Ophthalmic Manifestations of Hematological Malignancies

OPHTHALMIC MANIFESATIONS

OF HEMATOLOGICAL MALIGNANCIES

Dr PAAVAN KALRA

DEPARTMENT OF OPHTHALMOLOGY,

S P MEDICAL COLLEGE,

BIKANER

BASICS• Red blood corpuscles• Platelets• White blood corpuscles

Granulocytes

Neutrophils

Eosinophls

Basophils Mast cells

Agranulocytes

Monocytes Macrophages, Tissue Histiocytes

Lymphocytes

B cells Plasma Cells- Immunoglobulins

T cells ( CD 4+ , CD 8+)

NK cells

HEMATOPOIESIS

• LYMPHOID ORGANS

Primary – Bone Marrow & Thymus

Secondary – Spleen, Lymph nodes, Mucosa associated aggregates( e g payer’s patches, tonsils)

No Lymph nodes in Orbit

Mucosa associated lymphoid tissue present in sub conjunctiva and in lacrimal gland

Virchow (1845, 1863) first coined the terms LEUKEMIA and LYMPHOSARCOMA

‘ LEUKEMIA ‘ was defined as disease affecting the blood forming organs characterized by wide spread, rapid, disorderly proliferations of ‘leukocytes’ and their precursors and by the presence at some point during the course, of immature leukocytes in BLOOD often in large numbers

1st description of Hodgkin’s Disease – Carswell in 1828

Term “hodgkin’s disease” by Wilks in 1865. later also came to be known as Lymphadenoma

Term Lymphomas was initially used to describe benign counterparts of of Lymphosarcoma. Later came to be used to describe all forms of lymphoid neoplastic proliferations that arise as discrete tissue masses. ( c/w Reactive Lymphoid Hyperplasia)

EVOLUTION OF TERMS & CONCEPTS in HEMATONCOLOGY

• Gall & Mallory in 1942 – gave the first modern classification of Lymphomas(Non Hodgkin’s)

• Later classifications by Rappaport (1966), Lennert(1974), Working Formulation(1982)

• REAL classification (1994) : clubbed Leukemias of Lymphoid origin and Lymphomas(Hodgkin’s & NHL) in one classification

• FAB classification of Myeloid Neoplasms( leukemias)-1970s

• WHO classification of hematopoeitic and lymphoid neoplasms 2001 & 2008

(based on disease presentation, morphology, immunophenotype and genetics)

• Lymphoid neoplasms include a diverse group of tumors of B-cell, T-cell, and NK-cell origin ( including Multiple Myeloma and related disorders

• Myeloid neoplasms arise from early hematopoietic progenitors

a)acute myeloid leukemias, in which immature progenitor cells accumulate in the bone marrow

b)myelodysplastic syndromes, which are associated with ineffective hematopoiesis and resultant peripheral blood cytopenias

c)chronic myeloproliferative disorders, in which increased production of one or more terminally differentiated myeloid elements usually leads to elevated peripheral blood counts.

• The histiocytoses are uncommon proliferative lesions of macrophages and dendritic cells in the connective tissues

Leukemias : Hematological neoplasms with widespread involvement of Bone Marrow and Blood

• According to clinical presentation

Acute leukemias – appearance of clinical features early in the course with fatal outcome in couple of years if left untreated

Chronic leukemias – insidous onset of symptoms with relatively longer expected survival, terminating in Blast Crisis

PATHOGENESIS

• Tumors of hematopoietic origin are often associated with mutations that block progenitor cell maturation or abrogate their growth factor dependence

• In some instances, these tumors originate from transformed HSCs that retain the ability to differentiate along multiple lineages, whereas in other instances the origin is a more differentiated progenitor that has acquired an abnormal capacity for self-renewal.

• The net effect of such derangements is an unregulated clonal expansion of hematopoietic elements, which replace normal marrow progenitors and often spread to other hematopoietic tissues

PATHOGENESIS OF OPHTHALMIC MANIFESTATIONS

• INFILTRATION OF BONE MARROW

ineffective hematopoieseis- anemia, thrombocytopenia, thrombaesthenia, immunodeficiency, auto immunity

