Brief introduction of adult T-cell leukemia
The treatment strategy of adult T-cell leukemia depends on different clinical types. Chronic or smoky patients often take symptomatic support treatment, mainly to actively control infection and improve organ function. When the disease progresses or acute changes occur, active treatment measures can be considered. Although acute or lymphoma ATL has been actively treated by chemical and biological measures, the curative effect is not good, and the median survival time is 2 ~ 6 months.
Adult T-cell leukemia
3 English name *** Tcell leukemia
Adult T-cell leukemia, another name for adult T-cell leukemia; Adult t-cell leukemia; * * * cell leukemia/lymphoma; Adult T cell leukemia/lymphoma
5 classification hematology >; Leukocyte disease > leukemia
Oncology > Hematology >: Leukemia
6 ICD number C9 1.5
7 Epidemiology HTLV Ⅰ Ⅰ is the most direct cause of adult T-cell leukemia, and its main epidemic areas are located in southern Japan (such as Kyushu, Shikoku and Okinawa), the Caribbean, some special areas around South America, Central America and North America, and sub-Saharan Africa. HTLV Ⅰ Ⅰ infection is also prevalent in Taiwan Province province. In China, 1982 ~ 13252 serum samples from 28 provinces, municipalities and autonomous regions were investigated in 1988, and htlv Ⅰ antibody positive cases 19 cases were found. The incidence of HTLV ⅰ infection was 143/65438+ ten thousand people. 19 cases of positive infection, 9 cases were closely related to Japanese, and 10 cases had nothing to do with it. The incidence of HTLV type ⅰ infection is different in different regions of China, and the infection rate of HTLV type ⅰ in some coastal areas of Fujian is significantly higher than that in other inland areas. 1703 people detected HTLVⅰⅰ antibody, and the positive rate was 2.3%, among which the positive rate of ATL patients was as high as 7l%. Up to now, sporadic HTLVⅰⅰ infection and ATL cases have been reported all over the world.
The average age of patients infected with HTLV ⅰ in Japan is 57.6 years old. With the passage of time, the average age of patients infected with HTLV ⅰ outside Japan is lower, and the average age is about 45 years old. In epidemic areas, the prevalence rate of HTLVⅰ type I increased significantly with age before 70 years old, and decreased after 70 years old. The ratio of male to female varies with different reports and is generally close.
The prevalence of ATL is closely related to the prevalence of HTLV ⅰ infection in the population. Htlv Ⅰ usually occurs after a long incubation period of 20 ~ 30 years. Among the 65,438+0,000 ~ 2,000 people with positive serum antibody to HTLV Ⅰ, 65,438+0 people have ATL. A large number of data show that the lifetime risk range of ATL in HTLV ⅰ positive population is 0.5% ~ 7%, and most of them are 3% ~ 7%. It is reported that men are more dangerous than women.
There are three main modes of transmission of HTV ⅰ infection: ① Mother directly transmits it to her children, among which breastfeeding is the most common, and umbilical cord blood and saliva may also transmit HTV ⅰ. However, due to the congenital defects of HTLVⅰⅰ type ⅰ provirus and antibodies in cord blood and saliva, it is rare to spread through these two ways; ② Sexual transmission, mostly caused by sexual life, is more common for men to transmit to women, and relatively rare for women to transmit to men; ③ Blood-borne transmission, especially blood transfusion, blood products and sharing needles with drug users.
The etiology of ATL is related to the infection of human T cell leukemia virus type ⅰ (HTVⅰⅰ), and the patient's serum HTLVⅰⅰ is positive. The high incidence area is south of Kyushu Island in Japan, and 10% ~ 15% residents are positive for HTLV ⅰ antibody, but the incidence rate in other places is very low. It is not clear how to link the high incidence areas in Japan with the incidence rates in other regions.
Studies have shown that host susceptibility and/or common environmental conditions are related to HTLV ⅰ infection, and the positive rate of HTLV ⅰ antibody in family members is 3 ~ 4 times that of unrelated normal people. Htlv Ⅰ Ⅰ virus can be isolated from the sera of antibody-positive patients and normal outpatients.
