[3] There are four distinct types of anaplastic large-cell lymphomas that on microscopic examination share certain key histopathological features and tumor marker proteins.

[1] ALCL is defined based on microscopic histopathological examination of involved tissues which shows the presence of at least some ALCL-defining pleomorphic cells.

These "hallmark" cells have abnormal kidney-shaped or horseshoe-shaped nuclei, prominent Golgi, and express the CD30 tumor marker protein on their surface membranes.

WHO defined BIA-ALCL as an ALCL type provisionally, i.e. subject to redefinition if future studies should support such a change.

ALK is a tyrosine kinase that activities PI3K/AKT/mTOR, Ras-activated ERKs, Janus kinase-activated STAT proteins, and other cell signaling pathways as well as the expression of various genes by epigenetic mechanisms.

Activations of these signaling pathways and genes may stimulate cell growth, proliferation, survival, and/or other behaviors that promote malignancy.

pcALCL presents as a single or, less commonly, multifocal skin papules or tumors that typically are limited to the dermis without infiltrating to the subcutaneous tissues or spreading to other sites.

[4] ALK-positive ALCL occurs mostly but not exclusively in children and young adults and is slightly more common in males.

Involvement of the central nervous system or a leukemia-like circulation of malignant cells in the blood occurs only very rarely.

[9] 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.

[10] ALK-positive ALCL is diagnosed by histological and immunological examinations of involved tissues, typically lymph nodes.

[9] A recommended induction therapy for ALK-positive ALCL in individuals with lesions containing more than 10 percent CD30-positive cells consists of brentuximab vedotin (a drug consisting of an anti-CD30 antibody attached to a cell-killing agent, monomethyl auristatin E); two chemotherapy drugs, cyclophosphamide and the anthracycline doxorubicin; and the corticosteroid, prednisone.

For >60 year old and medically unfit individuals of any age, the standard CHOP regimen (cyclophosphamide, doxorubicin, prednisone, and the chemotherapeutic agent vincristine) is used.

[16] 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.

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.

The differential diagnoses of ambiguous cases may be helped by examining the tumor cells for the expression of certain marker proteins.

The aggressive treatments outline in the section on ALK-positive ALCL are used with the exception that patients with more favorable clinical and tumor tissue indicators as defined by having an International Prognostic Index score above 2 (particularly those who are under the age of 66) who obtain a complete remission after initial therapy are recommended for follow-up bone marrow transplantation.

[3] Individuals with pcALCL typically present with reddish masses that initially appear in the skin or, much less frequently, the lymph nodes or various organs.

In about 10% cases followed for many years, pcALCL presenting as skin lesions progresses to extracutaneous sites, mainly to regional draining lymph nodes.

[24] However, individuals with extensive disease and/or multiple tissue involvement respond poorly to front line treatment.

As currently recommended, brentuximab vedotin is use initially to treat widespread systemic disease; a single chemotherapeutic drug rather than aggressive combination chemotherapy with CHOP or similar regimens is used to treat patients not responding to brentuximab verdotin; aggressive chemotherapy regimens are used to treat widespread nodal and/of visceral disease and disease which failed on other regiments; and, although there is little data supporting this, employ allogeneic bone marrow transplantation for patients with multiple relapses that have progressed on systemic therapy.

This is due to the development of a tumor mass and/or swelling caused by an effusion (i.e. fluid) that accumulates between the breast implant surface and the fibrous capsule that has grown around it.

[27] Thus, about 17% of individuals present with a more aggressive disease that has spread from its original breast implant site to nearby lymph nodes, to areas outside of the capsule, or to more distal tissues.

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.

[27] 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.

[30] 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])[31] are very similar, commonly used, and summarized here.

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.

[4] Alternatively, the immunotherapeutic drug, brentuximab vedotin, may be used as initial therapy alone or in combination with a chemotherapy regimen to treat disseminated disease.

[30] While larger studies are needed, case reports suggest that brentuximab vedotin may be effective frontline monotherapy, either after surgical excision or as primary treatment for unresectable BIA-ALCL.