Leukemia is diagnosed in a variety of ways. Some diagnostic procedures include:

- A bone-marrow aspiration and biopsy; marrow may be removed by aspiration or a needle biopsy.

- A complete blood count, which is a measurement of size, number, and maturity of different blood cells in blood.

- Blood tests may include blood chemistry, evaluation of liver and kidney functions, and genetic studies.

- A lymph-node biopsy; lymph node tissue is surgically removed to examine under a microscope, to look for cancerous cells.

- A spinal tap: a special needle is placed into the lower back into the spinal canal, which is the area around the spinal cord. Cerebral spinal fluid is fluid that bathes the child's brain and spinal cord. A small amount of cerebral spinal fluid is sent for testing to determine if leukemia cells are present.

There are two internationally accepted treatment protocols, which are geographically based:

- North America: the Children’s Oncology Group (COG) JMML study

- Europe: the European Working Group for Myelodysplastic Syndromes (EWOG-MDS) JMML study

The following procedures are used in one or both of the current clinical approaches listed above:

Complete remission and long-term survival are more common in children than adults.

Prognosis depends upon the cause. One third of cases is associated with a t(1;22)(p13;q13) mutation in children. These cases carry a poor prognosis.

Another third of cases is found in Down syndrome. These cases have a reasonably fair prognosis.

The last third of cases may be heterogeneous, and carry a poor prognosis.

Primary myelofibrosis (PMF) is associated with the "JAK2V617F" mutation in up to 50% of cases, the "JAK2" exon 12 mutations in 1-2% of cases, and the MPL (thrombopoietin receptor) mutation in up to 5% of cases:

- Prefibrotic/cellular phase - increased, small and atypical megakaryocytes which cluster, reticulin fibrosis, later trichrome (collagenous) fibrosis, and increased myeloid precursors

- Fibrotic phase - collagenous fibrosis with lack of marrow elements

Following observation of the symptoms, the patients need to get complete blood counts and a bone marrow examination. If the patient has leukemia, the morphology and immunophenotype check is needed to make sure the type of leukemia.

The morphology of the blast in BAL is not certain. The cells could display both myeloid lineage and lymphoid or undifferentiated morphology. Therefore, the diagnosis cannot based on the morphology result. The immunophenotype check is the most important basis of the diagnosis of BAL.

Before 2008, the diagnosis of BAL was based on a score system proposed by the European Group for the Immunological Classification of Leukemias (EGIL) which could differentiate from other kinds of acute leukemia. The table shows this method.

If the score of only one lineage is higher than 2, the acute leukemia could be acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). According to the original EGIL scoring system BAL is defined when scores are over two points for both myeloid and T- or B- lymphoid lineages.

In 2008, WHO established a new and strict criteria standard for diagnosis of BAL. The presence of specific T-lymphoid antigens, cytoplasmic CD3 (cCD3), MPO and CD 19 became the most important standard for recognizing the lineage. Other B-lineage markers (CD22, CD79a, CD 10) and monocytic markers are also needed. Table 2 shows the method.

Compared with the EGIL scoring system, the current 2008 WHO criteria applied less but more specific markers to define the lineage of the blasts, and incorporated the intensity of markers expression into the diagnostic algorithm.

The diagnosis of BAL is so difficult that sometimes is misdiagnosed with AML or ALL because the morphology thus the therapy would not have a good effect.

Depending on the nature of the myeloproliferative neoplasm, diagnostic tests may include red cell mass determination (for polycythemia), bone marrow aspirate and trephine biopsy, arterial oxygen saturation and carboxyhaemoglobin level, neutrophil alkaline phosphatase level, vitamin B (or B binding capacity), serum urate or direct sequencing of the patient's DNA.

According to the WHO Classification of Hematopoietic and Lymphoid Neoplasms 2008 myeloproliferative neoplasms are divided into categories by diagnostic characteristics as follows:

The following criteria are required in order to diagnose JMML:

All 3 of the following:

- No Philadelphia chromosome or BCR/ABL fusion gene.

