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Imaging spectrum of IgG4 RELATED disease involving head and neck region MARYAM GUL, MD AMMAR CHAUDHRY, MD SUNEEL MOVVA, MD STEVEN CARSONS, MD LUBASLOV WOROCH, MD Presentation: eEdE-33 Disclosures No relevant disclosures Objectives Review clinicopathologic spectrum of IgG4related disease Discuss spectrum of imaging and pathologic findings in IgG4related disease in the head and neck region Review mimics with emphasis on key findings differentiating these entities Treatment, prognosis and followup recommendations for IgG4 syndrome Introduction IgG4-related disease is an increasingly recognized syndrome of unknown etiology with specific pathologic, serologic and clinical features Common shared features include mass-like swelling of the effected organ(s) with lymphoplasmacytic infiltrate enriched in IgG4-positive plasma cells Variable degree of fibrosis is seen that has a characterisitic “storiform” pattern Serum IgG4 titers are elevated in sixty-to-seventy percent of patients Inicidence and prevalence are unknown given rarity and different descriptions Age: all ages involved; most commonly between 59-68 y/o Introduction Inflammatory pseudotumor has been applied to a heterogeneous group of mass-forming lesions in various anatomic regions and organs characterized by a proliferation of fibroblasts or myofibroblasts admixed with an inflammatory infiltrate composed mainly of lymphocytes and plasma cells. sometimes used interchangeably with plasma cell granuloma and inflammatory myofibroblastic tumor (IMT), which leads to confusion both clinically and in the literature Unlike IMT, which is considered neoplastic with ALK-1 expression as a distinguishing feature, many inflammatory pseudotumors of the orbit and central nervous system likely represent a manifestation of inflammatory fibrosclerosis or idiopathic sclerosing inflammation. Analogous to retroperitoneal fibrosis, sclerosing mediastinitis, sclerosing cholangitis, Riedel sclerosing thyroidits and sclerosing pancreatitis, which have been linked to IgG4 sclerosing diseases IgG4 staining in inflammatory mass lesions has been proposed as a marker of lesions with an autoimmune or primary inflammatory etiology Pathogenesis Etiology: unknown, likely autoimmune trigerred molecular mimicry from certain infectious agents Specific auto-antigen has not been identified IgG4- titers are not specific Can be elevated in other diseases like Castleman’s disease, Churg-Strauss syndrome, etc Clinical Manifestations Mikulicz’s disease (dacryoadenitis and sialadenitis) Inflammatory orbital pseudotumor Chronic Sclerosing dacroadenitis IgG4-related Otic disease IgG4-related hypophysitis IgG4-related pachymeningitis Riedel’s thyroiditis Interstitial pneumonitis Autoimmune pancreatitis Intersitital nephritis IgG4-related sclerosing cholangitis Ormond’s disease (retroperitoneal fibrosis) Differential Diagnosis Lymphoproliferative conditions Lymphoid hyperplasia Lymphoma (non-Hodgkin’s) Must exclude HIV Sarcoidosis Wegner’s granulomatosis Infectious (tuberculosis, histoplasmosis) Metastasis (melanoma, breast, lung) Diagnosis Challenge in the diagnosis of inflammatory central nervous system and Head & Neck lesions is their relative rarity IgG4-related disease should be considered in patients with intra- or extracranial inflammatory mass lesions Biopsy should be performed to confirm the diagnosis Standard H&E evaluation Immunohistochemistry offers a complimentary approach for characterization of intracranial inflammatory mass Lymphoproliferative disorders should be excluded through flow cytometry, immunohistochemistry, and gene rearrangement studies. Treatment Systemic steroids are first-line therapy 80-85% of patients respond Dramatic and rapid improvement typical Recurrence after initial response in 25-40% Second-line therapies for nonresponsive or refractory cases or when steroids contraindicated Low-dose radiotherapy Long-term control rates 50% or higher 20-30 Gy, 2 Gy per fraction Cytotoxic chemotherapy Antimetabolite drugs (e.g., methotrexate, azathioprine) Other immunosuppressive agents Cyclosporin; monoclonal antibodies (e.g., against CD20, TNα) Prognosis Intermittent disease more likely in younger patients 5-10% resolve spontaneously Pattern of involvement affects prognosis Recurrence more likely with multifocal disease Poor outcome more likely in diffuse disease Systemic association in up to half with lacrimal disease, particularly if chronic or tumefactive Chronic sclerosing disease not as responsive, but therapy may slow progression Exclude additional organ involvement Case presentation Chief Complaint: Feeling of disequilibrium and hearing loss History of Present Illness: 48 year old male presented with intermittent ear heaviness and hearing loss in both ears for approximately 2 years. He was told he had otosclerosis leading to conductive hearing loss. Patient was referred to an ENT who performed a stapedectomy and prosthesis