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Imaging spectrum of IgG4 RELATED disease involving head and neck regionMaryam gul, mdAmmar Chaudhry, mdSUNEEL MOVVA, mdSteven Carsons, MDLubaslov Woroch, mdPresentation: eEdE-33

Presntation: EE-102

1DisclosuresNo relevant disclosuresObjectivesReview 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 syndromeIntroductionIgG4-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 descriptionsAge: all ages involved; most commonly between 59-68 y/o

IntroductionInflammatory 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 diseasesIgG4 staining in inflammatory mass lesions has been proposed as a marker of lesions with an autoimmune or primary inflammatory etiologyPathogenesisEtiology: unknown, likely autoimmune trigerred molecular mimicry from certain infectious agentsSpecific auto-antigen has not been identified

IgG4- titers are not specific Can be elevated in other diseases like Castlemans disease, Churg-Strauss syndrome, etc

Clinical ManifestationsMikuliczs disease (dacryoadenitis and sialadenitis)Inflammatory orbital pseudotumorChronic Sclerosing dacroadenitisIgG4-related Otic diseaseIgG4-related hypophysitisIgG4-related pachymeningitisRiedels thyroiditisInterstitial pneumonitisAutoimmune pancreatitisIntersitital nephritisIgG4-related sclerosing cholangitisOrmonds disease (retroperitoneal fibrosis)Differential DiagnosisLymphoproliferative conditions Lymphoid hyperplasiaLymphoma (non-Hodgkins)Must exclude HIV SarcoidosisWegners granulomatosisInfectious (tuberculosis, histoplasmosis)Metastasis (melanoma, breast, lung)DiagnosisChallenge 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 diagnosisStandard H&E evaluationImmunohistochemistry offers a complimentary approach for characterization of intracranial inflammatory mass Lymphoproliferative disorders should be excluded through flow cytometry, immunohistochemistry, and gene rearrangement studies.TreatmentSystemic steroidsare first-line therapy80-85% of patients respondDramatic and rapid improvement typicalRecurrence after initial response in 25-40%

Second-line therapies for nonresponsive or refractory cases or when steroids contraindicatedLow-dose radiotherapyLong-term control rates 50% or higher20-30 Gy, 2 Gy per fractionCytotoxic chemotherapyAntimetabolite drugs (e.g., methotrexate, azathioprine)Other immunosuppressive agentsCyclosporin; monoclonal antibodies (e.g., against CD20, TN)PrognosisIntermittent disease more likely in younger patients

5-10% resolve spontaneously

Pattern of involvement affects prognosisRecurrence more likely with multifocal diseasePoor outcome more likely in diffuse diseaseSystemic 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 presentationChief Complaint: Feeling of disequilibrium and hearing lossHistory 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 F, 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 ralesHEART: S1, S2, regular rate and rhythm.ABDOMEN: Soft, nontender, nondistended. No ascites or organomegaly was noted.EXTREMITIES: No clubbing, cyanosis, or edemaMUSCULOSKELETAL: With in normal limitsLabsComprehensive 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 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.

Fig: 1Fig: 3Fig: 2PathologyH & 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 left-side facial pain and swelling along with left eye pain proptosis and pain with left eye movementIll-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 sinusThere 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 sinusThere 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 wellDifferential DiagnosisSarcoidosisHande PC, Talwar I. Multimodality imaging of the orbit. Indian J Radiol Imaging 2012;22:227-39

(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)Polyangiitis with granulomatosis (formerly Wegners Granulomatosis)

Computed tomography (CT) scans of the sinuses.A,Normal maxillary sinuses in a recently diagnosed Wegeners 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 neo-ossification of all maxillary bony structures due to chronic inflammation.

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.Ferri's Clinical Advisor 2015 505-506.e1Clinical and Imaging Features Predictive of Orbital Granulomatosis with Polyangiitis and the Risk of Systemic Involvement, 2014-06-01Z, Volume 121, Issue 6, Pages 1304-1309,PNS along V3

Perineural Spread along the left infraorbital nerve (V3)

http://radiopaedia.org/cases/kallmann-syndromeNOTE: Seizure activity in lateral olfactory area may produce "uncinate fits: hallucinations of taste & odor

Kallman syndrome is a rare genetic disorder of hypogonadotropic hypogonadism (isolated GnRH deficiency) with anosmia.

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)

46 y/o M with head trauma (Cribriform plate fx or anterior temporal lobe injury) AnosmiaPNS Tumor Pterygopalatine Fossa

RotundumPPFConclusion: 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 systemIgG4related 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 inIgG4cells, 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. IgG4related otic and orbital disease is an important consideration in patients presenting with aggressive, erosive disease of cranial and facial bones. Recognizing this presentation ofIgG4related disease is critical to prevent end-organ damageEarl therapy is appears to be more successful in achieving disease remission, decrease recurrence and improved quality of lifeConsistent with previous studies our case confirms that serumIgG4levels 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 forIgG4cells.Pseudotumor isdiagnosis of exclusionAtypical onset, poor response, or recurrence should prompt biopsy for confirmationConsider other systemic causes with bilateral, multifocal, lacrimal, or apical involvement

Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012; 366: 539551.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):136571.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: 2633.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: 2633.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, 425438 (2012). References