History and exam

Key diagnostic factors

common

lymphadenopathy

Lymph node involvement is common in ALL. Enlarged lymph nodes can be an initial presenting sign.

Lymphadenopathy is classically generalized, and the enlarged nodes are painless and freely movable.[1][6]

hepatosplenomegaly

This is common at the time of initial diagnosis. Liver and spleen tend to be diffusely enlarged due to infiltration by leukemic lymphoblasts.[1][6] This abnormality can also manifest as symptoms of anemia, weight loss, abdominal pain or distension, or an abdominal mass.

pallor, ecchymoses, or petechiae

The most common findings on physical examination are pallor due to anemia, and ecchymoses or petechiae due to thrombocytopenia.[1][2]

constitutional symptoms (fevers, night sweats, weight loss)

Patients often present with constitutional symptoms (fevers, night sweats, weight loss).

Presence of infection should be excluded prior to attributing fever to the leukemia.

recurrent infections

Patients often present with recurrent infections due to neutropenia, which may cause fever.

fatigue, dizziness, palpitations, and dyspnea

Patients often present with fatigue, dizziness, palpitations, and/or dyspnea. These symptoms are caused by anemia, or systemic inflammatory cytokines.

bruising, epistaxis, heavy menstrual bleeding

Patients often present with easy bruising, epistaxis, and/or heavy menstrual bleeding. These symptoms are caused by thrombocytopenia or coagulopathy.

Other diagnostic factors

common

mental status changes, focal neurologic signs/deficits, headache, papilledema, nuchal rigidity, and meningismus

Central nervous system (CNS) involvement is a major complication of ALL, occurring in approximately 5% to 7% of patients at diagnosis; incidence is highest in patients with T-ALL (8%) and mature B-ALL (Burkitt lymphoma/leukemia, 13%).[9][55][56]​​​[57][58]

The meninges are the primary site of CNS disease.[59] Presenting features of CNS disease include mental status changes, focal neurologic signs/deficits (e.g., diplopia, chin numbness), headache, papilledema, nuchal rigidity, and meningismus.[3][7]​​[8]

Spinal cord and parenchymal brain involvement may occur, but is very rare.

renal enlargement

Renal enlargement is common at the time of initial diagnosis. This is caused by infiltration of leukemic lymphoblasts in the renal cortex. Despite this, renal function is rarely affected except in the case of urate nephropathy (subsequent to tumor lysis syndrome).[1][2]

bone pain

Bone pain is caused by pressure from infiltration of leukemic lymphoblasts in the medullary cavity and periosteum.[51]

uncommon

painless unilateral testicular enlargement

Testicular involvement typically presents with painless unilateral testicular enlargement, and occurs most commonly in children and adolescents with T-ALL.[54]

Testicular examination should be carried out at diagnosis in all male patients. The testes can represent a sanctuary site that is relatively protected from the effects of systemic therapy via the blood-testis barrier.[54]

Although uncommon at the time of initial diagnosis, recurrent ALL frequently involves the testes, and bilateral wedge biopsy may be warranted in such cases to reduce sampling error.[1]​​[6]

abdominal pain

Mainly left upper quadrant in location and is caused by splenomegaly due to infiltration of leukemic lymphoblasts in the spleen.

mediastinal or abdominal mass

T-ALL more commonly causes mediastinal masses whereas B-ALL more commonly causes abdominal masses.

The findings of stridor, wheezing, pericardial effusion, and superior vena cava syndrome may be associated with mediastinal masses.

Mature B-ALL (Burkitt lymphoma/leukemia) may initially present as a palpable large abdominal mass from a rapidly proliferating tumor.[34][53]

pleural effusion

Pleural effusions evident on chest radiograph should be tapped and samples sent for cytology and immunophenotyping.

skin infiltrations

Caused by infiltration of skin by leukemic lymphoblasts. Nodules are a common manifestation of skin infiltration.

Risk factors

strong

children <5 years of age

Peak ALL incidence occurs at ages 1-4 years (7.7 per 100,000 [2018-2022 data]).[11]​ Incidence decreases to 2.6 cases per 100,000 by ages 10-14 years (2018-2022 data).[11]​​

weak

genetic factors

The diagnosis of ALL in a monozygotic twin (at <6 years of age) is associated with a 10% to 15% likelihood that the second twin will develop ALL.[12]

ALL is associated with trisomy 21 and other genetic disorders (e.g., Li-Fraumeni syndrome, neurofibromatosis, Klinefelter syndrome, Fanconi anemia, Shwachman-Diamond syndrome, Bloom syndrome, and ataxia-telangiectasia).[13][14][15][16]

family history of ALL

Germline mutations linked to ALL are reported in approximately 4% of children with ALL.[14]

There is growing evidence suggesting a germline predisposition to ALL; hence, a family history may be noted.[14][17][18][19][20]

viral infections

Some viral infections (e.g., Epstein-Barr virus [EBV]) have been suggested to increase the risk of ALL.[1][22]

environmental factors

This includes radiation exposure and smoking.[1][2][21]

history of malignancy

Those presenting with ALL may have a history of malignancy.[21][23]​​

treatment with chemotherapy

Treatment with chemotherapy may be part of the presenting history of ALL.[21]

male sex

Incidence of ALL is slightly higher in males than in females.​[10]

Hispanic populations

Incidence in the US is highest in Hispanic people (3.1 per 100,000 and 2.4 per 100,000 for males and females, respectively [2018-2022 data]).[11]

folate metabolism polymorphisms

Folate metabolism polymorphisms have been associated with risk for ALL in case-control studies.[28][29][30][31]

poor maternal diet

Case-control data indicate that risk for ALL is inversely associated with maternal consumption of vegetables, protein sources, fruit, and legume food groups.[27]

A healthy maternal diet (e.g., a Mediterranean diet or a diet composed largely of vegetables and fruits, preconception use of folic acid, and intake of vitamins during pregnancy) has been found to be associated with decreased risk of ALL among offspring.[24][25][26]

Risk of ALL in offspring is associated with increased maternal intake of sugar.[24]

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