- Peripheral blood monocytosis >1 x 10/L.

- Less than 20% blasts (including promonocytes) in the blood and bone marrow (blast count is less than 2% on average)

Two or more of the following criteria:

- Hemoglobin F increased for age.

- Immature granulocytes and nucleated red cells in the peripheral blood.

- White blood cell count >10 x 10/L.

- Clonal chromosomal abnormality (e.g., monosomy 7).

- Granulocyte macrophage colony-stimulating factor (GM-CSF) hypersensitivity of myeloid progenitors in vitro.

These criteria are identified through blood tests and bone marrow tests.

Blood tests: A complete blood count (CBC) will be performed on a child suspected of having JMML and throughout the treatment and recovery of a child diagnosed with JMML.

The differential diagnosis list includes infectious diseases like Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, histoplasma, mycobacteria, and toxoplasma, which can produce similar symptoms.

Evidence is conflicting on the prognostic significance of chloromas in patients with acute myeloid leukemia. In general, they are felt to augur a poorer prognosis, with a poorer response to treatment and worse survival; however, others have reported chloromas associate, as a biologic marker, with other poor prognostic factors, and therefore do not have independent prognostic significance.

Acute erythroid leukemia is rare, accounting for only 3–5% of all acute myeloid leukemia cases. One study estimated an occurrence rate of 0.077 cases per 100,000 people each year. 64–70% of people with this condition are male, and most are elderly, with a median age of 65.

The morphology of cells was observed by means of bone marrow smear; the immunophenotype was detected by flow cytometry and immunohistochemistry assay.

Blasts more than 20%, with more than 50% of megakaryocytic phenotype.

In blood and bone marrow smears megakaryoblasts are usually medium-sized to large cells with a high nuclear-cytoplasmic ratio. Nuclear chromatin is dense and homogeneous. There is scanty, variable basophilic cytoplasm which may be vacuolated. An irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present. Megakaryoblasts lack myeloperoxidase (MPO) activity and stain negatively with Sudan black B. They are alpha naphthyl butyrate esterase negative and manifest variable alpha naphthyl acetate esterase activity usually in scattered clumps or granules in the cytoplasm. PAS staining also varies from negative to focal or granular positivity, to strongly positive staining. A marrow aspirate is difficult to obtain in many cases because of variable degree of myelofibrosis. More precise identification is by immunophenotyping or with electron microscopy (EM). Immunophenotyping using MoAb to megakaryocyte restricted antigen (CD41 and CD61) may be diagnostic.

Diagnosing ALL begins with a thorough medical history, physical examination, complete blood count, and blood smears. While many symptoms of ALL can be found in common illnesses, persistent or unexplained symptoms raise suspicion of cancer. Because many features on the medical history and exam are not specific to ALL, further testing is often needed. A large number of white blood cells and lymphoblasts in the circulating blood can be suspicious for ALL because they indicate a rapid production of lymphoid cells in the marrow. The higher these numbers typically points to a worse prognosis. While white blood cell counts at initial presentation can vary significantly, circulating lymphoblast cells are seen on peripheral blood smears in the majority of cases.

A bone marrow biopsy provides conclusive proof of ALL, typically with >20% of all cells being leukemic lymphoblasts. A lumbar puncture (also known as a spinal tap) can determine whether the spinal column and brain have been invaded. Brain and spinal column involvement can be diagnosed either through confirmation of leukemic cells in the lumbar puncture or through clinical signs of CNS leukemia as described above. Laboratory tests that might show abnormalities include blood count, kidney function, electrolyte, and liver enzyme tests.