placement. Post op patient developed excessive proliferation of granulation tissue, canal stenosis, and had an episode of facial paresis, as well as ear pain, complete left sided hearing loss, and a feeling of disequilibrium. CT and MRI imaging revealed complete opacification of the cochlea and labyrinth, a displaced prosthesis, and erosions of the ossicular and temporal bones. He was treated with high-dose corticosteroid with mild improvement in symptoms. The patient returned to the operating room for tympanomastoidectomy. The patient was referred to Rheumatology for workup of an autoimmune process. He complains of worsening symptoms but denies pain, fevers, chills, nausea, vomiting, arthralgias and rashes. Past Medical/Surgical History:. Bilateral otosclerosis and asthma Medications: Advair 100 mcg-50 mcg/dose powder for inhalation, Cefuroxime axetil 500 mg tablet, CIPRODEX 0.3 %-0.1 % Ear Drops, Montelukast 10 mg tablet and Proventil HFA 90 mcg. Physical Exam: Patient appears well developed/well nourished and in no apparent distress. VITAL SIGNS: B/P: 128/82, pulse 92, temperature 98.5 ºF, respiratory rate 17, O2 sat of 100% on room air. HEENT: Anicteric sclera, no conjunctival pallor, difficult to visualize tympanic membrane, no nasal ulcers, no mucosal inflammation, mucosa was moist without oral ulcers. Poor dentition. numerous caries. SKIN: Warm and dry, no rashes noted. LUNGS: Clear to auscultation, no wheezing and rales HEART: S1, S2, regular rate and rhythm. ABDOMEN: Soft, nontender, nondistended. No ascites or organomegaly was noted. EXTREMITIES: No clubbing, cyanosis, or edema MUSCULOSKELETAL: With in normal limits Labs Comprehensive Metabolic Panel : Sodium 144, potassium 4.6, chloride 105, bicarb 28, BUN 15, creatinine 1.22, glucose 96. CBC : White count 7.2, hemoglobin 16.2, hematocrit 47.0, platelets 283,000. ANA/MPO/PR3/anti-smith/RNP/RF/CCP/ESR were negative. IgG was slightly low, but other Ig's normal. Ace level normal. Serum IgG: 786 (694-1618 mg/dL), serum IgA: 133 (81-463 mg/dL), serum IgM 37 ( )(48-271mg/dL) IgG subclass1: 432mg/dL (382-929mg/dL), IgG subclass2: 266mg/dL (241-700mg/dL) IgG subclass3: 77mg/dL(22-178mg/dL) IgG subclass4: 28.4mg/dL(4.8-8.6mg/dL). Quantification of serum IgG4 level was normal at 26.1 mg/dL Imaging Fig: 1 Fig: 2 Fig: 3 Coronal and Axial T1FS w/ contrast: wreveal abnormal soft tissue mass with post-contrast enhancement within the left tympanomastoid cavity and petrous apex air cells which extends into the external auditory canal. There is abnormal enhancement seen within the fundus of the left IAC and membranous labyrinth. Nerves VII and VIII complexes appear grossly intact. Abnormal signal is seen in the cochlea, vestibule and semicircular canals demonstrating T2 hypointensity and mild T1 hyperintensity with post contrast enhancement. Pathology • H & E of biopsy specimens indicated a florid inflammatory response composed of mononuclear cells with areas of fibrous reaction. • Immunohistochemically, 60 % of plasma cells stained positive for IgG4 subtype. • Immunohistochemically showing IgG4 staining. Companion Case: 58 year old female with leftside facial pain and swelling along with left eye pain proptosis and pain with left eye movement • Ill-defined hyperdense mass is seen in the left orbit with infiltration and obliteration of the intra-orbital fat. There is left eye proptosis and thickening of the myotendinous junction of the extra-ocular muscles. The mass appears to extend posteriorly and involves the cavernous sinus • There is sclerosis of the orbital walls, ipsilateral maxilla, mandible and skull base • There is suggestion of extension of this mass in the left temporal fossa as well. • Ill-defined hyperdense mass is seen in the left orbit with infiltration and obliteration of the intra-orbital fat. There is left eye proptosis and thickening of the myotendinous junction of the extra-ocular muscles. The mass appears to extend posteriorly and involves the cavernous sinus • There is sclerosis of the orbital walls, ipsilateral maxilla, mandible and skull base • There is suggestion of extension of this mass in the left temporal fossa as well. • Ill-defined hyperdense mass is seen in the left orbit with infiltration and obliteration of the intra-orbital fat. There is left eye proptosis and thickening of the myotendinous junction of the extra-ocular muscles. The mass appears to extend posteriorly and involves the cavernous sinus • There is sclerosis of the orbital walls, ipsilateral maxilla, mandible and skull base • There is suggestion of extension of this mass in the left temporal fossa as well Differential Diagnosis Sarcoidosis (A-D): Magnetic resonance images show normal intraorbitaland intraocular contents (globe) in axial and coronal T1WI (A), (C) withbetter anatomic detail, T2WI (B) T2WI (D) with more contrast resolutionfor the soft tissues. Apex is very well visualized (asterisk) Hande PC, Talwar I. Multimodality imaging of the orbit. Indian J Radiol Imaging 