OphthalmologyClinicopathologic Case:

Eye Know the Cause of Death

Nancy Buchser, M.D.

1

Background

• 1 year, 10 month-old White Female

• 10 day history of upper respiratory tract infection

• Presents with the following:

2

Exam

• Cornea: clear • Sclera: unremarkable • Anterior chamber: quiet, angle open • Iris: unremarkable• Lens: Clear

• The following Fundus exam on autopsy:

3

Right Eye

4

Retinal hemorrhages(white centered)

5

White-centered hemorrhages

Left Eye

6

Retinal hemorrhages(white centered)

7

8

9

Differential Diagnosis for White-Centered Hemorrhages:

• Subacute bacterial endocarditis

• Leukemia• Elevated Venous pressure

– Neonatal birth trauma– Complicated delivery in

mothers– Child Abuse– Prolonged/difficult

intubation– Intracranial hemorrhage

from AVM

• Ischemia (w/ elevated venous pressure)– Anemia– Anoxia– CO poisoning

• Capillary fragility– Hypertensive retinopathy– Diabetic retinopathy– Oral contraceptives– Idiopathic

10

What are the white centers?

• Septic Emboli (Roth Spots)• Fibrin-Platelet thrombi• Aggregates of leukocytes• Antigen-antibody complexes• Swollen, infarcted, necrotic nerve fibers• Central clearing of hemorrhage

11

Pomeranz, H. D. Arch Ophthalmol 2002;120:1596.

Duane TD, Osher RH, Green WR. White centered hemorrhages: Their Significance. Ophthalmology. 1980 Jan;87(1):66-9.

A Little More History About Our Patient

• Homeless• Mother & 2 siblings have no known medical

problems• Symptoms worse x 10 days:

– Malaise– Weakness

• Was on Bus to hospital became obtunded & petechiae developed stopped bus and called 911 taken to hospital by EMS

• Died• Cause of death was not clear

12

Autopsy Findings• She was found to have

– Diffuse cerebral & cerebellar petechial hemorrhages– Petechial hemorrhages on labia mucosa, sclera, gastric mucosa,

& skin of left forearm– Pericardial & myocardial hemorrhage– Pulmonary consolidation & hemorrhage– Pericardial effusion– Pale kidneys– Thymic involution

• Toxicology: negative• HIV, Hanta, Arbo, Adeno viruses: negative• Bone Marrow Biopsy: all 3 marrow elements are present,

but with a heavy shift to the myeloid population. Atypical lymphocytes predominate.

13

Diffuse petechial hemorrhageson left forearm

Petechial hemorrhages

Diffuse cerebral & cerebellar petechial hemorrhages

Subarachnoid hemorrhage

Pulmonary consolidation & hemorrhage

Lung with peri-bronchial collections, edema, intra-alveolar hemorrhage, fibrin deposition, and infiltrating lymphocytic cells.

Heart with intraparenchymal hemorrhage

Heart with intraparenchymal hemorrhage

Liver- Portal tracts & sinusoids are infiltrated with atypical lymphocytes.

Bone Marrow with atypical lymphocytes

Bone Marrow with atypical lymphocytes

Autopsy: Left eye

25

Atypical lymphocytes in choroid

26

Lymphoblasts:•condensed chromatin•inconspicuous nucleoli•scant agranular cytoplasm•lack peroxidase-positive granules•contain cytoplasmic aggregates of PAS+ material

Choroid

27

deep retinal hemorrhage breaks through external limiting membrane & into subretinal space

28

TdT

CD10

CD3

CD20

Positive Stains:

Immunohistochemistry to identify abnormal lymphocytic population

TdT- Terminal Deoxynucleotidyl Transferase – tells you these cells are Blasts (immature precursor B or T lymphocytes)

• positive in >95%• expressed by pre-B & pre-T lymphoblasts

CD20- tells you cells are B lymphocytes

CD10-• Marker for germinal center cells and is expressed by immature B cells, some immature T cells, and

mature granulocytes• Positive in 75% of precursor B cell ALL, all subtypes of AML, Burkitt’s lymphoma and some cases of

large B cell lymphoma• Expressed by kidney, endometrial and other cell types, so it is not a lineage-specific marker, but is

used in classifying acute leukemias and lymphomas with a follicular growth pattern

