Introduction
Anaplastic large cell lymphoma(anaplasticlargecelllymphoma, ALCL) also known as ki-1 lymphoma, cell morphology is different, similar to RS cells, sometimes withHodgkin's lymphomaConfused with malignant histiocytosis. The cells are CD30+, which is Ki-1(+), often have t(2;5) chromosomal abnormalities, and often have skin invasions with or without lymph nodes and other external lesions. The immunophenotype can be a T cell type. Rapid clinical development, treatment of large cell lymphoma.
basic introduction
Anaplastic large cell lymphoma, an independent type of non-Hodgkin's lymphoma, was identified by the German pathologist Stein in 1985 using the Ki-1 (CD30) antibody, often characterized by anatropy, and was named anaplastic. Large cell lymphoma. The REAL classification classifies B cell phenotypes as diffuse large B-cell lymphomas. Currently, ALCL only includes the T phenotype and the Null (non-T non-B) phenotype. Approximately 60%-85% of ALCL cases express an anaplastic lymphoma kinase fusion protein due to aberrations in the ALK locus on chromosome 2. The most common is t(2;5)(p23;q35) to form the fusion gene NPM-ALK, which is composed of the nucleolar phosphoprotein B23 (NPM) gene located on chromosome 5 and the ALK gene located on chromosome 2. The fusion forms and expresses the fusion protein as NPM-ALK protein; recently, more fusion genes of ALK gene and other genes formed by chromosome translocation or chromosome reversal are found, such as t(1;2)(q25; P23) formed by the TPM3-ALK gene, TFG-ALKs gene produced by t(2;3)(p23;q21), TFG-ALKL gene and TFG-ALKxL gene, inv(2)(p23;q35) The ATIC-ALK gene, the CLTCL-ALK gene formed by t(2;17) (p23; q23) and the MSN-ALK gene formed by t(X; 2) (q11; p23).
Clinical manifestation
Clinically, ALCL is divided into primary (systemic and cutaneous) and secondary (transformed from other lymphoma), accounting for about 2% to 7% of all NHL. Since more and more studies have shown significant differences in ALK-positive and ALK-negative cases in primary systemic ALCL, ALK-positive and ALK-negative primary systemic ALCL were introduced.
1. ALK positive primary systemic ALCL
ALK-positive primary systemic ALCL occurs primarily in patients before the age of 30. Falini et al. also showed that the gender difference is obvious, the ratio of male to female is 6:1, and mainly occurs in the 20-30 age group. ALCL usually manifests as swelling of peripheral and abdominal lymph nodes. About 2/3 of the patients have fever or stage III/IV. In about 60% of cases, there is extranodal involvement, and about 40% have two or more extranodal involvement. Skin (21%), bone (17%), and soft tissue (7%) are the most common external sites involved. Numerous studies have shown that ALK-positive ALCL has a significantly better prognosis than ALK-negative cases.
2. ALK negative primary systemic ALCL
ALK-negative primary systemic ALCL and ALK-positive cases have many morphological, immunophenotypic, and clinical features, and detection of ALK fusion genes is the only way to distinguish them. ALK-negative primary systemic ALCL is more common in older patients, and these patients have a poorer prognosis.
3. Primary cutaneous ALCL
Primary cutaneous ALCL accounts for about 10% of cutaneous lymphoma. It has been shown to be two different entities with ALK-negative primary systemic ALCL. Primary cutaneous ALCL occurs mostly in elderly patients, with an average age of about 60 years old, ALK negative and lack of cytotoxic phenotype. The lesion appears as a solid, asymptomatic skin or a subcutaneous purple-red mass. Ulcers can occur on the surface. It is less common that multiple forms of tumor nodules are characterized by invasion of peripheral areas or multiple sites, and multi-center tumors. In about 25% of patients, some or all of them may resolve, and local excision and chemotherapy have a good prognosis.
Organizational characteristics
Some or all of the lymph node structure is destroyed, and some only invade the lymphatic sinus. The tumor cells often involve the lymph node paracortical area first, and then diffusely spread in the nest or along the lymphatic sinus. When the lymph node structure is partially destroyed, the tumor cells often invade the paracortical area and the follicular area, and the vascular infiltration is more obvious. The common fibrous tissue hyperplasia is characterized by thickening of the capsule, and the fibrous cord surrounds the tumor cell nest. Proliferating neoplastic cells may be singular or accompanied by other components such as small lymphocytes, plasma cells, neutrophils, tissue cells, etc., a few visible phagocytic cells and necrosis.
