Table 1.
The spectrum of IgG4-related disorders (IgG4-RD): synopsis of clinical manifestations, differential diagnoses, pathology features and therapeutic approaches. A consensus on hystopathological features diagnostic for IgG4-RD has not been reached for all possible affected organs
| Organ involvment (Ref.) | Nomenclature (previous name) | Clinical presentation |
|---|---|---|
| Head and Neck | ||
| Orbits and periorbital tissue 31–33 | IgG4-related orbital disease (orbital inflammatory pseudotumour) | Exophthalmos, haemianopsia, ocular movement restriction, ptosis, headache, scleritis, xerophthalmia |
| Salivary glands and lacrymal glands 34,35 | IgG4-related sialoadenitis (Mikulicz’s disease, Kuttner’s tumour) | Parotid or submandibular gland swelling, xerostomia |
| Thyroid gland 19 | IgG4-related thyroiditis (Riedel’s rhyroiditis) | Neck pressure, neck mass, malaise, recurrent laryngeal nerve palsy, hypothyroidism |
| Ear, nose and throat 17,36 | IgG4-related sinusitis/midline destructive lesion/pharyngitis | Nasal crusting, nasal obstruction, rhinorrhoea, polyposis, sinusitis, nasal septum perforation, laryngeal obstruction, middle ear effusion |
| Thorax | ||
| Lungs 11,12 | IgG4-related lung disease | Cough, sputum, dyspnoea, chest pain |
| Pleura 12 | IgG4-related pleural disease | Chest pain, dyspnoea, pleural effusion |
| Mediastinum 46 | IgG4-related mediastinitis (fibrosing mediastinitis) | Mediastinal mass, compression of mediastinal structures, dyspnoea, chest pain |
| Breast 50 | IgG4-related mastitis | Painless breast mass |
| Abdomen and pelvis | ||
| Retroperitoneum 27–30 | IgG4-related retroperitoneal fibrosis (Ormond’s disease) | Back/flank pain, leg oedema, hydronephrosis, deep venous thrombosis, varicocele |
| Pancreas 1,21,22 | IgG4-related autoimmune pancreatitis (type1 autoimmune pancreatitis) | Obstructive jaundice, diabetes mellitus, abdominal pain, pale stool, malabsorption |
| Biliary tree/gallbladder 23,24 | IgG4-related sclerosing cholangitis | Jaundice, weight loss, abdominal pain |
| Liver 24 | IgG4-related hepatitis (hepatic inflammatory pseudotumour) | Mainly asymptomatic, transaminitis, hepatic mass |
| Kidney 37–39 | IgG4-related tubule-interstitial nephritis/glomerulonephritis | Elevated serum creatinine, proteinuria, haematuria, nephritic/nephrotic syndrome |
| Gastrointestinal tract 49 | IgG4-related gastrointestinal disease | Epigastric pain, chronic/acute abdominal pain, intestinal obstruction or dysmotility, nausea |
| Mesentere 47 | IgG4-related sclerosing mesenteritis | Abdominal pain, abdominal mass, vomiting, nausea |
| Prostate 44 | IgG4-related prostatitis | Mass, lower urinary tract symptoms, dysuria |
| Testis 45 | IgG4-related epididymo-orchitis (testicular inflammatory pseudotumour) | Scrotal mass, scrotal pain |
| Nervous system | ||
| Central nervous system 43 | Dementia, hemiparesis, multi-focal neurological defects | |
| Pituitary gland 14 | IgG4-related hypophysitis | Hypopituitarism, diabetes insipidus, headache |
| Peripheral nerves 42 | IgG4-related neuropathy | Sensory-motor polyneuropathy, multiplex mononeuritis, perineural mass |
| Meninges 15,16 | IgG4-related pachymeningitis (hypertrophic pachymeniningitis) | Headache, cranial nerve palsies, vision disturbance, motor weakness, limb numbness, sensorineural hearing loss, seizures |
| Cardiovascular system | ||
| Heart and pericardium 41 | IgG4-related cardiac disease | Acute chest pain (coronary syndrome), dyspnoea, pericardial rub |
| Aorta 30,40 | IgG4-related periaortitis (chronic periaortitis/inflammatory aortic aneurism) | Back pain, leg oedema, bruits, acute aneurysm rupture |
| Lymph nodes 13 | IgG4-related lymphadenopathy | Usually asymptomatic, lymph node enlargement |
| Skin 18 | IgG4-related skin disease | Skin plaques, subcutaneous nodules, brown papules, dermatitis |
| Bone 48 | IgG4-related disease of the bone | Headache, tinnitus, skull base destructive lesion, tumefactive sinus lesion |
