LEUKEMIA

Dr. Devdutta Nayak

BIRATNAGAR EYE HOSPITAL

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

Hematopoieticstem cell

Neutrophils

Eosinophils

Basophils

Monocytes

Platelets

Red cells

Myeloidprogenitor

Lymphoidprogenitor

B-lymphocytes

T-lymphocytes

Plasmacells

naïve

ALL

AML

• 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 conjunctiva and in lacrimal gland

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

• 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.

• In 1860, Liebreich first described Leukemic Retinopathy

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

EVOLUTION OF TERMS & CONCEPTS in HEMATONCOLOGY

• 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.

What is leukemia?

Leukemia is cancer of the white blood cells. White blood cells help body fight infection. In leukemia, however, the bone marrow produces abnormal white blood cells. These cells crowd out the healthy blood cells, making it hard for blood to do its work.

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

Signs and Symptoms• Most of the signs and symptoms are due to: 1-Anemia. 2-Leukopenia. 3-Thrombocytopenia.

• Bicytopenia,Pancytopenia.

• All symptoms associated with leukemia can be attributed to other diseases, consequently, leukemia is always diagnosed by laboratory investigations.

Causes• Leukemia,like other malignancies, results from somatic

mutations in the DNA.

• Certain mutations produce leukemia byactivating oncogenes or deactivating tumor suppressor genes.

• These mutations may occur spontaneously or as a result of exposure to radiation or carcinogenic substances and likely to be influenced by genetic factors.

Causes-cont’d.• Ionizing radiation

• Viruses: Human T-lymphotropic virus (HTLV-1)

• Chemicals: Benzene,chemotherapy

• Smoking: slight increase in leukemia incidence

• Genetic predisposition toward developing leukemia: Down syn.,Fanconi anemia

Classification• Multiple classification systems.

• FAB classification:

French-American-British Classification.

• FAB Classification relies on morphologic, cytochemical,and immunophenotyping criteria to define

8 major subtypes (M0-M7).

FAB vs WHO Classification

• French-American-British (FAB) Cx• Cellular morphology and cytochemical stain• Acute leukemia as > 30% bone marrow blasts• Widely used

• World Health Organization Cx• Cellular morphology and cytochemical stain• Immunologic probes of cell markers, cytogenetics,

molecular abnormalities & clinical syndrome• Acute leukemia as > 20% bone marrow blasts• Standard for diagnosis

Acute myeloid leukemias (AML) Classification - FAB

1. M0: minimally differentiated

2. M1: myeloblastic leukemia without maturation

3. M2: myeloblastic leukemia with maturation

4. M3: hypergranular promyelocytic leukemia

5. M4: myelomonocytic leukemia

6. M4Eo: variant, increase in marrow eosinophils

7. M5: monocytic leukemia

8. M6: erythroleukemia (DiGuglielmo's disease)

9. M7: megakaryoblastic leukemia

AML classification - WHO

AML not otherwise categorized1. AML minimally differentiated2. AML without maturation3. AML with maturation4. Acute myelomonocytic leukemia5. Acute monocytic leukemia6. Acute erythroid leukemia7. Acute megakaryocytic leukemia8. Acute basophilic leukemia9. Acute panmyelosis with myelofibrosis

Acute vs Chronic Leukemia

Acute Chronic

Age Children & young adults

Middle age and elderly

Onset Sudden insidious

Duration weeks to months years

WBC count Variable High

Acute vs Chronic Leukemia

Acute Chronic

Platelets Low Early: Normal/ HighLate: Low

Anemia High (>90%) None/ mild

Predomi-nant cells

Blast cells Mature cells

AML = myeloblastALL= lymphoblast

CML=granulocytesCLL=lymphocytes

Acute vs Chronic Leukemia

Acute Chronic

Marrow cellularity

>20% marrow blasts (WHO)> 30% marrow blasts (FAB)

>70% marrow cellularity (hypercellular); No dysplasia

Diagnosis PBS, BM exam, cytochemical stains, surface markers,chromosome

PBS (peripheral blood smear)

Acute Myeloid Leukemia

Definition• Acute myeloid leukemia (AML): acute myelogenous

leukemia, acute non-lymphocytic leukemia.

• AML consists of a group of relatively well-defined hematopoietic neoplasms, involving precursor cells committed to the myeloid line(WBCs, RBCs, PLTs).

Chracteristics• AML is characterized by a clonal proliferation of

myeloid precursors with a reduced capacity to differentiate into mature cellular elements.

• Accumulation of leukemic blasts or other immature forms in the BM, peripheral blood and

other tissues with a variable reduction in the production of normal RBCs, platelets and mature granulocytes.

