I. Etiology
In recent years, a group of growth factors associated with connective tissue proliferation, such as platelet-derived growth factor (PDGF), megakaryocyte-derived growth factor (MKDGF), epithelial growth factor (EGF), and β-transforming growth factor (β-TGF) have been found to be synthesized in megakaryocytes and stored in the alpha granules of platelets.PMF has ineffective megakaryopoiesis and destroys megakaryocytes releasing large amounts of PDGF, EGF, and β-TGF synergistically stimulate fibroblast proliferation and secrete collagen, while releasing platelet factors. The latter inhibits the activity of collagenase, which reduces collagen degradation and leads to the formation of bone fibrils. When parathyroid function or vitamin D metabolism is disturbed, it can also lead to bone marrow fibrosis.
II. Clinical manifestations
The onset of the disease is slow, and some patients have no conscious symptoms at the time of diagnosis or only show weakness, excessive sweating, weight loss, and epigastric distention due to splenomegaly. Severe patients may have bone pain, fever, anemia and bleeding; a few patients may have kidney stones and some may have gouty arthritis due to hyperuricemia. Hearing loss can be caused by otosclerosis in individual patients. Most of the fever can be caused by infection, and there may be unexplained diarrhea. Almost all patients have splenomegaly because extramedullary hematopoiesis can cause symptoms in the corresponding organs. In about 10% to 20% of cases, cirrhosis is combined with increased portal blood flow due to obstruction of the blood vessels surrounding the hepatic sinusoids and extramedullary hematopoiesis of the hepatic sinusoids. A small number of patients may have jaundice due to ineffective erythropoiesis.
Three, examination
1.Blood picture: Most patients have mild to severe anemia at the time of consultation, and late stage may have severe anemia, usually of orthocytic and orthopigmented type. Mature red blood cells have significant teardrop-like changes and anomalies. Folic acid deficiency may be secondary to, in addition, a relative increase in blood volume, as well as ineffective red blood cell production. Reticulocyte counts are mildly increased, in the range of 2% to 5%; in about 70% of patients, the presence of young granular and juvenile red blood cells in the peripheral blood is also a feature of the disease. The leukocyte count is increased, generally at (10-30) × 109/L, rarely exceeding 50 × 109/L. In a few patients, the leukocyte count can be reduced to (2-4) × 109/L. Mature neutrophils predominate in the classification, but intermediate and late granulocytes, even progranulocytes and early granulocytes can be seen. Eosinophils and basophils were mildly increased. The platelet count varies, with about 1/3 of cases having increased platelets, individually up to 1000×109/L. Large, malformed platelets may be seen in the peripheral blood, and occasionally megakaryocyte fragments or megakaryocytes may be seen. Platelet function is defective.
2. Bone marrow aspiration smear and biopsy: about 1/3 of the cases of bone marrow aspiration have the phenomenon of “dry aspiration”. Bone marrow smear often has low proliferation of nucleated cells, which can also be proliferative. A bone marrow biopsy with a large amount of reticulo-fibrous tissue is the basis for the diagnosis of the disease.
3. Spleen puncture smear: Spleen puncture smear shows proliferation of lymphocytes and granulocytes, red and megakaryocytes. The diagnostic value of spleen puncture smear is greater, but there is a risk of bleeding and must be considered carefully.
4. Liver puncture and biopsy: As with the spleen there is extramedullary hematopoiesis. Naïve red blood cells and megakaryocytes are seen in the hepatic sinusoids; naïve granulocytes are more common in the portal area.
5.X-ray examination: some cases have osteosclerotic signs on X-ray, with a heterogeneous increase in bone density, accompanied by speckled translucent areas, forming the so-called “hairy glass”-like changes; osteoporosis, new bone formation and lace-like thickening of the periosteum can also be seen. Bone changes are especially noticeable in the epiphysis of long bones, spine, pelvis, long bones of lower limbs, humerus and ribs, etc. Some cases also have cranial changes.
6.Radionuclide bone marrow scan: radioactive colloids (99Tc, 52Fe, 111Indium, etc.) appear as areas of radioactive concentration for scanning uptake of red marrow, spleen, liver, etc. in bone. In patients with myelofibrosis, a large amount of radionuclides are accumulated in the hepatic and splenic extramedullary hematopoietic areas, while the red marrow with fibrous tissue hyperplasia changes such as the proximal end of long bones cannot show radioactive concentration areas.
7, chromosome detection: about half of the chromosomes are abnormal, commonly group C chromosomes are trisomic, there can also be del (13q), del (20q). Ph chromosomes were not seen.
8. Other: serum alkaline phosphatase, uric acid, lactate dehydrogenase, vitamin B12 and histamine are increased. 2/3 of chronic cases have increased serum alkaline phosphatase due to bone disease changes. However, it gradually decreases as the disease progresses.