Pathogenesis HTLV Ⅰ Ⅰ infection requires a long incubation period, which may eventually lead to a few people suffering from ATL, which in itself shows the complexity of ATL. So far, the pathogenesis of ATL has not been finally clarified, and many data show that the pathogenesis of ATL may be related to the following mechanisms.
9. 1 regulating protein tax There is a long terminal repeat (LTRs) at the end of HTLVⅰ Ⅰ provirus. LTRs contains the regulatory part of the virus, including the promoter sequence, and consists of U3, R and U5 (unique 3'- terminal, repetitive and 5'- terminal) sequences. The main function of Tax is to trans-activate the transcription function of HTLV Ⅰ Ⅰ through 5 ′ ltr sequence, thus regulating virus replication. It activates the transcription of virus and cell genes through at least two different host transcription factor pathways, involving CAMP reactive component protein, activated transcription factor (ATF) and transcription factor NF/κB/CRel family respectively. Tax may play the following roles in the pathogenesis of ATL: ① Activating IL-2 promoter and IL-2α subunit, secreting and growing T cells autonomously, and even initiating the formation of immortalization of T cells, which eventually leads to the occurrence of ATL: including IL-2 and IL-2RA, cfos, cjun and PTHrP. The release of these cytokines by ATL cells can cause a series of pathological manifestations: IL-2 and IL-2RA can lead to the activation and proliferation of T cells, resulting in autonomous growth; PTHrP can * * * osteoclasts, making patients hypercalcemia; Cfos gene may be involved in the proliferation of T cells. ②Tax can accelerate the process of G 1 phase in cell proliferation cycle, and make it enter S phase, so that the cell proliferation cycle expressing tax becomes shorter. The acceleration of cell growth kinetics may be related to the occurrence of H ⅱ ⅳ-ⅰ related diseases. ③ the change of NFκB activity mediated by ③Tax. It may play a role in tumorigenesis.
9.2 The decrease of immune function of HTLV type ⅰ infection can increase the expression levels of activated transforming factor β 1 and TGFβ 1, thus inhibiting human cellular immunity and humoral immunity. After HTLVⅰⅰ infects cells, new antigenic determinants of HLA ⅰ and HLA ⅱ encoded by the virus can appear, which leads to immune dysfunction and the decline of the body's defense ability, creating conditions for the occurrence and development of tumors.
9.3 Activation of oncogenes and inactivation of anticancer genes Although HTLVⅰ Ⅰ does not encode oncogenes, the cis-activation mechanism can still exist. For example, Tax can activate cfos gene, which indicates that the highly effective trans-activating protein Tax may be related to the initiation of malignant transformation.
Another minor event is the mutation of p53. P53 is a nuclear phosphoprotein, which has tumor inhibition function. The loss of p53 activity caused by mutation has been found in many malignant diseases, and ATL is no exception. Many patients with acute ATL have detected p53 mutation, but few patients with chronic ATL have such mutation. Some data show that p53 mutation is related to ATL. However, recent studies by Portis and others believe that p53 gene inactivation does not cause tumor occurrence, but may promote malignant proliferation in the late stage of tumor.
Many petal-like or polymorphonuclear lymphocytes (flower cells) can be seen in peripheral blood. These lymphocytes vary in size, and their nuclei are polymorphic, twisted, deformed or lobulated, with deep concave nuclei and two or more leaves, or folded like baseball, gloves and petals, so they are also called flower cells. Cytochemical staining showed that oxidase was negative and acid phosphatase and β glucuronidase were positive. Immunomarker detection confirmed that flower cells were mature T lymphocytes.
Skin lesions are mostly caused by a large number of abnormal lymphocyte infiltration. Two-thirds of patients with skin lesions have focal epidermal infiltration and Pautrie's tiny abscess. In addition, a large number of abnormal lymphocyte infiltration can also occur in lymph nodes, liver, spleen, lung and gastrointestinal tract, which is characterized by swelling and dysfunction of related organs.
Abnormal lymphocyte infiltration in ATL is related to the increased level of vascular endothelial growth factor (VEGF) in plasma. The data showed that ATL cell line expressed VEGF mRNA and secreted it into the extracellular environment. At the same time, ATL cell line also expresses the mRNA and protein of VEGF receptor Flt 1(fms-like tyrosine kinase 1), but VEGF can only effectively bind to Flt 1 expressing cells, which leads to the enhancement of the chemotactic activity of ATL cells and the infiltration of ATL cells into tissues and organs.