CD10 & 20- positive in ALL• negative in AML would then do myeloperoxidase stain to show AML

CD3- most sensitive & specific marker for T lymphocytes (here only mild staining, compared to the B lymphocytes)

29

Final Diagnosis

• Acute Lymphocytic LeukemiaWith involvement of the

heart, lung, liver, brain, bone marrow

“Eye Know the Cause of Death”

30

Leukemia• Leukemias are the most common cancers in

children– 33% of cancers in ages 0-14 years

• Various types:– Acute or Chronic– Lymphocytic or Myelogenous

• Acute Lymphocytic Leukemia (ALL) – most common form in children

• Systemic signs of leukemia include:– Easy bruising or bleeding– Paleness or fatigue– Malaise, fever, lymphadenopathy 31

Ocular Involvement in Leukemia

• Duke-Elder (1967) - found that 90% of patients with leukemia have fundus involvement at some point in their disease process

• Allen & Straatsma (1961)- ocular involvement 4x more frequent in acute than in chronic leukemia

32Duke-Elder S. System of Ophthalmology. Retina. Vol X. St. Louis, CV Mosby, 1967, pp 387-393.Allen RA, Straatsma BR. Ocular involvement in leukemia and allied disorders.Arch Ophthalmol. 1961 Oct;66:490-508.

Leukemic Retinopathy- History• First described by Richard

Liebreich in 1861– Intraretinal hemorrhages– White-centered hemorrhages– Cotton-wool spots

• Before the advent of bone marrow biopsies, ophthalmologists were routinely consulted to assist in the diagnosis of leukemia by looking for leukemic retinopathy

33

Findings in Leukemic Retinopathy• 1. 1st change- veins become more dilated & tortuous (sausage-like)• 2. Yellowish color to arteries & veins & fundus (due to decreased RBC

count & increased WBC count)• 3. Retinal hemorrhages: (related to thrombocytopenia, stasis, leukemic

infiltration)• 4. Microaneurysms (may be related to increased viscosity from elevated

WBC count)• 5. retinal vascular sheathing - Gray-white streaks along retinal vessels

(perivascular infiltration of leukemic cells)• 6. hard yellow-white exudates (indicative of vascular insufficiency)• 7. soft exudates/cotton wool spots (Due to ischemia from anemia,

hyperviscosity, leukemic infiltration)• 8. Cytoid bodies• 9. peripheral retinal neovascularization

34

Leukemic Retinopathy

35Leach MJ. Images in clinical medicine. Retinal hemorrhages in acute leukemia. N Engl J Med. 2002 Jun 6;346(23):e6.

White-centered hemorrhages Tortuous veins

(usually 1st change)

Subhyaloid hemorrhage

Leukemic Retinopathy

36Reddy SC, Jackson N. Retinopathy in acute leukaemia at initial diagnosis: correlation of fundus lesions and haematological parameters. Acta Ophthalmol Scand. 2004 Feb;82(1):81-5.

Cotton-wool spots

Retinal hemorrhages

On Histology, retinal hemorrhages are present at all levels of the retina:

• Inner retinal • Outer retinal• Subretinal

37

38

Inner retinal hemorrhage- white-center = fibrin & platelets

Clinically, this would look flame shaped (in RNFL).may lead to vitreous hemorrhage if breaks through ILM

Focal collections of leukemic cells within retina, especially in inner retina and perivascular areas

39

Outer retina hemorrhage

Clinically, this would look like Dot/Blot

40

Subretinal Hemorrhage

Relationship between fundus lesions & hematologic parameters

Guyer et al (1988)

• Intraretinal hemorrhages– Associated with: Hct & Platelet count

• White-centered hemorrhages– Associated with: Hct

• Cotton-wool spots– No association with Hct, Leukocyte, or Platelet

count

41

Guyer DR, Schachat AP, Vitale S, Markowitz JA, Braine H, Burke PJ, Karp JE,Graham M. Leukemic retinopathy. Relationship between fundus lesions and hematologic parameters at diagnosis. Ophthalmology. 1989 Jun;96(6):860-4.

