Chronic granulocytic leukemia (CML) is a clonal disease that occurs at the level of hematopoietic stem cells. It is characterized by malignant cell proliferation, impaired cell maturation, and a chronic clinical course with a large infiltration of leukemic cells causing marked splenomegaly and increased metabolism.
Clinical manifestations
The age of onset of the disease is mostly 30-40 years old, but is rare in children.
I. Slow onset
It may be asymptomatic in the early stage and is often detected occasionally during blood tests due to splenomegaly or other reasons. It is difficult for patients to define the time of onset of the disease.
2. Early conscious symptoms
Weakness, low fever, excessive sweating and night sweats, weight loss and other metabolic hyperactivity are the main manifestations.
Splenomegaly
It is a distinctive feature of chronic granulocytic leukemia, sometimes reaching below the umbilicus or even the pelvis, firm in quality, without pressure pain, and in case of splenic infarction or peripleural inflammation, severe pain may occur, aggravated by breathing, and friction sensation and friction sound may appear. The presence of a giant spleen causes abdominal distension and a feeling of falling abdomen. The liver may be mildly enlarged.
IV. Other rare manifestations
1. Bone destruction.
The incidence is 29%, and the X-ray changes are mainly osteolytic damage, but there are also chisel-like changes similar to multiple myeloma.
2. Central nervous system involvement.
The incidence of autopsy meningeal leukemia is 20-50%, but the diagnosis is rarely confirmed clinically in the chronic phase, and the incidence of acute changes is 3.5-6.9%.
3. Portal hypertension.
It is thought to be caused by increased resistance to portal blood flow caused by infiltration of the hepatic sinusoids, and may be manifested by esophageal varices, vomiting, jaundice, ascites, etc.
4. Leukocyte stasis.
Leukocyte >50×109 often occurs as intravascular stasis, and >200×109/L can almost always occur. There may be persistent penile erection, central nervous system hemorrhage, and manifestations of respiratory distress syndrome.
5, bone marrow fibrosis.
It is a signal of acute change of CML and is an indication of poor prognosis. CML patients with extensive myelofibrosis are poorly tolerant of chemotherapeutic drugs and can often lead to severe myelosuppression.
6. Alkalophilia and hyperhistaminemia.
It may manifest as asthma, urticaria, skin scratching, neuroedema, diarrhea, and increased gastric acid secretion
Laboratory tests
I. Blood picture
1. Total leukocyte count is significantly increased, often above 50×109/L. Half of the patients have 100-400×109/L, a few can reach 1000×109/L, very few <50×109/L. Neutrophils, neutrophils and rod-shaped nuclei account for most of the blood film. The percentage of progranules and early granules was often <10%. The percentage of alkalophilic granulocytes is increased, and the alkaline phosphate of neutrophils is often reduced or negative. Platelets are often increased and can be as high as 1000×1012/L. ③Red blood cells and hemoglobin are normal or increased, or may be mildly decreased. Reticulocytes are mostly increased. The size of mature red blood cells in blood film is uneven, and nucleated red blood cells, heterogeneous red blood cells, multi-colored red blood cells and dotted red blood cells can be seen, but there are no teardrop red blood cells.
Bone marrow picture
The bone marrow cell proliferation is obviously active or extremely active, and the granulocyte-red ratio is as high as 10-50:1, and the classification count is similar to that of blood. In late stage, bone marrow biopsy may show increased fibrous tissue.
Chromosome examination
More than 90% of CML patients have an abnormal chromosome, i.e., one long arm of chromosome 22 is missing and the missing part is translocated to the end of one of the long arms of chromosome 9. That is, t(9q+,22q -). The missing long arm of chromosome 22 is called the Philadelphia Chromosome (ph’).
Ph’ chromosome can also be found in other series of cells of the patient (such as young red blood cells, megakaryocytes and lymphocytes, etc.) Patients with negative Ph’ chromosome have a worse prognosis than those with positive chromosome.