10 Clinical manifestations of adult T-cell leukemia ATL patients have various clinical manifestations, including acute leukemia-like type, lymphoproliferative lymphoma type, chronic type with good prognosis and smoking status (latent type).
Almost all patients have lymphadenopathy. Many patients have extensive lymphadenopathy, most of them have retroperitoneal lymphadenopathy, but mediastinal masses are rare. Leukemia cells are often infiltrated in bone marrow. Other common sites involved are lung, liver, skin, gastrointestinal tract and central nervous system.
About 2/3 patients may have skin involvement, and most patients with skin infiltration can see focal ATL cell infiltration or portal's microabscess.
The main clinical manifestations of each type
1. acute type: the median age of the patient is 40 years old. Typical manifestations are: acute onset, mainly rapid skin damage, hypercalcemia, or both. There are many kinds of skin lesions, such as scattered tumor masses, fused nodules, plaques, papules and nonspecific erythema. Patients with hypercalcemia usually show fatigue, apathy, insanity, polyuria and polydipsia.
2. Chronic type: lymphadenopathy, hepatosplenomegaly, skin and lung infiltration, no hypercalcemia, no infiltration of central nervous system, bones and gastrointestinal tract, no ascites and pleural effusion.
3. Lymphoma type: lymph node histology confirmed lymphadenopathy, without leukemia cell infiltration.
4. Smoke type: Skin lesions are erythema, papules and nodules. There may be lung infiltration. Generally, there is no hypercalcemia, lymph node enlargement, hepatosplenomegaly and bone marrow infiltration is light; No central nervous system infiltration.
1 1 Complication infection of adult T-cell leukemia is the most common complication, which can be secondary to bacterial, fungal and pneumocystis carinii infection.
12 Laboratory examination 12. 1 Peripheral blood is different from other acute leukemia. ATL patients generally do not have anemia and thrombocytopenia, even if they have anemia and thrombocytopenia, the degree is mild, and severe anemia and thrombocytopenia are rare. The number of white blood cells often increases, especially in acute and chronic patients. Lymphocytes account for 10% ~ 90%, and lymphocytosis is also mainly seen in patients with acute and chronic ATL.
12.2 bone marrow lymphocytes can be less than 30% or more than 60%. Seeing polymorphonuclear lymphocytes is one of the characteristics of this disease, accounting for more than 10% of peripheral blood. Cytochemistry showed that PAS was positive, acid phosphatase was positive, TdT was negative and peroxidase was negative.
12.3 The most common immunophenotype is CD4CD8, but some patients show CD4CD8, CD4CD8 or CD4CD8. The common co-expressions of ATL cells are CD2, CD3, CD4, CD8 and CD25.
There is no single significant chromosome translocation in 12.4 cytogenetic ATL, but 28% of them are related to q32 on chromosome 14, and 15% are related to q 1 1. Triploid chromosomes 7, 6q, 13q, 14q+ and 3p+ are also common.
12.5 virological examination Anti-HTLV Ⅰ antibody can be detected by enzyme immunoassay or indirect immunofluorescence; RTPCR can detect the expression of HTLV ⅰ virus RNA in tumor cells, especially the positive HTLV protovirus DNA is of great significance for the diagnosis of this disease. Detection of HTLV Ⅰ Ⅰ pre-viral load by PCR is helpful for early evaluation of ATL tumor load.
12.6 biochemical examination showed hypercalcemia, and GOT, GPT, LDH, bilirubin and alkaline phosphatase increased.
13 auxiliary examination 13. 1 X-ray chest film can show diffuse infiltration of both lungs, and osteolytic damage can often be seen in osteoiliac x-ray film.
13.2 B ultrasound can indicate superficial lymphadenopathy, retroperitoneal lymphadenopathy and hepatosplenomegaly.
13.3 lymph node pathological examination and skin biopsy showed ATL cell infiltration.
14 diagnosis 14. 1 1. Domestic diagnostic criteria (1984 ATL cooperation meeting of some provinces and cities in China) (1) Clinical manifestations of leukemia: ① adult onset; ② Superficial lymph nodes are swollen, and there are no mediastinal or thymic tumors.
