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Ophthalmology Clinicopathologic Case: Eye Know the Cause of Death Nancy Buchser, M.D.

Ophthalmology Clinicopathologic Case: Eye Know the Cause of Death Nancy Buchser, M.D. Background. 1 year, 10 month-old White Female 10 day history of upper respiratory tract infection Presents with the following:. Exam. Cornea: clear Sclera: unremarkable

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Ophthalmology Clinicopathologic Case: Eye Know the Cause of Death Nancy Buchser, M.D.

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  1. Ophthalmology Clinicopathologic Case: Eye Know the Cause of Death Nancy Buchser, M.D.

  2. Background • 1 year, 10 month-old White Female • 10 day history of upper respiratory tract infection • Presents with the following:

  3. Exam • Cornea: clear • Sclera: unremarkable • Anterior chamber: quiet, angle open • Iris: unremarkable • Lens: Clear • The following Fundus exam on autopsy:

  4. Right Eye Retinal hemorrhages (white centered)

  5. White-centered hemorrhages

  6. Left Eye Retinal hemorrhages (white centered)

  7. 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

  8. 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 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.

  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

  10. 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.

  11. Diffuse petechial hemorrhages on left forearm

  12. Petechial hemorrhages

  13. Diffuse cerebral & cerebellar petechial hemorrhages Subarachnoid hemorrhage

  14. Pulmonary consolidation & hemorrhage

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

  16. Heart with intraparenchymal hemorrhage

  17. Heart with intraparenchymal hemorrhage

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

  19. Bone Marrow with atypical lymphocytes

  20. Bone Marrow with atypical lymphocytes

  21. Autopsy: Left eye

  22. Atypical lymphocytes in choroid

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

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

  25. Positive Stains: TdT CD3 CD20 CD10

  26. 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)

  27. Final Diagnosis • Acute Lymphocytic Leukemia With involvement of the heart, lung, liver, brain, bone marrow “Eye Know the Cause of Death”

  28. 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

  29. 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 Duke-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.

  30. 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

  31. 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

  32. Leukemic Retinopathy White-centered hemorrhages Tortuous veins (usually 1st change) Subhyaloid hemorrhage Leach MJ. Images in clinical medicine. Retinal hemorrhages in acute leukemia. N Engl J Med. 2002 Jun 6;346(23):e6.

  33. Leukemic Retinopathy Cotton-wool spots Retinal hemorrhages Reddy 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.

  34. On Histology, retinal hemorrhages are present at all levels of the retina: • Inner retinal • Outer retinal • Subretinal

  35. Focal collections of leukemic cells within retina, especially in inner retina and perivascular areas Inner retinal hemorrhage- white-center = fibrin & platelets Clinically, this would look flame shaped (in RNFL). may lead to vitreous hemorrhage if breaks through ILM

  36. Outer retina hemorrhage Clinically, this would look like Dot/Blot

  37. Subretinal Hemorrhage

  38. Relationship between fundus lesions & hematologic parametersGuyer 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 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.

  39. Histology of Ocular LeukemiaAllen & Straatsma (1961), Kincaid & Green (1983), Rosenthal (1983), & Schachat et al (1989)

  40. 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

  41. Choroidal infiltrate

  42. Choroid is thickened with neoplastic cells.

  43. Possible to get Massive direct infiltration of the optic nerve head by leukemic cells T Sharma, J Grewal, S Gupta, and P I Murray.Ophthalmic manifestations of acute leukaemias: the ophthalmologist's role. Eye (2004) 18, 663–672.

  44. In our case, there was no optic nerve infiltration

  45. No Optic nerve infiltration

  46. Sclera not involved

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

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