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Clinicopathologic Conference

Clinicopathologic Conference. Resident: Dr. Natalia Gonzalez Pathologist: Dr. Clayton Wiley 8/21/2017. Patient F.L. 18 yo girl Initially presented April 2015 with 3-4 weeks of fatigue, night sweats, fevers, cough, 35 lb weight loss, and chest/shoulder pain. Past Medical History: None

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Clinicopathologic Conference

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  1. Clinicopathologic Conference Resident: Dr. Natalia Gonzalez Pathologist: Dr. Clayton Wiley 8/21/2017

  2. Patient F.L. • 18 yo girl • Initially presented April 2015 with 3-4 weeks of fatigue, night sweats, fevers, cough, 35 lb weight loss, and chest/shoulder pain

  3. Past Medical History: None • Family History: Mother with Hashimotos • Social History: Jehovah’s witness. About to start 12th grade. Sexually active. Cats at home.

  4. CT showed mediastinal, abdominal lymphadenopathy and an L5nvertebral fracture • Bronchoscopy for FNA of a lymph node • CD30+ anaplastic large cell lymphoma • Spinal tap negative

  5. Complete chemotherapy with ALCL 99 • addition of vinblastine to 5 chemo courses followed by weekly vinblastine for total one year therapy compared to standard therapy without maintenance) • (Standard therapy: doxorubicin, prednisone, vincristine, methotrexate, 6-mercaptopurine) • Course complicated by R atrial clot s/p anticoagulation • Remission

  6. April 2017 • Sudden increase in right cervical lymphadenopathy, 10 lb weight loss • FNA negative • Open biopsy CD30+ anaplastic large cell lymphoma • LP negative • Parents refused autologous stem cell transplant, restricted by their beliefs (Jehovah’s witnesses)

  7. Started Brentuximab -> 1st dose on 7/14/17 • Monoclonal antibody that targets CD30 and delivers MMAE (antimitotic agent monomethyl auristatin E) • Side effects • Peripheral neuropathy (54-67%), headache, myalgia, PML • Fever, fatigue, rash, pain, headache, neutropenia, anemia, thrombocytopenia, peripheral edema, insomnia, chills, night sweats, pruritis, arthralgias, back pain, infections, GI erosion

  8. Within a day, had malaise, headache and fevers. Went camping during this time, but reportedly left the tent very little since she already felt unwell. • 7/17/17 presented with acute abdominal pain • OSH ED eval negative (labs, CXR, CT abd/pelv). Sent home. • Has worsening abdominal pain, emesis • Presented 7/25 and admitted with the same and tachycardia

  9. BP 105/68, HR 81 • Exam with diffuse abdominal pain, but soft, nondistended • Na 140, BUN 6, Cr 0.79, glucose 170, ALT 168, AST 83, ammonia 69 • WBC 5.8, Hgb 12.9, Plt 262, INR 1.2

  10. 7/26/17 • sleepy and increasingly agitated, confused, still vomiting • T 38.1 • Respiratory alkalosis, RR 50s • Lactate 4.2. CRP 4. • Rapid progression of tachycardia, tachypnea, then shock • Intubated and placed on pressors. Broad spectrum antimicrobials. • CT abdomen/pelvis with hepatic steatosis, ileal wall thickening suggestive of enteritis

  11. Neurologic examination: • PERRL • Not following commands • Moving arms symmetrically • Brisk reflexes

  12. Head CT 7/26

  13. 7/27 • Ammonia 100, Creatinine 2.18 • Tachycardic to 140s • EEG triphasic waves, diffuse slowing (on cEEG with same) • Unstable for MRI or LP -> had to be paralyzed for ARDS? • Repeat HCT…

  14. Head CT 7/27

  15. Workup • Lactate 4.2 -> 14 • ALT and AST improved • Ammonia peaked at 2/13 on 8/4 • LDH 3600 (late in admission) • Fibrinogen low 100-60s • Ferritin normal -> 3,000s • T max 39 on 8/4 • Infectious workup: Blood cx, BAL, HIV, hepatitis panel, HSV1/2, CMV, EBV, RVP, enterovirus, bartonella, ehrlichia, anaplasma, Cryptococcus ag all negative • WBC 5.8 -> 62 (85% neutrophils) • Hgb mostly stable • Plts 262 -> 19 • Na 140-> 160s (in setting of hypertonic saline) • Glucose 170->290s • BUN 6 -> 130s • Cr 0.79 -> 2.5 • INR 1.2 -> 3.3 • PTT increased • CRP 4 -> 16

  16. In summary • Cerebral edema • Fevers of unclear source • Shock • ARDS • Liver failure leading to hyperammonemia, thrombocytopenia and coagulopathy • Renal failure

  17. 8/5 • No edema on ophtho evaluation • Repeat HCT improved…

  18. 8/8 • Pt reached the point where CRRT was necessary, but parent’s refused due to contradictions with their beliefs as Jehovah’s witnesses • Given poor prognosis however, a GOC discussion resulted in focusing on comfort care, and she was extubated and promptly passed

  19. Autopsy, gross results • Cardiomegaly • Hepatomegaly • Diffuse steatosis • Splenomegaly • Cholelithiasis • Renal subcapsular hemorrhage and soft pale cortices b/l

  20. Differential • Cerebral edema 2/2 to • Hyperammonemia • Azotemia • Hypoxia • Infection (meningoencephalitis) • PML (2/2 brentuximab) • Venous sinus thrombosis • PRES • HLH

  21. Mechanism of cerebral edema in HE • Ammonia crosses blood-brain barrier • Taken up by astrocytes which are rich in glutamine synthetase • Ammonia converted to glutamine • Glutamine draws water via osmosis to astrocytes • Metabolic dysfunction of astrocytes

  22. Meningitis • Gross findings: • Bacterial - Pus in the meninges • Fungal – thickened, opaque meninges • Micro: • Bacterial: Neutrophils in the subarachnoid space, leptomeningeal vein infiltrates causing hemorrhages • Viral: Perivascular inflammation, microglial nodules, neuronophagia

  23. Hemophagocytic Lymphohistiocytosis (HLH) • Secondary/acquired HLH (from infection or malignancy) • NK cells, lymphocytes, macrophages activated and secrete high levels of cytokines and chemokines • Fever, hepatosplenomegaly, cytopenias • Hepatitis, rash, neurologic symptoms (meningismus, seizures, PRES), pulmonary dysfunction, lymphadenopathy • High ferritin, high triglycerides, low fibrinogen • Elevated transaminases, abnormal coagulations studies, hyponatremia

  24. References • Esteban Y, de Jong J, Tesher M. An Overview of Hemophagocytic Lymphohistiocytosis. Pediatr Ann. 2017; 46: e309-e313. doi: 10.3928/19382359-20170717-01 • Neuropathology, 2nd Edition. Grayson. 2012.

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