eMedicine Specialties > Ophthalmology > Hematologic & Cardiovascular Disorders

Leukemias

Author: Lihteh Wu, MD, Consulting Surgeon, Department of Ophthalmology, Vitreo-Retinal Section, Instituto De Cirugia Ocular, Costa Rica
Coauthor(s): Teodoro Evans, MD, Retina Fellow, Vitreo-Retinal Section, Instituto De Cirugia Ocular, Costa Rica; Joaquin Martinez, MD, Consulting Staff, Department of Ophthalmology, Hospital Nacional de Ninos and Clinica Dr. Clorito Picado; Director of Retinal and Vitreous Clinic at Hospital Nacional de Ninos; Consulting Staff in Ultrosonography and Angiography, Clinica Oftalmologica Costarricense; Private Practice, San Rafael de Escazu, San Jose, Costa Rica
Contributor Information and Disclosures

Updated: Jul 20, 2007

Introduction

Background

Leukemias are a group of heterogeneous neoplastic disorders of white blood cells. Based on their origin, myeloid or lymphoid, they can be divided into 2 types. Leukemias traditionally have been designated as acute or chronic, based on their untreated course. Acute leukemias usually present with hemorrhage, anemia, infection, or infiltration of organs.

Many patients with chronic leukemias are asymptomatic. Other leukemias present with splenomegaly, fever, weight loss, malaise, frequent infections, bleeding, thrombosis, or lymphadenopathy. Some chronic leukemias enter a blast phase where the clinical manifestations are similar to the acute leukemias.

Chronic myelogenous leukemia (CML) is characterized by an uncontrolled proliferation of granulocytes. An accompanying proliferation of erythroid cells and megakaryocytes is usually present. Many patients are asymptomatic but may present with splenomegaly, weight loss, malaise, bleeding, or thrombosis.

Chronic lymphocytic leukemia (CLL) represents a monoclonal expansion of lymphocytes. In 95% of cases, CLL is a predominantly malignant clonal disorder of B lymphocytes. The remainder is secondary to a T-cell clone. The neoplastic cell is a hypoproliferative, immunologically incompetent small lymphocyte. There is primary involvement of the bone marrow and secondary release into the peripheral blood. The recirculating lymphocytes selectively infiltrate the lymph nodes, the spleen, and the liver. Most patients are asymptomatic at diagnosis. As the disease progresses, lymphadenopathy, splenomegaly, and hepatomegaly develop. A secondary immune deficiency with hypogammaglobulinemia exists.

Acute lymphocytic leukemia (ALL) is a malignant clonal disorder of the bone marrow lymphopoietic precursor cells. In ALL, progressive medullary and extramedullary accumulations of lymphoblasts are present that lack the potential for differentiation and maturation. An inhibition of the normal development of hematopoietic cell elements occurs. The clinical presentation is dominated by progressive weakness and fatigue secondary to anemia, infection secondary to leukopenia, and bleeding secondary to thrombocytopenia. When 50% of the bone marrow is replaced, then peripheral blood cytopenias are observed.

Acute myelogenous leukemia (AML) is a group of neoplastic disorders of the hematopoietic precursor cells of the bone marrow. AML is subdivided by the French-American-British system into 6 categories depending on the morphology. AML is not a disorder of rapidly proliferating neoplastic cells. The time for one cell division is prolonged with respect to that of normal bone marrow blast cells. A failure of maturation of the neoplastic cell clone exists. The bone marrow is gradually replaced by blast cells. Therefore, the most important complications are progressive anemia, leukopenia, and thrombocytopenia.

Pathophysiology

In leukemias, a clone of malignant cells may arise at any stage of maturation, that is, in the lymphoid, myeloid, or pluripotential stage. The cause for this clonal expansion is poorly understood in most cases, but it appears to involve some rearrangement of the DNA. External factors, such as alkylating drugs, ionizing radiation, and chemicals, and internal factors, such as chromosomal abnormalities, lead to DNA changes.

Chromosomal rearrangements may alter the structure or regulation of cellular oncogenes. For instance, in the B-cell lymphocytic leukemias, chromosomal translocations may put the genes that normally regulate heavy and light chain immunoglobulin synthesis next to the genes that regulate normal cellular activation and proliferation. This results in proliferation of lymphoblasts. As the population of cells expands, the bone marrow starts to fail. Pancytopenia is typical and results in part from the physical replacement of normal marrow elements by the immature cells. In addition, the abnormal cells may secrete factors that inhibit normal hematopoiesis.

As the bone marrow becomes replaced, the abnormal cells spill into the circulation and infiltrate other organs, such as the liver, the spleen, and the eye. The ocular manifestations may be secondary to direct infiltration of the leukemic cells, as a result of either abnormal systemic hematological parameters or opportunistic infections.

Frequency

United States

In 1999, 30,200 newly diagnosed cases of leukemia occurred. Of the leukemias diagnosed in the United States, 10,100 (33%) were AML; 7,800 (26%) were CLL; 4,500 (15%) were CML; and 3,100 (10%) were ALL. Incidence of AML, CML, and ALL in adults is 2.3, 1.3, and 1 per 100,000 people per year, respectively.

