Dra. Viviana Riquelme S y col. Revista Chilena de Radiología. Vol. 18 Nº 1, año 2012; 24-29. Imaging studies in early diagnosis of childhood

Drs. Viviana Riquelme S(1), Cristián García B(2).

1. Physician, School of Medicine Graduate, Pontificia Universidad Católica, Santiago, Chile. 2. Departments of Radiology and Pediatrics. School of Medicine, Pontificia Universidad Católica, Santiago, Chile.

Imaging studies in early diagnosis of childhood leukemia

Abstract: Leukemia is the most commonly encountered in children under the age of 15 and accounts for approximately 35-40% of all at that age. Acute lymphoblastic leukemia (ALL) is the most com- mon type of leukemia affecting young children between the ages of 2 and 5 years; it accounts for around 80 % of all childhood leukemia cases. Initial clinical and laboratory findings may be non-specific. Imaging studies in patients with bone pain and extramedullary involvement may provide the clinician with valuable supplementary information when the first symptoms result from tissue infiltration and haematological series show a discrete and asymptomatic involvement. The purpose of this work is to review the initial radiological manifestations of leukemia in children. Given the systemic nature of this disease, the goal is to identify the key elements found in the study of the different affected organs, in order to facilitate an early diagnosis of this condition. Late-stage alterations or treatment complications, such as osteonecrosis, by opportunistic pathogens, graft-versus-host disease, etc. –where magnetic resonance imaging (MRI) and computed tomography (CT) play a fundamental role– will not be reviewed. Keywords: Child, Imaging, Leukemia, Pediatrics.

Resumen: La leucemia es el cáncer más frecuente en niños menores de 15 años y corresponde aproxi- madamente al 35-40% de todos los cánceres a esa edad. Se presenta con mayor frecuencia entre los 2 y 5 años de edad y la forma más frecuente es la leucemia linfoblástica aguda, que corresponde al 80% de los casos. Las manifestaciones clínicas y de laboratorio pueden ser inicialmente inespecíficas. El estudio imagenológico en pacientes con dolor óseo y compromiso extramedular, puede entregar valiosa información complementaria al clínico cuando los primeros síntomas derivan de la infiltración de los teji- dos y el compromiso de las series hematológicas es discreto y asintomático. El propósito de este trabajo es revisar las manifestaciones radiológicas iniciales de la leucemia en el niño. Considerando que es una enfermedad sistémica, el objetivo es identificar los elementos claves en el estudio de los distintos órganos comprometidos, que permitan al radiólogo sospechar el diagnóstico en la etapa precoz de la enfermedad. No se revisarán las alteraciones de la fase tardía o de complicaciones del tratamiento, como osteonecro- sis, infecciones por gérmenes oportunistas, enfermedad de injerto vs. huésped, etc., donde la resonancia magnética (RM) y la tomografía computada (TC) juegan un rol fundamental. Palabras clave: Imágenes, Niño, Leucemia, Pediatría.

Riquelme V y cols. Estudios de imágenes en el diagnóstico precoz de leucemia en pediatría. Rev Chil Radiol 2012; 18(1): 24-29. Corresponding. Dr. Cristián García B. / [email protected] Manuscript received November 24th, 2011; accepted for publication March 19th, 2012.

Introduction Since the beginning of the Program Cancer in The expected incidence of cancer in children the Child in 1988, an average of 100-110 new cases under 15 years is 110-150/1.000.000 children a year, of lymphoblastic leukemia and 30 cases of myeloid being slightly more common in men(1). Leukemia is the leukemia per year have been reported in the public most commonly encountered cancer and accounts for health sector(1). around 35-40% of all cancers at that age(1). The signs and symptoms that suggest leukemia are U.S. statistics establish an incidence rate of one varied and recommendations for diagnostic suspicion case of leukemia every 7,000 children per year(2). are clearly detailed in the Clinical Guide: Leukemia in In Chile, the preliminary report of the National Re- Children Under 15 years, Chilean Ministry of Health(1). gistry of Population (RENCI) revealed In general, diagnosis should be suspected in any in 2007 an incidence of of 42.7/1.000.000(1). child with not associated with bleeding, fever

