Diagnostic Applications of Nuclear Medicine: Leukemias
Leukemias are a group of acute and chronic hematological neoplasias characterized by the dissemination of the cancer cells originating in the bone marrow via the bloodstream. In 2016 the estimated number of new leukemia cases was more than 110,000 in all of Europe and 47,000 in the USA. Leukemias, cause of 4% of all cancer deaths and account for 3.6% of all cancers. Historically, leukemias have been divided into four major categories further classified into subtypes based on specific features of cells: acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML). A revised classification of myeloid/lymphoid neoplasms and leukemias has recently been published to better characterize each disease. This updated classification incorporated new scientific and clinical information to refine diagnostic criteria for previously described neoplasms and introduced newly recognized disease entities. In this chapter the main entities of leukemia, with specific regard to imaging for diagnosis, treatment response assessment, and follow-up, will be treated according to what reported in the clinical guidelines.
KeywordsLeukemia Imaging Bone cancer Hematological malignancies
Array comparative genomic hybridization
Atypical chronic myeloid leukemia
Anaplastic large-cell lymphoma
Acute lymphoblastic leukemia, also defined as “acute lymphocytic leukemia”
Acute myeloid leukemia, also defined as “acute myelogenous leukemia”
B-cell acute lymphoblastic leukemia
Gene encoding for the B-cell lymphoma 2 protein
Gene encoding for the B-cell lymphoma 6 protein
Fusion gene formed by a translocation between chromosomes 9 and 22 [t(9;22)]
Chimeric transcript created by the inversion (16)(p13;q22)
Gene encoding for the protein CCAAT/enhancer-binding protein alpha
Chemotherapy based on cyclophosphamide, vincristine, doxorubicin, and dexamethasone
Chronic lymphocytic leukemia, also defined as “chronic lymphocytic leukemia”
Chronic myeloid leukemia, also defined as “chronic myelogenous leukemia”
Chronic myelomonocytic leukemia
Chronic neutrophilic leukemia
Central nervous system
Cytokine receptor-like factor 2
X-ray computed tomography
Gene fusion created by the t(6;9)(p23;q34) translocation
Diffuse large B-cell lymphoma
European Society of Medical Oncology
European Treatment and Outcome Study
Receptor tyrosine kinase for the fibroblast growth factor family
Fluorescence in situ hybridization
Gene encoding for a protein called GATA binding protein 2, a transcription factor
Gene expression profiling
Hairy cell leukemia
Human leukocyte antigen
Intrachromosomal amplification of chromosome 21
Immunoglobulin heavy chain
Fusion gene created by the t(5;14)(q31;q32) translocation
Immunoglobulin heavy chain
International Working Group on CLL
Signaling pathway that transmits information from extracellular chemical signals to the nucleus resulting in DNA transcription and expression of genes involved in immunity, proliferation, differentiation, apoptosis, and oncogenesis
Gene encoding for Janus kinase 2, a non-receptor tyrosine kinase
Juvenile myelomonocytic leukemia
Gene encoding for histone-lysine (K)-specific N-methyltransferase 2A
Gene encoding for lysine (K)-specific methyltransferase 2C
Mucosa-associated lymphoid tissue
Monoclonal B lymphocytosis
Mantle cell lymphoma
Myelodysplastic syndrome with ring sideroblasts
Gene econding for the protein MDS1 and EVI1 complex locus protein EVI1, also known as ecotropic virus integration site 1 protein homolog, or positive regulatory domain zinc finger protein 3
Monoclonal gammopathy of undetermined significance
Gene fusion created by the t(9;11)(p22;q23) translocation
Mixed phenotype acute leukemia
Minimal residual disease
Magnetic resonance imaging
Avian myelocytomatosis viral oncogene homolog
Gene encoding for the protein nucleophosmin
Not otherwise specified
Notch homolog 1, translocation-associated (Drosophila), a human gene encoding for a single-pass transmembrane receptor
Non-small-cell lung cancer
Gene fusion created by the t(8;9)(p22;p24) translocation which leads to the activation of the Janus kinase 2PCM1 gene encoding for the pericentriolar material 1
Platelet-derived growth factor receptor
Gene encoding for the platelet-derived growth factor receptor alpha
Gene encoding for the platelet-derived growth factor receptor beta
Positron emission tomography
Positron emission tomography/Computed tomography
Intracellular signaling pathway important in regulating the cell cycle
Gene fusion created by the t(15;17)(q22;q12) translocation
Posttransplant lymphoproliferative disorders
Reverse transcriptase polymerase chain reaction
Gene fusion created by the t(8;21)(q22;q22) translocation
Runt-related transcription factor 1
Sudan Black B, a nonfluorescent lysochrome (fat-soluble) diazo dye used for tissue staining
Stem cell transplantation
Surveillance, Epidemiology, and End Results Program of the National Cancer Institute (National Institutes of Health of the United States)
Small lymphocytic lymphoma
T-cell acute lymphoblastic leukemia
Transient abnormal myelopoiesis
Tyrosine kinase inhibitor
T-cell acute lymphoblastic leukemia
Chimeric gene created by the t(1;19)(q23;p13) translocation
T follicular helper
World Health Organization
Leukemias are a group of acute and chronic hematological neoplasias characterized by the dissemination in the bloodstream of the cancer cells originating in the bone marrow. The incidence of acute leukemia in adult (either myeloid – AML or lymphoblastic – ALL) is about 4/100,000/year, that of the chronic myeloid leukemia (CML) 1.5/100,000/year, and that of the chronic lymphocytic leukemia (CLL) of 5/100,000/year. Thus, in 2016 the estimated number of new leukemia cases is more than 110,000 in all of Europe and 47,000 in the USA. Leukemias, cause of 4% of all cancer deaths and account for 3.6% of all cancers, with CLL being the most frequent type (60%), followed by AML (25%). Leukemias are most frequently diagnosed among people aged 65–74 years, but all age groups can be affected. ALL are the most common pediatric tumor (about 35% of cancers in children aged 0–14 years), but all age groups can be affected. Approximately 9% were diagnosed before age 20, 9% between 20 and 44, 10% between 45 and 54, 18% between 55 and 64, 22% between 65 and 74, 21% between 75 and 84, and 11% after 85 years of age .
Acute lymphocytic leukemia (ALL)
Chronic lymphocytic leukemia (CLL)
Acute myelogenous leukemia (AML)
Chronic myelogenous leukemia (CML)
Revised classification of myeloid/lymphoid neoplasms and leukemias according to the 2016 WHO classification.
