Early Ophthalmological Manifestations of Acute Myeloid Leukemia: Current Perspectives.

Acute myeloid leukemia (AML) is a hematological malignancy affecting different organ systems including the eye. The purpose of this review is to present and evaluate the medical literature regarding the early ophthalmological manifestations of acute myeloid leukemia. AML affects the ocular system through direct infiltration of tissues, secondary to hematological abnormalities, or in the form of chloroma or myeloid sarcoma in the brain or orbit consequently leading to a variety of manifestations depending on the ocular tissue involved. It is imperative for ophthalmologists to be aware of the early ophthalmological manifestations of AML which will allow for earlier diagnosis and treatment of this life-threatening disease.

Introduction

Acute myeloid leukemia (AML) is a malignant disorder of the hematopoietic stem cells characterized by abnormal proliferation of myeloid blast cells in the bone marrow and blood, preventing them from further differentiating into the specialized cells of the bone marrow and thus causing pancytopenia.1 Consequently, AML can affect various tissues and organs (liver, skin, central nervous system), including the eye and orbit.

Ophthalmic manifestations of leukemia are more frequent with acute than chronic leukemia and can affect all intraocular structures.2,3 The reported prevalence of ocular involvement with acute leukemia ranges from 32% to 35.5%.4–6 They are caused by direct neoplastic cell infiltration or indirect complications secondary to hematologic abnormalities (thrombocytopenia, anemia and hyperviscosity state).

Ophthalmic involvement can be the initial manifestation of the systemic disease or the first sign of relapse. Some studies associated ocular involvement with poorer prognosis7–10 while others found no difference in fatality.11 The purpose of this review is to present and evaluate the medical literature on the early ophthalmological manifestations of acute myeloid leukemia, which physicians should be aware of for an earlier and more efficient diagnosis and treatment.

Methodology

A literature review accessing PubMed, Embase, Science Direct, and Medline databases was performed between November and December 2021. PubMed, Embase, and Science Direct databases were searched with the keywords [(Acute Myeloid Leukemia) OR (AML)] AND (Ophthalmic Manifestations). Medline database was searched with the MeSH terms [(ocular.mp.) OR (exp Eye/ or exp Eye Abnormalities/) OR (ophthalmic.mp.) OR (opthamology.mp. or exp Ophthalmology/)] AND (acute myeloid leukemia.mp. exp *Leukemia, Myeloid, Acute/). Two hundred and ninety-seven studies were found after an initial search conducted by 2 independent reviewers. All peer-reviewed case reports published in the literature were included. Duplicates, non-English, and unavailable studies were removed. Titles and abstracts were screened for relevancy and full texts were obtained and evaluated for extractable data, resulting in 95 remaining studies.

Ocular Adnexa

Orbit

Myeloid sarcoma, also known as chloroma, granulocytic sarcoma or myeloblastoma is a type of extramedullary myeloid tumor. It is a rare manifestation of AML, accounting for 2.5% to 9.1% of AML cases.12 It most commonly affects children13 and is a highly unusual presentation in adults.14,15

In the pediatric population, the orbit is one of the most common sites of occurrence of myeloid sarcoma.12 The incidence of pediatric orbital chloroma varies by region16,17 but has been reported to be higher in Africa, Asia, Latin America and the Middle East.18 It can precede,17–21 appear synchronous18,21–23 or occur after a systemic leukemia diagnosis.17,18,21,24 It can also be a manifestation of leukemia relapse,25 even after bone marrow transplant.26,27 When granulocytic sarcoma precedes AML, the diagnosis can be difficult, especially as it has no clear characteristic radiologic features.18,23 Histopathological confirmation can also be challenging, seeing as the tumor is often not well differentiated.13,18 In this category of patients, systemic features usually develop within a year.12

The clinical features of orbital chloroma are variable. Proptosis is the most common presentation.20,21,23 Other symptoms include ptosis,28 eyelid swelling, decreased vision and diplopia. While the clinical presentations described above are not specific for granulocytic sarcoma, one constant feature of this type of tumor observed is its superior or supero-temporal location.13,23 Chloromas are also most often unilateral, but bilateral orbital involvement is considered a strong predictor of a diagnosis of myeloid sarcoma.29

As previously established, orbital involvement by AML is most frequently in the form of chloroma but can, less frequently, be secondary to infiltration of the lacrimal gland or extraocular muscles by leukemic cells.30–32 There is also a solitary report of a diagnosis of AML made in a patient presenting with dacryocystitis responding partially to antibiotics and fully to chemotherapy.33

Many authors have suggested that orbital involvement is a poor prognostic sign for AML patients,17,34 while others observed no change in prognosis.21,24 The latter group attributes this improvement in prognosis to earlier diagnosis of the disease, relating to advances in orbital imaging and better treatment modalities.