Light mirror feature
Light microscopy characteristics of tumor cells: the cells are large or medium in size, round, elliptical or irregular. The nucleus is round, oval or irregular, with an embryonic nucleus, its nucleus is curved, one side of the nuclear membrane is smooth and slightly convex, and the other side is recessed with multiple notches. Some tumor cell nuclei resemble Hodgkin's RS cell-like binuclear cells, but no diagnostic RS cells. Sometimes, multi-nuclear giant cells arranged in a horseshoe shape or a flower ring shape can be seen, the chromatin is thick and the nucleolus is obviously eosinophilic.
Electron microscopy
Electron microscopic characteristics of tumor cells: tumor cells have various shapes, irregular nuclear, partial position, large nucleoli, and abundant cytoplasm. A large number of ribosomes and rough endoplasmic reticulum were found in the cytoplasm. The cytoplasm is scattered in the membrane-coated high electron density particles and transparent vesicles, whether it is perforin or granzyme, yet to be confirmed. The Golgi apparatus is located in the depression of the nuclear membrane. Tumor cells are occasionally connected to the original cells, but no desmosomes.
Subtype classification
According to the main morphological characteristics of tumor cells, it is divided into three subtypes.
Normal type (70%)
The lesions of the lymph nodes are thickened, and all or part of the lymphatic sinus is involved. The tumor cells infiltrate along the lymphatic sinus and paracortex, and grow around small blood vessels in the early stage. Commonly characterized embryonic, garland-like and RS-like giant cells.
Lymphoid tissue cell type (10%)
The organizational structure is basically the same as the normal type. Tumor cells are small to medium in size, scattered or small. It is accompanied by a large number of tissue cells. CD30 positive tumor cells are scattered.
Small cell type (smallcellvariant 5%-10%)
The lymph node structure is partially or completely destroyed, the tumor cells are small in size, the nucleus is irregular, and some of them are cerebral gyrus, and the chromatin is dense. Large cells with no obvious atypia scattered or clustered can be seen between the tumor cells. CD30-positive tumor cells are characteristically clustered around the high endothelial vein.
It should be pointed out that the above types can coexist in the same biopsy lesion or appear in different biopsy lesions in the same case, indicating that ALCL has a wide morphological spectrum.
Molecular mechanism
Little is known about the exact pathogenesis of ALCL. The study found that about 30-80% of patients have a translocation of chromosome 2 anaplastic lymphoma kinase gene, resulting in a carcinogenic abnormal ALK fusion protein. The most common karyotype abnormality in ALK-positive ALCL is the t(2;5)(p23;q35) translocation, ie, the ALK gene is fused to the nucleophosmin (NPM) gene of chromosome 5 to express the NPM-ALK fusion protein. Since the wild-type NPM fraction contains a nuclear localization site, the NPM-ALK fusion protein can enter the nucleus, which accounts for about 75% of the ALK-positive ALCL. Recently, more fusion genes of ALK gene and other genes formed by chromosome translocation or chromosome reversal have been discovered, such as the TPM3-ALK gene formed by t(1;2)(q25;p23), t( 2; 3) TFG-ALKs gene (p23; q21), TFG-ALKL gene and TFG-ALKxL gene, inv(2) (p23; q35) ATIC-ALK gene, t(2;17) P23; q23) The formed CLTCL-ALK gene and the MSN-ALK gene formed by t(X; 2) (q11; p23).
Genetic characteristics
ALK gene characteristics
The receptor-type tyrosine kinase anaplastic lymphoma kinase (ALK) was first discovered in the anaplastic large cell lymphoma (ALCL), which was formed by chromosome 2 and 5 translocations. The fusion protein comprises the 3'-end intracellular domain of ALK and the 5'-end domain of Nucleophosmin (NPM). Subsequent studies have found that normal ALK is specifically expressed in the nervous system, such as the brain and nerve cords, especially in the brains of newborns.