2016 WHO classification
Myeloid neoplasm and acute leukemia classification
Mature lymphoid, histiocytic, and dendritic neoplasms
Myeloproliferative neoplasms (MPN)
Mature B-cell neoplasms
Chronic myeloid leukemia (CML), BCR-ABL1
Chronic lymphocytic leukemia/small lymphocytic lymphoma
Chronic neutrophilic leukemia (CNL)
Monoclonal B-cell lymphocytosisa
Polycythemia vera (PV)
B-cell prolymphocytic leukemia
Primary myelofibrosis (PMF)
Splenic marginal zone lymphoma
PMF, prefibrotic/early stage
Hairy cell leukemia
PMF, overt fibrotic stage
Splenic B-cell lymphoma/leukemia, unclassifiable
Essential thrombocythemia (ET)
Splenic diffuse red pulp small B-cell lymphoma
Chronic eosinophilic leukemia, not otherwise specified (NOS)
Hairy cell leukemia variant
Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2
Monoclonal gammopathy of undetermined significance (MGUS), IgMa
Myeloid/lymphoid neoplasms with PDGFRA rearrangement
μ heavy-chain disease
Myeloid/lymphoid neoplasms with PDGFRB rearrangement
γ heavy-chain disease
Myeloid/lymphoid neoplasms with FGFR1 rearrangement
α heavy-chain disease
Provisional entity: myeloid/lymphoid neoplasms with PCM1-JAK2
Monoclonal gammopathy of undetermined significance (MGUS), IgG/Aa plasma cell myeloma solitary plasmacytoma of bone
Myelodysplastic/myeloproliferative neoplasms (MDS/MPN)
Chronic myelomonocytic leukemia (CMML)
Monoclonal immunoglobulin deposition diseasesa
Atypical chronic myeloid leukemia (aCML), BCR-ABL1
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)
Juvenile myelomonocytic leukemia (JMML)
Nodal marginal zone lymphoma
MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)
Pediatric nodal marginal zone lymphoma
Myelodysplastic syndromes (MDS)
In situ follicular neoplasiaa
MDS with single-lineage dysplasia
Duodenal-type follicular lymphomaa
MDS with ring sideroblasts (MDS-RS)
Pediatric-type follicular lymphomaa
MDS-RS and single-lineage dysplasia
Large B-cell lymphoma with IRF4 rearrangementa
MDS-RS and multilineage dysplasia
Primary cutaneous follicle center lymphoma
MDS with multilineage dysplasia
Mantle cell lymphoma
MDS with excess blasts
In situ mantle cell neoplasiaa
MDS with isolated del(5q)
Diffuse large B-cell lymphoma (DLBCL), NOS
Germinal center B-cell typea
Provisional entity: refractory cytopenia of childhood
Activated B-cell typea
Acute myeloid leukemia (AML) and related neoplasms
T-cell/histiocyte-rich large B-cell lymphoma
AML with recurrent genetic abnormalities
Primary DLBCL of the central nervous system (CNS)
AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1
Primary cutaneous DLBCL, leg type
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH1
EBV+ DLBCL, NOSa
APL with PML-RARA
EBV+ mucocutaneous ulcera
AML with t(9;11)(p21.3;q23.3);MLLT3-KMT2A
DLBCL associated with chronic inflammation
AML with t(6;9)(p23;q34.1);DEK-NUP214
AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM
Primary mediastinal (thymic) large B-cell lymphoma
AML (megakaryoblastic) with t(1;22)(p13.3;q13.3);RBM15-MKL1
Intravascular large B-cell lymphoma
Provisional entity: AML with BCR-ABL1
ALK+ large B-cell lymphoma
AML with mutated NPM1
AML with biallelic mutations of CEBPA
Primary effusion lymphoma
Provisional entity: AML with mutated RUNX1
HHV8+ DLBCL, NOSa
AML with myelodysplasia-related changes
Therapy-related myeloid neoplasms
Burkitt-like lymphoma with 11q aberrationa
High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangementsa
AML with minimal differentiation
High-grade B-cell lymphoma, NOSa
AML without maturation
B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma mature
AML with maturation
Mature T and NK neoplasms
Acute myelomonocytic leukemia
T-cell prolymphocytic leukemia
Acute monoblastic/monocytic leukemia
T-cell large granular lymphocytic leukemia
Pure erythroid leukemia
Chronic lymphoproliferative disorder of NK cells
Acute megakaryoblastic leukemia
Aggressive NK-cell leukemia
Acute basophilic leukemia
Systemic EBV+ T-cell lymphoma of childhooda
Acute panmyelosis with myelofibrosis
Hydroa vacciniforme-like lymphoproliferative disordera
Adult T-cell leukemia/lymphoma
Myeloid proliferations related to Down syndrome
Extranodal NK-/T-cell lymphoma, nasal type
Transient abnormal myelopoiesis (TAM)
Enteropathy-associated T-cell lymphoma
Myeloid leukemia associated with Down syndrome
Monomorphic epitheliotropic intestinal T-cell lymphomaa
Blastic plasmacytoid dendritic cell neoplasm
Indolent T-cell lymphoproliferative disorder of the GI tracta
Acute leukemias of ambiguous lineage
Hepatosplenic T-cell lymphoma
Acute undifferentiated leukemia
Subcutaneous panniculitis-like T-cell lymphoma
Mixed phenotype acute leukemia (MPAL) with t(9;22)(q34.1;q11.2); BCR-ABL1
MPAL with t(v;11q23.3); KMT2A rearranged
MPAL, B/myeloid, NOS
Primary cutaneous CD30+ T-cell lymphoproliferative disorders
MPAL, T/myeloid, NOS
Primary cutaneous anaplastic large-cell lymphoma
B-lymphoblastic leukemia/lymphoma, NOS
Primary cutaneous γδ T-cell lymphoma
B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma
B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2);BCR-ABL1
Primary cutaneous acral CD8+ T-cell lymphomaa
B-lymphoblastic leukemia/lymphoma with t(v;11q23.3);KMT2A rearranged
Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disordera peripheral T-cell lymphoma, NOS
B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1
Angioimmunoblastic T-cell lymphoma, follicular T-cell lymphomaa
B-lymphoblastic leukemia/lymphoma with hyperdiploidy
Nodal peripheral T-cell lymphoma with TFH phenotypea
B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3) IL3-IGH
Anaplastic large-cell lymphoma, ALK+
B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3);TCF3-PBX1
Anaplastic large-cell lymphoma, ALK−a
Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like
Breast implant-associated anaplastic large-cell lymphomaa
Provisional entity: natural killer (NK) cell lymphoblastic leukemia/lymphoma
Nodular lymphocyte predominant Hodgkin lymphoma
Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21
Classical Hodgkin lymphoma
Nodular sclerosis classical Hodgkin lymphoma
Provisional entity: early T-cell precursor lymphoblastic leukemia
Lymphocyte-rich classical Hodgkin lymphoma
Provisional entity: natural killer (NK) cell lymphoblastic leukemia/lymphoma
Mixed cellularity classical Hodgkin lymphoma
Lymphocyte-depleted classical Hodgkin lymphoma
Posttransplant lymphoproliferative disorders (PTLD)
Plasmacytic hyperplasia PTLD
Infectious mononucleosis PTLD
Florid follicular hyperplasia PTLDa
Monomorphic PTLD (B- and T-/NK-cell types)
Classical Hodgkin lymphoma PTLD
Histiocytic and dendritic cell neoplasms
Langerhans cell histiocytosis
Langerhans cell sarcoma
Indeterminate dendritic cell tumor
Interdigitating dendritic cell sarcoma
Follicular dendritic cell sarcoma
Fibroblastic reticular cell tumor
Disseminated juvenile xanthogranuloma
Acute Lymphocytic Leukemia (ALL) in Adult
In 2016, the estimated number of new cases of ALL was about 6,500, accounting for 0.4% of all new cases of cancer. The number of new cases of ALL was 1.7 per 100,000 per year based on 2009–2013 cases, according to the SEER database. ALL is most frequently diagnosed among people aged <20 (57%); it is most common in children, adolescents, and young adults, with a median age at diagnosis of 15 years. ALL is most common in Hispanics and Whites . ALL occurs both in children and adults. Predisposing risk factors for adult ALL are not known, contrary to childhood ALL . In adults, the age of appearance is one of the most important prognostic determinants. Although the two forms share some common features, fundamental biologic differences may account for the striking variation in outcome. However, although survival in adult patients (>19 years old) remains inferior to that achieved for children with ALL , recent advances in molecular testing, the development of new targeted agents, and an improved understanding of the importance of minimal residual disease (MRD) could soon translate into improved prognosis . Recurrent numerical and/or structural cytogenetic abnormalities are found in 70% of adults and 90% of children with ALL and provide important prognostic and certain drug resistance information . Literature data [9, 10] suggest that routine characterization of ALL can aid in the design of more tailored treatment plan.
Furthermore, many chromosomal abnormalities identified in adult ALL have also been found to correlate with prognosis [11, 12, 13, 14]. The most important cytogenetic abnormality in adult ALL (found in 15–30%) is the Philadelphia (Ph’) chromosome. Ph’ chromosome is defined as t(9;22)(q34;q11.2), which results in the BCR-ABL1 fusion gene, with a constitutive and uncontrolled tyrosine kinase activity . A novel subtype of ALL was recently identified by gene expression profiling which clusters with BCR-ABL1 positive ALL. This entity is now referred to as “Ph’-like” disease and represents 15–20% of the adolescent and young adult ALL. These patients have an unfavorable outcome and 5-year disease-free survival of only 25.8% ; this subtype has high frequency of kinase-activating alterations providing the lymphoblasts with proliferation advantage. Some of these fusions are sensitive in vitro to tyrosine kinase inhibitors (TKIs), leading to clinical trials assessing their integration into ALL armamentarium . Some advances have been made in the identification of molecular markers of T-cell leukemogenesis. Activating mutations of NOTCH1 (a class I transmembrane heterodimeric glycoprotein that is normally involved in T-cell development and regulation) have been detected in almost 60% of human T-ALL . These activating mutations led to clinical testing of gamma-secretase inhibitors that prevent NOTCH1 activation [18, 19, 20].
