LASOP Resident/Fellow

Symposium 2012

Kiran Qidwai, MD (PGY-2)

LAC+USC Medical Center

Clinical History

• 62 year old female presented to ENT

clinic with a right submandibular mass

• 4 years ago parotidectomy showed

reactive lymphoid hyperplasia

• 2 years ago lacrimal gland biopsy

showed reactive lymphoid hyperplasia

Current Physical Exam Findings

• Non-tender, firm right submandibular lymph nodes

• Bilateral cervical lymphadenopathy

• Left parotid enlargement

CBC Results

• WBC: 5.2 K/cumm

• Hgb: 13.4 g/dL

• Plt: 386 K/cumm

Differential:

• Segs: 45.3%

• Lymphs: 37.8%

• Monos: 10.8%

• Eos: 5.0%

• Basos: 1.1%

Imaging Studies

Submandibular Gland

CD 138

IgG

IgG4

Diagnosis??

IgG4 Related Disease

IgG4-Related Disease

• “Newly recognized fibroinflammatory

condition characterized by tumefactive

lesions, a dense lymphoplasmacytic

infiltrate rich in IgG4-positive plasma

cells, storiform fibrosis, and, often but

not always, elevated serum IgG4

concentrations”.

Stone JH, et al. IgG4-Related Disease, N Engl J Med 2012; 366: 539-551.

IgG4-Related Disease

• First reported in autoimmune pancreatitis

• Recognized as systemic condition in 2003,

when extrapancreatic manifestations

identified in patients with autoimmune

pancreatitis.

Stone JH, et al. IgG4-Related Disease, N Engl J Med 2012; 366: 539-551.

Solitary or Multiorgan

Involvement

• Biliary tree (Sclerosing

Cholangitis)

• Salivary glands

(Mikulicz’s Disease)

• Periorbital tissue

(Sclerosing

Dacryoadenitis)

• Soft tissue

(Retroperitoneal

Fibrosis)

• Lymph node

• Meninges

• Aorta

• Breast

• Prostate

• Thyroid

• Pericardium

• Skin

• Lung

• Kidney

Lacrimal Gland Biopsy

(2010)

Immunohistochemistry

CD 138

IgG

IgG4

Parotidectomy

(2008)

Immunohistochemistry

CD 138

IgG

IgG4

Epidemiology

• Male predominance; questionable

• Median age: 50 (range 12-83)

• Incidence: 2.63-10.2/million people (Japan)

• Sub-acute

• Often identified incidentally

Associated Laboratory Findings

• Elevated serum IgG and/or IgG4

• Elevated IgE

• Antinuclear Antibodies (ANA)

• Rheumatoid Factor

Additional Lab Results

• ANA screen: Pos

• RF: 74 IU/mL (< 14)

• Immunoglobulins:

– IgG: 1073

– IgM: 57

– IgA: 65

– IgE: 45

IgG subclass (mg/dL)