Specific:• M2 : Chloroma:- presents as a mass lesion, ‘tumor of

leukemic cells’

• M3 : DIC

• M4/M5 : Infiltration of soft tissues, gum infiltration, skin deposits, Meningeal involvement-headache, vomiting, eye symptoms.

A

B

C

Chloromas

NEJM 1998

Gum hypertrophy

Leukostasis

• accumulation of blasts in microcirculation with impaired perfusion

• lungs: hypoxemia, pulmonary infiltrates

• CNS: stroke

• only seen with WBC >> 50 x 109/L

Pathological Features• CBC and differential.

• Blood film (smear).

• Bone marrow examination: BM aspirate and trephine biopsy.

1-Morphology.

2-Immunephenotyping.

3-Cytogenetics and molecular biology.

Jemshidi trephine & Salah aspiration needle

Bone marrow in acute leukemia

• necessary for diagnosis

• useful for determining type

• useful for prognosis

• Acute leukemia are defined by the presence of > 20% blasts in bone marrow (% of nucleated marrow cells).

• Bone marrow aspirate & trephine: Hypercellular

• blast cells ( > 20%), • presence of Auer rods - AML type

• Cytochemistry : Special stains to differentiate AML from ALL ;

Positivity with Sudan black & Myeloperoxidase

(MPO) in AML.

WBC Count in AML• WBC count in AML can be high, normal or low.

• Median WBC count in AML is 15 000/uL.

• 20% of patients have > 100 000/uL.

• 25-40% of patients have <5000/uL.

• 95% of patients have blast cells on blood

film.

Distinguishing AML from ALL

• light microscopy• AML: Auer rods, cytoplasmic (azurophilic) granules• ALL: no Auer rods or granules.

• flow cytometry

• special stains (cytochemistry)

Cytochemical Stains

• Since the early 20th century, cytochemical staining of cells has been a useful tool in differentiating hematopoietic diseases.

• Smears and imprints made from bone marrow, lymph nodes, spleen, or peripheral blood are preferred.• In enzymatic techniques, fresh smears are used to

ensure optimal enzyme activity

• Certain elements may be inhibited during the fixation of smears and imprints

Myeloperoxidase (MPX/MPO)• The peroxidase enzyme reacts with H2O2 &

release O2, which oxidizes the indicator dye and produce orange-brown granules in the cells (3-amino-9-erythrocarbazol)

• Enzyme MPX is found in the 1o granules of granulocytes, neutrophils and precursors (from the promyelocyte stage on) & eosinophils

• Monocytes may be weakly pos

• Leukemic myeloblasts are usually pos and Auer rods stain very strongly

• Used for differentiating AML (+) from ALL (-)

MPO (right) & Sudan black (left) showing intense localised positivity in blasts

Myeloperoxidase

(MPO)

p-Phenylene diamine + Catecol + H2O2

MPO > Brown black deposits

Chloracetate (Specific) Esterase

Myeloid Cell Line

Naphthol-ASD-chloracetate CAE > Free naphthol compounds

+ Stable diazonium salt (eg, Fast Corinth) > Red deposit

Non-Specific Esterase (NSE)• Nonspecific esterase liberates alpha-naphthyl

from the substrate alpha-naphthyl acetate. Alpha-naphthyl couples with the dye molecule to form dark reddish-brown granules

• Monocytes, monblasts, macrophages, histiocytes, megakaryocytes and some carcinomas are NSE pos.

• Abnormal erythroblasts are strongly pos.

• Lymphocytes are neg or may show dot positivity.

Non-Specific Esterase

Monocytic Line

Naphthyl acetate ANAE > Free naphthyl compounds +Stable diazonium salt (eg, Fast blue RR) > Brown deposits

NSE (continued)

• Used for differentiating myelomonocytic and monocytic leukemia (+) from granulocytic leukemia (-)

• Monocyte NSE are fluoride sensitive.

http://www.healthsystem.virginia.edu/internet/hematology/hessedd/malignanthematologicdisorders/leukemias/aml-m4.cfm

Double Esterase in M4

NSE with Fl inhibition

Histiocyte

Periodic Acid Schiff (PAS)• Periodic acid oxidizes glycogen, mucoproteins,

and other high-molecular weight carbohydrates to aldehydes.

• Aldehydes react with colorless Schiff reagent, staining them a bright red-pink.

• Megakaryocytes and platelets stain strongly pos.

• Normoblasts will stain Pos.

• Lymphoblasts in ALL show course and granular positivity.

PAS (continued)

• Myeloblasts are Neg.