• INFILTRATION OF VESSEL WALLS – weakening & endothelial damage

• INFILTRATION OF TISSUES

skin, occular adnexa, orbit, eye ball, optic nerve, visual pathway, meninges

• MECHANICAL EFFECTS : tumor mass • INCREASED INTRAVASCULAR CELL MASS• HYPER VISCOSITY – paraproteinemia, increased cell

mass• HYPERCOAGULABILITY

• ISCHEMIA & INFARCTION

• METABOLIC EFFECTS : Hypercalcemia, renal failure

• PARANEOPLASTIC SYNDROME : cerebellar degeneration in lymphoma

• EFFECT OF THERAPY

CHANGES DUE TO HEMATOLOGIC ABNORMALITIES

ANEMIA

• Conjunctival pallor

• Ophthalmoscopic signs ( Hb < 50%)

generalized pallor of fundus and optic disc

dilatation of retinal arteries and veins- equal calibre and color

retinal hemorrhage

extra retinal hemorrhage – choroidal, pre retinal/ sub hyaloid

retinal edema

retinal exudates –hard exudates

cotton wool spots

Multiple intraretinal and preretinal hemorrhages and Roth's spots – case of severe anemia

• Ischemic optic neuropathy

• Pseudotumor cerebri

THROMBOCYTOPENIA AND THROMBOASTHENIA

• Lid ecchymosis• Sub conjunctival hemorrhage – petechiae to ecchymosis • Hematidrosis ( bloody tears)• Hyphema • Vitreous hemorrhage• Retinal hemorrhages – variable colour• Intracranial hemorrhage –

posterior visual pathway – homonymous hemianopia

cerebellum and brain stem – nystagmus & diplopia

• Bleeding tendency in leukemias contributed by the perivascular infiltration

• Rarely massive intra orbital bleed causes sudden proptosis

compartment syndrome , compressive optic neuropathy

THROMBOTIC TENDENCY : Virchow’s Triad

endothelial damage ( infiltration of the vessel wall)

altered blood flow – stasis or turbulence

hypercoagulable states – altered function of platelets

HYPERVISCOSITY – Stasis of blood flow

paraproteinemia -Waldenstrom Macroglobulinemia > MM

(Rouleaux formation)

increased cell mass- polycythemia, thrombocythemia, and leukocytosis

STASIS also contributed by mechanical compression of vessels

ISCHEMIA and INFARCTION

Polycythemia- increases RBCs

• Dilated tortuous arteries and veins• disc edema• Multiple Retinal hemorrhages, • venous thrombosis

• Ischemic optic neuropathy

• Carotid and vertibro-basilar insufficiency.. Angio spasm, thrombosis

• Cavernous Sinus Thrombosis

• conjunctival congestion

• NAION

• CRVO

• BRVO

• STROKE

MECHANICAL EFFECTS

• Lids

Ptosis

Entropion

• Orbit

Occular deviation, restriction of movements

Proptosis – orbital and lacrimal gland involvement

Disc edema

• Vascular compression- arterial, venous• Compressive Neuropathy

• Blockage of trabecular meshwork by neoplastic cells- 2ndary glaucoma

METABOLIC ABNORMALITIES

OCULAR HYPERCALCEMIA

• hematologic malignant neoplasms (multiple myeloma, leukemia, or lymphoma) can elevate calcium levels

• the basement membranes and epithelial cells are more likely to be affected. It is suggested that these sites are relatively alkaline, favoring the deposition of calcium salts. Calcification of corneal epithelium and Bowman’s layer

• In the conjunctival epithelium, white perilimbal deposits

occur. • band keratopathy.• Scleral calcification can be seen by computed

tomography and may appear clinically as white flecks.• Pigmented layers of the iris, ciliary body, and choroid

may also demonstrate calcium deposits

DD• dystrophic calcification, bony metastasis in solid tumors,

granulomatous diseases such as sarcoidosis, hyperthyroidism, vitamin A intoxication, and renal failure

• the disease process• Altered functions of neutrophils, macrophages and

lymphocytes – both innate and adaptive immune system affected

• Effect of the therapy

IMMUNODEFICIENCY

• Opportunistic infections

• CMV Retinitis

• herpes virus • toxoplasmosis • fungal infections

Sub retinal abscess

• most cases of subretinal abscess are due to Nocardia, branching gram-positive filamentous bacteria

• Other causes Pseudomonas, Klebsiella, and viridans streptococci

• chronic myeloid leukemia and bone marrow transplant Sub retinal abscess with

exudative RD

• Rhino cerebral mucormycosis

MANIFESTATIONS

vis a vis

TISSUES

RETINA

Retinal veins become distended and tortuous- first change

(most often because of anemia)

Retinal edema – maximal over optic disc

As disease progresses, retinal arteries become distended and venous column becomes broken by AV crossings into turgid sausage like segments

• Retinal infiltrates take the form of grayish white nodules associated with local hemorrhage

• Sheathing of retinal vessels and intravascular margination. Perivascular infiltrates, widest along convexities of veins

( also seen in active chorioretinitis)

• Hard exudates and cotton wool spots may be seen; the cotton wool spots may result from actual leukemic infiltration of the retina or from nerve fiber layer infarction

• AML – extensive retinal hemorrhages- sub hyaloid extending to macula, flame shaped, subhyaloid, Roth spots

• Leukemic infiltration

• Roth Spots - leukemic infiltrates surrounded by hemorrhages

• DD

endocarditis

anemia

retinopathy in HIV

hypertensive or diabetic retinopathy

• COTTON-WOOL SPOTS consist of accumulations of cytoid bodies in the axons of the nerve fiber layer. The accumulation of material is thought to be related to disruption of axoplasmic transport by focal ischemia.

