pathology histopathology exam md residency

1. IgG4 Related
Diseases
Dr. Akshay Agarwal
Moderator: Dr. Ujwala M.

2. Introduction
 IgG4-related disease is a newly recognized
fibro-inflammatory condition
 Tumefactive lesions in multiple sites
 Elevated serum IgG4 concentrations
 Initially recognized in pancreas
 Known as Autoimmune Pancreatitis in 2001.
 Two types: Type 1 is now renamed as IgG4 RD

3.  Organs involved are:
 Biliary tree, salivary glands, periorbital tissues,
kidneys, lungs, lymph nodes, meninges, aorta,
breast, prostate, thyroid, pericardium and skin.
 The histopathological features bear strikingly
similar and unique histopathological
appearance.

4.  2.2 cases per 100,000
 Middle aged to elderly men with sporadic
reports of paediatric cases
 Multi-organ systemic disorder

8. Immunopathology of IgG4-RD
 IgG4 antibodies are produced after long-term
antigen exposure in response to IL-4 & IL-10.
 Complement activation
 Activate CD4+ T cells

9. Pathogenesis

10. FAB Arm Exchange

11.  Putative autoantigens have been proposed as
targets of antibody response in a proportion of
patients with IgG4 RD.
 Molecular mimicry of H. pylori and pancreatic
self-proteins has been proposed.

12. B Lymphocytes
 IgG4 RD has been associated with an
increased risk of malignant lymphoid
transformation, FISH and IHC has failed to
identify monoclonality.
 There is oligoclonal expansion of somatically
hypermutated IgG4+ B cell clones supporting
antigen-specific affinity maturation.
 CD19, CD27 & CD38 positive; CD20-

13.  Activated IgG4+ B cells and plasmablasts
indirectly activate CD4+ T cells surving as
effective antigen presenting cells.
 Extensive T helper cell dependent activation
leads to sustained myofibroblast activation &
production of profibrotic cytokines.

14. B cell depletion
 Treatment with anti-CD20 monoclonal
antibody induces a prompt clinical response
with drastic reduction in plasmablasts.
 B cell depletion abrogates the secretion of
profibrotic cytokins by pathogenic T cell
populations.

15. T Lymphocytes
 Dense fibrotic tissue and abundant IgG4+
plasma cells suggest an underlying Modified
Th2 immune response
 IL-13 & TGF-β : Deposition of extracellular
matrix by activated fibroblasts.
 IL-4 & IL-10 : Major inducer of IgG4 class
switch in naïve B Lymphocytes.

16.  IHC and molecular studies have showed
variable amounts of Th1, Th2 and T regulatory
cytokines.
 Altered IL-21 expression by follicular T helper
cells has been associated with autoantibody
production.

17. Macrophages
 Activated macrophages
 contribute to angiogenesis,
immunomodulation,
 wound-healing and fibrosis
 TGF-β and PDGF
 CD163+ macrophages correlate with tissue
fibrosis.

19. Ophthalmic IgG4-RD
 Orbital or periorbital:
 Orbital inflammatory pseudotumor
 Lacrymal Gland:
 Mikulicz’s Disease

20. Clinical Features
 indolent
 High spiking fevers absent
 Weight loss
 Long standing history of allergies in 40% of pt.
 Pseudotumor-like lesions
 Mechanical compression, fibrotic masses

21. Exophthalmos

22. haemianopsia

23. Ptosis

24. Headache

25. Scleritis

26. Xerophthalmia

27. Johann von Mikulicz-Radeck,
1888

28. Mikulicz Disease
 idiopathic, bilateral, painless, and symmetrical
swelling of the lacrimal, parotid, and
submandibular glands.
 considered as a subtype of Sjogren
Syndrome.
 The enlargement of lacrimal and salivary
glands is persistent and secretory dysfunction
is either not detectable or slight.

30. Laboratory Diagnosis
 Based solely on Histopathological
examination and clinical features
 Serological and radiological lack sensitivity
and specificity

31. Serology:
 Increase serum C-Reactive Protein
 Increase ESR
 Eosinophilia
 Increased IgE in 30%
 Increased IgG4 in 60-70% patients
 Low titer antinuclear antibody
 Positive for anti-sjogren syndrome and ANCA
implicate other autoimmune disorders.

32. Radiology
 Edema with sausage shaped pancreas

33.  PET scan identifies active inflammation

34. Histopathological Findings
 Dense storiform fibrosis
 Obliterative phlebitis
 Lymphoplasmacytic infiltrate
 Mild to moderate eosinophilic infiltrate

35. Storiform Fibrosis
 Irregularly whorled organization of collagen
bundles due to activation of myofibroblasts
following profibrotic stimuli provided by
inflammatory infiltrate

36. Storiform Fibrosis

39. Obliterative Phlebitis
 Parital / complete occlusionof the lumina of
small and medium sized veins by
lymphoplasmacytic infiltrate
 Extrinsic compression

43. Lymphoplasmacytic Infiltrate
 Polyclonal or oligoclonal B and T
lymphocytes.
 B lymphocytes tend to be organized in
germinal centers.

46. Tissue Eosinophilia and
Macrophages
 Eosinophils are positive in 50% of cases.
 Granulomas argue strongly against IgG4 RD.
 Neutrophils and Necrosis are classically
absent.

51. Treatment
 Corticosteroids
 plasmapheresis

52. Conclusion
 IgG4-related disease is a recently recognized
multiorgan system condition with pathological
features that are largely consistent across a
wide range of organ systems.
 Its presence in tissue in association with
plasma cells provides a robust biomarker for
diagnosis when interpreted in the proper
histopathological and clinical contexts.

53.  The diagnosis of IgG4-related disease requires
collaboration between the pathologist and the
treating physician.
 The diagnosis of IgG4-related disease rests on
the combined presence of the characteristic
histopathological appearance and increased
numbers of IgG4 plasma cells.
 Tissue IgG4 counts and IgG4:IgG ratios are
secondary in importance.

54. Thank You