IV. Diagnosis
The diagnostic criteria proposed by WHO in 2008.
1, the main criteria: ① megakaryocyte proliferation and aggregation with anomalies (megakaryocytes of different sizes, inconsistent nuclear to plasma ratio, chromatin concentration, globular or irregular folding), often accompanied by reticular or (and) collagen fibrous hyperplasia. If reticulofibrillary hyperplasia is absent, megakaryocyte changes must be accompanied by proliferation of myeloid cells, mainly granulocytic, with reduced red lineage hyperplasia (pre-fibrosis); ② Excluding PV, BCR-ABL1(+) CML, MDS or other myeloid tumors; ③ With JAK2V617 mutation or other clonal markers (e.g. MPLW515K/L), or in the absence of clonal markers Infection, autoimmune disease or other chronic inflammatory disease, hairy cell leukemia or other lymphatic lineage tumor, metastatic tumor or chronic neutrophilic myelopathy.
2. Secondary criteria: ① young granulocytes; ② increased serum LDH level; ③ anemia; ④ splenomegaly.
The diagnosis can be made by meeting three main criteria and two secondary criteria.
V. Treatment
There is a lack of specific measures for the treatment of myelofibrosis. Treatment should be based on the degree of myelofibrosis tissue hyperplasia and clinical manifestations, and corresponding measures should be given. The main purpose of treatment is to improve the hematopoietic function of bone marrow, correct anemia and bleeding, and relieve the compression symptoms caused by splenomegaly.
1. Correction of anemia
Androgens and protein and synthetics have the effect of improving the hematopoietic function of bone marrow. About 50% of patients have better efficacy on androgens, and some patients can also increase white blood cells and platelets; use with caution in liver disease. Testosterone propionate is injected intramuscularly every other day, and long-acting testosterone enanthate is also available for intramuscular injection, or oral stanozolol, hydroxyandrosterone, hydroxymethandrostene-isofazole, etc.
2.Cytotoxic drug treatment
It can inhibit the abnormal proliferation of bone marrow hematopoietic tissue, and at the same time can inhibit the immunopathogenesis; thus preventing the further development of bone marrow fibrous tissue. It is generally used in cases with large spleen, bone marrow in proliferative stage and slightly more peripheral blood cells. Commonly used are (i) azelaic acid phenylbutyrate combined with prednisone to maintain better hemoglobin levels and reduce splenomegaly. (ii) Hydroxyurea, closely monitored for splenomegaly and white blood cell and platelet counts. A small number of patients can improve their symptoms within one year of drug administration. (③) Leucovorin or 6-mercaptopurine (6-TG), the liver and spleen can shrink and hemoglobin can increase after 6-9 weeks.
3.Splenectomy
Splenectomy is the main extramedullary hematopoietic organ of the disease. In 10%-25% of patients, splenectomy can cause rapid enlargement of the liver, significant increase in platelets and risk of infection. Therefore, splenectomy is generally limited to: (i) patients with a giant spleen with obvious compression symptoms or persistent pain due to splenic infarction. ②Patients with intractable hemolysis or thrombocytopenia due to hypersplenism, which is ineffective with drug therapy and requires long-term repeated transfusion but has not completely lost hematopoietic function. (iii) Those with portal hypertension complicated by ruptured esophageal varices and bleeding. For those with high platelet count, intravenous thrombosis is likely to occur after surgery, which is generally regarded as a contraindication to surgery.
4.Spleen area irradiation
For patients with obvious splenomegaly, irradiation can reduce the symptoms and shrink the spleen, but the effect is short-lived, and the spleen will be enlarged again after 4-6 months, and there is a side effect of further reduction of peripheral blood picture.
5.Interferon-α
It has the effect of inhibiting the proliferation of normal granulocytes and megakaryocytes, and is often treated with alpha-2b interferon, but only a few cases have achieved a certain degree of relief of clinical symptoms and signs.
6.1,25 dihydroxyvitamin D3
In vitro 1,25 dihydroxyvitamin D3 can inhibit the proliferation of megakaryocytes and induce the transformation of myeloid cells into monocytes and macrophages, thus promoting the reduction of collagen fiber formation and the increase of lysis.
7.Hematopoietic stem cell transplantation
Hematopoietic stem cell transplantation is considered to be a promising treatment. Allogeneic or allogeneic transplantation can change the course of myelofibrosis, and there is an anti-fibrotic effect of the graft.
8.Other
Treatment with high-dose methylprednisolone has been reported to result in improvement of anemia and spleen reduction. This was followed by oral prednisone maintenance and gradual reduction and discontinuation of the drug.