24 Revista Chilena de Radiología. Vol. 18 Nº 1, año 2012; 24-29. IMÁGENES PEDIÁTRICAS associated or not with pallor, visceromegaly and CBC The purpose of this paper is to review the initial with anemia and/ or neutropenia (sometimes leuko- radiological manifestations of leukemia in children. cytosis), bone pain not associated with trauma, with Whereas it is a systemic disease, the goal is to identify CBC with cytopenia. the key elements in the study of the various organs Leukemia should be included in the differential involved, thus allowing the radiologist to suspect diagnosis in the presence of combination of the fo- diagnosis in the early stages of the disease. llowing signs and symptoms: Fever of unknown origin; Late-stage alterations or treatment complications, bone pain not associated with trauma; spontaneous such as osteonecrosis, infections by opportunistic bruising or associated with minor trauma; nasal or pathogens, graft-vs host disease, etc., where magnetic gingival bleeding; recurrent infections; lymphadeno- resonance imaging (MRI) and computed tomography pathy (persisting for more than 4 weeks; lymph nodes (CT) play a fundamental role will not be reviewed. larger than 3 cm; generalized palpable lymph nodes), and splenomegaly(1-4). Leukemia. Bone and extramedullary manifestations There are genetic as well as environmental fac- Due to extramedullary tissue infiltration, viscero- tors associated with its pathogenesis. Clearly, there megaly (hepatomegaly, splenomegaly, nephromegaly, is an increased risk associated with genopathies enlargement of the pancreas), polyadenopathies, such as Klinefelter syndrome and , central nervous, renal and testicular system involve- the latter posing a relative risk 15 times higher than ment may be observed(1,3,4), the latter being the least that faced by the general population (2.3). Exposu- common pathology. Its frequency varies depending re to chemicals, such as benzene, pesticides and on the type of leukemia. are modifiable factors involved in Imaging findings on those most frequently affected its etiology(2). organs, will be reviewed. Acute lymphoblastic leukemia (ALL) is defined by the presence of more than 20% lymphoblasts in Liver, , kidneys (2,3) and represents the most common An estimated 60-70% of patients with ALL present type of leukemia in childhood, accounting for 80% with hepatosplenomegaly(3), while AML occurs in no of cases(3,4) It predominates in men and occurs most more than half of the cases(5). It is often a finding on often between the ages of 2 and 5 years(3.4). physical examination and rarely causes functional (AML) represents 17% of impairment(1). Bilateral nephromegaly is also a com- leukemias(2). Its occurrence is similar in both sexes mon finding, though less frequent. with no predominance for any given age range(4). Ultrasonography (US) studies allow depiction of Initial clinical manifestations are usually nonspecific increased size of these organs, which may be asso- and the most common clinical presentation includes: ciated with decreased liver and splenic parenchymal pallor, fatigue, bleedings, fever and recurrent infections echogenicity and increased echogenicity of the renal as a result of an existing spinal cord dysfunction(2,4). The parenchyma, conditions that can be reversed with CBC may reveal anemia, thrombocytopenia and / or treatment(6.7) (Figure 1). Along with nephromegaly, neutropenia with normal, decreased or increased WBC CT scans reveal multiple low- attenuation areas in the count(3,4). In 95% of cases, ALL manifests itself with renal parenchyma, usually presenting bilaterally(7,8) some cytopenia in the CBC, whilst anemia is present in (Figure 2). 99% of cases. The WBC is normal in 50% of children(3), being anemia the alarm symptom in these cases. In AML, 44% of patients present with anemia at diagnosis, while 69% has neutropenia and 25% exhibits leukocytosis with CBC count over 100.000/microliter(3); complications such as cerebral, and liver infarction as a result of leukocytosis may be present(1,3). Although definitive diagnosis is achieved by studying the bone marrow, the imaging study, mainly in patients with bone pain and extramedullary involvement, may provide the clinician with valuable complementary in- formation when the first symptoms derive from tissue infiltration and involvement of haematological series appears discrete and asymptomatic. The chance of cure depends on the type of leu- Figure 1. Six-month infant with ALL. Abdominal ultrasound kemia, the presence of associated adverse factors revealed bilateral nephromegaly. On a sagittal section of the and the response to treatment, being about 73% for right flank, enlarged kidney on that side (sagittal diameter of lymphoblastic leukemia and 50% for myeloid leukemia(1). 9.0 cm) and slightly increased echogenicity are observed.