Epigenetic changes including hypermethylation of tumor suppressor genes or microRNAs and hypomethylation of oncogenes have also been studied in ALL. It represents a novel area of investigation for targeted drugs, such as DNA methyltransferase inhibitors [21, 22, 23].
CRLF2 is located in the pseudoautosomal region at Xp22.3/Yp11.3; it is rearranged in 50% of Down syndrome-related ALL and also in Ph’-like ALL . Cells with CRLF2 mutations exhibit activation of the JAK/STAT and of the downstream PI3K/mTOR pathway; thus, in these subtypes, everolimus, temsirolimus, and ruxolitinib could be useful targeted treatments . Other possible targets of interest in ALL include the 22q11.22 deletion and platelet-derived growth factor receptor alpha (PDGFR-alpha) gains that are associated with poor outcome and could predict therapeutic responses to TKIs able to inhibit PDGFR-alpha, such as imatinib .
Imaging for Diagnosis and Staging of ALL
A comprehensive diagnostic approach requires the study of cell morphology, immunophenotype, genetics/cytogenetics, and genomics, as detailed in the 2008 World Health Organization (WHO) classification  and recently reviewed [4, 27] (Table 1). The initial diagnostic work-up must confirm ALL diagnosis, distinguishing leukemia originating from the B or T lymphocytes, from precursors or more mature cells, and those Ph’ positive, allowing the most appropriate treatment (anti-CD20, anti-CD19, anti-CD22 antibodies, tyrosine kinase inhibitors) .
Aspiration of bone marrow and bone marrow biopsy represent the standard procedure; the bone marrow must contain at least 20% blast cells, as a criterion to differentiate ALL from lymphoblastic lymphoma, but the proportion of circulating blasts is highly variable. ALL blasts are atypical lymphoid or undifferentiated cells. The immunophenotype study plays the key diagnostic role, demonstrating commitment of the blast cell population to the B- or T-cell lineage. The European Group for the Immunological Characterization of Leukemias recognized distinct BCP/T-ALL subsets, providing a rational immunological classification along with criteria for differential diagnosis  subsequently updated and improved [30, 31, 32]. The early diagnostic step is completed by a rapid molecular screening by means of reverse transcriptase polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization (FISH) assays, primarily for the detection of BCR-ABL1 rearrangement, sensitive to tyrosine kinase inhibitors (TKIs) . Results from cytogenetics, genetics, and genomics are available at a later stage, allowing the recognition of several ALL syndromes with prognostic and/or therapeutic implications. The more prognostically favorable cytogenetic/genetic subsets are represented by t(12;21)(p13;q22)/TEL-AML1 (rare in adults), the hyperdiploid ALL, and T-ALL with NOTCH-1/FBXW7 mutations. The integration of the conventional studies (karyotype, FISH, qualitative, and quantitative PCR) with the new ones [array comparative genomic hybridization (aCGH), gene expression profiling (GEP), single-nucleotide polymorphism (SNP) array analysis, next-generation sequencing (NGS)] led to the recognition of highly specific poor-risk conditions, whose global incidence is 30%. These assays are not still regularly carried out in clinical practice, but are recommended to improve the risk classification and support targeted therapies .
The diagnostic phase is completed by the search for a sensitive molecular marker or an aberrant leukemia-associated immunophenotype (LAIP) for the detection and monitoring of minimal residual disease (MRD) . Human leukocyte antigen (HLA) typing of patients and relatives is recommended at this stage, to facilitate subsequent application of the allogeneic stem cell transplantation (SCT) when necessary .
Patients with ALL typically present with constitutional symptoms, bleeding, infections, and/or bone pain, with less than 10% of individuals having symptomatic central nervous system (CNS) involvement at diagnosis. Mature B-ALL can also present as extramedullary (gastrointestinal or testicular) diseases. Mediastinal mass with wheezing and stridor can be a presenting feature of T-cell ALL .
Symptomatic CNS involvement is more frequent in patients with mature B-ALL; these patients may present with cranial nerve deficiencies (especially cranial nerves VI, III, IV, and VII), leading to double vision, abnormal ocular movements, facial dysesthesia, and facial droop . Patients with T-ALL frequently present with a mediastinal mass on chest X-ray. If the mass is sufficiently large, it results in stridor, wheezing, pericardial effusions, and superior vena cava syndrome . Involvement of the skin, testicles, kidneys, joints, and bones is uncommon in adults [38, 39]. Approximately 15–25% of ALL patients of all ages have leukemia with a T-cell phenotype, which is associated with higher initial WBC counts, mediastinal mass, male gender, and higher incidence of CNS involvement. In children, the frequency of T-lineage ALL increases with age.
Physical examination may reveal pallor, ecchymoses, or petechiae. Lymphadenopathy and hepatosplenomegaly are infrequent; patients present with signs and symptoms of metabolic hyperactivity, including profound constitutional symptoms, weight loss, and often large abdominal and (especially in children) testicular masses . Involvement of the gastrointestinal tract is also frequent and may cause bleeding or rupture.
Microscopy and cytochemical stains are still essential in the initial work-up: bone marrow is usually hypercellular and replaced with a homogenous population of leukemic blasts .
In contrast to lymphoma, leukemia is not staged because it involves the bone marrow, and leukemic cells circulate throughout the bloodstream to all parts of the body.
Ultrasound and CT scan are generally used to assess extramedullary involvement in the abdomen, and MRI is indicated to assess the CNS for leukemic infiltration, infections or multifocal leukoencephalopathy.
Renal involvement does not necessarily imply a significant organ impairment, because elevated creatinine may occur due to lymphadenopathy compressing renal vessels and/or ureter. Nephromegaly is a common finding in children . Additionally causes of renal parenchymal abnormalities in childhood ALL include infection, lymphoma transformation, nephroblastomatosis, cysts, angiomyolipomas, and metastases. Furthermore, atypical infection with microabscesses in the liver, spleen, and kidneys appear as focal small non-enhancing areas of parenchymal abnormality  on CT, especially in children. In patients with possible CNS infection and negative cultures, MRI may be helpful in revealing the presence of the disease and in the assessment to response to treatment. Early diagnosis of neurologic involvement is essential to insure effective therapy and for detection of treatment-related neurotoxicity, secondary brain tumors, infections, and cerebrovascular disease [48, 49, 50]. MRI abnormal enhancement of the meninges and/or nerve roots may result from leptomeningeal or subarachnoid disease/relapse or infection, rarely, both. Other causes of nerve root enhancement on MRI include postsurgical arachnoiditis, mechanical root compression associated with inflammation, cytomegalovirus polyradiculopathy or inflammatory demyelinating polyradiculoneuropathy (Guillain-Barrè syndrome), and rarely spontaneous spinal hematomas . Promising results have been reported in the identification of the extramedullary involvement, specially in recurrent disease, using [18F]FDG-PET/CT [51, 52].
Imaging for the Evaluation of Treatment Response of ALL
The definition of treatment response in ALL does not require any imaging. However, imaging plays an important role for detecting and monitoring treatment.
Treatment-related CNS complications include white matter lesions, small-vessel calcifications, cerebrovascular disorders, treatment-induced tumors, infections, and enlargement of ventricles and/or widening of sulci (sign of cortical atrophy). Leukoencephalopathy is the most common neurotoxicity, usually due to methotrexate in ALL patients. It appears as white matter hyperintensities on T2-weighted MRI, and it may be persistent or transient . Mineralizing microangiopathy is a delayed form of neurotoxicity typically detectable as dystrophic calcifications in the basal ganglia and subcortical white matter.
The detection of iron overload, particularly in myocardium in patients receiving chronic red cell transfusions, is mandatory to prevent ventricular dysfunction. MRI-T2*-weighted images using gradient-echo MRI-T2* allow the determination of myocardial iron amount and may be used both for diagnosis and monitoring myocardial iron overload during and after antileukemic treatment with blood transfusions .
