Transcript Ophthalmology Clinicopathologic Case

Ophthalmology
Clinicopathologic Case:
Eye Know the Cause of Death
Nancy Buchser, M.D.
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Background
• 1 year, 10 month-old White Female
• 10 day history of upper respiratory tract
infection
• Presents with the following:
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Exam
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Cornea:
clear
Sclera:
unremarkable
Anterior chamber: quiet, angle open
Iris:
unremarkable
Lens:
Clear
• The following Fundus exam on autopsy:
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Right Eye
Retinal hemorrhages
(white centered)
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White-centered hemorrhages
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Left Eye
Retinal hemorrhages
(white centered)
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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
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Hypertensive retinopathy
Diabetic retinopathy
Oral contraceptives
Idiopathic
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What are the white centers?
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Pomeranz, H. D. Arch Ophthalmol 2002;120:1596.
Septic Emboli (Roth Spots)
Fibrin-Platelet thrombi
Aggregates of leukocytes
Antigen-antibody complexes
Swollen, infarcted, necrotic nerve fibers
Central clearing of hemorrhage
Duane TD, Osher RH, Green WR. White centered hemorrhages: Their Significance. Ophthalmology. 1980
Jan;87(1):66-9.
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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
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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.
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Diffuse petechial hemorrhages
on 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
Atypical lymphocytes in choroid
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Choroid
Lymphoblasts:
•condensed
chromatin
•inconspicuous
nucleoli
•scant agranular
cytoplasm
•lack peroxidasepositive granules
•contain cytoplasmic
aggregates of PAS+
material
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deep retinal hemorrhage breaks through external limiting
membrane & into subretinal space
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Positive
Stains:
TdT
CD20
CD3
CD10
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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)
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Final Diagnosis
• Acute Lymphocytic Leukemia
With involvement of the
heart, lung, liver, brain, bone marrow
“Eye Know the Cause of Death”
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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
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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. 32
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
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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
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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.
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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.
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On Histology, retinal hemorrhages are
present at all levels of the retina:
• Inner retinal
• Outer retinal
• Subretinal
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Inner retinal hemorrhagewhite-center = fibrin & platelets
Focal collections of leukemic
cells within retina, especially in
inner retina and perivascular
areas
Clinically, this would look flame shaped (in RNFL).
may lead to vitreous hemorrhage if breaks through ILM
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Outer retina
hemorrhage
Clinically, this would look like
Dot/Blot
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Subretinal Hemorrhage
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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
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. 41
Histology of Ocular Leukemia
Percentage of patients with ocular leukemia
invovlement
Allen & Straatsma (1961), Kincaid & Green (1983), Rosenthal (1983), & Schachat et al
(1989)
70%
65%
60%
50%
40%
30%
20%
10%
35%
30%
19%
18%
17%
14%
7%
4%
4%
2%
0%
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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
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Choroidal infiltrate
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Choroid is
thickened with
neoplastic cells.
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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.
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In our case, there was no optic nerve infiltration
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No Optic nerve infiltration
Sclera not involved
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Normal anterior segment
-no iris infiltration
-no Trabecular meshwork infiltration
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Prognostic importance of fundus
findings in patients receiving chemo
Days
Mean Survival Time
700
600
500
400
300
200
100
0
641
609
332
622
599
326
248
169
Retinopathy Present
Retinopathy Absent
Abu el-Asrar AM, al-Momen AK, Kangave D, Harakati MS. Prognostic importance of retinopathy in acute
leukemia. Documenta Ophthalmologica 1996. 91: 273-281.
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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
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.
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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%
Ohkoshi K, Tsiaras WG. Prognostic importance of ophthalmic manifestations in childhood leukemia. Br J
Ophthalmol. 1992;76:651-655.
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Treatment
• Systemic Chemotherapy
• “Pharmacologic sanctuaries”:
– Optic nerve involvement• Orbital radiation
– Iris & Anterior chamber• Low dose local anterior segment irradiation
– CNS• Prophylactic radiation & intrathecal methotrexate
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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
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Special Thanks:
• Sander Dubovy, MD
– Associate Professor of Ophthalmology and
Pathology, Bascom Palmer Eye Institute, University
of Miami, FL
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Abstract
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Title: Eye Know the Cause of Death
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Keywords: Acute Lymphocytic Leukemia (ALL), leukemic retinopathy, white-centered hemorrhages
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Diagnosis: Acute Lymphocytic Leukemia (ALL)
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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.
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References
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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.
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References
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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.
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•
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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.
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