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2a nodes are usually hypoechoic and nodal hilum may be absent or eccentrically placed due to tumor invasion(10,11). On color Doppler studies it usually shows hilar vascular flow within it. Though none of the aforementioned signs is pathognomonic of leukemia, their presence in the appropriate clinical context increases the index of suspicion(11).

Bone involvement Bone pain is the most commonly encountered symptom secondary to proliferation of neoplastic cells in the bone marrow(7,12,13). An estimated 30% of patients with ALL present with bone pain(4) and sometimes this may be the only alarm symptom in the presence of a CBC without 2b leukocytosis, which may occur in 1% of cases(3). It may affect any part of the skeleton, being the pelvis, vertebrae and long bones of lower extremities the most commonly affected sites(3). Clinically, pain is usually insidious in onset, cons- tant, not related to physical activity and exacerbated at night, progressive in intensity and refractory to the use of analgesia. It may be accompanied by claudi- cation and rarely presents initially with pathological bone fractures(4,13). Though unusual, it may occur as migratory oligoar- thralgies of large joints, asymmetrically distributed, with or without arthritis. Similarity with diseases such as juvenile idiopathic arthritis may cause a delay in diagnosis of leukemia(13). Despite the wide variety of imaging methods currently available, simple radiography remains the (14) Figure 2. Four-year-old boy with ALL. Abdominal CT initial method of choice for evaluation of bone pain . scan shows in axial (a) and coronal reconstruction (b), An estimated 50-70% of patients with leukemia re- enlargement of both kidneys, with multiple areas of low veal evident bone changes on radiographic studies attenuation in the parenchyma (arrows). The child also at diagnosis(15,16). had hepatosplenomegaly. These alterations encompass: 1. Radiolucent, fine, transverse metaphyseal bands. They represent the most common Lymphadenopathies finding suggestive of preschool children The involvement of cervical, axillary and/or leukemia. In patients under 2 years of age, inguinal nodes occurs in up to 50% of patients their specificity decreases, and may be with ALL and in 25% of patients with AML(3,5). found in other chronic diseases that also Ultrasound is useful in the study of lymph nodes, alter osteogenesis(6,12,15).They are usually since along with confirming their presence it allows located in the proximal and radio distal their appropiate characterization(9,10). humerus, and distal femur(7,14), the latter Generally, adenopathies associated with he- being the most frequent site(7,13) (Figures patosplenomegaly(9), are painless, fast growing, 3 and 4). local or generalized(10). Lymph nodes hard in con- 2. Local or diffuse osteopenia, that may pre- sistency, with anteroposterior diameter greater than sent with back pain or lumbar pain due to 1.0 cm in cervical and axillary nodes and greater vertebral crushing(6,7,15) (Figure 5). than 1.5 cm in the inguinal region are considered 3. Focal or generalized osteolysis of long and as suspicious(9). flat bones (skull, pelvis, ribs and shoulder- The normal oval nodal morphology may be girdle)(14). It may have a “moth-eaten bone” preserved or may exhibit a more rounded shape; appearence or bone rarefaction, caused they are commonly grouped in bunches(9). Lymph by the presence of small lytic areas with

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ill-defined margins(17). 4. Periosteal and subperiosteal reaction, co- rresponding to areas of thickening of the periosteum due to new bone formation(6,7,15) (Figure 6). 5. Osteosclerosis, a late and infrequent ma- nifestation(6). 6. Soft tissue swelling, juxta-articular osteo- porosis and joint effusion(15). Metaphyseal bands and osteolytic lesions may be observed in up to 70% of cases, whereas osteopenia is seen in up to 25% of patients and fractures in only 10% of children(16).