Chronic Lymphocytic Leukemia (CLL)
CLL is characterized by a progressive accumulation of monoclonal B lymphocytes and is part of a spectrum of diseases grouped as low-grade lymphoproliferative disorders. CLL is the most common form of all leukemias among adult populations of the Western world and is more common in men. Since this disease is characterized by relatively longer survival rate, its prevalence rate is the highest among all leukemias. In 2016, the estimated number of new cases of CLL is about 19,000, accounting for 1.2% of all new cases of cancer. CLL is rare in people younger than 50 years, but after this age a fairly rapid rise in incidence takes especially after 55 years. Approximately 9% of cases are diagnosed between 45 and 54 years, 22% between 55 and 64, 28% between 65 and 74, 26% between 75 and 84, and 13% after 85 years of age (about 2% in patients <44 years) .
Genetic, rather than environmental, factors are the most likely explanation for the geographic and ethnic differences in incidence. There is an inherited genetic susceptibility for CLL, with a six to ninefold increased risk for family members of CLL patients. There are no clearly identified etiologic factors known in CLL .
The diagnosis of CLL is established by the presence in the peripheral blood of ≥5 × 109/L monoclonal B lymphocytes (clonality of the circulating B lymphocytes needs to be confirmed by flow cytometry or assessment of the immunoglobulin heavy chain (IgH) clonal rearrangement by PCR). In the peripheral blood smear, the leukemic cells appear as small, mature lymphocytes with a narrow border of cytoplasm and a dense nucleus lacking discernible nucleoli and with partially aggregated chromatin. Larger, atypical lymphocytes or prolymphocytes may be seen, but they must not exceed 55% .
Immunophenotype is useful for distinguishing CLL from other indolent lymphomas, such as the marginal zone, the lymphoplasmacytic, and the mantle cell (MCL) : indeed, in addition to the B markers (CD20, CD19), common to all B lymphomas, the co-expression of CD5 (that occurs also in MCL); the CD79, CD11c, CD103, and FMC7 negativity; and the CD200 and CD23 positivity characterize the B-CLL.
In the WHO classification, small lymphocytic lymphoma (SLL) and CLL are considered as a single entity (Table 1).
The diagnosis of SLL requires the presence of lymphadenopathy and/or splenomegaly with a number of B lymphocytes in the peripheral blood not exceeding 5 × 109/L. SLL cells show the same immunophenotype as CLL. The diagnosis of SLL should be confirmed by histopathological evaluation of a lymph node or tumor mass biopsy, whenever possible. In the absence of lymphadenopathy, organomegaly, cytopenia, and clinical symptoms, the presence of fewer than 5 × 109/L monoclonal B lymphocytes is defined as “monoclonal B lymphocytosis” (MBL) [55, 56, 57] which can be detected in 5% of subjects with normal blood count. As described for monoclonal gammopathies and multiple myeloma, progression to CLL occurs in 1–2% of MBL cases per year .
CLL cells co-express the CD5 antigen and B-cell surface antigens CD19, CD20, and CD23. The levels of surface immunoglobulin, CD20, and CD79b are characteristically low compared with normal B cells. Each clone of leukemia cells is restricted to expression of either kappa or lambda immunoglobulin light chains .
The pathophysiology of CLL involves inhibition of apoptosis . Accumulation of mature B cells that have escaped programmed cell death and undergone cell cycle arrest in the G0/G1 phase is the hallmark of CLL . These cells have a low proliferative activity, and data lend support to the hypothesis that in vivo defective apoptosis accounts for accumulation of B cells.
CLL is generally considered an indolent disease associated with a prolonged chronic course; more than one-third of patients die for other causes and the natural history is very heterogeneous: some patients die within 2–3 years from the diagnosis, mainly because of complications or causes directly related to CLL. Nevertheless, the majority of cases present relatively benign initial course (5–10 years), followed by a terminal phase lasting 1–2 years with considerable morbidity, both from the disease itself and from complications of therapy. The most frequent causes of death are severe systemic infections (especially pneumonia and septicemia), bleeding, and inanition with cachexia. In about 3% of CLL patients, a diffuse large-cell immunoblastic lymphoma supervenes terminally (Richter’s transformation), associated with a rapidly progressive course, refractoriness to all chemotherapy, and death within 6 months . Another possible terminal event is the morphologic transformation of blood lymphocytes from the typical small, mature-appearing cell to larger cells with distinct nucleoli and less dense chromatin in the nucleus, called prolymphocytoid transformation . Acute leukemia is rarely observed as a terminal event; it occurs independently by treatment with alkylating agents, and when it does occur, it is myeloid in origin (myelocytic, myelomonocytic, or acute erythroleukemia). There is no widely accepted effective therapy for these terminal transformations of CLL. Patients with CLL are considered to be at a somewhat higher risk than the general population of developing another cancer, usually of lung or gastrointestinal tract. Skin cancers occur with considerably greater frequency among CLL patients than among the general population, but these do not result in higher mortality.
Rai (2A) and Binet (2B) staging systems
High levels of lymphocytes
Swollen lymph nodes
Enlarged spleen or liver
Low levels of platelets
Yes or no
Yes or no
Yes or no
Yes or no
Yes or no
Yes or no
Number of lymph node areas
Low levels of platelets
3 or more
Yes (or low platelets)
Yes (or anemia)
The Rai staging system  is based on the concept that in CLL there is a gradual and progressive increase in the burden of leukemic lymphocytes, resulting in sequential clinical manifestations of the disease starting in the blood and bone marrow and then involving the lymph nodes, spleen, and liver or other lymphoid sites. The earliest stage (stage 0) is characterized by no stigmata of disease other than the minimum diagnostic requirements of CLL. About 20–25% of patients at the time of initial diagnosis of CLL are in the earliest clinical stage (stage 0, median survival from the time of diagnosis = 150 months), 25% are in the advanced stages (stages III and IV, median survival = 19 months), and the remaining 50% are in stage I or II (median survival = 101 and 71, respectively). In 1987, however, the system was simplified to consist of only three groups: low (Rai stage 0), intermediate (Rai stages I and II combined), and high (Rai stages III and IV combined) (140). Binet’s method  classifies all patients with anemia (defined as hemoglobin below 100 g/L) and/or thrombocytopenia (platelets less than 100 × 109/L) as stage C. All of the remaining patients are divided into two groups. This staging takes into consideration five areas: cervical, axillary, and inguinal lymph nodes (whether unilateral or bilateral, each area is counted as one) and the spleen and liver. The International Working Group on CLL (IWCLL) recommended that, in practice, an integrated system using both methods should be used . According to this recommendation, each Binet stage is to be further identified by the appropriate Rai stage (i.e., A-0, A-I, A-II, B-I, B-II, C-III, C-IV). However, this integrated system has not been widely accepted, and most clinicians today use either the Rai’s or Binet’s method for patient management and therapeutic investigation.
Both the Rai’s or Binet’s staging systems rely solely on a physical examination and standard laboratory tests, whereas the role of various imaging procedures (ultrasound, computed tomographic scan, or magnetic resonance imaging [MRI]) has not been validated for staging of CCL. The Binet’s method may require some modification in the future, since CT has become a routine part of initial investigations and may reveal enlargement of retroperitoneal or mediastinal nodes that are currently not included among the five sites of palpably enlarged lymphoid areas.
The Rai’s or Binet’s clinical staging systems alone are not sufficient to estimate the individual prognosis reliably, particularly for patients with early-stage disease. Therefore, additional parameters have been sought to more accurately assess the prognosis of patients with CLL. This search has provided a steadily increasing number of laboratory tests, which predict the response to treatment, progression-free survival, or overall survival of patients with CLL. Several prognostic factors have been tested, including extent of blood lymphocytosis, morphologic features of blood lymphocytes (i.e., the relative proportion of prolymphocytes), presence of normal or abnormal chromosomal karyotype, phenotypic profile of B lymphocytes, age, sex and levels of serum immunoglobulins, molecular genetics makers, beta-2 microglobulin, and adhesion molecules . The mutational status of IgH genes on CLL lymphocytes seems promising: VH gene mutations correlate with significantly longer survival and a relatively more benign disease course than unmutated genes. Testing for gene mutations, however, is not routinely done in hospitals, but perhaps CD38 expression, a readily available test, holds the promise of being useful as a surrogate marker. Patients with mutated VH genes showed a strong correlation with low expression of CD38 and ZAP70 on CLL lymphocytes . These findings were especially strong prognostic indicators for patients in the intermediate-risk category patients, but at the moment these molecular features don’t really lead the therapeutic strategy. In fact, CLL cells with unmutated IGVH status have a higher genetic instability with a higher risk of gaining unfavorable genetic mutations. OS and time to treatment intervention are significantly shorter in this patient group. The expression of CD38 and ZAP70 correlates to some extent with the IGHV mutational status, but has no therapeutic impact and is therefore not required.
