April 22, 2024

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ALCL: Anaplastic large cell lymphoma and related treatment

ALCL: Anaplastic large cell lymphoma and related treatment

ALCL: Anaplastic large cell lymphoma and related treatment



ALCL: Anaplastic large cell lymphoma and related treatment.  

Anaplastic large cell lymphoma (ALCL), also known as ki-1 lymphoma, has different cell morphology, similar to R-S cells, and can sometimes be confused with Hodgkin’s lymphoma and malignant histiocytosis.


The cells are CD30+, which is Ki-1(+), often have t (2; 5) chromosomal abnormalities, and often have skin invasion in the clinic, with or without lymph nodes and other extranodal lesions.

The immunophenotype can be T cell type. The clinical development is rapid, and the treatment is the same as that of large cell lymphoma.


Anaplastic large cell lymphoma

Anaplastic large cell lymphoma, which is an independent type of non-Hodgkin's lymphoma, was identified by the German pathologist Stein in 1985 using Ki-1 (CD30) antibody. It often exhibits anaplastic features and is named anaplastic Large cell lymphoma.

The REAL classification classifies persons with a B-cell phenotype as diffuse large B-cell lymphoma.


Currently, ALCL only includes T phenotype and Null (non-T, non-B) phenotype. About 60%-85% of ALCL cases express anaplastic lymphoma kinase (ALK) fusion protein, which is caused by the aberration of the ALK gene locus on chromosome 2.


The most common one is t(2;5)(p23;q35) to form the fusion gene NPM-ALK, which is composed of the nucleophosphate protein B23 (NPM) gene located on chromosome 5 and the ALK gene located on chromosome 2.


Fusion is formed, and the expressed fusion protein is NPM-ALK protein; recently, more ALK genes and other genes have been discovered through chromosome translocation or chromosome inversion to form fusion genes, such as t(1; 2) (q25; p23) TPM3-ALK gene formed by t(2; 3) (p23; q21) TFG-ALKs gene, TFG-ALKL gene and TFG-ALKxL gene, formed by inv(2) (p23; q35) ATIC-ALK gene, CLTCL-ALK gene formed by t(2;17)(p23;q23) and MSN-ALK gene formed by t(X;2)(q11;p23).


Clinical features

Clinically, ALCL is divided into primary (systemic and skin) and secondary (transformed from other lymphomas), accounting for about 2%-7% of all NHL.

As more and more studies have shown that the manifestations of ALK-positive and ALK-negative cases in primary systemic ALCL are significantly different, the ALK-positive and ALK-negative primary systemic ALCL are introduced separately.


ALK-positive primary systemic ALCL

ALK-positive primary systemic ALCL mainly occurs in patients before the age of 30. The research of Falini et al. also showed that the gender difference is very obvious, the male to female ratio is 6:1, and it mainly occurs in the 20-30 age group. ALCL usually presents as enlarged peripheral and abdominal lymph nodes.

About two-thirds of patients have fever or stage III/IV. In about 60% of cases, extranodal involvement is involved, and about 40% have two or more extranodal involvements. The skin (21%), bone (17%) and soft tissue (7%) are the most commonly affected extranodal sites.

Numerous studies have shown that the prognosis of ALK-positive ALCL is significantly better than that of ALK-negative cases.


ALK negative primary systemic ALCL

ALK-negative primary systemic ALCL and ALK-positive cases have many morphological, immunophenotypic, and clinical features that are the same. The detection of ALK fusion genes is the only way to distinguish them. ALK-negative primary systemic ALCL is more common in older patients, and the prognosis of these patients is poor.


Primary cutaneous ALCL

Primary cutaneous ALCL accounts for about 10% of skin lymphomas. It has been confirmed that it and ALK-negative primary systemic ALCL are two different entities. Primary cutaneous ALCL mostly occurs in elderly patients, the average age is about 60 years old, ALK negative and lack of cytotoxic phenotype.

The lesions appear as solid, asymptomatic skin or purple-red masses under the skin. Ulcers can occur on the surface, and it is less common that the form of multiple tumor nodules invades the surrounding area or multiple sites and multiple centers are characterized by tumors.

In about 25% of patients, there may be partial or complete regression, and local resection and chemotherapy have a good prognosis.