Pathological examination, cytogenetics (in particular the presence of Philadelphia chromosome), and immunophenotyping establish whether the leukemic cells are myeloblastic (neutrophils, eosinophils, or basophils) or lymphoblastic (B lymphocytes or T lymphocytes). Cytogenetic testing on the marrow samples can help classify disease and predict how aggressive the disease course will be. Different mutations have been associated with shorter or longer survival. Immunohistochemical testing may reveal TdT or CALLA antigens on the surface of leukemic cells. TdT is a protein expressed early in the development of pre-T and pre-B cells, whereas CALLA is an antigen found in 80% of ALL cases and also in the "blast crisis" of CML.

Medical imaging (such as ultrasound or CT scanning) can find invasion of other organs commonly the lung, liver, spleen, lymph nodes, brain, kidneys, and reproductive organs.

Information on prognosis is limited by the rarity of the condition. Prognosis appears to be no different to AML in general, taking into account other risk factors. Acute erythroid leukemia (M6) has a relatively poor prognosis. A 2010 study of 124 patients found a median overall survival of 8 months. A 2009 study on 91 patients found a median overall survival for erythroleukemia patients of 36 weeks, with no statistically significant difference to other AML patients. AEL patients did have a significantly shorter disease free survival period, a median of 32 weeks, but this effect was explained by other prognostic factors. That is, AEL is often associated with other risk factors, like monosomal karyotypes and a history of myelodysplastic syndrome. Prognosis is worse in elderly patients, those with a history of myelodysplastic syndrome, and in patients who had previously received chemotherapy for the treatment of a different neoplasm.

Definitive diagnosis of a chloroma usually requires a biopsy of the lesion in question. Historically, even with a tissue biopsy, pathologic misdiagnosis was an important problem, particularly in patients without a clear pre-existing diagnosis of acute myeloid leukemia to guide the pathologist. In one published series on chloroma, the authors stated that 47% of the patients were initially misdiagnosed, most often as having a malignant lymphoma.

However, with advances in diagnostic techniques, the diagnosis of chloromas can be made more reliable. Traweek et al. described the use of a commercially available panel of monoclonal antibodies, against myeloperoxidase, CD68, CD43, and CD20, to accurately diagnose chloroma via immunohistochemistry and differentiate it from lymphoma. Nowadays, immunohistochemical staining using monoclonal antibodies against CD33 and CD117 would be the mainstay of diagnosis. The increasingly refined use of flow cytometry has also facilitated more accurate diagnosis of these lesions.

White blood counts exceeding 100 x 10^9 / L (100,000 / microL) present symptoms of tissue hypoxia and may signal possible neurological and respiratory distress. Continuing research has shown that patients have suffered from hypoxia at leukocyte levels below 100 x 10^9 / L (100,000 / microL), therefore patients with leukemia need regular neurological and respiratory monitoring when leukocyte counts are approaching 100 x 10^9 / L (100,000 / microL) to decrease chances of tissue hypoxia. Biopsy's acquired are examined for damage to microvasculature, which serves as evidence of hypoxia through the identification of leukocyte blockage within the tissue. Due to a biopsy's invasive nature and the risks associated with the procedure, it is only used when deemed necessary.

Measurements for arterial pO2 have shown to be falsely decreased in patients with hyperleuckocytosis because of white blood cells ability to utilize oxygen. Pulse oximetry should be used to more accurately assess pO2 levels of a patient suspected to be suffering from leukocytosis.

Automated blood cell counters may be inaccurate due to fragments of blast cells being labeled on blood smears as platelets. The most accurate form of confirming platelet counts is by using a manual platelet count and review of a peripheral smear.

Serum potassium levels may also be artificially elevated caused by a release from leukemic blasts during in vitro clotting process, therefore serum potassium levels should be monitored by herparinized (the addition of herapin prevents coagulation) plasma samples in order to obtain accurate results of potassium levels.

Disseminated intravascular coagulation may occur in a significant amount of patients with presentation of various degrees of thrombin generation, followed by decreased fibrinogen and increased fibrinolysis.