| Differential diagnoses | Pathology features: IgG4/HPF diagnostic for IgG4-RD*† | Therapeutic strategies |
|---|---|---|
| Lymphoma–granulomatosis with polyangiitis–sarcoidosis–Graves’ orbitopathy, Sjögren’s syndrome | >10/HPF† | GC–MTX–CTX–RTX–BTZ–surgery |
| Lymphoma–Sjögren’s syndrome–sialodocholithiasis–sarcoidosis | >100/HPF* | GC–AZA–MTX–RTX |
| Thyroid lymphoma–differentiated thyroid carcinoma–other malignancies | >10/HPF† | GC–MTX–RTX |
| Allergic disease–Churg–Strauss syndrome–granulomatosis with polyangiitis–chronic infections–sarcoidosis | >10/HPF† | GC |
| Malignancy–sarcoidosis–granulomatosis with polyangiitis–infections–interstitial lung disease–inflammatory miofiroblastic tumour–Churg–Strauss syndrome | >50/HPF (surgical specimen) >20/HPF (biopsy)* | GC–AZA–CTX–RTX–BTZ |
| Mesothelioma–infections | >50/HPF* | GC |
| Lymphoma–sarcoidosis–histoplasmosis–malignancies–mycobacterial infection | >10/HPF† | GC |
| Malignancies–mastitis | >10/HPF† | GC–surgery |
| Lymphoma–sarcoma- Erdheim–Chester disease–periaortitis–idiopathic retroperitoneal fibrosis | >30/HPF* | GC–AZA–MMF–RTX |
| Pancreatic cancer–Type II autoimmune pancreatitis | >50/HPF (surgical specimen) >10/HPF (biopsy)* | GC–MTX–AZA–RTX |
| Pancreatic cancer–cholangiocarcinoma–primary sclerosing cholangitis | >50/HPF (surgical specimen) >10/HPF (biopsy)* | GC–AZA–MMF–RTX |
| Cholangiocarcinoma–hepatocellular carcinoma–autoimmune hepatitis | >50/HPF (surgical specimen) >10/HPF (biopsy)* | GC–RTX |
| Lymphoma–renal-cell carcinoma–drug-induced tubulointerstitial nephritis–vasculitis–systemic lupus erythematosus | >30/HPF (surgical specimen) >10/HPF (biopsy)* | GC–surgery |
| Malignancies–GERD | >10/HPF† | GC |
| Lymphoma–fibromatosis–peritoneal carcinosis | >10/HPF† | GC |
| Benign prostatic hypertrophy–malignancies–infections | >10/HPF† | GC |
| Seminoma–lymphoma–inflammatory miofibroblastic tumour | >10/HPF† | Surgery |
| Central nervous system vasculitis–infections–malignancies | >10/HPF† | GC |
| Neoplasms–histiocytosis–primary hypophisytis–sarcoidosis | >10/HPF† | GC |
| POEMS syndrome–metabolic neuropathy–vasculitis–other demyelinating neuropathies | >10/HPF† | GC |
| Chronic infections–lymphoma–Langherhans-cell histiocytosis–giant-cell arteritis–sarcoidosis–idiopathic hypertrophic pachymeniningitis | >10/HPF* | GC–CTX–MTX–RTX |
| Infections–inflammatory pericarditis–cardiac mixoma–acute coronary syndrome | >10/HPF† | GC |
| Takayasu arteritis–giant cell arteritis–lymphoma–infectious aortitis–sarcoidosis–histiocytosis | >50/HPF* | GC–MTX–RTX |
| Multi-centric Castleman disease–lymphoma–systemic lupus erythematosus–sarcoidosis–infections | >100/HPF* | GC–RTX |
| Cutaneous lymphoma–drug eruption–psoriasis vulgaris–multi-centric Castleman disease | >200/HPF* | GC–RTX |
| Malignancy–osteomielitis | >10/HPF† | GC |
For the organs included in the ‘Consensus Statement on the pathology of IgG4-RD’3* a ‘highly suggestive’ diagnosis of IgG4-RD requires (i) specific cut-offs of IgG4+ plasma cells/high-power field (HPF)*, (ii) an IgG4+/IgG+ plasma cell ratio > 40% and (iii) two or more of the following histological features: dense lymphoplasmacytic infiltrate, storiform fibrosis and obliterative phlebitis. For the organs not included in the ‘Consensus Statement’, ‘Comprehensive diagnostic criteria’4† are still adopted. In this case, a ‘definite’ diagnosis of IgG4-RD requires (i) an infiltration of > 10 IgG4+ plasma cells/HPF† and an IgG4+/IgG+ plasma cells ratio > 40%, together with (ii) diffuse/localized swelling or masses in single or multiple organs and (iii) serum IgG4 concentrations > 135 mg/dl. Abbreviations: glucocorticoids (GC: 0·5–1 mg/kg/day); methotrexate (MTX: 10–20 mg/week); cyclophosphamide (CTX: 500–1200 mg/m2/month); rituximab (RTX: 1000 mg in two doses 15 days apart); azathioprine (2–2·5 mg/kg/day); mycophenolate mofetil (MMF: 750–1000 mg twice daily); bortezomib (BTZ: 1·5 mg/m2/week). IgG4-RD = immunoglobulin G4-related disorders; HPF = high-power field; GERD = gastroesophageal reflux disease.