General organizational characteristics

The structure of the lymph node is partially or completely destroyed, and some only invade the lymphatic sinus. Tumor cells often first involve the paracortical area of ​​the lymph node, and then become nested or diffusely spread along the lymphatic sinus.

When the structure of the lymph node is partially destroyed, the tumor cells often invade the paracortical area and the side of the follicle, the blood vessel infiltration is obvious, and the fibrous tissue hyperplasia is common, which is manifested as the thickening of the capsule and the fibrous cord surrounding the tumor cell nest.

The proliferating tumor cells can be single or accompanied by other components such as small lymphocytes, plasma cells, neutrophils, histiocytes, etc. A few can see phagocytes and necrosis.


Light microscopic features of tumor cells

The cells are large or medium in size, round, oval or irregular. The nucleus is round, oval or irregular, with an embryo-like nucleus, with a curved nucleus. One side of the nuclear membrane is smooth and slightly convex, and the other side is sunken with multiple notches.

Some tumor cell nuclei are similar to Hodgkin's R-S cell-like binucleoma cells, but there are no diagnostic R-S cells. Sometimes you can see multinucleated giant cells arranged in a horseshoe shape or a flower ring, with thick chromatin and obvious eosinophilic nucleoli.


Features of tumor cells under electron microscopy

Tumor cells are diverse in morphology, with irregular nuclei, offset, large nucleoli, and rich cytoplasm. A large number of accumulated ribosomes and rough endoplasmic reticulum are seen in the cytoplasm.

Whether the high electron density particles and transparent vesicles scattered in the cytoplasm are perforin or granzyme remains to be confirmed.

The Golgi apparatus is located in the depression of the nuclear membrane. Tumor cells occasionally connected with primitive cells, but no desmosomes.


Histopathological classification

According to the main morphological characteristics of tumor cells, they are divided into 3 subtypes.


Normal type (70%)

The envelope of the diseased lymph node is thickened, and all or part of the lymphatic sinus is involved. The tumor cells infiltrate along the lymphatic sinus and the paracortical area, and grow around small blood vessels in the early stage. Common characteristic embryo-like, rosette-like and R-S-like giant cells.


Lymphoid tissue cell type (10%)

The organizational structure is basically the same as the ordinary type. The tumor cells are small to medium in size, scattered or distributed in small foci. At the same time accompanied by a large number of tissue cells. CD30 positive tumor cells are scattered.


Small cell type (smallcellvariant5%-10%)

The structure of the lymph node is partially or completely destroyed, the tumor cells are small in size, the nucleus is irregular, some are gyrus-like, and the chromatin is dense.

Scattered or clustered large cells with no obvious atypia can be seen among the tumor cells. CD30-positive tumor cells are characteristically clustered around high endothelial veins.

It should be pointed out that the above types can occasionally coexist in the same biopsy lesion or appear in different biopsy lesions in the same case successively, indicating that ALCL has a broad morphological spectrum.



Molecular mechanism

Little is known about the exact pathological mechanism of ALCL. Studies have found that about 30-80% of patients have anaplastic lymphoma kinase (ALK) gene translocation on chromosome 2, producing abnormal ALK fusion proteins that are carcinogenic.


The most common karyotype abnormality in ALK-positive ALCL is the t(2;5)(p23;q35) translocation, that is, the ALK gene is fused with the nucleophosmin (NPM) gene of chromosome 5 to express the NPM-ALK fusion protein Because the wild-type NPM part contains nuclear localization sites, the NPM-ALK fusion protein can enter the nucleus, and this karyotype abnormality accounts for about 75% of ALK-positive ALCL.


Recently, more ALK genes and other genes have been found to be fusion genes formed by chromosome translocation or chromosome inversion, such as the TPM3-ALK gene formed by t(1;2)(q25;p23), t( 2; 3) TFG-ALKs gene, TFG-ALKL gene and TFG-ALKxL gene produced by (p23;q21), ATIC-ALK gene formed by inv(2)(p23;q35), t(2;17)( p23; q23) CLTCL-ALK gene and t(X; 2) (q11; p23) MSN-ALK gene.