Imaging for Diagnosis and Staging of CLL
Diagnosis of CLL is essentially based on symptoms, laboratory tests, and physical examination. Before any treatment, history, and physical examination including a careful palpation of all lymph node areas, the spleen, and the liver, a complete blood cell count and differential count, serum chemistry including lactate dehydrogenase, bilirubin, serum immunoglobulins, and direct antiglobulin, should be performed. Particular attention should be paid to the history and status of relevant infections (i.e., hepatitis B and C, cytomegalovirus, human immunodeficiency virus) in order to avoid virus reactivation during chemoimmunotherapy or allogeneic stem cell transplantation (alloSCT) . The diagnostic work-up should include FISH analysis for the detection of deletion of the chromosome 17 [del (17p)] affecting the tumor protein p53 expression and in the absence of del(17p) molecular genetics for the detection of TP53 gene mutation (at least exons 4–10, eventually exons 2–11) .
Although a bone marrow biopsy is not really necessary for diagnosis, nevertheless it is recommended for assessing the pattern of bone marrow infiltration and for the diagnostic evaluation of unclear cytopenias. An extended FISH analysis (for chromosome 11, 12, 13, 17) is recommended before the start of therapy because the detection of additional cytogenetic abnormalities [del(11q) or trisomy 12] may have therapeutic consequences. In particular, deletion of chromosome 17 and/or of TP53 is indicative of a worse prognosis or for the possibility of employing the Bruton kinase inhibitor ibrutinib in first line of therapy. CT scans may be helpful to assess the tumor load or to determine the cause of unclear symptoms, but they should not generally be used in asymptomatic patients or for clinical staging. In addition, CT scans may be useful for baseline and final assessment in clinical trials. In elderly patients, abdominal ultrasound might be considered instead [55, 56].
Abdominal ultrasound and CT may be helpful to detect splenomegaly or bulky disease, findings that may influence therapy planning [56, 67]. Muntanola et al.  suggested that the presence of abdominal involvement (splenomegaly or lymphadenopathy) in patients with Rai stage 0 predicts a more aggressive clinical course of the disease with shorter time to progression compared to patients with normal CT findings. Furthermore, abnormal abdominal CT findings correlate with severity of bone marrow infiltration, ZAP-70 expression, and shorter lymphocyte doubling time.
MRI does not provide significant information for CLL management, except in rare cases of central nervous system localization of the disease, as typical for cases of childhood leukemia.
The value of [18F]FDG-PET/CT for the detection of Richter’s transformation has been reported in 37 CLL patients with very high sensitivity (91%) and negative predictive values (97%) . False-positive results in this series were caused by other malignancies (i.e., Hodgkin disease or NSCLC), as frequently observed in CLL patients. The accelerated phase of CLL, an early transition to lymphomatous transformation characterized by increased numbers of more immature cells within the bone marrow and by lymphoid tissue with a higher rate of cell turnover, may represent an additional false-positive [18F]FDG-PET/CT. Finally, infection can also cause false-positive findings on [18F]FDG-PET/CT; the CT component of the PET/CT exam may be employed to improve accuracy in this specific setting. When [18F]FDG-PET/CT is used to guide biopsies, histological analysis remains the gold standard. The prognostic role of [18F]FDG-PET/CT in CLL should be confirmed by histopathology .
Treatment Evaluation of CLL
CT scan parameters required to assess the treatment response in clinical trials according to Hallek et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia : a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines 
Complete remission (CR)
Partial remission (PR)
Progressive disease (PD)
Lymph nodes should not be >1.5 cm in diameter and no hepatomegaly or splenomegaly
Reduction in lymphadenopathy defined as: decrease in lymph node size ≥50% either in the sum products of up to 6 lymph nodes or in the largest diameter of the enlarged lymph node(s) detected prior to therapy and no increase in any lymph node and no new enlarged lymph node. In small lymph nodes (<2 cm), an increase <25% is not considered to be significant and a reduction in the noted pretreatment enlargement of the spleen or liver ≥50%
Appearance of any new lesion (such as enlarged lymph nodes >1.5 cm or other organ infiltrates) or increase in the previously noted enlargement of lymph nodes ≥50% or an increase in the previously noted enlargement of the liver or spleen ≥50% or the de novo appearance of hepatomegaly or splenomegaly
Recently, the next-generation sequencing (NGS) techniques allowed the possibility of recognizing a disease-specific B clone and following it after treatment. The new therapies (rituximab plus bendamustine, ibrutinib, obinutuzumab plus chlorambucil, idelalisib) seem to offer higher rates of molecular remission and correlate with longer disease-free survivals [74, 75, 76, 77].
Follow-Up and Long-Term Implications in CLL
CLL is an incurable disease. Therefore, lifelong observation and follow-up is recommended for all patients in order to identify the moment when re-treatment will be necessary. Follow-up of asymptomatic patients should include a blood cell count and clinical evaluation (palpation of the lymph nodes, liver, and spleen) every 3–6 months, depending on the dynamics of the leukemic development. Special attention should be paid to the appearance of autoimmune cytopenias. Moreover, CLL patients have a two to sevenfold increased risk of developing secondary malignancies (mostly solid cancers, but also secondary myelodysplastic syndromes or acute myeloblastic leukemia). The transformation into a diffuse large B-cell lymphoma (DLBCL) or Hodgkin’s lymphoma (HL) occurs in 2–15% of CLL during the course of disease . The transformation into DLBCL (Richter’s transformation) usually has a very poor prognosis that required therapies used in DLBCL, such as rituximab plus CHOP (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), but response duration is typically short, and an allogeneic HSCT should be recommended in case of available donor and sufficient fitness. The transformation of CLL into Hodgkin’s disease represents a separate entity, where conventional chemotherapy against HL often achieves long-lasting remissions .
Hairy Cell Leukemia (HCL)
Classical hairy cell leukemia (HCL) is a B-cell chronic lymphoproliferative disorder characterized by splenomegaly, pancytopenia, and bone marrow involvement with fibrosis. HCL represents 2% of all adult leukemias . Approximately 1,600 new cases per year are diagnosed in Europe, with a median age of 52 years at the time of diagnosis . In the USA, a higher frequency of HCL is observed among White Americans than among African-Americans or Asians, as well as in patients following exposure to the herbicide “Agent Orange ,” used during the Vietnam War . HCL variant (HCL-V) is classified among mature B-cell neoplasias . HCL-V is an uncommon disorder, accounting for approximately 0.4% of chronic lymphoid malignancies and 10% of all HCL cases, without sexual predominance and a median age at diagnosis of 71 years.