(2) Laboratory examination: Peripheral white blood cells are often increased, and polymorphonuclear lymphocytes (flower cells) account for more than 10%; T cell types with mature T cell surface markers; Serum anti-HTLV Ⅰ Ⅰ antibody was positive.
14.2 2.ATL lymphoblastic leukemia proved by foreign diagnostic criteria (Schimoyama Metal, 199 1) (1) histology and/or cytochemistry.
(2) Peripheral blood must have abnormal T lymphocytes, including typical adult T lymphocyte leukemia cells (also known as flower cells and small mature T cells with notched or lobulated nuclei).
(3) Anti-human T-lymphoblastic leukemia virus type Ⅰ (HTLV Ⅰ Ⅰ) antibody was positive.
14.33. Diagnostic criteria of ATL subtype (Gessaial, 1992) (1):
① Abnormal T cells in peripheral blood ≥5%.
② The total number of lymphocytes is normal.
③ No hypercalcemia, LDH≤ 1.5× normal value.
④ No lymphadenopathy; Liver, spleen, central nervous system, bones and gastrointestinal tract are not involved.
⑤ No ascites or pleural effusion.
⑥ There may be skin and lung injuries.
⑦ If the abnormal T cells are less than 5%, there should be histologically confirmed skin and lung damage.
(2) Chronic type:
① The absolute number of lymphocytes increased (≥4× 109/L), and the number of T cells was > 3.5× 109/L, including abnormal T cells and occasional petaloid cells.
② No hypercalcemia, LDH≤2× normal value.
③ No central nervous system, bones and gastrointestinal tract were involved, and there was no hydrothorax and ascites.
④ Lymph nodes, spleen, liver, lung and skin may be involved.
(3) lymphoma type:
① There was no increase in lymphocytes, and abnormal lymphocytes were ≤ 65438 0%.
② Histologically positive lymphadenopathy.
(4) Acute type:
① In addition to the above-mentioned type 3 ATL patients, they are often accompanied by leukemia and lymphadenopathy.
② T-lymphocyte tumor confirmed by histology and/or cytology.
③ In addition to lymphoma ATL, there should be abnormal T lymphocytes in peripheral blood, including typical "petal" cells and mature small T lymphocytes with notch and lobulated nuclei.
④ Lhv 1 antibody was positive.
15 differential diagnosis 15. 1 mycomycomycosis fungoides/Sezary's syndrome mycomycomycosis fungoides/Sezary's syndrome (MF/SS) is a malignant disease with mature differentiation. Similar to ATL, both of them have skin infiltration lesions. In the new WHO classification of leukemia and lymphoma, they are all classified as mature (peripheral) T-cell tumors. The differences are as follows: ①ATL leukemia cells generally do not infiltrate the epidermis; ② The morphology of ②ATL cells is different from that of typical sezary cells, and the nucleus of the former is mostly lobulated; ③ATL often involves bone marrow; ④ The clinical course of ④ATL is more invasive than MF/SS.
15.2 T-cell chronic lymphoblastic leukemia (TCLL) T-cell chronic lymphoblastic leukemia (TCLL) is also a mature T-cell malignant tumor. The differences from ATL are as follows: ① The morphology of ATL cells is different from that of TCLL cells; ② The clinical progress of ②ATL is invasive; ③ In patients with ③ATL, HTLVⅰ antibody was positive, while TCLL was negative.
15.3 Most cutaneous T-cell lymphomas are chronic prophase, and the slow onset has nothing to do with HTLV 1 infection.
Treatment of adult T-cell leukemia 16 The treatment strategy of adult T-cell leukemia is determined according to different clinical types. Patients with chronic or moyamoya disease often use symptomatic support treatment, mainly to actively control infection and improve organ function. Only when the disease progresses or changes sharply can active treatment be considered. Although acute or lymphoma ATL has been actively treated by chemical and biological measures, the curative effect is not good, and the median survival time is 2 ~ 6 months.