• Aids in diagnosis of ALL, erythroleukemia, and megakaryoblastic leukemia.

• Normal bone marrow smear used for control slides

http://www.pathologyoutlines.com/leukemia.html

Periodic Acid Schiff

Periodic acid + Glycogen oxidation > Aldehyde + Schiff reagent

(para-rosaniline, Na metabisulfite) > Red deposit

AML

AML

Auer rods in AML

Auer Rods

P. Smear AML

MO: Minimally differentiated

• Undifferentiated Blasts (No maturation)

• Myeloid phenotype - CD13, CD33, CD34

• (-) SBB, MPO• Negative: Auer rods,

Esterase

M1 AML without maturation > 30% myeloblasts Large cells, round nucleus Nucleoli (+) scanty cytoplasm >3% MPO, SBB (+) <20% NSE (+) CD 13, 33, 117

M2 AML with maturation

• Common type• >30% myeloblasts• >10% granulocyte• Kidney shape nucleus• Nucleoli (+)• (+) Auer rods • Eosinophilic granules• >50% MPO, SBB (+)• CD 13, 33

M3 (hypergranular promyelocytic)

• Promyelocyte-predominant • Large, kidney shape (faggot

cells) • (+) Auer rods• basophilic, bi-lobed nuclei• CD 13,33• High incidence of DIC

Acute myeloid leukemia with very abnormal cells (AML M3/ t15;17)

M4 Acute myelomonocytic

• >30% myeloblast (FAB)• >20% granulocyte• >20% promonocytes and

monocytes• CD 11, 13, 33,14• (+) Auer rods common• High serum lysozyme level

M5: acute monocytic leukemia

1. M5a – without maturation• Monoblasts , few promonocytes

2. M5b – with maturation • Blast, Promonocytes (BM), Monocytes (Blood)

M5a

• Monoblasts ameboid with round to oval nuclei,

• prominent nucleoli, • <20%

promonocytes/monocytes• Vacuolated cytoplasm

M5b

• > 20% promonocytes, monocytes

• Promonocytes with folded, convulated nucleus

• Azurophilic granules

M6 - erythroleukemia

Large, bizarre,round-to-oval cells

(+) nucleoli > 50% Erythroblasts > 30 % Myeloblasts CD 45,71 Glycophorin A CD 13, 15,33 myeloblast PAS (+)

M7 – acute megakaryoblastic

• >30% megakaryoblasts• platelet like granules on

PAS stain• NSE (+) • Myeloid blasts may

show SBB or MPO (+) • CD 41,42,61

Megakaryoblast

Acute Nonlymphocytic Leukemias

Acute lymphoblastic leukemia

• 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.

• FAB Classification of ALL :

L1: Small homogeneous blasts; mostly in children

L2: Large heterogeneous blasts; mostly in adults

L3: “Burkitt” large basophilic B-cell blasts with vacuoles

WHO Classification of Lymphoproliferative Syndromes

Precursor B Lymphoblastic Leukemia/Lymphoma (ALL/LBL) --

ALL in children (80-85% of childhood ALL); LBL in young adults and rare; (FAB L1 or L2)

Precursor T ALL/LBL --

15% of childhood ALL and 25% of adult ALL.

Burkitt Leukemia/Lymphoma -- (FAB L3)

• Confirmation:

• Immunophenotyping• Molecular genetics• Cytogenetics: Chromosomal

abnormalities

ALL L1

L3L2

Burkits / ALL L3

Prognostic factors

• High WBC – relapse in testis /cns

• Infants <1 yr, children >10 yr poor outcome

• L1- good prognosis

• L2,3- bad prognosis

Prognosis• The response to treatment and overall survival of

patients with ALL are heterogenous.

• Prognostic factors are related to patient and tumor characteristics:

1- Age 2- Performance status 3- Karyotype

Chronic Myeloid Leukemia

• Characterized by an uncontrolled proliferation of granulocytes.

• Accompanying proliferation of erythroid cells and megakaryocytes usually present.

• Many patients are asymptomatic but may present with splenomegaly, weight loss, malaise, bleeding, or thrombosis.

• Ch 22 – 09 translocation (bcr – abl)

Philadelphia Chromosome.

3 Phases:

• Chronic Phase (90%)• Accelerated Phase (<10%)• Blast Crisis (Rare)

Chronic Phase pts. usually asymptomatic.

Accelerated Phase implies worsening Dx. (Sokal Index/WHO criteria)

Blast crisis behaves like an acute leukemia.