The examination of peripheral blood films and immunophenotyping are usually sufficient the diagnosis in the majority of cases. The neoplastic cells are twice the size of small lymphocytes and have a round or kidney-shaped nucleus with excess chromatin and abundant pale cytoplasm with projections. Monocytopenia and macrocytosis are very common; other cytopenias may be present. A diagnosis of HCL based on cytology can be effectively confirmed by flow cytometry studies using anti-B-cell monoclonal antibodies such as CD19, CD20, or CD22, together with a panel of antibodies such as CD11c, CD25, CD103, and CD123, which are more specific to HCL; this combination will allow the differentiation of HCL from other B-cell leukemias and lymphomas with circulating villous cells, such as the marginal lymphoma [78, 81, 82]. In addition, strong expression of CD200 is characteristic of HCL and may be useful as distinctive feature in difficult cases . HCL-V typically presents with high lymphocyte counts, with the cells being nucleolated and lacking monocytopenia. Flow cytometry will indicate the cells to be CD11c+ and often CD103+ but very rarely CD25+ and CD123+. As the bone marrow can rarely be aspirated (“dry tap”) in classical HCL, diagnosis is typically performed by a bone marrow trephine biopsy. The degree and pattern of infiltration varies from mild interstitial to diffuse, and the lymphoid cells are surrounded by a clear halo due to the abundant cytoplasm, giving the characteristic “fried egg” pattern. In difficult cases, BRAF V600E mutation of exon 15 may be useful to diagnose classical HCL and MDR . This mutation has been described in 100% of classical HCL, but is absent in HCL-V and in cases with VH4-34 rearrangement [78, 85, 86]. It has also a clinical impact, because the anti-RAF compounds, such as vemurafenib, have been shown to be very effective in relapsed patients . In HCL-V, the infiltration is either intrasinusoidal or interstitial. Immunohistochemistry with the monoclonal antibodies CD20, CD72 (DBA44), CD11c, CD25, CD103, annexin A1, and tartrate-resistant acid phosphatase stain will highlight the lymphoid infiltrates and support the diagnosis of classical HCL . However, annexin A1 is not suitable for detecting residual disease after treatment as it stains myeloid cells. Cyclin D1 may be weakly positive but differential diagnosis with mantle cell lymphoma rarely arises. HCL does not have a distinct chromosomal abnormality. The majority of the cases have mutations of the immunoglobulin heavy chain (IGHV) gene, suggesting that the disease arises on a memory B cell. Unlike other splenomegalic disorders such as splenic marginal zone lymphoma or HCL-V, there is no evidence of specific IGHV, IGHD, and IGHJ repertoires or stereotypes in HCL [88, 89, 90]. Although HCL-V patients lack the BRAF mutation, TP53mutations are present in one-third of cases . There is no worldwide accepted staging system for HCL. In addition to the diagnostic tests on the blood and bone marrow trephine biopsy, a staging work-up should include full blood cell counts with differential and reticulocytes, renal and liver biochemistry, serum immunoglobulins, β2 microglobulin, direct antiglobulin test, Coombs test, and hepatitis virus B and C and human immunodeficiency virus screening. Computed tomography (CT) imaging is desirable at the time of diagnosis (as around 10% of HCL patients have abdominal lymphadenopathy) and should be performed at relapse [78, 92]. MRI is being evaluated as a means for assessing total body burden of disease in the marrow .
Imaging During Follow-Up of HCL
A follow-up of asymptomatic patients should include a complete history, physical examination, the blood cell count, and routine chemistry every 3–12 months. CT scan is not necessary outside clinical trials . The frequency of second malignancies is increased in HCL patients, whether treated or untreated. Solid and hematological malignancies develop in 10% of HCL patients, particularly chronic lymphoproliferative diseases (multiple myeloma, Hodgkin’s and non-Hodgkin’s lymphoma), melanoma, and thyroid cancer [94, 95].
Acute Myeloid Leukemia (AML)
In 2016, the estimated number of new cases of AML is about 20,000, accounting for 1.1% of all new cases of cancer. The number of new cases of AML was 4.1 per 100,000 per year based on 2009–2013 cases according to the SEER database . AML affects adults of all ages, but is especially common among people aged 65–74.
Currently, thanks to advances in transfusion and infectious disease supportive care  as well as serial evaluations of different chemotherapeutic approaches, more than 80% of young adults and 60% of all patients can achieve complete remission. Varying with patient age and other factors, from 15% to 50% of these complete responders can be expected to achieve long-term survival with the likelihood that most of these individuals are cured of their disease. Acquired genetic changes in bone marrow stem cells that cause a complete or partial block in normal hematopoietic stem cell maturation are the basis of the development of the disease. The genetic changes may involve mutations that lead to activation of growth-promoting proto-oncogenes, inactivation of tumor suppressor genes, or alterations in transcription factors. Mutations in codons 12, 13, or 61 of the N-ras gene encoding a 21 kd guanosine nucleotide-binding protein involved in signal transduction have been noted in a consistent patients with AML. The greatest insight regarding AML pathogenesis has been provided by the identification of genes at cytogenetic breakpoints involved in balanced translocation. The fusion proteins generated by the translocation generally result in disruption of transcription factors believed to be critical in myeloid differentiation . Many of these chromosomal abnormalities [e.g., t(8;21), t(15;17), inv16] are associated with specific AML subtypes and carry prognostic importance. Although the acquired genetic lesions that lead to leukemia are being rapidly defined, DNA damage from a known cause accounts for a small fraction of patients with AML. There have been a number of epidemiologic studies that have attempted to link environmental exposures to leukemia . There may be a small increased risk associated with cigarette smoking , whereas exposure to electromagnetic radiation  seems an unlikely cause of AML. Occupational exposures, particularly to benzene  or petrochemicals , have been implicated in the development of AML. Alkylating agents have been associated with deletions of chromosome 5 and 7, whereas etoposide (used in childhood ALL) and high-dose anthracycline/cyclophosphamide combinations may cause 11q23-associated disease. With these few exceptions, however, there is no clear relationship between environmental exposures and the occurrence of acute leukemia.
AML can present either as a de novo leukemia, without an apparent antecedent illness, or as an evolution from previous marrow disorders, such as myelodysplasia, aplastic anemia, chronic myeloid leukemia (CML), and Fanconi’s anemia , or after the administration of therapy for other types of cancers or nonmalignant disorders.
The natural history of AML arising de novo in young adults is believed to be a disease of the committed stem cell that is vastly different from the same disease arising from the pluripotent stem cell, as occurs in secondary AML .
The diagnosis of AML requires the examination of peripheral blood and bone marrow specimens. The work-up of these specimens should include morphology, cytochemistry, immunophenotyping, cytogenetics, and molecular genetics (PCR, FISH) . In most patients, it is relatively simple to distinguish between AML and ALL on morphologic grounds. In general, the blasts from patients with AML are larger, with more abundant cytoplasm and more prominent, often multiple nucleoli. The definitive diagnosis depends, however, on the presence of Auer rods, on concentrations of myeloid-containing granules (present in 50% of those with AML), or on demonstration of at least 3% granulated precursors . The cells are often reactive with antibodies directed against CD34. Terminal deoxynucleotidyl transferase (TdT) is generally absent, but can sometimes be detected in a minority of blasts. While historically sorted by the largely descriptive French-American-British (FAB) criteria , AML are now classified according to the WHO classification . The FAB morphologic classification names the AML according to the normal marrow elements that they most closely resemble . The WHO classification incorporates, in addition to morphological criteria, cytogenetic data, molecular genetics, immunophenotype data, and clinical information into a diagnostic algorithm to delineate clinically significant disease entities. In the WHO classification, the term “myeloid” includes all cells belonging to the granulocytic, monocyte/macrophage, erythroid, megakaryocytic, and mast cell lineage. Despite the dilemma and controversy regarding how to incorporate recently described and clinically important genetic lesions into the revised scheme, the framework of the classification proved flexible enough so that new, well-defined entities could be incorporated as provisional entities, those for which more data need to be collected so that they can be better characterized. One of the major challenges in the revision of the WHO classification is how to incorporate important and/or recently described genetic aberrations into a classification scheme of AML and yet adhere to the WHO principle of defining homogeneous, biologically relevant, and mutually exclusive entities based not only on the prognostic value of a genetic abnormality, but on morphologic, clinical, phenotypic, and/or other unique biologic properties. According to the last version of the WHO classification, different subgroups of AML and related neoplasm may be identified (Table 1): the AML with recurrent genetic abnormalities, the AML with myelodysplasia-related changes, the therapy-related myeloid neoplasms, the AML not otherwise specified, the myeloid sarcoma, the myeloid proliferations related to Down syndrome, and the blastic plasmacytoid dendritic cell neoplasm. A specific section is reserved for acute leukemias of ambiguous lineage.
Recently, a meta-analysis of 9 studies including 4,509 patients affected by AML was performed: the frequency of NPM1 mutations ranged from 7% to 56%. Nevertheless, all data confirmed the positive prognostic value of this mutation, with a double probability of achieving complete remission compared with NPM1 wild type and a significant advantage also on disease-free survival and overall survival .