ALK gene features voice

The receptor-type tyrosine kinase Anaplastic lymphoma kinase (ALK) was first discovered in Anaplastic large cell lymphoma (ALCL), formed by the translocation of chromosomes 2 and 5 The fusion protein contains the 3'intracellular domain of ALK and the 5'domain of nucleophosmin (NPM).

Subsequent studies found that normal ALK is exclusively expressed in the nervous system, such as the brain and nerve cord, especially in the brain of newborns.


The ALK gene is located at the 2p23 site of chromosome. Under normal circumstances, human alk can be transcribed to produce an mRNA with a size of 6222bp.

It consists of 29 exons and encodes a 1,620 amino acid sequence of 200KDa I type penetrating protein ALK, which is a kind of protein. Receptor tyrosine kinase (RTK) is a member of the RTK insulin superfamily. The complete ALK has a typical RTK three-part structure, namely the extracellular domain, lipophilic penetrating domain and intracytoplasmic tyrosine kinase.

According to reports in the literature, ALK protein is expressed in 60%-85% of primary systemic ALCL, except for a few diffuse large B-cell lymphomas. It is a relatively specific immune response to primary systemic ALCL. Phenotypic characteristics.


The abnormal expression of ALK in some ALCL originates from different chromosomal translocations. The genomic breakpoints of ALK translocations mostly occur in the introns between exons 16 and 17, while exons 17-26 encode the ALK intracellular domain. Each translocation produces a different fusion protein.

The 5'end of the body is fused with the 3'end of the ALK tyrosine kinase domain. In most cases, the partner at the 5'end has a domain that can form homodimers or heterodimers, so that the ALK kinase domain is phosphorylated interactively, the interaction is enhanced, and a variety of downstream proteins are phosphorylated.

The increased activity of the unregulated ALK makes its function similar to that of the proto-oncoprotein. These fusion proteins are located in different subcellular regions, which may lead to different cell function changes.


About 70-80% of ALK-positive ALCLs express NPM-ALK, which is caused by the translocation of chromosome t(2;5)(p23;q35). The 5'end of npm fuses with the 3'end of alk, resulting in NPM The amino terminus of the tyrosine kinase is fused with the tyrosine kinase functional region at the base end of the ALK shuttle.

The npm located on chromosome 5 encodes a cell cycle regulating NPM. The protein has a molecular weight of 38kd and is related to pro-ribosomal particle transport and ribosomal biogenesis, regulation of cell division, DNA repair, transcription and genome stability.

NPM contains nuclear localization signals and dimer domains, which can produce large homodimers and heterodimers. NPM is very important for the transformation function of the NPM-ALK fusion protein.

The mutant lacking the NPM dimer domain can transform cells, suggesting that dimerization is a key factor in signal transmission. Research results in transgenic model mice show that NPM-ALK can cause malignant lymphoma.


Under normal circumstances, ALK is only expressed in the nervous system. The expression level of ALK gene in the human body decreases with the development and maturity of the brain.

The amount in mature brain tissue is very low, and the expression has a certain regionality; the expression of ALK is not found in other systems, especially the hematopoietic system.

The lack of expression of ALK gene in most non-hematopoietic tumors and normal tissues indicates that the distribution range of ALK protein is extremely narrow.

ALK protein is an important molecular marker of ALCL and has a high value in the diagnosis of ALCL.



NPM protein feature

Also called B23, it was first identified in the late 70s and early 80s. NPM is a nucleolar protein with a molecular weight of 38kD encoded by chromosome 5.

The NPM molecule can bind to the nucleoprotein through an oligomerization region template at the N-terminus and two nuclear localization signals at the C-terminus (shuttle base), and participate in Cytoplasmic/nuclear transport and assembly nuclear transport of the pre-nucleosome particles of the cell.


NPM constantly shuttles between the nucleolus and the cytoplasm, so it can be used as a carrier to transfer newly synthesized proteins to the nucleolus. NPM has a domain with oligomerization function. Under normal circumstances, it will oligomerize itself, and it can also form heteropolymers with NPM-ALK, which will lead to the aggregation of NPM-ALK protein in the nucleus.



NPM-ALK gene features

NPM-ALK: t(2;5)(p23;q35) chromosomal rearrangement results in the expression of an 80KD fusion protein, which includes the first 117aa of NPM fused to the C-terminal 1058-1620 residues of ALK. The breakpoint of the ALK genome sequence is at the 1935bp intron, which is located between the exons encoding the transmembrane and proximal regions of ALK.