Clinical series show variable data regarding prevalence and incidence of ocular involvement in patients with leukemia. These differences arise from the differences in study design. In some studies, patients were examined at different stages of the disease. In others, ophthalmologists examined only symptomatic patients. In most studies, no distinction is made between the different leukemias.

Three prospective studies reveal that 14-53% of patients had ocular manifestations of the disease prior to the start of chemotherapy. Leukemia is responsible for 2-6% of orbital tumors in children. Furthermore, up to 11% of children with proptosis will have some form of acute leukemia.

Autopsy series show the highest frequency of ocular involvement. It is presumed that dying patients have a higher disease burden. In addition, histopathological methods allow detection of lesions that are not clinically detectable. About 28-80% of cases have intraocular manifestations. An autopsy study reports 8-12% have orbital involvement.

Despite changes in treatment and survival over the past decades, ocular involvement, as examined by histopathological methods, has remained fairly constant in the past 70 years.

International

An estimated 231,000 new cases of leukemia were diagnosed globally during 1990. It has been estimated that in Western countries, CLL constitutes the most frequent type of leukemia with 25% of cases, CML represents 20% of cases, and AML represents 20% of cases.

Mortality/Morbidity

The breakdown of deaths according to the different subtypes is as follows:

• Deaths secondary to ALL and AML have been reported at 1,400 and 6,900, respectively.
• In children with ALL, 90% of patients achieve a complete remission, and up to 80% can remain disease free at 5 years following treatment. In adults with ALL, remissions occur in 60-80%, while 20-35% will maintain a leukemia-free survival.
• Currently, 65-70% of patients with AML attain remission. The 5-year survival rate during the period 1989-1994 was 43%.
• Secondary to CLL, 5,100 deaths have occurred; secondary to CML, 2,300 deaths have occurred; and secondary to other leukemias, 6,400 deaths have occurred.
• In CLL, the natural history is highly variable. The median survival is 6 years, and the natural history is not altered by therapy. Infection is the leading cause of death. The median survival of CML with treatment is 5 years. Granulocytic sarcoma of the orbit, also known as chloroma, represents an extramedullary site of AML or CML. Survival has been reported to range from 1-30 months after the onset of ocular signs and symptoms. Some studies suggest that the presence of intraocular leukemic infiltrates correlates with CNS involvement and with decreased survival.

Race

In the United States, ALL and CLL are more common in whites than in blacks.

Sex

Of the estimated 231,000 new cases diagnosed in the world, 130,000 were males and 101,000 were females.

Of the 30,200 new cases of leukemia diagnosed in the United States during 1999, 16,800 cases were reported in males and 13,400 cases in females.

During 1999, the breakdown of new cases of leukemia by gender and category were as follows:

• CLL: 4,500 cases were reported in males and 3,300 cases in females.
  
• CML: 2,700 cases were reported in males and 1,800 cases in females. The age-adjusted incidence is higher in men than in women (1.7 vs 1.0).
  
• ALL: 1,800 cases were reported in males and 1,300 cases in females. Childhood ALL demonstrates a notable male predominance.
  
• AML: 4,900 cases were reported in males and 5,200 cases in females. The age-adjusted incidence of AML is higher in men than in women (2.9 vs 1.9).
  
• In other leukemias, 2,900 cases were reported in males and 1,800 cases in females.

Age

Most childhood leukemias are acute.

• ALL is the most common malignancy in children, especially affecting those aged 2-10 years. ALL is seen in only 20% of adult acute leukemias and behaves more aggressively than the childhood type.
• AML constitutes 15-20% of acute leukemias in children. Incidence of AML increases with age; in persons younger than 65 years, the incidence is 1.3, and in persons older than 65 years, the incidence is 12.2.
• CML constitutes less than 5% of childhood leukemias. The incidence of CML increases slowly with age until the middle 40s, when the incidence starts to rise rapidly.
• Incidence of CLL is over 10 per 100,000 for persons older than 70 years but is less than 1 per 100,000 for those younger than 50 years. Mean age at diagnosis of CLL is 60 years.

Clinical

History

• In most patients, a diagnosis of leukemia has been made before presenting to an ophthalmologist. However, in some patients, ocular symptoms and examination lead to a diagnosis of leukemia.
• Most patients do not develop symptoms as a result of intraocular involvement.