The ALK gene is located at chromosome 2p23. Normally, human alk can be transcribed to produce 6222 bp mRNA, consisting of 29 exons, encoding a 1620 amino acid sequence of 200 kDa type I transmembrane protein ALK, which is a kind of protein. The receptor tyrosine kinase (receptortyrosine kinase, RTK) is a member of the RTK insulin superfamily. The intact ALK has a typical RTK three-part structure, namely the extracellular domain, the lipophilic transmembrane region, and the intracytoplasmic tyrosine kinase. According to reports in the literature, ALK protein is expressed in 60% to 85% of primary systemic ALCL, except for expression in a small number of diffuse large B-cell lymphomas. It is a relatively specific immunity of primary systemic ALCL. Phenotypic characteristics.
Abnormal expression of ALK in certain ALCLs is derived from different chromosomal translocations. The genomic breakpoint of the ALK translocation occurs mostly in the middle of the 16 and 17 exons, while the exons 17-26 encode the ALK intracellular domain. Each translocation produces a different fusion protein, by the spouse. The 5' end of the body is fused to the 3' end of the ALK tyrosine kinase domain. In most cases, the 5'-end partner has a domain that can form a homo- or heterodimer, allowing the ALK kinase domain to be cross-phosphorylated, with enhanced interactions and phosphorylation of various downstream proteins. The loss of regulated ALK activity increases its function to approximate proto-oncoproteins, which are localized in different subcellular regions and may therefore result in different cellular functional changes.
Approximately 70-80% of ALK-positive ALCL expresses NPM-ALK, which is caused by the translocation of chromosome t(2;5)(p23;q35), and the 5' end of npm is fused to the 3' end of alk, resulting in NPM The amino terminus is fused to the tyrosine kinase domain of the ALK shuttle end. Npm, located on chromosome 5, encodes a cell cycle-regulating NPM that has a molecular weight of 38 kd and is involved in pre-ribosomal particle trafficking and ribosomal biogenesis, regulating cell division, DNA repair, transcription, and genomic stability. NPM contains nuclear localization signals as well as dimeric domains that can produce large homodimers and heterodimers. NPM is very important for the transformation function of NPM-ALK fusion protein. The mutant small energy capable of transforming cells with NPM dimer domain suggests that dimerization is a key factor in signal transmission. Studies in transgenic model mice have shown that NPM-ALK can cause malignant lymphoma.
Normally ALK is only expressed in the nervous system. The expression level of ALK gene in human body decreases with the development and maturity of the brain. The amount of mature brain tissue is very low, and the expression has a certain regionality; the expression of ALK is not found in other systems, especially hematopoietic system. The ALK gene is absent in most non-hematopoietic tumors and normal tissues, indicating that the distribution of ALK proteins is extremely narrow. ALK protein is an important molecular marker of ALCL and has high value in the diagnosis of ALCL.
NPM-ALK gene characteristics
NPM-ALK:t(2;5)(p23;q35) chromosomal rearrangement resulted in the expression of an 80KD fusion protein comprising the first 117 aa of NPM fused to the C-terminal 1058-1620 residue of ALK. The breakpoint of the ALK genomic sequence is at the 1935 bp intron, which is located between the exons encoding the ALK transmembrane and proximal membrane regions. The breakpoint of the NPM gene sequence is located at intron 4 of the NPM. Almost all fusion proteins including ALK contain the same 563aa which constitutes the cytoplasmic part of ALK. Only MSN-ALK is located at the exon of the ALK gene near the membrane and the ALK part is slightly shorter than others, but the structure It is also very similar.
The cytoplasmic end of the ALK molecule carries a tyrosine kinase domain, and t(2;5) brings the gene portion of the N-terminal domain encoding NPM closer to the gene encoding the cytoplasmic portion of the entire ALK protein, resulting in ALK. The gene is regulated by the NPM promoter, which induces complete, universal transcription of the NPM-ALK fusion gene, producing an 80kd fusion protein called NPM-ALK or P80, which is the most common ALK fusion in ALCL. Protein, which is currently the most studied, has the best prognosis of lymphoma.