In most cases, chemotherapy was used as the standard of treatment while radiation therapy has no well-defined role.35,36 While suggested by Puri et al,19 there is no evidence that chemotherapy for the treatment of isolated orbital chloroma can improve the prognosis if implemented prior to the development of systemic disease.

Conjunctiva

Myeloid sarcoma affecting the conjunctiva is rare. In postmortem studies, it was shown that ocular granulocytic sarcoma affects the conjunctiva in 2–4% of cases.37 It can present as an initial manifestation of primary disease37–41 or relapse,40,42–48 and can occur even in the absence of documented systemic relapse.43 Studies have found that extramedullary involvement in general, and conjunctival leukemic infiltrates in particular, were more common in myelomonocytic and monocytic leukemia than other forms of AML.49 Many authors suggested chemotherapy as the treatment of choice50 while others advocate local radiotherapy.37 Even with appropriate treatment, conjunctival granulocytic sarcoma has been associated with a poor prognosis.49 One case of bilateral subconjunctival hemorrhage in an infant as an initial AML manifestation has also been reported.51

Neuro-Ophthalmology and Strabismus

Neuro-ophthalmologic manifestations of AML are diverse and depend on the affected region of the nervous system. Gaze palsy has been reported as an initial presentation in patients with AML and was related to multiple different causes, namely, chloroma,52,53 brain infarction,54 leptomeningeal spread,55 hypercoagulable state56 or cranial nerve palsy.53,55,57 Chloroma of the central nervous system is rare and comprises only 1–6% of all chloromas.58,59 It was described causing gaze palsy in a patient with dorsal pons involvement52 and another with petrous apex involvement.53

An interesting presentation of a patient diagnosed with one and a half syndrome was reported by Hsu et al, and it was caused by brainstem infarction from AML.54 Cranial nerve palsy secondary to leukemia and involving the oculomotor nerve53,57 and the abducens nerve55 has also been documented. Pupillary abnormalities such as tonic pupil were reported in relapsed AML with choroidal thickening postulated to be due to damage to the ciliary nerve at the suprachoroidal level.60

Another rare but detrimental neuro-ophthalmic manifestation of AML is optic nerve infiltration. In a histopathological study by Allen and Straatsma, the optic nerve was affected in 34% of ocular leukemic cases, mostly in acute leukemia.61 While the optic nerve is a known site of disease relapse in patients with systemic or meningeal leukemia, it is rarely reported as an initial isolated presentation of disease without systemic relapse.62 It usually presents as a swollen optic nerve, often pale gray in color and with associated hemorrhages. It is considered a medical emergency, as severe, irreversible vision loss can occur.63 The recommended treatment is radiation therapy,64 as systemic chemotherapy is not shown to be beneficial and intrathecal chemotherapy is not enough to eradicate leukemic cells in the paraneural space of the optic nerve.62

Anterior Segment

Rare cases of hypopyon as an initial manifestation of AML have been documented,65–67 but most reported cases are in the context of relapsing disease. While acute lymphocytic leukemia (ALL) relapse presents as a pseudo-hypopyon in 2.5% of the cases in children, it remains very rare for acute myeloid leukemia relapse to present as hypopyon.68–73 In a prospective 2-year study of 53 patients undergoing treatment for AML, no patient presented with hypopyon uveitis.74 A review of 14 AML cases with leukemic hypopyon by Matano et al in 2000 concluded a more frequent occurrence of hypopyon in AML with monocytic blasts than other forms of AML.71 While leukemic hypopyon is strongly associated with the presence of extramedullary infiltration, especially CNS leukemia, some rare cases of isolated ocular relapse have been reported.70,72,75,76 Authors have suggested that leukemic hypopyon is associated with systemic relapse even when systemic evaluation does not detect leukemia and concluded that systemic chemotherapy combined with local therapy is advised in these patients.71

A few case reports have been published documenting other anterior segment presentations of AML such as corneal pseudomembrane in a patient with MDS,77 bilateral marginal corneal ring ulcers78,79 and iris leukemic infiltration.21,80,81 It is thus prudent to consider any atypical anterior segment sign as a masquerader for malignancy.