• IgG 1: 893

• IgG 2: 195

• IgG 3: 84

• IgG 4: 49.4*

*Normal in this case

Clinical Features

• Tumefactive lesions mimicking

malignancy

• Allergic Disease

Allergic Disease and IgG4

• Common – 40%

–Asthma

–Chronic Sinusitis

–Atopy

–Eczema

–Mild Eosinophilia

Diagnostic Criteria

• Histopathologic features

• Immunohistochemical features

Histopathologic Features

• Inflammatory infiltrate composed of

mixture of T and B cells

• Stromal/vascular proliferation

• Polyclonal light chain expression

• Late phase of organ involvement has

fewer plasma cells and more fibrosis

Histologic Patterns

in Lymph Nodes

• Multicentric Castleman disease-like

• Follicular hyperplasia

• Interfollicular expansion

• Progressive transformation of germinal

centers

• Inflammatory pseudotumor-like areas

Histologic Features

in Lymph Nodes

• Dense lymphoplasmacytic infiltrate

• Perifollicular granulomas

• Mild-to-moderate eosinophil infiltrate

• Capsular and interfollicular fibrosis

with storiform pattern

Histologic Features

in Lymph Nodes

• Increase in intrafollicular plasma cells

• Increase in interfollicular plasma cells

–Cytologically mature

–Russell bodies and Mott cells

• Prominent Immunoblasts

Histologic Features

in Exocrine Glands

• Dense lymphoplasmacytic infiltrate

• Obliterative phlebitis

• Mild-to-moderate eosinophil infiltrate

• Storiform fibrosis with parenchymal

damage

Histologic Features

in Exocrine Glands

• Infiltrate often surrounds ductal structures

• Obliterative phlebitis often present in

pancreas and submandibular glands, less

often in lacrimal glands and not seen in

lymph nodes.

Immunohistochemical

Diagnostic Criteria

• IgG4 plasma cells > 50 cells in a

40X high-power field AND

• > 40% of IgG-positive plasma cells

positive for IgG4

Serum IgG4

• Elevated IgG4 serum level (> 135 mg/dl)

is a helpful but nonspecific diagnostic

marker

• Also seen in:

–Pancreatic Adenocarcinoma

–Primary Sclerosing Cholangitis

– Inflammatory Bowel Disease

–Hashimoto’s Thyroiditis

–Atopic Dermatitis

Differential Diagnosis

in Lymph Nodes

• Non-Hodgkin Lymphoma

• Follicular Hyperplasia

• Nonspecific Interfollicular Hyperplasia

• Progressive Transformation of

Germinal Centers

Differential Diagnosis

in Lymph Nodes

• Plasma Cell Castleman’s Disease

• Infectious Lymphadenitis

–Luetic Lymphadenitis

• Autoimmune Lymphadenitis

–Rheumatoid Lymphadenitis

Differential Diagnosis

in Salivary Glands

• Chronic Sialadenitis

• Sjogren’s Syndrome

• Lymphoepithelial Sialadenitis

Treatment Options

• Surgical Excision

• Corticosteroids

• Azathioprine

• Mycophenolate mofetil

• Methotrexate

• Rituximab

Summary

• IgG4-related disease is a newly

described clinicopathologic entity

• Diagnostic criteria and

clinicopathologic manifestations

continue to evolve

• Diagnosis is important due to marked

steroid responsiveness in most cases

References

• Divatia M, Kim SA, et al: IgG4-Related Sclerosing Disease, an Emerging Entity: A Review of a Multi-System Disease, Yonsei Med J 2012; 53 (1):15-34.

• Geyer JT, Ferry JA, et al: Chronic Sclerosing Sialadenitis (Kuttner Tumor) Is an IgG4-associated Disease, Am J Surg Pathol 2010; 34:202-210.

• Geyer JT, Deshpande V: IgG4-associated sialadenitis, Current Opinion in Rheumatology 2011; 23:95-101.

• Go H, Kim JE, et al: Ocular adnexal IgG4-related disease: comparative analysis with mucosa-associated lymphoid tissue lymphoma and other chronic inflammatory conditions, Histopathology 2012; 60:296-312.

• Grimm K, Barry TS, et al: Histopathological findings in 29 lymph node biopsies with increased IgG4 plasma cells, Modern Pathology 2012; 25: 480-491.

• Kamisawa T, Okamoto A: IgG4-related sclerosing disease, World J Gastroenterol 2008; 14 (25): 3948-3955.

• Masaki Y, Kurose N, et al: IgG4-Related Disease: A Novel Lymphoproliferative Disorder Discovered and Established in Japan in the 21st Century, J Clin Exp Hematopathol May 2011; 51 (1): 13-20.

• Siddiqi IN, Brynes RK, et al: Perifollicular granulomatous inflammation in reactive lymph nodes: a possible morphologic marker for IgG4 plasmacytosis, J of Hematopathol 2011; 4: 207-214.

• Stone JH, Zen Y, et al: IgG4-Related Disease, N Eng J Med 2012; 366: 539-551.