2012;22:227-39 Polyangiitis with granulomatosis (formerly Wegners Granulomatosis) Computed tomography (CT) scans of the sinuses . A, Normal maxillary sinuses in a recently diagnosed Wegener’s granulomatosis (WG) patient. B, Sinus CT scan of a patient with long-standing WG: nasal septal deviation to the left, destruction of the medial walls of the right maxillary sinus, opacification of both sinuses with soft tissue densities (arrows), and neoossification of all maxillary bony structures due to chronic inflammation. Ferri's Clinical Advisor 2015 505-506.e1 Clinical and Imaging Features Predictive of Orbital Granulomatosis with Polyangiitis and the Risk of Systemic Involvement, 2014-0601Z, Volume 121, Issue 6, Pages 1304-1309, A, Soft-tissue axial computed tomography showing left proptosis due to a soft-tissue mass extending along the medial wall and floor of the left orbit, occupying the extraconal and intraconal compartments, with involvement of the neighboring extraocular muscles. Note the site of prior left dacryocystorhinostomy ( arrow). B, Coronal reformats show the soft tissue mass extending along the orbital floor and medial wall and completely enveloping the inferior rectus and inferior aspect of the medial rectus. The infraorbital groove ( arrow) is widened and filled with enhancing soft tissue density material, suggestive of infiltration. PNS along V3 Perineural Spread along the left infraorbital nerve (V3) Esthesioneuroblastoma arises from the olfactory epithelium in the nasal vault; key dx feature is cyst at tumor-brain junction best seen on post-contrast images (red arrow) Kallman syndrome is a rare genetic disorder of hypogonadotropic hypogonadism (isolated GnRH http://radiopaedia.org/cases/kallmann-syndrome deficiency) with anosmia. NOTE: Seizure activity in lateral olfactory area may produce "uncinate fits: hallucinations of taste & odor 46 y/o M with head trauma (Cribriform plate fx or anterior temporal lobe injury) Anosmia PNS Tumor – Pterygopalatine Fossa PPF Rotundum Conclusion: IgG4 related disease First, recognized in the early 2000s for its presentation as a form of autoimmune pancreatitis it is now known that the disease can affect nearly every organ system IgG4 related disease is a systemic inflammatory process with a spectrum of presentation depending on specific organ involvement. Significant proportion of patients have years of asymptomatic disease involvement until they present with signs of organ injury secondary to compressive mass lesions. Affected organs share histopathologic findings characterized by lymphoplasmacytic infiltrate rich in IgG4 cells, and fibrosis in a “storiform” pattern resulting in tumor like swelling. Otic involvement is scarcely reported in the literature perhaps because affected patients are labeled as having an “inflammatory pseudotumor”. IgG4 related otic and orbital disease is an important consideration in patients presenting with aggressive, erosive disease of cranial and facial bones. Recognizing this presentation of IgG4 related disease is critical to prevent end-organ damage Earl therapy is appears to be more successful in achieving disease remission, decrease recurrence and improved quality of life Consistent with previous studies our case confirms that serum IgG4 levels alone are a poor diagnostic test for this disease process. Rather, the serum levels are best utilized in conjunction with clinical suspicion on the basis of history and physical exam, imaging findings, and histopathological findings including immunohistochemical staining for IgG4 cells. Pseudotumor is diagnosis of exclusion Atypical onset, poor response, or recurrence should prompt biopsy for confirmation Consider other systemic causes with bilateral, multifocal, lacrimal, or apical involvement References Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012; 366: 539–551. Saeki T, Nishi S, Ito T, Yamazaki H, Miyamura S, Emura I, et al. Renal lesions in IgG4-related systemic disease. Intern Med. 2007;46(17):1365– 71. D Takagi, Y Nakamaru, S Fukuda et al. Otologic Manifestations of Immunoglobulin G4-Related Disease. Annals of Otology, Rhinology. 2014 Mar 28. Wallace ZS, Khosroshahi A, Jakobiec FA, Deshpande V, Hatton MP, Ritter J, et al. IgG4-related systemic disease as a cause of “idiopathic” orbital inflammation, including orbital myositis, and trigeminal nerve involvement. Surv Ophthalmol 2012; 57: 26–33. Wallace ZS, Khosroshahi A, Jakobiec FA, Deshpande V, Hatton MP, Ritter J, et al. IgG4-related systemic disease as a cause of “idiopathic” orbital inflammation, including orbital myositis, and trigeminal nerve involvement. Surv Ophthalmol 2012; 57: 26–33. Rauch SD, Ruckenstein MJ. Autoimmune inner-ear disease. In: Cummings CS, Haughey BH, Thomas JR, Harker LA, Flint PWCummings otolaryngology: head and neck surgery. 4th ed. Philadelphia (PA): Elsevier Mosby; 2005. pp. 2926-2933. Guma, M. & Firestein, G. S. IgG4-related diseases. Best Pract. Res. Clin. Rheumatol. 26, 425–438 (2012).