Posterior Segment

The retina and choroid are the most common ocular tissue affected by leukemia.82 Duke-Elder estimated that up to 90% of patients with leukemia will show fundus changes at some point in their disease course.83 Overall, ocular manifestations are more common in acute versus chronic and in myelogenous versus lymphocytic leukemia,84 which suggests that posterior segment changes may be a presenting sign of AML. The prevalence of ocular changes at the time of AML diagnosis was reported to be as high as 35%.5

Posterior segment involvement with leukemia may occur from direct invasion of tissue, known as “leukemic infiltrate”, or secondary to leukemic blood dyscrasia (anemia and thrombocytopenia), known as “leukemic retinopathy”.82,85 While leukemic retinopathy is the most commonly reported clinical ophthalmic manifestation, autopsy studies suggest that subclinical choroidal infiltration is the most common ophthalmic involvement by leukemia.84 Ocular involvement in general and posterior segment infiltrate (not retinopathy) in particular, entails a poorer prognosis, and is associated with a higher rate of bone marrow relapse and CNS involvement.82,86 Studies have shown that more than 50% of cases with intraocular leukemia have CNS involvement and this incidence is even higher in those with posterior segment infiltrates.87

Leukemic retinopathy is present in around 31.6% of all leukemia5 and is the most commonly reported ophthalmic manifestation.84 It is frequently asymptomatic,88 and presents as white centered hemorrhages known as Roth spots,89 cotton wool spots,90 vascular tortuosity and dilatation,91 microaneurysms and neovascularizations.88,92,93 Hemorrhages are predominantly intraretinal but may occasionally be subretinal, sub-internal limiting membrane or subhyaloid (Figure 1).88,90 In AML, intraretinal hemorrhages are statistically correlated with low platelet count.94 No direct treatment for leukemic retinopathy is needed and the focus is on the treatment of the primary hematological disease.83

Figure 1

Five-line high definition spectral domain-optical coherence tomography (SD-OCT) through the macula showing subretinal (*) as well as sub-internal limiting membrane (**) hemorrhages due to a low platelet count.

Central retinal vein occlusion (CRVO) is a very rare manifestation of leukemia, most likely caused by hyperviscosity associated with leukocytosis.88 However, it is important not to overlook retinal vein or artery occlusions simply as a manifestation of hypercoagulability, as they can be caused by leukemic infiltration (Figure 2). In a study of 288 patients known to have leukemia with ocular involvement, 3 developed CRVO.5 Infiltration causing vein/artery occlusion often presents with optic disc edema and/or subretinal infiltrates. Khair et al reported a case of bilateral retinal artery occlusions as a first manifestation of CNS involvement in relapsed AML, but the patient did not have disc edema or retinal infiltrates. This suggests that vein/artery occlusions can result from microscopic infiltration.95 Therefore, in cases of vein/artery occlusions, work-up of CNS involvement (imaging, lumbar puncture, etc.) is critical for treatment strategy and patient prognosis.

Figure 2

(A) Fundus photo showing acute myeloid leukemic infiltration of the optic nerve and retinal vessels causing both retinal vein and artery occlusions. (B) SD-OCT of the optic nerve of the same patient documenting the marked thickening of the retinal nerve fiber layer.

While clinically apparent leukemic choroidal infiltrates are infrequently reported, histologically detected choroidal leukemic infiltration has been found in up to 65% of patients with leukemia87 and in 31% of post-mortem eyes of fatal leukemia.96 This makes it the most common ophthalmic involvement by leukemia.84 It is more common in relapsing leukemia than in primary disease87 and is most commonly associated with CNS and systemic relapse.

Choroidal involvement usually presents clinically as serous retinal detachment,91 which has been documented as a presenting symptom of AML in adults and children.97 The suggested theory is that leukemic choroidal infiltration causes decreased blood flow to the choriocapillaris, inducing ischemia of the retinal pigment epithelium (RPE). This causes disruption of the inter-cellular tight junctions and thus of the ability of the RPE to effectively pump fluid,98 consequently inducing exudative retinal detachment.99 Choroidal infiltration has been also reported to cause angle closure glaucoma.98,100 To our knowledge, only two cases of choroidal infiltration as first manifestation of leukemic relapse in the absence of CNS involvement or systemic relapse have been reported.87,101 Biopsy of the involved choroid is the most appropriate diagnostic tool in this category of patients.

Conclusion

Ophthalmological manifestations of acute myeloid leukemia can be an initial presentation of the primary disease or a sign of relapse and can affect different parts of the eye and orbit. The retina and choroid are the most commonly affected ocular tissues in the form of direct leukemic infiltration or secondary to blood dyscrasia, mostly manifesting as intraretinal hemorrhages. In the orbit, AML mainly presents as an extramedullary myeloid tumor or chloroma, most commonly inducing proptosis. Rarely, AML can affect the anterior segment in the form of pseudo-hypopyon, usually in the context of relapsing disease. AML can also present as gaze palsy related to infarctions, brain chloroma or cranial nerve palsies. It can infiltrate the optic nerve, resulting in severe decrease in vision, and this constitutes a medical emergency requiring urgent radiation therapy. Intraocular leukemic involvement has been associated with CNS disease in 50% of cases, and the incidence is higher with posterior segment involvement. Recognizing ocular signs of AML is therefore crucial in expediting diagnosis and subsequent treatment, which may aid in saving patients from this life-threatening disease.