Figure 5. Twelve-year-old child with bone involvement in leukemia. Lateral radiograph of the thoracic spine depicts diffuse osteopenia and depression of all visible thoracic vertebrae (D4-D10).

6a 6b

Figure 3. Five-year-old boy with bone involvement in leukemia. Anteroposterior radiograph of left ankle shows well-defined radiolucent bands in the metaphyseal region of the distal tibia and fibula (arrows).

Figure 6. Bone involvement in leukemia in a of 8-year- old child. (a) Anteroposterior radiograph of right knee (a) reveals metaphyseal radiolucent bands in the femur and tibia (arrows). (b) Anteroposterior radiograph of right ankle showing osteolytic area in the lateral border of the distal tibial metaphysis and periosteal reaction of distal shaft in its medial border (arrows).

Mediastinum Mediastinal involvement typically occurs in ALL(1). An estimated 15% of these patients present with -like clinical features, of which 61% exhibit mediastinal lymph nodes(18,19). Clinical presentation may vary; it may present with cough, stridor, orthopnea, dyspnea, superior vena cava syndrome or respiratory distress syndrome(1,3,4). Radiologically, it corresponds to an anterior Figure 4. Bone involvement in leukemia. Anteroposterior mediastinal mass, detectable on plain RX views and radiograph of both knees revealing diffuse osteopenia and confirmed by computed tomography (CT) scans metaphyseal radiolucent bands relatively poorly defined in (Figure 7). The differential diagnosis mainly includes both femurs and tibias (arrows). lymphoma.

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7a 7b tion and involvement of haematological series is discrete and asymptomatic. • For this reason, the radiologist should be aware of initial radiological manifestations of the disease in children, especially extramedullary involvement, in order to suspect the diagnosis of leukemia in its early stage. • In particular, the radiologist should considered leukemia in the differential diagnosis of bone pain, visceromegaly 7c 7d and anterior mediastinal masses in children.

Figure 7. A 13-year-old girl with ALL presenting with mediastinal mass and stridor. Chest CT scan shows a large anterior mediastinal mass, displacing the vascular structures and reveals (a) compression and displacement of the trachea (arrow), (b) marked narrowing of the left main bronchus (arrow), (c) pericardial effusion (arrow). In a 3D reconstruction of the airway (d) compression of the Figure 8. A 9-year-old boy. Treated ALL in remission. left main bronchus is clearly seen (arrow). Testicular volume increased due to testicular relapse. Scrotal transverse color Doppler US image showing an enlarged left testicle, with an area of lower signal intensity and increased Mammary region vascular flow in the testicular anterior half (arrows). Breast involvement in leukemia is manifested as a lump or breast mass, most often unilateral, which may be present at disease onset or during their evolution. On physical examination, they often appear as well- References defined, fast-growing, and sometimes painful tumors 1. Ministerio de Salud de Chile: Guía Clínica Leucemia en menores de 15 años. Actualizado 2010. Disponible (20). On US studies they appear as hypoechoic nodu- (18,19) en: http://www.minsal.gob.cl/portal/url/item/7220fd les of well- or ill-defined margins, usually unique . c433e944a9e04001011f0113b9.pdf Consultado 25 They are rarely found as multiple bilateral lesions. Septiembre 2011. Additionally, diffuse edema of surrounding tissue and 2. Hutter J. Childhood Leukemia. Pediatr Rev. 2010; 31: axillary lymph nodes may be observed(20.21). 234-241. 3. Maloney K, Foreman N, Giller R, Quinones R et al : Testicles Neoplastic Disease. Hay W, Jr., En: Levin M, Sondhei- Infiltration of the testes mainly occurs in patients mer J, Deterding R: Current Diagnosis and Treatment: under 20 years of age(21). Leukemia rarely affects this Pediatrics. 20th Edition, 2011. Chapter 29. Disponible en: http://www.accessmedicine.com/resourceTOC. organ primarily; rather, it is often a site of recurrence. aspx?resourceID=14. The clinical picture is that of a testicular tumor 4. Pearce J, Sills R. Consultation with the Specialist: causing pain, heaviness and/or increased scrotal Childhood Leukemia. Pediatr Rev 2005; 26; 96-104. volume that may be unilateral or bilateral(22,23). 5. Aquino V. Acute myelogenous leukemia. Current Problems On ultrasonographic studies, an increase in testi- in Pediatric and Adolescent Health Care 2002; 32: 50-8. cular size determined by focal (with multiple nodules) 6. Rosenfield N: Part I. Early findings. En: The Radiology or diffuse involvement, with increased or decreased of Childhood Leukemia and its therapy. Second edition. echogenicity may be observed, being diffuse invol- Warren H. Green, INC. St Louis, U.S.A, 1982; 5-19. vement more frequently encountered(23,24) (Figure 7. Guillerman RP, Voss SD, Parker BR. Leukemia and Lymphoma. Radiol Clin N Am 2011; 49: 767-797. 8). In some cases of ALL, there is also infiltration of 8. Hilmes MA, Dillman JR, Mody RJ, Strouse PJ.Pediatric the epididymis. On color Doppler study an increased renal leukemia: spectrum of CT imaging findings. Pe- (24) blood flow is observed . diatric Radiology 2007; 37: 896-907. 9. Friedmann AM. Evaluation and management of lympha- Conclusions denopathy in children. Pediatr Rev 2008; 29: 53-60. • Symptoms and signs that suggest an acute leukemia in 10. Restrepo R, Oneto J, Lopez K, Kukreja K. Head and children are varied and initial manifestations are often neck lymph nodes in children: the spectrum from normal nonspecific. to abnormal. Pediatr Radiol 2009; 39: 836-46. • The imaging study can provide the clinician with valuable 11. Ahuja AT, Ying M. Sonographic evaluation of cervical information, when first symptoms result from tissue infiltra- lymph nodes. Am J Roentgenol 2005; 184: 1691-1699.