• These spots occur in

diabetes mellitus,

hypertension,

collagen vascular diseases,

anemia

• In chronic leukemias & paraproteinemia ( hyperviscosity)

Microaneurysms in the retinal periphery adjacent to areas of ischemia and nonperffusion.

rarely progress to frank neovascularization in a sea-fan pattern.

DD – Sickle cell anemia

Central and branch retinal vein occlusions

VITREOUS

Infiltration of the vitreous is rare but hematological malignancies account for most no of cases of tumors involving vitreous

• Vitreous involvement may be the only ocular sign of an intraocular malignancy

• The most common primary intraocular malignancy to involve the vitreous is primary intraocular lymphoma

• Vitreous involvement may be purely inflammatory as these malignancies can mimic posterior uveitis

• Clinically, the tumor cells in the vitreous

often adhere to create opacities that are larger than the vitreous cells typically seen in

inflammatory vitritis.

UVEAThe acute leukemias are more commonly associated with choroidal involvement .

Overlying retinal pigment epithelial degeneration and clumping leads to ‘leopard spot’ pattern which is thought to be due to invasion or compression of the choriocapillaris by leukemia cellsDD - chronic subretinal fluid collection e g Uveal effusion syndrome, CSR

Leukemic nodular choroidal infiltrates with overlying vitritis in a patient with leukemia.

• Choroidal masses with exudative RD

• cases with choroidal vessel infiltration – peculiar colour of fundus yellow to light pink

• POSTERIOR CILIARY BODY CYSTS

Multiple myeloma &

Waldenstrom macroglobulinemia

(plasmacytoma)

• IRIS INFILTRATE

T Cell Lymphoma

• ANTERIOR AND POSTERIOR UVEITIS

(MASQUERADE SYNDROMES)

PSEUDOHYPOPYON

• SECONDARY GLAUCOMA

OPTIC NERVE

• prelaminar fluffy, white infiltrate superficial to the lamina cribrosa on the optic nerve head

• as a retrolaminar infiltrate visible on neuroimaging in association

• An important distinction between direct infiltration by leukemia cells and disk edema from elevated intracranial pressure due to leukemic meningitis must be made. As Orbital radiation can benefit in infiltrative disease

ORBITInsiduous painless, proptosis, edema

mild restriction of occular movements, inability to close the lids

Bilateral orbital deposits in few cases

if pain + , pseudotumor is an important differential (30-40 yrs)

LYMPHOMA – ( old age)

GRANULOCYTIC SARCOMA myeloid infiltrates in child (<10y)

• LACRIMAL GLAND

painless, rubbery mass fixed to the

orbital rim

Downward and medial deviation

of the eyeball . Non axial Proptosis

CT scans usually show a homogeneous consistency with indistinct borders characteristic of the infiltrative nature of this lesion

• MICKULICZ syndrome

• LACRIMAL SAC LYMPHOMA : 2nd most common neoplastic cause of ephiphora

• Conjunctival leukemic infiltrate- Soft, hyperemic

SALMON PATCH

• LIDS

Mycosis Fungoides : ill defined spongy tumors of the lids. This is a form of T-cell lymphoma.

elevated tumor with central erosion

NEUROLOGY

Elevated Intracranial Pressure

Leukemic infiltration

Pseudotumor cerebri

Papilloedema

Cranial Nerve palsies – 3rd , 4th , 6th and 7th

• Strokes

involving visual pathway

cerebellum : nystagmus

OCCULAR ADVERSE EFFECTS OF TREATMENT

• Pseudotumor cerebri therapy for acute promyelocytic leukemia with all-trans retinoic acid (a vitamin A derivative) and with arsenic Trioxide

• Steroid cataract

• Bone Marrow transplant : Graft versus Host Disease

cojunctival hyperemia, conjunctival chemosis, pseudomembranous conjunctivitis, corneal sloughing

KCS, filamentary keratitis, immune mediated optic neuritis

• Radiotherapy

Optic atrophy and peripapillary RPE changes

Radiation retinopathy

Radiation cataract

THANK YOU