IgG4-Related Disease: Puzzles and Pitfalls

Transcription

1 IgG4-Related Disease: Puzzles and Pitfalls Roberto Novoa, MD Section of Dermatopathology Departments of Pathology and Dermatology Stanford University Medical Center Stanford, CA

2 Disclosures I have no relevant disclosures Consultant: Zebra Medical Technologies

3 Overview Case Criteria Pitfalls How to Proceed

4 Case 72 year-old woman with a 3-year history of pruritic rash on cheeks, neck, chest, and upper arms Treated with doxycycline, topical steroids without relief

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6 Slide consult requested by clinician

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10 Case My signout: SUPERFICIAL AND DEEP PERIVASCULAR AND PERI-ADNEXAL LYMPHOPLASMACYTIC INFILTRATES WITH EOSINOPHILS (SEE COMMENT)

11 Case Clinical Ddx Rosacea Photodrug Dermal hypersensitivity Granuloma faciale

12 Case Clinical Ddx Rosacea Photodrug Dermal hypersensitivity Granuloma faciale Histopathologic Ddx Rosacea (but bad distribution!) Dermal hypersensitivity Borrelia Granuloma faciale (no neuts!) Cutaneous lymphoid hyperplasia

13 PMH: Thyroiditis, unspecified ROS: 60 lb weight loss a/mild_spoilers_didnt_pick_up_on_this_the_first_time/

14 PMH: Thyroiditis, unspecified ROS: 60 lb weight loss a/mild_spoilers_didnt_pick_up_on_this_the_first_time/

15 Case Challenging fellowship case of patient with proptosis, weight loss, and similar-appearing biopsy specimens

16 Courtesy of Sotonye Imadojemu, MD

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19 IgG IgG4

20 After treatment Courtesy of Sotonye Imadojemu, MD

21 Back to our case Called the clinician and had a conversation Clinician thought it worth investigating Ordered outside block

22 Kappa Lambda Kappa Lambda

23 IgG

24 IgG4

25 Case 112 IgG4+ cells/hpf IgG4:IgG ratio ~70% Mixed B-cells and T-cells SPEP/UPEP negative, other labs normal Serum IgG4 301 mg/dl Diagnosis: Probable IgG4 related-disease

26 IgG4-Related Disease Chronic fibroinflammatory disease Multiple organ systems Characteristic findings Increased IgG4+ cells Corticosteroid-responsive

27 IgG4-Related Disease Stone JH et al. N Engl J Med 2012;366:

28 Pathogenesis Oligoclonal, antigen-driven immune response Expansion of plasmablasts (CD19+ CD20- CD27+ CD38+) Expansion of CD4+ cytotoxic T-cells Expansion of Tfh2 T-cells Bozzala Cassione et al. 2017

29 IgG4 disease criteria Evidence of organ involvement Pathology Lymphoplasmacytic infiltrate with eosinophils Storiform fibrosis (not everywhere) Phlebitis IgG4 predominance IgG4/IgG cells >40% Increased IgG4+ cells/ HPF Cutaneous cutoffs remain ill-defined (10? 200?) Bennett et al average of 133 IgG4+ cells/hpf (CI 33) Elevated IgG4 levels Deshpande V et al., Mod Pathol 2012

30 Cutaneous IgG4 RD- a meta-analysis Charrow et al, JAAD Cases 2 excluded 15 definite 7 probable 18 possible 16 neg for criteria 66% male Mean age: 59 Head and neck Most common systemic involvement: Head and neck (parotid, lacrimal, sialadenitis, proptosis)

31 Bennett et al (Int J Derm 2016) 79% of pts with IgG4-RD w preceding systemic dz Most common sites Salivary Lymphatic Lacrimal Orbit

32 Cutaneous IgG4-RD Tokura et al, Brit J Derm, 2014

33 Cutaneous IgG4-RD Bhabha FK et al, Australas J Derm 2016

34 Cutaneous IgG4 disease: Manifestations Tokura et al, Brit J Derm, 2014

35 Monach PA et al. N Engl J Med 2017;376:

36 IgG4 disease: Serum tests IgG4 serum: >135mg/dL is elevated elevated in 50% of pts with IgG4-RD Wide range of conditions with elevated IgG4 Wallace ZS et al. Arth Rheum 2015

37 Carruthers et al, 2015

38 IgG4 RD: Serum tests Cutoff- 135 mg/dl Prozone phenomenon in up to 26% of pts Increasing cutoff to 270 mg/dl decreased sensitivity to 35% increased specificity to 90% Our patient: 301 mg/dl Carruthers et al, 2015 Khosroshahi A et al. Arthritis Rheumatol 2014

39 IgG4-RD: Serum tests Wide variety of other changes (varying frequency) Hypergammaglobulinemia Hypocomplementemia Eosinophilia Circulating plasmablasts may be better test Flow cytometry (cutoff 900/mL) Wallace ZS et al. Ann Rheum Dis 2015

40 Cutaneous IgG4-RD: Benign Mimics Clinical Sarcoid Granuloma faciale Sjögren s disease Cutaneous lymphoid hyperplasia EGPA Rosai-Dorfman

41 Cutaneous IgG4-RD: Benign Mimics Clinical Sarcoid Granuloma faciale Sjögren s disease Cutaneous lymphoid hyperplasia EGPA Rosai-Dorfman Histopathological Cutaneous lymphoid hyperplasia Angiolymphoid hyperplasia with eosinophils Granuloma faciale Erythema elevatum diutinum

