Anaplastic large-cell lymphoma
Anaplastic large-cell lymphoma | |
---|---|
Other names | ACL |
Micrograph of an anaplastic large-cell lymphoma. H&E stain. | |
Specialty | Hematology, oncology |
Types | ALK-positive ALCL, ALK-negative ALCL, primary cutaneous ALCL, breast implant-associated ALCL |
Anaplastic large-cell lymphoma (ALCL) refers to a group of
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.[4] 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.[4][5]
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.[4] This chimeric gene overproduces a fusion protein with excessive ALK activity. 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.[6][7] 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.[4]
pcALCL and BIA-ALCL are far less aggressive lymphomas that tend to be localized to one or a very few sites. 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.[1] Its neoplastic cells may contain some gene translocations including, in very rare cases, ones with the ALK gene that are similar to those in ALK-positive ALCL. BIA-ALCL is caused by and develops around a breast implant.[4] It typically presents many years after the surgical implantation as a deformation, textural change, and/or pain emanating in the area around implanted breast. In most cases, the disease is localized to the involved breast.[8] 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.[4]
ALK-positive anaplastic large-cell lymphoma
Signs and symptoms
ALK-positive ALCL occurs mostly but not exclusively in children and young adults and is slightly more common in males. Most individuals present with
Diagnosis
Gene and molecular abnormalities
In 80–85% of cases, the ALK detected in ALK-positive ALCL is a NPM1-ALK fusion protein. It is made by a fusion of NPM1 gene, which makes
Treatment and prognosis
A recommended
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.[17][18][19][20] These and other drugs are undergoing clinical trials to determine there safety and effectiveness in treating ALK-positive ALCL.[21] (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.[9] 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.[10]
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 histological of this disease may overlap with and be difficult to distinguish from other CD30-positive
Gene and molecular abnormalities
ALK-negative ALCL tumor cells show products made by chimeric genes:
Treatment and prognosis
The various treatments of ALK-negative ALCL generally follow those used for ALK-positive ALCL. However ALK-negative individuals more often present at an advanced stage of disease that requires intensive therapy. 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.[16] The International T-Cell Project reported on the treatment of 220 patients with ALK-negative ALCL; 15 received only supportive care, 168 were treated with anthracycline-containing chemotherapeutic regimens, 31 with anthracycline plus etoposide–containing chemotherapeutic regimens, 6 with other regimens; 16 with high-dose chemotherapy plus autologous stem cell bone marrow transplantation, and 4 with radiotherapy alone. Of the 205 patients that had more that supportive therapy, the overall and complete response rates were 77% and 63%, respectively. After a median follow-up of 52 months, the median progression free and overall survival times were 41 months and 55 months, respectively; 3- and 5-year progression-free rates were 52% and 43%, respectively; and 3- and 5-year overall survival rates were 60% and 49%, respectively. Chemotherapy treatments containing both anthracycline and etoposide were associated with superior overall survival rates (3- and 5-years of 76% and 69%, respectively) compared to chemotherapy treatment regiments containing an anthracycline but not etoposide (3- and 5-year overall survival rates of 56% and 44%, respectively). Progression-free survival rates with the latter two types of chemotherapy treatment regimens were not appreciably different.[23]
Primary cutaneous anaplastic large-cell lymphoma
Signs and symptoms
pcALCL is the second most common lymphoma
Diagnosis
pcALCL lesions exhibit large malignant T-cells or null cells (i.e. cells lacking many T-cell receptor proteins) with "Hallmark" cell features of anaplasia, pleomorphism, and kidney- and horse shaped-nuclei.[24] These lesions are often limited to the dermis but can extend into the surrounding subcutaneous tissue and/or epidermis. Rarely, the lesions, termed pyrogenic variants, are rich in polymorphonuclear neutrophils. The neoplastic cells strongly express CD30 (100% of cases), CD2 (78%), CD4 (54–90% of cases), cytotoxicity marker proteins, and various other marker proteins that help distinguish it from other ALCL, cutaneous T-cell lymphomas, and cancers. While these cells typically are ALK-negative, they do express ALK-containing fusion proteins in rare cases. The latter cases have a relatively benign course compared to ALK-positive ALCL and are treated as variants of pcALCL rather than ALK-positive ALCL.[24]
Gene and molecular abnormalities
Similar to ALK-negative ALCL, pcALCL have chromosomal rearrangements in their
Treatment and prognosis
Most pcALCL individuals present with isolated lesions that are effectively managed with radical surgical excision and/or radiation therapies; this approach is regarded as
Breast implant-associated anaplastic large-cell lymphoma
Signs and symptoms
BIA-ALCL is a complication of silicon-filled and saline-filled
Diagnosis
In most individuals with BIA-ALCL, the affected breast has a thickened capsule around the implant and effusion fluid between the capsule and implant. Neoplastic cells are located in and typically limited to the capsule and effusion. Histological examination of the capsules shows large anaplastic cells but cells with all the features of ALCL "hallmark" are often difficult to detect. In addition to these neoplastic cells, the capsule lesions contain, sometimes in a large excess that makes diagnosis difficult, a variety of non-malignant cells such as small
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.[9] 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.[4] The development of BIA-ALCL, it has often been suggested, may be at least in part a T-cell-induced, inflammation-driven cancer response to the implant.[29]
Treatment and prognosis
The treatment regimens for BIA-ALCL recommended by 1) a multidisciplinary expert review panel, 2) the
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External links
- Information on Anaplastic Large Cell (Ki-1 / CD-30) Lymphomas from Lymphoma Information Network