Protein characteristics
NPM protein characteristics
Also known as B23, it was first identified in the late 1970s and early 1980s. NPM is a nucleolar protein encoded by chromosome 5 and has a molecular weight of 38 kD. NPM molecules can participate in nuclear protein binding through an N-terminal oligomeric template and a C-terminal (spinyl) two nuclear localization signal. Cytoplasmic/nuclear transport and assembly nuclear transport of pre-granule granules. NPM keeps moving between the nucleolus and the cytosol, so it can be used as a carrier to transport newly synthesized proteins to the nucleolus. NPM has an oligomeric domain, which normally undergoes its own oligomerization, and can also form a heteropolymer with NPM-ALK, which leads to the accumulation of NPM-ALK protein in the nucleus.
Treatment prognosis
ALCL is a heightMalignant lymphomaThe 5-year survival rate was 52%. Treatment can be carried out by radiotherapy, chemotherapy, bone marrow transplantation and other methods. Chemotherapy is most appropriate, with complete remission (CR) in most cases, low recurrence rate, and high 3- and 5-year survival rates. Radiotherapy has a good initial effect, but it is prone to recurrence in the long term.
Bone marrow transplantation is considered to be an effective emergency treatment. In general, ALCL has a better prognosis than other large cell lymphomas. The prognosis was related to the age of onset, presence or absence of symptoms, primary site, clinical stage and immunological typing, and had no significant relationship with histological classification. Children and young people respond well to treatment, and the 5-year survival rate is much higher than that of adults. Clinically asymptomatic patients have a better prognosis than those with symptoms, and the prognosis is better in the primary node than in the nodules. The clinical I and II cases were higher than the III and IV cases, and the histological type was not related to the prognosis. Primary skin on the skin ALCL, especially limited to the skin, due to a good prognosis (4-year survival rate of 80%), and some cases can be self-healing (17%) and the efficacy of the lesions alone or local radiotherapy and treatment The systemic multi-chemotherapy or autologous bone marrow transplantation of high-grade lymphoma is equally effective and is considered to be a unique type of low-grade malignancy.
Related Information
Correlation between prognosis of anaplastic lymphoma and ALK
Many scholars believe that the prognosis of patients with ALCL is related to whether or not the chromosome is translocated. In aggressive NHL in children and young patients, ALK-positive systemic ALCL is most likely to be cured, and the prognosis is superior to any other form of peripheral T-cell lymphoma. The difference in prognosis between ALK-positive and ALK-negative ALCL was first reported by Shiota et al. They noted that the 5-year survival rate of ALK-positive cases (79.8%) was much better than that of ALK-negative cases (32.9%), P < 0.01.
Brunangelo Falini et al. performed prognostic statistics on 78 patients with ALCL (ALK positive 53, ALK negative 25). 77.3% of ALK positive cases achieved complete remission, 15.0% achieved partial remission, and the remission rate reached 92.3%, while 4 cases (7.7 %) tolerant to chemotherapy; 56.0% of ALK-negative cases achieved complete remission, 28.0% achieved partial remission, remission rate reached 84.0%, and 4 (16.0%) were resistant to chemotherapy; median survival of all cases For 2.1 years (0.07-13.17 years), the overall survival rate of ALK positive cases (71.0% ± 6.0%) was much better than ALK negative cases (15.0% ± 11.0%), P < 0.0007.
The 10-year disease-free survival rate of ALK-positive cases (82.0%±6.0%) was also much better than ALK-negative cases (28.0%±14.0%), P<0.0001. Randy D and other studies also showed that the 5-year survival rate of ALK-positive ALCL cases (93.0%) was much better than ALK-negative ALCL cases (37.0%), P <0.00001. Numerous studies have shown that the prognosis of ALCL cases with ALK fusion gene is significantly better than that of negative cases, but the exact mechanism is unclear. Brunangelo Falini and other studies show that ALK-positive cases are significantly less resistant to chemotherapy (7.7%) than ALK-negative cases (16.0). At the same time, ALK-positive cases have significantly better chemotherapy than ALK-negative cases. Although the exact mechanism is unclear, one thing is certain. The prognosis of ALK-positive ALCL is significantly better than ALK-negative cases, so for clinical diagnosis. It is necessary to detect the presence or absence of the ALK fusion gene in ALCL. At present, chromosomal translocation and expression of ALK have been designated by WHO as one of the clinical diagnostic indicators of ALCL.
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