16. 1 The most commonly used chemotherapy regimen is VEPA regimen (vincristine 1mg/ week for 6 weeks; Cyclophosphamide 300 mg/d on the 8th, 22nd and 29th days; Prednisone 40 ~ 60 mg/d, 3 days a week; 322 cases were treated with doxorubicin (40 ~ 60 mg/d, day/kloc-0, day 22), and 7 cases (22%) were completely relieved. The classic CHOF regimen was not satisfactory, and 10 cases (17%) were completely relieved. Other available schemes include CVP scheme, MACOPB scheme, ProMACEMOPP scheme, etc. The treatment effect is not ideal. Recently, Japanese scholars used LSG 15 regimen (7-cycle VCAF, AMP and VECP regimen) plus granulocyte growth factor (GCSF) to treat 96 patients with advanced ATL, with 33 cases (35.5%) in complete remission and 42 cases (45.2%) in partial remission. The median survival time was 13 months, and the 2-year disease-free survival rate reached 100%. At present, chemotherapy is still the main method to treat advanced ATL.
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16.2 tretinoin (all-trans retinoic acid) tretinoin (ATRA) may affect or block the Tax/NFKB signal channel in ATL cells, which has been used in clinical treatment of chemotherapy-resistant ATL patients, and the clinical efficacy needs further verification.
16.3 interferon 2b can be used for ATL treatment, but the effect is not good when used alone. Recently, it has been reported that interferon α2α2b combined with antiviral drug zidovudine (azido thymidine) is used to treat ATL patients, and has achieved certain curative effect. White et al. treated 65,438+ATL patients with interferon α 2α 2α 2b 2.5 million ~ 654.38+100 million U, subcutaneous injection 65,438+0 times /d, and zidovudine (AZT) 50 ~ 200 mg, oral administration 5 times /d, of which 65,438+could not evaluate the curative effect. Matutes et al. treated 15 cases of ATL patients who had received various treatments in the past by the above method, of which 8 cases were completely or partially relieved and the other 7 cases were ineffective.
The monoclonal antibody 16.4(Tac) of IL2R immunotherapy can be used for ATL therapy. Clinical data showed that 1 case had short-term unlimited remission in 20 cases of ATL treated with anti-Tac. Partial remission in 4 cases and complete remission in 2 cases. Anti-Tac can also be cross-linked with immunoradionuclides (90Y) to treat ATL patients. 15 patients, 8 cases were in partial remission and 2 cases were in complete remission.
16.5 hematopoietic stem cell transplantation Utsunomiya et al. treated 10 ATL patients with alloHSCT, including 9 relatives and/kloc-0 unrelated donors, with a median disease-free period of 1 7.5 months, indicating that allo HSCT can achieve certain curative effect in treating ATL.
16.6 treatment of osteolytic lesions and hypercalcemia If osteolytic lesions and hypercalcemia occur, 90mg of pamidronate disodium can be injected intravenously once a month/kloc-0.
17 Prognosis Adult T-cell leukemia has a very poor prognosis. The Japanese lymphoma research group reported 854 cases of ATL patients. The median follow-up time (from the time of diagnosis) was 65438 04 months, with 585 cases (68.5%) dead and 269 cases (365438 0.5%) alive. The median survival time is only 6 months, and the expected survival rates of 2 years and 4 years are 28% and 65438+ respectively. The factors related to poor prognosis are: ① poor general condition; ② Hyperlactate dehydrogenase; ③ Age > 40 years; ④ Multi-site participation; ⑤ Hypercalcemia; ⑥CD4, CD8CD4+, CD8 or CD4, CD8; ⑦Ki67 > 18%。
18 prevention of adult t-cell leukemia The infection and transmission route of adult t-cell leukemia is clear, mainly through mother-to-child, blood and sexual contact. Therefore, preventive measures should do the following:
1. Carry out health education on STD prevention and treatment.
2. Promote safe sex and actively promote the use of condoms.
3. Prevent mother-to-child transmission of HTLV 1, avoid mother-to-child feeding and reduce infant infection.
4. When using blood, blood or blood products, it must undergo strict inspection to avoid unnecessary injection, blood transfusion and use of blood products.
19 related drugs: oxygen, glucose, vincristine, cyclophosphamide, prednisone, adriamycin, retinoic acid, interferon, zidovudine, pamidronate disodium, pamidronate disodium.
20 related inspection