Histology of Ocular Leukemia Allen & Straatsma (1961), Kincaid & Green (1983), Rosenthal (1983), & Schachat et al

(1989)

42

Involvement

• Although Clinically, the Retina shows the most involvement,

• Histologically, the Choroid is most involved.

• Extent of involvement corresponded to number & arrangement of blood vessels present– Choroidal infiltrate is greatest in posterior portion of

eye b/c blood vessels are most numerous, especially in macula

43

44

Choroidal infiltrate

45

Choroid is thickened with neoplastic cells.

46T Sharma, J Grewal, S Gupta, and P I Murray. Ophthalmic manifestations of acute leukaemias: the ophthalmologist's role. Eye (2004) 18, 663–672.

Possible to get Massive direct infiltration of the optic nerve head by leukemic cells

47

In our case, there was no optic nerve infiltration

No Optic nerve infiltration

49

Sclera not involved

50

Normal anterior segment-no iris infiltration-no Trabecular meshwork infiltration

Prognostic importance of fundus findings in patients receiving chemo

51Abu el-Asrar AM, al-Momen AK, Kangave D, Harakati MS. Prognostic importance of retinopathy in acute leukemia. Documenta Ophthalmologica 1996. 91: 273-281.

Prognostic importance of fundus findings

• Reddy et al (1998)-– IRH: significantly shorter median survival

• (72 days vs 345 days)

– High WBC (>50 x109/l) and older age (>40 yo) were associated with poorer survival

• Ridgway et al (1976) – – 80% of children with acute leukemia died

within 10 months of ocular involvement

52

Reddy SC, Quah SH, Low HC, Jackson N. Prognostic significance of retinopathy at presentation in adult acute leukemia. Ann Hematol (1998) 76: 15-18.Ridgway EW, Jaffe N, Walton DS. Leukemic Ophthalmopathy in children. Cancer 1976; 38:1744-1749.

Prognostic importance of fundus findings

• Ohkoshi et al (1992) – – 96.4% of children w/ acute leukemia died within

28 months from onset of ocular manifestations and 83 months after onset of leukemia

– 5 year survival:• w/ eye involvement- 21.4% (15d-31m)• w/o eye involvement- 45.7%

53Ohkoshi K, Tsiaras WG. Prognostic importance of ophthalmic manifestations in childhood leukemia. Br J Ophthalmol. 1992;76:651-655.

Treatment

• Systemic Chemotherapy• “Pharmacologic sanctuaries”:

– Optic nerve involvement-• Orbital radiation

– Iris & Anterior chamber-• Low dose local anterior segment irradiation

– CNS-• Prophylactic radiation & intrathecal methotrexate

54

55

Conclusions

• Fundus exam can give prognostic value in a patient with leukemia

• Although survival is much improved with current therapy, ocular manifestations of leukemia are associated with decreased survival

• Abuse is a diagnosis of exclusion– In this case, the widespread petechia in the

systemic autopsy rule out this diagnosis

56

Special Thanks:

• Sander Dubovy, MD– Associate Professor of Ophthalmology and

Pathology, Bascom Palmer Eye Institute, University of Miami, FL

57

Abstract• Title: Eye Know the Cause of Death

• Keywords: Acute Lymphocytic Leukemia (ALL), leukemic retinopathy, white-centered hemorrhages

• Diagnosis: Acute Lymphocytic Leukemia (ALL)

• Abstract: 1 year, 10 month-old homeless girl with progressively worsening symptoms of upper respiratory tract infection, malaise, and weakness for the last 10 days acutely deteriorated, was unresponsive to therapy, and died. Autopsy revealed diffuse systemic leukemic infiltrate, petechiae, and hemorrhage in multiple organs. The eyes had white-centered hemorrhages and abnormal leukemic infiltrates in the choroid bilaterally. Gram stain was negative for bacteria and immunohistochemistry stains were positive for B cell leukemia, making the diagnosis of Acute Lymphocytic Leukemia (ALL). Ocular involvement is prevalent in leukemia, especially in acute forms. Thrombocytopenia and anemia are important in the etiology of leukemic retinopathy. Although chemotherapy has dramatically improved survival in ALL, patients with ocular involvement have a poor prognosis.