42 Pitfalls: Multicentric Castleman s Marked lymphadenopathy Much less fibrosis, glandular infiltration Thrombocytosis Elevated IL-6 Elevated CRP Disease Courtesy of Ryanne Brown, MD, MBA

43 Cutaneous Castleman s Disease Meets pathologic criteria Absent fibrosis, e/o hyper IL-6 Takeuchi M et al. Pathol Res Pract 2012

44 American Journal of Surgical Pathology. 33(11): , November Cutaneous lymphoid hyperplasia Cheuk W et al, archival CLH cases 2 w increased IgG4+ cells Limited clinical info IgG4-related Sclerosing Disease: A Potential New Etiology of Cutaneous Pseudolymphoma. Cheuk, Wah; Lee, King-Chung; Chong, Lai-Yin; Yuen, Siu-Tsan; Chan, John

45 Pitfalls: Malignant Mimics Clinical MALT lymphoma Angioimmunoblastic T-cell lymphoma CTCL variants Histopathological IgG4-restricted myeloma IgG4-restricted MZL Lowe GC et al. Int J Derm 2015

46 Pitfalls: Marginal Zone Lymphoma De Souza et al., % of cutaneous plasmacytic MZLs are IgG4 Light chain restriction Systemic MZL Lower IgG4 rate Orbital MALT lymphoma (clinical pitfall for IgG4RD Light chain restriction Clonality

47 IgG4-RD and Malignancy Malignancy 2.5x more common in IgG4-RD pts 19% lymphoma Slightly different cohort

48 Challenging patients

49 Challenging patients IgG4!!

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54 Kappa Lambda

55 IgG IgG4

56 IgG4

57 Diagnosis: Chronic actinic dermatitis

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62 IgG IgG4

63 Diagnosis: Rosacea for now

64 35 yo woman with proptosis, infiltrated plaques involving eyes, preauricular cheeks (parotid?)

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71 Diagnosis: T-cell lymphoma Work in progress

72 Conclusions 1. IgG4 disease varied morphologies, but esp think in clinical scenario with dermal nodules on face, neck, upper body 2. If thinking about CLH and pt has systemic sx, consider IgG4 3. Criteria are still evolving, but application of strict criteria probably best at present time (>100 IgG4+ cells/hpf, Ig4/IgG ratio >40%) 4. Serum IgG4 can be useful, but circulating plasmablasts may be better test 5. Thorough evaluation for malignancy 6. Beware of pitfalls!

73 References 1. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med Feb 9;366(6): doi: /NEJMra Tokura Y, Yagi H, Yanaguchi H, Majima Y, Kasuya A, Ito T, Maekawa M, Hashizume H. IgG4-related skin disease. Br J Dermatol Nov;171(5): doi: /bjd Epub 2014 Oct Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, Klöppel G, Heathcote JG, Khosroshahi A, Ferry JA, Aalberse RC, Bloch DB, Brugge WR, Bateman AC, Carruthers MN, Chari ST, Cheuk W, Cornell LD, Fernandez-Del Castillo C, Forcione DG, Hamilos DL, Kamisawa T, Kasashima S, Kawa S, Kawano M, Lauwers GY, Masaki Y, Nakanuma Y, Notohara K, Okazaki K, Ryu JK, Saeki T, Sahani DV, Smyrk TC, Stone JR, Takahira M, Webster GJ, Yamamoto M, Zamboni G, Umehara H, Stone JH. Consensus statement on the pathology of IgG4-related disease. Mod Pathol Sep;25(9): Bennett AE, Fenske NA, Rodriguez-Waitkus P, Messina JL. IgG4-related skin disease may have distinct systemic manifestations: a systematic review. Int J Dermatol Nov;55(11): Bhabha FK, Turner JJ, Bleasel K, Sladden MJ. Immunoglobulin Type Gamma 4-Related Disease Presenting with Cutaneous Plaques. Australas J Dermatol Feb;57(1): Monach PA, Stone JH, Sharma A, Nazarian RM. Case A 57-year-old woman with fatigue, sweats, weight loss, headache, and skin lesions. N Engl J Med Feb 23;376(8): Wallace ZS, Deshpande V, Mattoo H, Mahajan VS, Kulikova M, Pillai S, Stone JH. IgG4-Related Disease: Clinical and Laboratory Features in One Hundred Twenty-Five Patients. Arthritis Rheumatol Sep;67(9): Takeuchi M, Sato Y, Takata K, Kobayashi K, Ohno K, Iwaki N, Orita Y, Yoshino T. Cutaneous multicentric Castleman's disease mimicking IgG4- related disease. Pathol Res Pract Dec 15;208(12): doi: /j.prp Epub 2012 Oct Cheuk, Wah; Lee, King-Chung; Chong, Lai-Yin; Yuen, Siu-Tsan; Chan, John. IgG4-related Sclerosing Disease: A Potential New Etiology of Cutaneous Pseudolymphoma. American Journal of Surgical Pathology. 33(11): , November Lowe GC, Bogner RR, el-azhary RA, Gonzalez-Santiago TM, Kindle SA, Lehman JS, Gibson LE. Cutaneous manifestations of immunoglobulin G4- related disease: what dermatologists need to know. Int J Dermatol Apr;54(4): doi: /ijd De Souza A, Ferry JA, Burghart DR, Tinguely M, Goyal A, Duncan LM, Kutzner H, Kempf W. IgG4 Expression in Primary Cutaneous Marginal Zone Lymphoma: A Multicenter Study.Appl Immunohistochem Mol Morphol Feb 1.