Biochemical examination
1. The significant increase in serum vitamin B12 and B12 binding power (which can be 15 times higher than normal) is due to the fact that mature granulocytes contain B12 binding protein (transcobalamin protein). In CML patients, granulocytes are broken and decomposed, and B12 binding protein is released, so serum B12 increases. When CML is in remission, although the white blood cell count has returned to normal, the serum B12 value is still 4 times higher than normal, and it is believed that there is ineffective granulocyte production.
2, hyperuricemia Due to the proliferation of leukocytes, nucleic acid metabolism is accelerated, causing hyperuricemia, especially during treatment, the collapse of a large number of leukocytes, often leading to hyperuricemic nephropathy, kidney stones, can also occur gout.
3.Lactate dehydrogenase is elevated and decreases when the disease is in remission.
4.Neutrophil alkaline phosphatase activity is significantly reduced, and the score is often O. It may be increased in case of infection or acute change of CML, but its increased score is not as obvious as that of leukemia-like reaction.
Clinical staging
The natural course of CML can be divided into a chronic phase and an acute phase, and there may be a migratory phase between the two phases, called the accelerated phase.
I. Chronic phase
This phase is stable, with an average of 3 years, and some individuals may have the disease for 10-20 years. In recent years, due to effective treatment, it is possible to return the acute phase to the chronic phase and obtain a second stable phase.
II. Accelerated phase
It refers to patients who show various signs of progression in the course of treatment in the chronic phase, but have not yet reached the criteria of acute. The signs of this phase include: blood and bone marrow primitive cells >5% and <20%; increased collagen fibers in bone marrow; anemia and thrombocytopenia or increased platelets (>1000×109/L) without other causes; new nuclear abnormalities, abnormal growth of GMCFU in vitro and increased thymidine deoxyriboside uptake by leukocytes, etc. can be used as indicators to determine the accelerated phase.
Third, the acute phase
Bone marrow or peripheral blood primitive cells ≥ 20%; or primitive plus promyelocytes, peripheral blood up to 30%, bone marrow up to 50%; or the appearance of extramedullary primitive cell infiltration. The cell morphology of acute changes is 60% acute granulomatous; 20% acute lytic; 15% undifferentiated; the rest can be red, megakaryocytic or mixed. Once acute changes occur, a second complete remission is obtained in <30%, with a median survival of 2-6 months.
Diagnosis and differential diagnosis
Typical cases can be correctly diagnosed based on clinical manifestations, blood and bone marrow features, but in some cases it is fashionable to differentiate from the following diseases.
I. Leukemia-like reactions
Leukoid reactions are caused by other diseases and have many similarities with slow-onset leukocytes, such as a marked increase in total leukocyte count, infantile cells in peripheral blood, and splenomegaly. However, the degree of myeloproliferation in leuko-like white is less severe. It is usually dominated by neutrophils in the mature stage, accompanied by a marked increase in alkaline phosphatase score. There is no Ph’ chromosome, and it may resolve on its own with the cure of the primary disease.
II. Other myeloproliferative diseases
CML is one of the myeloproliferative disorders. The common feature of this group of diseases is that all of them have cell proliferation and can transform into each other. However, each of them has its own characteristics. Bone marrow fibrosis often has teardrop-like red blood cells, bone marrow aspiration often occurs “dry aspiration”, and bone marrow biopsy shows fibrotic lesions. In true erythrocytosis, erythropoiesis is predominant, with a decrease in the ratio of granulocytes to red, and the clinical manifestations of megaloblastic changes in young red blood cells and polycythemia vera. In primary thrombocytosis and slow granulocytosis, although both diseases have significant proliferation of megakaryocytes, the former is often distinguished by the presence of piles of platelets surrounding the megakaryocytes and a more normal granulocyte-red ratio.
Other splenomegaly diseases
The spleen can be enlarged in black fever and advanced cirrhosis, and is often confused with slow granulocytosis. However, blood and bone marrow images can be used to differentiate them.