2. DIAGNOSTIC SLIDE SESSION CASE 8 Michelle Madden Felicella, MD Juan Bilbao, MD Arie Perry, MD Clinical history, follow-up and MR images kindly provided by Dr. Todd Mainprize

3. CLINICAL HISTORY 42-yo woman with headache and left transverse sinus occlusion Treated with warfarin and followed by neurology MRI: prominent dural thickening and nodularity of cerebral hemispheres including the falx and tentorium Repeat MRI a few months later: worsened thickening Referred to neurosurgery for biopsy of the left temporal lobe

13. DIAGNOSIS???

14. EMA

15. CD3 CD20

16. Kappa Lambda

17. IgG4 IgG

18. SPECIAL STAINS CD3, CD5: numerous reactive T-cells CD20, CD21, CD23, CD10, BCL6: small lymphocytes in germinal centers BCL2: positive in scattered interstitial small lymphocytes Cyclin D1: negative EMA: positive in meningothelial cells (limited to surface) and numerous plasma cells ISH for kappa and lambda: polyclonal Ki-67: moderate LI IgG4: 80 plasma cells/HPF IgG4/IgG: 15%

19. DIAGNOSIS Chronic pachymeningitis with meningothelial proliferation and increased IgG4-positive plasma cells Most likely represent IgG4 sclerosing disease and meningothelial hyperplasia

22. DIAGNOSTIC POINTS Differential diagnosis: Lymphoplasmacyte rich meningioma Idiopathic hypertrophic pachymeningitis Lymphoproliferative disorder IgG4-related hypertrophic pachymeningitis IgG4-related hypertrophic pachymeningitis Key Histologic features: Dense lymphoplasmacytic infiltrate with many plasma cells Storiform Fibrosis Phlebitis Scattered eosinophils Average count of 5 HPF in the area of greatest concentration: Our case: 80 IgG4 + cells/HPF and 518 IgG + cells/HPF IgG4:IgG ratio of 15%. Normal ratio in serum is <5% Average IgG4 PCs in other inflammatory conditions <10 HPF Differential diagnosis: Lymphoplasmacyte rich meningioma Idiopathic hypertrophic pachymeningitis Lymphoproliferative disorder IgG4-related hypertrophic pachymeningitis IgG4-related hypertrophic pachymeningitis Key Histologic features: Dense lymphoplasmacytic infiltrate with many plasma cells Storiform Fibrosis Phlebitis Scattered eosinophils Average count of 5 HPF in the area of greatest concentration: Our case: 80 IgG4 + cells/HPF and 518 IgG + cells/HPF IgG4:IgG ratio of 15%. Normal ratio in serum is <5% Average IgG4 PCs in other inflammatory conditions <10 HPF

23. Although cut-offs well established in other organ systems, they are not well established for meningeal disease Can form a mass or a more diffuse plaque-like growth pattern. More commonly is mass forming in other organs. Highly steroid responsive Serum IgG4 levels may be helpful in some cases and should be done Hyper-eosinophilia also common DIAGNOSTIC POINTS

24. FOLLOW-UP Rx after bx: high dose steroids for about 2 months CT scans of neck, chest, abdomen negative for systemic evidence of a lymphoproliferative disorder. MRI at 2 months showed significant improvement. She was tapered from steroids subsequently due to side effects. Follow-up MRI scans show continued improvement. She is much improved clinically although she still has transverse sinus occlusion and is on warfarin.

25. PRE-RX

26. POST-RX

27. REFERENCES Smyrk TC. Pathological features of IgG4-related sclerosing disease. Curr Opin Rheumatol 2011;23(1):74-9. Cheuk W, Chan JK. IgG4-related sclerosing disease: a critical appraisal of an evolving clinicopathologic entity. Adv Anat Pathol 2010;17(5):303-32. Lindstrom KM, Cousar JB, Lopes MB. IgG4-related meningeal disease: clinico-pathological features and proposal for diagnostic criteria. Acta Neuropathol 2010;120(6):765-76. Stone JH, Zen Y, Deshpande V. IgG4 related disease. N Engl J Med 2012;366:539-51.