WHO criteria for diagnosis of Accelerated Phase:• 10–19% myeloblasts in the blood or bone marrow

• >20% basophils in the blood or bone marrow

• Platelet count <100,000, unrelated to therapy

• Platelet count >1,000,000, unresponsive to therapy

• Cytogenetic evolution with new abnormalities in addition to the Philadelphia chromosome

• Increasing splenomegaly or white blood cell count, unresponsive to therapy

Blast Crisis:

final phase in the evolution of CML, with rapid progression and short survival.

Blast crisis is diagnosed if any of the following are present in a patient with CML –

• >20% myeloblasts or lymphoblasts in the blood or bone marrow

• Large clusters of blasts in the bone marrow on biopsy

• Development of a chloroma (solid focus of leukemia outside the bone marrow)

Prognosis:

• Before advent of tyrosine kinase inhibitors (e.g. – Imatinib Mesylate,Dasatinib, Nilotinib) median survival was 3-5 years.

• Current survival rate approaching 95.2% at end of 8 years akin to rate in general population.

Chronic Lymphocytic Leukemia

• 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.

• Primary involvement of the bone marrow and secondary release into the peripheral blood.

• Asymptomatic at diagnosis. As the disease progresses, lymphadenopathy, splenomegaly, and hepatomegaly develop.

• Secondary hypogammaglobulinemia exists.

• Most (>75%) people newly diagnosed with CLL are over the age of 50.

• More prevalent in Men.

• Asymptomatic in early stages, diagnosed incidentally.

• Swollen lymph nodes, spleen, and liver, and eventually anemia and infections.

• CD5 & CD23 +

• Flow cytometry, FISH

• Smudge cells in PBS.

Prognosis:

•  Depends on the subtype:

IgVh Mutation – Worst Prognosis del 17p del 11q trisomy 12 del13q -- Best Prognosis

• Some subtypes have a median survival of 6–8 years, while others have a median survival of 22 years.

• Very slow progressing.

Unfavourable

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

• 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 (NAAION)

• 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- increased RBCs

• Dilated tortuous arteries and veins• Disc edema• Multiple Retinal hemorrhages • Venous thrombosis• Ischemic optic neuropathy• Carotid and vertebro-basilar insufficiency• Cavernous Sinus Thrombosis• Conjunctival congestion

• NAAION

• 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.

• Basement membranes and Epithelial cells - more likely 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, granulomatous diseases such

as sarcoidosis, hyperthyroidism, vitamin A intoxication, and renal failure.

• 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

• Mostly in chronic myeloid leukemia and bone marrow transplant pts..

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

• 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.• 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 cells.DD - chronic subretinal fluid collection e g Uveal effusion syndrome, CSCR.

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.

• Retrolaminar infiltrate visible on neuroimaging.

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

• Steroid induced cataract

• Bone Marrow transplant : Graft versus Host Disease

Conjunctival 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

Treatment• Most treatment protocols use systemic chemotherapy

with or without radiotherapy.

• The basic strategy is to eliminate all detectable disease

by using cytotoxic agents.

• To attain this goal, 3 phases are typically used, as follows:

remission induction phase consolidation phase maintenance therapy phase.

• The initial treatment of ALL uses various combinations of vincristine, prednisone, and L-asparaginase until a complete remission is obtained.

• Maintenance therapy with mercaptopurine is continued for 2-3 years following remission.

• Use of intrathecal methotrexate with or without cranial irradiation to cover the CNS.

• Daunorubicin, cytarabine, and thioguanine currently are used to obtain induction and remission of AML.

• Maintenance therapy for 8 months may lengthen remission. Once relapse has occurred, AML generally is curable only by bone marrow transplantation.

• Presently, treatment of CLL is palliative.

• CML is characterized by a leukocytosis greater than 100,000 cells. Emergent treatment with leukopheresis. Otherwise, busulfan or hydroxyurea may control WBC counts. During the chronic phase, treatment is palliative.

• CML blastic phase treatment with vincristine and prednisone.

• Newer drugs for CML – Imatinib Mesylate, Dasatinib, Nilotinib (for maintainance).

• Allogenic bone marrow transplant is the only curative therapy for CML. High early mortality rate.

• Leukemic retinopathy usually not treated directly.

• As the hematological parameters normalize with systemic treatment, many of the ophthalmic signs resolve.

• Leukopheresis for hyperviscosity also may alleviate intraocular manifestations.

• When definite intraocular leukemic infiltrates fail to respond to systemic chemotherapy, direct radiation therapy is recommended.

• Relapse, manifested by anterior segment involvement, should be treated by radiation.

• In certain cases, subconjunctival chemotherapeutic agents have been injected.

• Optic nerve head infiltration in patients with ALL is an emergency and requires prompt radiation therapy to try to salvage some vision.

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