The breakpoint of the NPM gene sequence is located at intron 4 of NPM. Almost all fusion proteins that include ALK contain the same 563aa that constitutes the cytoplasmic part of ALK.

Only MSN-ALK has the breakpoint located at the exon near the membrane region of the ALK gene and the ALK part is slightly shorter than the others, but the structure Also very similar.


The cytoplasmic tail end of the ALK molecule carries a tyrosine kinase decomposition region. t(2;5) makes the gene encoding the N-terminal domain of NPM close to the gene encoding the cytoplasmic part of the entire ALK protein.

As a result, ALK The gene is regulated by the NPM promoter, thereby inducing the complete and universal transcription of the NPM-ALK fusion gene to produce an 80kd fusion protein named NPM-ALK or P80. NPM-ALK is the most common type of ALK fusion in ALCL Protein is also the most studied and the best prognosis for lymphoma.


Anaplastic Lymphoma Treatment and Prognosis

ALCL is a highly malignant lymphoma with a 5-year survival rate of 52%. Treatment can be carried out by radiotherapy, chemotherapy, bone marrow transplantation and other methods.

Chemotherapy is the most suitable, most cases can be completely remitted (CR), the recurrence rate is low, and the 3-year and 5-year survival rates are both high.

The initial effect of radiotherapy is good, but it is easy to relapse in the long term. Bone marrow transplantation is considered an effective emergency treatment measure.

Generally speaking, ALCL has a better prognosis than other large cell lymphomas.


The prognosis is related to the age of onset of the tumor, the presence or absence of symptoms, the primary location, clinical stage and immunological classification, but 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. The prognosis of asymptomatic patients is better than that of symptomatic patients, and the prognosis of patients with primary nodules is better than those outside nodules.


The 3-year survival rate of clinical stage I and stage II cases is higher than that of stage III and IV cases, and histological classification has nothing to do with the prognosis.

ALCL originating from the skin, especially those confined to the skin, has a good prognosis (4 years survival rate of 80%), and some cases can heal spontaneously (17%), as well as the efficacy and treatment of simple resection or local radiotherapy.

Systemic multiple chemotherapy for high-malignant lymphoma or autologous bone marrow transplantation has the same effect, and it is considered to be a unique type of low-grade malignant tumor.



The correlation between the prognosis of anaplastic lymphoma and ALK speech

Many scholars believe that the prognosis of ALCL patients is related to whether the chromosome translocation occurs.

Among aggressive NHLs in children and young patients, ALK-positive systemic ALCL is the most likely to be cured, and the prognosis is better than 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 pointed out that the 5-year survival rate (79.8%) of ALK-positive cases was much better than that of ALK-negative cases (32.9%), P<0.01. The prognostic statistics of 78 patients with ALCL (ALK positive 53, ALK negative 25) by Brunangelo Falini et al. showed that 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 %) resistant to chemotherapy; 56.0% of ALK-negative cases achieved complete remission, 28.0% achieved partial remission, and the remission rate reached 84.0%.

At the same time, 4 cases (16.0%) were resistant to chemotherapy; the median survival time of all cases For 2.1 years (0.07 years to 13.17 years), the overall survival rate of ALK-positive cases (71.0%±6.0%) is much better than that of 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%) is also much better than that of ALK-negative cases (28.0%±14.0%), P<0.0001.

Randy D and other studies also showed that the 5-year survival rate (93.0%) of ALK-positive ALCL cases was much better than that of 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.

However, if the exact mechanism is not known, Brunangelo Falini and other studies have shown that ALK-positive cases are significantly less resistant to chemotherapy (7.7%) than ALK-negative cases (16.0). %).


At the same time, the chemotherapy effect of ALK-positive cases is significantly better than that of ALK-negative cases.

Although the exact mechanism is not clear, one thing is certain, that is, the prognosis of ALK-positive ALCL is significantly better than that of ALK-negative cases, so for clinical diagnosis It is necessary to detect the presence or absence of ALK fusion genes in ALCL.

At present, chromosomal translocation and the expression of ALK have been specified by WHO as one of the clinical diagnostic indicators of ALCL.




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