Spontaneous tumor lysis syndrome is present in approximately 10 percent of patients with leuckostasis, lab tests are used to measure the potential of elevated serum concentrations such as uric acid, potassium, phosphate, and hyocalcemia.

Disseminated intravascular coagulation and spontaneous tumor lysis syndrome have the ability to develop before and after chemotherapy treatment. Patients undergoing this type of therapy need to be closely monitored before and after in addition to undergoing prophylactic measures to prevent possible complications.

The prognosis for BAL patients is not good which is worse than ALL and AML. Medical Blood Institute reported cases of CR rate was 31.6%, with a median remission are less than 6 months

The median survival time is only 7.5 months. The life quality is also low because the immune function of patient is damaged seriously. They have to stay in hospital and need 24h care.

In another study, the results showed that young age, normal karyotype and ALL induction therapy will have a better prognosis than Ph+, adult patients. The study shows median survival of children is 139 months versus 11 months of adults, 139 months for normal karyotype patients versus 8 months for ph+ patients.

Hydroxycarbamide and anagrelide are contraindicated during pregnancy and nursing. Essential thrombocytosis can be linked with a three-fold increase in risk of miscarriage. Throughout pregnancy, close monitoring of the mother and fetus is recommended. Low-dose low molecular weight heparin (e.g. enoxaparin) may be used. For life-threatening complications, the platelet count can be reduced rapidly using platelet apheresis, a procedure that removes platelets from the blood and returns the remainder to the patient.

The first clue to a diagnosis of AML is typically an abnormal result on a complete blood count. While an excess of abnormal white blood cells (leukocytosis) is a common finding with the leukemia, and leukemic blasts are sometimes seen, AML can also present with isolated decreases in platelets, red blood cells, or even with a low white blood cell count (leukopenia). While a presumptive diagnosis of AML can be made by examination of the peripheral blood smear when there are circulating leukemic blasts, a definitive diagnosis usually requires an adequate bone marrow aspiration and biopsy as well as ruling out pernicious anemia (Vitamin B12 deficiency), folic acid deficiency and copper deficiency.

Marrow or blood is examined under light microscopy, as well as flow cytometry, to diagnose the presence of leukemia, to differentiate AML from other types of leukemia (e.g. acute lymphoblastic leukemia - ALL), and to classify the subtype of disease. A sample of marrow or blood is typically also tested for chromosomal abnormalities by routine cytogenetics or fluorescent "in situ" hybridization. Genetic studies may also be performed to look for specific mutations in genes such as "FLT3", nucleophosmin, and "KIT", which may influence the outcome of the disease.

Cytochemical stains on blood and bone marrow smears are helpful in the distinction of AML from ALL, and in subclassification of AML. The combination of a myeloperoxidase or Sudan black stain and a nonspecific esterase stain will provide the desired information in most cases. The myeloperoxidase or Sudan black reactions are most useful in establishing the identity of AML and distinguishing it from ALL. The nonspecific esterase stain is used to identify a monocytic component in AMLs and to distinguish a poorly differentiated monoblastic leukemia from ALL.

The diagnosis and classification of AML can be challenging, and should be performed by a qualified hematopathologist or hematologist. In straightforward cases, the presence of certain morphologic features (such as Auer rods) or specific flow cytometry results can distinguish AML from other leukemias; however, in the absence of such features, diagnosis may be more difficult.

The two most commonly used classification schemata for AML are the older French-American-British (FAB) system and the newer World Health Organization (WHO) system. According to the widely used WHO criteria, the diagnosis of AML is established by demonstrating involvement of more than 20% of the blood and/or bone marrow by leukemic myeloblasts, except in the three best prognosis forms of acute myeloid leukemia with recurrent genetic abnormalities (t(8;21), inv(16), and t(15;17)) in which the presence of the genetic abnormality is diagnostic irrespective of blast percent. The French–American–British (FAB) classification is a bit more stringent, requiring a blast percentage of at least 30% in bone marrow (BM) or peripheral blood (PB) for the diagnosis of AML. AML must be carefully differentiated from "preleukemic" conditions such as myelodysplastic or myeloproliferative syndromes, which are treated differently.