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12. Vargas L, Miranda M. Manifestaciones osteoarticulares in children. Am J Roentgenol 1992; 158: 825-832. en la presentación inicial de la leucemia linfoblástica 19. Meyer JS, Nicotra JJ. Tumors of the pediatric chest. aguda del niño. Rev Chil. Pediatr 1995; 66: 98-102. Semin Roentgenol 1998; 33: 187-198. 13. Serra-Bonett N, Guzmán Y, Rodríguez E, Millana A, 20. Chung EM, Cube R, Hall GJ, González C, et al. From Rodríguez M. Leucemia aguda en niños con diagnós- the archives of the AFIP: breast masses in children tico erróneo de artritis idiopática juvenil. Reumatol Clin and adolescents: radiologic-pathologic correlation. 2008; 4: 70-73. Radiographics 2009; 29: 907-931. 14. Wyers M. Evaluation of pediatric bone lesions. Pediatr 21. García CJ, Espinoza A, Dinamarca V, Navarro O, et al. Radiol 2010; 40:468-473. Breast US in children and adolescents. Radiographics 15. Resnick D, Haguigui P. Enfermedades Mieloprolife- 2000; 20: 1605-1612. rativas. En: Resnick D. Huesos y articulaciones en 22. Kundra V. Testicular cancer. Seminars in Roentgenology imagen. Madrid: Editorial Marbán 2001; 625-627. 2004; 39: 437-450. 16. Davies JH, Evans BA, Jenney ME, Gregory JW. Ske- 23. Woodward PJ, Sohaey R, O’ Donoghue MJ, Green DE. letal morbidity in childhood with acute lymphoblastic From the archives of the AFIP: tumors and tumor-like leukaemia. Clin Endocrinol 2005; 63: 1-9. lesions of the testis: radiologic-pathologic correlation. 17. Miller T. Radiography of Bone Tumors and Tumor-like Radiographics 2002; 22: 189-216. Conditions: analysis with conventional radiography. 24. Aso C, Enríquez G, Fité M, Torán N, et al. Gray-scale Radiology 2008; 246: 662-674. and color Doppler sonography of scrotal disorders in 18. Merten D. Diagnostic imaging of mediastinal masses children: an update. Radiographics 2005; 25: 1197-1214.

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