In the subgroup of AML with recurrent genetic abnormalities, variant RARA translocations should be diagnosed as AML with the variant partner specifically designated . For all other entities within the category of AML with recurrent genetic abnormalities, 20% or more blasts must be present in the PB or BM to establish the diagnosis of AML [26, 105]. Although these leukemias are recognized as unique entities, it is important to realize that additional genetic abnormalities may coexist and influence their biologic and clinical behavior, including response to therapy and the overall survival. Studies of AML associated with the chromosomal rearrangements t(6;9)(p23;q34); DEK-NUP21, inv(3)(q21q26.2), or t(3; 3)(q21;q26,2); RPN1-EVI1 and t(1;22)(p13;q13); and RBM15-MKL1 have provided evidence that these genetic rearrangements, although uncommon, are associated with distinctive morphologic and clinical features that argue for their incorporation in the revised listing of AML with recurrent genetic abnormalities [110, 111, 112]. A more controversial issue is whether leukemia initially demonstrating a blastic myeloid proliferation associated with the Ph’ chromosome or BCR-ABL1 is a distinct and easily defined entity. Although BCR-ABL1-positive AML has been reported [113, 114, 115], criteria for its distinction from CML initially manifesting in a blast phase are not entirely convincing, and for this reason, BCR-ABL1-positive AML is not recognized in this classification. Many cases of BCR-ABL1-related acute leukemia will meet the criteria for ALL or mixed phenotype acute leukemia, provided that a blast phase of a previously unrecognized CML can be excluded. In addition to the newly listed leukemias associated with cytogenetically detectable rearrangements, AML with mutated NPM1 or CEBPA have been added to the classification as “provisional entities.” Mutated FLT3 frequently accompanies other genetic lesions, and although it is not included as a defining criterion for any distinct entity in the revised WHO classification, the mutational status of FLT3 should always be ascertained in AML, particularly in cytogenetically normal AML, because of its prognostic importance.
The AML with myelodysplasia-related changes is diagnosed when patients have 20% or more blasts in the PB or BM and (1) evolve from previously documented MDS or MDS/MPN, (2) have specific myelodysplasia-related cytogenetic abnormalities, or (3) exhibit dysplasia in 50% or more of the cells in two or more myeloid lineages .
The therapy-related myeloid neoplasms included t-AML/t-MDS and t-AML/t-MDS/MPN. Most patients who develop therapy-related myeloid neoplasms have received alkylating agents and/or radiation as well as topoisomerase II inhibitors. It has been argued that 90% of patients with therapy-related neoplasms have cytogenetic abnormalities identical to those observed in AML with myelodysplasia-related features or in AML with recurrent cytogenetic abnormalities; therefore, such cases would be more appropriately classified in those categories rather than in a separate, therapy-related category. However, the majority of patients with therapy-related myeloid neoplasms have a worse outcome than do their de novo counterparts with the same genetic abnormalities [3, 26, 116, 117, 118, 119, 120].
The group of AML not otherwise specified (AML NOS) encompasses those cases that do not fulfill the criteria for any of the other AML categories. The AML NOS will continue to diminish as more genetic subgroups are recognized.
The myeloid sarcoma is a pathologic diagnosis for an extramedullary proliferation of blasts of one or more of the myeloid lineages that disrupts the normal architecture of the tissue (any, particularly the skin, gastrointestinal tract, lymph nodes, and bone) in which it is found . Most often, myeloid sarcoma is found concurrently in a patient with previously or recently recognized AML, but it may also precede the appearance of blood or bone marrow disease. In this latter case, the diagnosis of myeloid sarcoma should be considered as synonymous with AML, and the tumor should be evaluated for morphologic, phenotypic, and genetic features that would allow it to be classified further into one of the subgroups of AML. A myeloid sarcoma is evidence of relapse in a patient thought to be in remission of a previously diagnosed AML, is evidence of evolution to AML in a patient with a previously diagnosed MDS or MDS/MPN, and is blast transformation in a patient with MPN .
The myeloid proliferations related to the Down syndrome, which include transient abnormal myelopoiesis and myeloid leukemia, have unique morphologic, immunophenotypic, clinical, and molecular features, including GATA1 mutation, that justify their separation from other myeloid neoplasms [122, 123, 124, 125].
The blastic plasmacytoid dendritic cell neoplasm recognizes virtually all cases of a tumor that is derived from precursors of a specialized subset of dendritic cells, plasmacytoid dendritic cells, and hence is a myeloid-related neoplasm. This subgroup includes most cases previously designated as “blastic natural killer cell leukemia/lymphoma” . It is a clinically aggressive neoplasm that is usually characterized at its onset by solitary or multiple skin lesions, often with associated regional lymphadenopathy. Many cases will ultimately progress to involve the PB and BM as well. The blasts in such cases do not express myeloperoxidase or cases of AML with minimal differentiation that do not show any lymphoid-associated antigens [126, 127, 128, 129].
Imaging for Diagnosis and Staging of AML
AML patients generally present with anemia (median hemoglobin 8 g/dL), thrombocytopenia (median platelet count 40–50 × 109/L), and leukocytosis (median white blood cell count 10–20 × 109/L). Most patients are neutropenic, and morphologic abnormalities (hypogranulation, nuclear hyperlobulation, Pelger-Huët anomaly) are often noted in the remaining neutrophils. Careful examination will detect blasts in most patients, although it can be difficult to distinguish among leukemia subtypes (or occasionally even to be confident of the diagnosis of acute leukemia) in patients with a low number of circulating blasts.
Initial symptoms are typically related to complications of pancytopenia including weakness, easy fatigability, infections of variable severity, or hemorrhagic findings, such as gingival bleeding, ecchymoses, epistaxis, or menorrhagia. Combinations of these symptoms are common. Occasionally patients present because of prominent extramedullary sites of leukemia usually related to either cutaneous or gingival infiltration by leukemia cells. Bone pain is infrequent in adults with AML, although some individuals describe sternal discomfort or tenderness, occasionally with aching in the long bones, particularly of the lower extremities. Most patients have had more subtle evidence of leukemia for weeks, to perhaps months, before diagnosis. The findings on physical examination are variable and generally nonspecific. If fever is present, it is almost always related to infection, and an infectious site must be vigorously sought and generally treated empirically with broad-spectrum antibiotics. Examination of the skin can reveal pallor. Infiltrative skin lesions are suggestive of leukemic involvement. Other coutaneous manifestations may be infection either primary or embolic, or, most commonly, petechiae or ecchymoses related to thrombocytopenia and/or coagulopathy. Examination of the fundus reveals hemorrhages and/or exudates in the majority of patients. Careful examination of the oropharynx and teeth is important because of the occasional occurrence of leukemia involvement and the value of applying effective dental prophylaxis, if time permits, prior to chemotherapy. Palpable adenopathy is uncommon; significant lymph node enlargement is rare as well as hepatomegaly and splenomegaly. None of these findings is diagnostic of acute leukemia, and the final diagnosis and categorization depends on appropriate evaluation of peripheral blood and bone marrow. Routine chemistry including liver and kidney parameters and coagulation profile, as well as blood group and HLA typing of patient and family members, are required as part of the initial work-up of AML. Radiological diagnostic examinations must include dental survey and chest/abdomen CT scan or chest X-ray and abdominal ultrasound .
Extramedullary disease in lymph nodes, the CNS, or soft tissue is observed particularly in case of relapse after allogeneic stem cell transplantation or bone marrow transplantation .
Response Evaluation and Follow-Up in AML
AML response to treatment is monitored with serial peripheral blood counts and repeated bone marrow examinations. To design the best regimen, the first bone marrow exam is performed at the day +30. Cytogenetic/molecular abnormalities detected at diagnosis and morphological/immunophenotypical response, patients should continue conventional chemotherapy or should be switched to a more intensive treatment, such as autologous or allogeneic transplantation. During intensive chemotherapy, bone marrow should be examined in the aplastic phase to monitor blast clearance, persistence, or early relapse. The usual criteria of response are blast clearance in the bone marrow to <5% of all nucleated cells, a recovered normal hematopoiesis, and return of the peripheral blood cell count to normal levels. Although sensitive PCR methods as well as immunophenotyping are available, permitting molecular follow-up and detection of minimal residual disease in patients with suitable markers (mostly specific chromosomal translocations or typical antigen expression profiles, respectively), the early detection of molecular relapse in the absence of morphological evidence for recurrent AML is of uncertain therapeutic consequence. Specifically, evidence that early re-induction treatment of such patients still in hematological remission would be of any benefit is lacking .
Chronic Myeloid Leukemia (CML)
In 2016, the estimated number of new cases of CML is about 8,200, accounting for 0.5% of all new cases of cancer. The number of new cases of AML was 1.8 per 100,000 per year based on 2009–2013 cases according to the SEER database .
CML is a clonal myeloproliferative disorder of a pluripotent stem cell  with a specific cytogenetic abnormality, the Philadelphia chromosome that identifies the chromosome (22q-) resulting from the balanced translocation between the long arm of chromosome 9 and 22.