58

References• Duke-Elder J: System of Ophthalmology. Retina. Vol X. St. Louis: CV

Mosby; 1967:387-393.• Kincaid MC, Green WR: Ocular and orbital involvement in leukemia. Surv

Ophthalmol. 1983; 27: 211-232.• Duane TD, Osher RH, Green WR. White centered hemorrhages: their

significance.Ophthalmology. 1980 Jan;87(1):66-9. • Roth M. Uber netzhautaffecstionen bei wundfiebrin. Deutsch A Chir.

1872; 1:471-84.• Allen RA, Straatsma BR. Ocular involvement in leukemia and allied

disorders.Arch Ophthalmol. 1961 Oct;66:490-508. • Holt JM, Gordon-Smith EC. Retinal abnormalities in diseases of the

blood.Br J Ophthalmol. 1969 Mar;53(3):145-60. • Tower P. Richard Liebreich and His Atlas of Ophthalmoscopy. Archives of

Ophthalmology. June 1961;65:792-797.

59

References• Liebreich R. Uber Retinitis leucaemica und uber Embolie der Arteria centralis retinae.

Dtsch Klinik. 1861; 13:495-497. • Leach MJ. Images in clinical medicine. Retinal hemorrhages in acute leukemia. N Engl J

Med. 2002 Jun 6;346(23):e6. • Guyer DR, Schachat AP, Vitale S, Markowitz JA, Braine H, Burke PJ, Karp JE,Graham M.

Leukemic retinopathy. Relationship between fundus lesions and hematologic parameters at diagnosis. Ophthalmology. 1989 Jun;96(6):860-4.

• Ballantyne AJ, Michaelson IC. Textbook of the Fundus of the Eye. Edinburgh: Livingstone, 1962; 216.

• Merin S, Freund M. Retinopathy in severe anemia. Am J Ophthalmol. 1968; 66: 1102-6.• Rosenthal AR. Ocular Manifestations of Leukemia: A Review. Ophthalmology. August

1983; 90 (8): 899-905.• Schachat AP, Markowitz JA, Guyer DR, Burke PJ, Karp JE, Graham ML. Ophthalmic

manifestations of leukemia. Arch Ophthalmol. 1989 May;107(5):697-700.

60

• Kazuaki M, Satoshi K, Yoshihito H. Serous retinal detachment caused by leukaemic choroidal infiltration during complete remission. British Journal of Ophthalmology 2000;84:1318a

• T Sharma, J Grewal, S Gupta, and P I Murray. Ophthalmic manifestations of acute leukaemias: the ophthalmologist's role. Eye. 2004;18,663–672.

• Reddy SC, Quah SH, Low HC, Jackson N. Prognostic significance of retinopathy at presentation in adult acute leukemia. Ann Hematol. 1998;76:15-18.

• Abu el-Asrar AM, al-Momen AK, Kangave D, Harakati MS, Ajarim DS. Correlation of fundus lesions and hematologic findings in leukemic retinopathy. Eur J Ophthalmol. 1996 Apr-Jun;6(2):167-72.

• Abu el-Asrar AM, al-Momen AK, Kangave D, Harakati MS. Prognostic importance of retinopathy in acute leukemia. Documenta Ophthalmologica. 1996;91:273-281.

• Ridgway EW, Jaffe N, Walton DS. Leukemic Ophthalmopathy in children. Cancer. 1976; 38:1744-1749.

• Ohkoshi K, Tsiaras WG. Prognostic importance of ophthalmic manifestations in childhood leukemia. Br J Ophthalmol. 1992;76:651-655.

61