Because acute promyelocytic leukemia (APL) has the highest curability and requires a unique form of treatment, it is important to quickly establish or exclude the diagnosis of this subtype of leukemia. Fluorescent "in situ" hybridization performed on blood or bone marrow is often used for this purpose, as it readily identifies the chromosomal translocation [t(15;17)(q22;q12);] that characterizes APL. There is also a need to molecularly detect the presence of PML/RARA fusion protein, which is an oncogenic product of that translocation.

The diagnosis of HCL may be suggested by abnormal results on a complete blood count (CBC), but additional testing is necessary to confirm the diagnosis. A CBC normally shows low counts for white blood cells, red blood cells, and platelets in HCL patients. However, if large numbers of hairy cells are in the blood stream, then normal or even high lymphocyte counts may be found.

On physical exam, 80–90% of patients have an enlarged spleen, which can be massive. This is less likely among patients who are diagnosed at an early stage. Peripheral lymphadenopathy (enlarged lymph nodes) is uncommon (less than 5% of patients), but abdominal lymphadenopathy is a relatively common finding on computed tomography (CT) scans.

The most important lab finding is the presence of hairy cells in the bloodstream. Hairy cells are abnormal white blood cells with hair-like projections of cytoplasm; they can be seen by examining a blood smear or bone marrow biopsy specimen. The blood film examination is done by staining the blood cells with Wright's stain and looking at them under a microscope. Hairy cells are visible in this test in about 85% of cases.

Most patients require a bone marrow biopsy for final diagnosis. The bone marrow biopsy is used both to confirm the presence of HCL and also the absence of any additional diseases, such as Splenic marginal zone lymphoma or B-cell prolymphocytic leukemia. The diagnosis can be confirmed by viewing the cells with a special stain known as TRAP (tartrate resistant acid phosphatase). More recently, DB44 testing assures more accurate results.

It is also possible to definitively diagnose hairy cell leukemia through flow cytometry on blood or bone marrow. The hairy cells are larger than normal and positive for CD19, CD20, CD22, CD11c, CD25, CD103, and FMC7. (CD103, CD22, and CD11c are strongly expressed.)

Hairy cell leukemia-variant (HCL-V), which shares some characteristics with B cell prolymphocytic leukemia (B-PLL), does not show CD25 (also called the Interleukin-2 receptor, alpha). As this is relatively new and expensive technology, its adoption by physicians is not uniform, despite the advantages of comfort, simplicity, and safety for the patient when compared to a bone marrow biopsy. The presence of additional lymphoproliferative diseases is easily checked during a flow cytometry test, where they characteristically show different results.

The differential diagnoses include: several kinds of anemia, including myelophthisis and aplastic anemia, and most kinds of blood neoplasms, including hypoplastic myelodysplastic syndrome, atypical chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, or idiopathic myelofibrosis.

Because the cause is unknown, no effective preventive measures can be taken.

Because the disease is rare, routine screening is not cost-effective.

Conventionally, a leukocytosis exceeding 50,000 WBC/mm with a significant increase in early neutrophil precursors is referred to as a leukemoid reaction. The peripheral blood smear may show myelocytes, metamyelocytes, promyelocytes, and rarely myeloblasts; however, there is a mix of early mature neutrophil precursors, in contrast to the immature forms typically seen in acute leukemia. Serum leukocyte alkaline phosphatase is normal or elevated in leukemoid reaction, but is depressed in chronic myelogenous leukemia. The bone marrow in a leukemoid reaction, if examined, may be hypercellular but is otherwise typically unremarkable.

Leukemoid reactions are generally benign and are not dangerous in and of themselves, although they are often a response to a significant disease state (see "Causes" below). However, leukemoid reactions can resemble more serious conditions such as chronic myelogenous leukemia (CML), which can present with identical findings on peripheral blood smear.