In the great majority of patients, a causative factor cannot be identified. Nevertheless, it is well known that ionizing radiations are leukemogenic, although the most common type of leukemia following radiations is AML . The median age of onset of CML is 64 years; the peak incidence occurs during the ages of 65–74 years . The first phase of the disease, the chronic phase, could terminate, trough an accelerated phase, in acute leukemia (blastic phase), characterized by a short survival .
The translocation of the ABL1 gene from chromosome 9–22 t(9;22)(q3.4;q1.1) leads to the formation of a new, hybrid, fusion gene (BCR-ABL1) that codes for an oncoprotein (P210, more rarely P190 or P230) that is located in the cytoplasm and has a strong, constitutively activated tyrosine kinase activity, resulting in the activation of several downstream signals that transform hematopoietic stem cells . Cells carrying the BCR-ABL1 gene show an abnormal interaction with the actin and the stroma, an increased proliferation, and a reduced apoptosis rate due to the activation of the RAS/ERK and PI3K/AKT pathways .
Moreover, BCR-ABL-positive cells are genetically unstable and are prone to develop multiple and heterogeneous genomic abnormalities, resulting in the transformation of the leukemic phenotype from chronic to acute, hence leading to the progression from chronic to accelerated and blastic phase . One important event associated with progression is the development of point mutations in the kinase domain (KD) of the ABL1 gene, leading to resistance to the tyrosine kinase inhibitors (TKI), such as imatinib, dasatinib, nilotinib, and bosutinib [141, 142]. Ponatinib is the unique TKI able to bypass the gatekeeper mutation T315I, except in the cases when it is associated with other ABL1 mutations (compound mutations) [143, 144]. BM biopsies taken from untreated patients at diagnosis show increased cellularity due to proliferation of the granulocytic series that turns in different stages of maturation, although myelocytes and segmented forms predominate . No substantial features of dysplasia are found. Eosinophils may be prominent. Blasts must account for <5% of the whole examined population. Megakaryocytes are smaller than normal with hypolobulated nuclei. Although their number may be normal or slightly decreased, in about 50% of cases there is a moderate to extensive megakaryocytic proliferation. Moderate to marked reticulin fibrosis is encountered in 30% of cases. Pseudo-Gaucher cells and sea-blue histiocytes are usually observed. Notably, the BM picture undergoes important changes (e.g., reduction of the granulocytic cellularity, normalization of megakaryopoiesis, regression of fibrosis, and increase in apoptosis associated with decrease in proliferative activity), particularly following long-term treatment with TKIs .
According to the European Leukemia Net guidelines , CML patients have to be carefully monitored by cytogenetic and molecular tests: the achievement of a BCR-ABL1/ABL1 ratio lower than 10% at 3 months of therapy (early molecular response), of 1% at 6 months, and of 0.1% at 12 months (MR3) and the achievement of the complete cytogenetic response at 12 months in the absence of additional chromosome abnormalities characterize the optimal responder subject. On the contrary, cases with a BCR-ABL1/ABL1 ratio higher than 10% at 6 months or 1% at 12 months are categorized as failed patients and so for a different treatment. Nevertheless, TKIs allowed prolong long-term survival up to 90%.
The recognition of disease progression from CP to BP is relevant for prognosis and treatment.
Many studies tempted to characterize the genomic alteration characterizing the transition to the blastic phase: the myeloid one is characterized by the TP53, WT1, RAS, NPM1, IDH1/2, and RB1 mutations, while the lymphoblastic transformation shows acquired mutations of IKZF1, IDH1/2, and CDKN2A .
Nevertheless, it is important to remember that the probability of developing a blastic phase is about 6% with imatinib and 2% with nilotinib .
Imaging for Diagnosis and Staging of CML
CML symptoms are not specific, including weight loss, asthenia, small fever, sweats, and malaise, and are not frequent, since in more than 40% of cases, the diagnosis is fortuitous, being based on abnormal blood counts. In most cases, diagnosis is based on blood counts (leukocytosis and frequently also thrombocytosis) and differential (immature granulocytes, from the metamyelocytes to the myeloblasts, and basophilia). Splenomegaly is present in half of the cases in the initial chronic phase, but the majority of these patients are asymptomatic . Symptoms and signs usually develop insidiously and include fatigue, anemia, progressive splenomegaly, and leukocytosis. In the chronic phase, the white blood cell count approximates 2,000 × 109/L. The myeloid cells in the peripheral blood show all stages of differentiation, but the myelocytes predominate. More than half of the patients have platelet counts above 1,000 × 109/L, but thrombotic phenomena are unusual. A slight degree of anemia is common. The striking biochemical abnormality in CML is the reduction of leukocyte alkaline phosphatase activity, both in intensity and in the number of neutrophil band forms that stain positively for the enzyme. As the disease evolves, varying degrees of fibrosis occur . Clinically, the most reliable finding is the presence in the peripheral blood, bone marrow, or both of myeloblasts and promyelocytes exceeding 30% of the differential distribution (70% of the cases) . In the absence of frank blast crisis, other criteria include the development of fever of undetermined origin, increasing splenomegaly, a rising white blood cell count, basophilia, an increasing degree of anemia, and thrombocytopenia and refractoriness to previously effective therapy. High blast cell counts may lead to pulmonary and/or cerebral leukostasis and hemorrhage. The median survival after blastic transformation is approximately 3–6 months.
Currently, no imaging modalities are used for CML diagnosis or staging. [18F]FDG-PET in the chronic phase of CML has diffuse increased uptake in the bone marrow . The appearance of [18F]FDG is very similar to the hematopoietic cytokine-mediated [18F]FDG bone marrow uptake . When patients with CML are evaluated under treatment or after cessation of treatment, reduced FDG uptake has been observed in the bone marrow. [18F]FDG-PET/CT may be useful for the diagnosis of granulocytic sarcomas, rare extramedullary manifestations of myeloid (or lymphoblastic leukemia) that may develop anywhere, but most commonly arise in the skull, orbits, and sinuses . Preclinical studies suggested a potential role of [18F]FLT as quantitative and semiquantitative uptake measurement for metabolic imaging .
Many prognostic scoring systems have been proposed, including the Sokal , the Euro , and the EUTOS  scores. The first and the second have been developed in the interferon era, based on age and on the percentage of circulating blasts, basophils, and eosinophils and of spleen size weighted as continuous variables. The EUTOS has been proposed after the introduction of imatinib and is based on the spleen dimensions and the basophil count. These risk scores distinguish among three categories the Sokal and Euro and between two categories the EUTOS risk score. The introduction in the clinical practice of the second-generation TKIs reduced the impact of the risk categories on survival. These prognostic classifications are important because case selection and the results of interferon treatment may influence the presumed therapeutic effect of interferon or other forms of nontransplant treatment.
Imaging for Monitoring Treatment of CML
In CML, responses are classified as hematological (complete if the spleen dimension and blood count is normal), cytogenetic (complete if Ph’ metaphases are absent), and molecular. The molecular responses are defined as logarithmic reduction of BCR-ABL1/ABL1 ratio in respect of 100% of diagnosis. MR3 (0.1%) is now considered the goal of treatment at 12 months; nevertheless, today the major attention has been taken to the deep molecular response (4, 4.5, 5 logarithms reduction); indeed, patients treated for more than 5 years with imatinib and with a deep molecular response lasting more than 2 years have a 50% likelihood of remaning in remission after TKI discontinuation [157, 158]. More rapid and deeper molecular responses can be achieved by second-generation TKIs used as first line of treatment [159, 160].
No imaging techniques exist that would be used as surrogate for the molecular response categorization.
Monitoring is essential for treatment optimization and for a cost-effective outcome: at the beginning and during the first 3 months, biochemical and hematological monitoring is recommended every 2 weeks, to ensure the compliance of the patient and exclude relevant toxicities. From the third month on, cytogenetics is recommended every 6 months until the confirmed complete cytogenetic response, and quantitative PCR is recommended every 3–6 months. Screening for ABL1 mutations is recommended only in the case of failure or suboptimal response; ultra-deep sequencing techniques significantly increased the possibility of detecting mutations in cases resulting unmutated after conventional sequencing. This item is clinically relevant because some mutations are TKI specific and induce to change the drug.
As reported at diagnosis, also in the monitoring of responses, no role for imaging modalities is recognized by the current ESMO Clinical Practice Guidelines .
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