Physical

• Posterior segment manifestations
  
  
  • The posterior segment manifestations are protean in nature and may be secondary to direct invasion of the leukemic cells.
  • They result from systemic hematological abnormalities, such as anemia, thrombocytopenia, and hyperviscosity or opportunistic infections secondary to the immune dysfunction.
  • Direct infiltration
    
    
    • Retinal grayish white nodules that may be surrounded by hemorrhage manifest direct infiltration.
    • Perivascular sheathing may be another manifestation of a leukemic infiltrate.
    • Roth spots, white-centered retinal hemorrhages, may represent a cluster of leukemic cells. On the other hand, septic emboli or platelet-fibrin material gives a similar funduscopic finding.
    • Rarely, pale gray swelling of the optic nerve head may indicate optic nerve infiltration.
  • Leukemic retinopathy
    
    
    • Retinal lesions are the most common ocular manifestation of leukemia. They are found most often in adults and in patients with myeloid leukemia.
    • Retinal hemorrhages are the most common finding in most series and are thought to be secondary to anemia and thrombocytopenia. These hemorrhages may be dot-shaped, flame-shaped, intraretinal, subretinal, or subhyaloid.
    • Cotton-wool spots are known to represent nerve fiber layer infarcts. However, they are not correlated with hematological parameters of anemia or blood viscosity.
    • Retinal vein tortuosity and dilation are thought to be secondary to hyperviscosity.
    • Peripheral retinal microaneurysms and retinal neovascularization may be seen, particularly in patients with CML. They are thought to occur as a result of peripheral nonperfusion and ischemia from hyperviscosity.
    • Sea fans reminiscent of sickle cell retinopathy may be seen.
    • Neovascularization of the disc has been reported in a case where no apparent ischemia was present. It was recognized that angiogenic factors secreted from the tumor may play a role in the pathogenesis of retinal and optic nerve head neovascularization.
    • The vitreous seldom is involved.
    • The choroid is the most commonly affected ocular structure in pathological studies. Clinically, it often is difficult to detect the subtle choroidal changes.
    • Occasionally, serous retinal detachments and retinal pigment epithelium (RPE) changes have been reported. In rare cases, they can be the first sign of relapsing leukemia.
  • Opportunistic infections include cytomegalovirus retinitis, toxoplasma chorioretinitis, endogenous fungal endophthalmitis, and herpetic retinitis.
• Anterior segment manifestations
  
  
  • Anterior segment involvement in leukemia is rare but significant because it often is an extramedullary site of relapse. Anterior segment manifestations occur more commonly in ALL than in all the other types of leukemia.
  • A change in iris color, iris nodules, hyphema, hypopyon, glaucoma, a sterile corneal ring ulcer, and a pannus all have been described in patients with leukemia.
  • Corneal involvement is rare. Scleral, episcleral, and conjunctival involvement usually is silent and is limited to perivascular infiltration that can be demonstrated on pathological sections.
• Orbital manifestations
  
  
  • Leukemic cells may infiltrate the orbit during the course of acute or chronic leukemia. Unusual orbital involvement with leukemia has been reported to include infiltration of the lacrimal gland and drainage system, rectus muscles, and dermis.
  • Orbital involvement in children is more common in acute leukemias, whereas orbital involvement in adults is more common in chronic leukemias.
  • The leukemic infiltrate may range from insignificant, where it is virtually asymptomatic, to a space occupying lesion with its concomitant symptoms.
  • The patient may have proptosis, ecchymosis, chemosis, diplopia, visual disturbance, or motility disturbances.
  • In children, the orbital involvement is characterized by an acute and rapid process that may be confused with orbital cellulitis. In general, these infiltrates are bilateral and do not destroy bone.
  • Granulocytic sarcoma of the orbit, also known as chloroma, is an extramedullary form of myelogenous leukemia. 
  • Unilateral, painless proptosis develops over weeks to months prior to a diagnosis of leukemia. Eyelid redness or violaceous discoloration may be present, which turns into ecchymosis that may be confused with rhabdomyosarcoma or metastatic neuroblastoma. If AML or CML is already present, then a rapid and fulminant bilateral proptosis is characteristic.

Causes

• The etiology of the leukemias appears to be multifactorial. Genetic, viral, and environmental factors, such as ionizing radiation, drugs, and chemicals, have been implicated in the pathogenesis of leukemia.
  
• It is believed that the final common pathway is damage to the DNA. This damage may rearrange the genetic material, thereby allowing previously silent oncogenes to be expressed.
  
• Patients with an abnormal number of chromosomes (eg, trisomy 21) and chromosomal translocations are at an increased risk of developing ALL.
  
• Risk factors implicated in the development of AML include the following:
  
  • Myelotoxic agents (eg, ionizing radiation, benzene, alkylating agents)
    
  • Chromosomal abnormalities (eg, Down syndrome, chromosomal instability syndromes)
    
  • Predisposing hematological disorders (eg, aplastic anemia, chronic myeloproliferative disorders, paroxysmal nocturnal hemoglobinuria)
    
• Chromosomal abnormalities, especially trisomy 12, are common in patients with CLL. Familial case clusters have been reported in CLL. HTLV-1 infection has also been implicated in CLL.
  
• Damage to the bone marrow by agents, such as benzene and ionizing radiation, may cause CML.
  
• Of patients with CML, 90% have an acquired chromosomal abnormality, the Philadelphia chromosome, which is a translocation of half of the long arm of chromosome 22 to another chromosome, usually chromosome 9.

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