Historically, various clues including the leukocyte alkaline phosphatase score and the presence of basophilia were used to distinguish CML from a leukemoid reaction. However, at present the test of choice in adults to distinguish CML is an assay for the presence of the Philadelphia chromosome, either via cytogenetics and FISH, or via PCR for the BCR/ABL fusion gene. The LAP (Leukocyte Alkaline Phosphatase) score is high in reactive states but is low in CML. In cases where the diagnosis is uncertain, a qualified hematologist or oncologist should be consulted.

CML accounts for 8% of all leukaemias in the UK, and around 680 people were diagnosed with the disease in 2011.

The following revised diagnostic criteria for essential thrombocythaemia were proposed in 2005. The diagnosis requires the presence of both A criteria together with B3 to B6, or of criterion A1 together with B1 to B6. The criteria are as follows:

- A1. Platelet count > 450 × 10/µL for at least 2 months.

- A2. Acquired V617F JAK2 mutation present

- B1. No cause for a reactive thrombocytosis

- normal inflammatory indices

- B2. No evidence of iron deficiency

- stainable iron in the bone marrow or normal red cell mean corpuscular volume

- B3. No evidence of polycythemia vera

- hematocrit < midpoint of normal range or normal red cell mass in presence of normal iron stores

- B4. No evidence of chronic myeloid leukemia

- But the Philadelphia chromosome may be present in up to 10% of cases. Patients with the Philadelphia chromosome have a potential for the development of acute leukemia, especially acute lymphocytic leukemia.

- B5. No evidence of myelofibrosis

- no collagen fibrosis and ≤ grade 2 reticulin fibrosis (using 0–4 scale)

- B6. No evidence of a myelodysplastic syndrome

- no significant dysplasia

- no cytogenetic abnormalities suggestive of myelodysplasia

Cytogenetic analysis has shown different proportions and frequencies of genetic abnormalities in cases of ALL from different age groups. This information is particularly valuable for classification and can in part explain different prognosis of these groups. In regards to genetic analysis, cases can be stratified according to ploidy, number of sets of chromosomes in the cell, and specific genetic abnormalities, such as translocations. Hyperdiploid cells are defined as cells with more than 50 chromosomes, while hypodiploid is defined as cells with less than 44 choromosomes. Hyperdiploid cases tend to carry good prognosis while hypodiploid cases do not. For example, the most common specific abnormality in childhood B-ALL is the t(12;21) "ETV6"-"RUNX1" translocation, in which the "RUNX1" gene, encoding a protein involved in transcriptional control of hemopoiesis, has been translocated and repressed by the "ETV6"-"RUNX1" fusion protein.

Below is a table with the frequencies of some cytogenetic translocations and molecular genetic abnormalities in ALL.

Since leukostais/ hyperleukostasis is associated with leukemia, preventative treatments are put into action upon diagnosis.

Patients with hyerleukocystois associated with leukemia are always considered candidates for tumor lysis syndrome prophylaxis in addition to aggressive intravenous hydration with allopurinol or rasburicase to decrease serum uric acid levels.

Acute promyelocytic leukemia can be distinguished from other types of AML based on microscopic examination of the blood film or a bone marrow aspirate or biopsy as well as finding the characteristic rearrangement. Definitive diagnosis requires testing for the "PML/RARA" fusion gene. This may be done by polymerase chain reaction (PCR), fluorescent in situ hybridization (FISH), or conventional cytogenetics of peripheral blood or bone marrow. This mutation involves a translocation of the long arm of chromosomes 15 and 17. On rare occasions, a cryptic translocation may occur which cannot be detected by cytogenetic testing; on these occasions PCR testing is essential to confirm the diagnosis. Presence of multiple Auer rods on peripheral blood smear is highly suggestive of acute promyelocytic leukemia.