The staging preferably employs the TMN system designed to stage solid tumors. This is based on historical data suggesting that BIA-ALCL progresses locally like solid tumors rather than liquid tumors such as other lymphomas. BIA-ALCL patients have surgical removal of the implant, capsule, and associated masses. Patients with localized disease (e.g. TMN stage 1A to 2A) that is completely excised by removal of the implant, the entire capsule, and any masses (must leave negative resection margins) receive no further therapy. About 85% of all BIA-ALCL patients should qualify to receive this treatment regimen. Patients with unresectable chest wall invasion, regional lymph node involvement (i.e. TMN Stage 2B to 4), or residual disease after surgery receive an aggressive adjuvant chemotherapy regimen such as EPOCH, CHOP, or CHOP plus etoposide.