The Laryngoscope C 2014 The American Laryngological, V
Rhinological and Otological Society, Inc.
Systematic Review
Sinonasal and Ventral Skull Base Inflammatory Pseudotumor: A Systematic Review Stuti V. Desai, BA; Eleonora F. Spinazzi, BA; Christina H. Fang, BS; Grace Huang, BS; Senja Tomovic, MD; James K. Liu, MD, FACS; Soly Baredes, MD, FACS; Jean Anderson Eloy, MD, FACS Objectives/Hypothesis: Inflammatory pseudotumor is a benign idiopathic inflammatory process often misdiagnosed as an infection or neoplasm. This review analyzes all reported cases of sinonasal and ventral skull base inflammatory pseudotumor to date, and provides a framework for evaluation and management of this uncommon condition. Data Sources: MEDLINE/PubMed database. Review Methods: A search for articles related to sinonasal and ventral skull base inflammatory pseudotumor, along with bibliographies of those articles, was performed. Demographics, presentation, radiographic findings, treatment, follow-up, and outcome were analyzed. Results: Thirty-three articles were reviewed, including a total of 87 patients. The most common presenting symptom was vision change (58.6%). Sinonasal and ventral skull base inflammatory pseudotumor was found in the cavernous sinus in 46.0% of cases. The lesion appeared isointense (66.7% of cases) and homogeneously enhancing on T1-weighted magnetic resonance imaging (MRI), whereas it appeared hypointense on T2-weighted MRI in 90.7% of cases. Inflammatory pseudotumor appeared hyperdense on computed tomography in 78.9% of cases. Histopathological analysis of biopsied specimens revealed presence of inflammatory cells (94.4%) and fibrosis (80.3%). Corticosteroids alone were the most common treatment modality (55.2%), resulting in disease-free patients in 22.9% of cases over a median follow-up period of 17.6 months. Surgical management alone was uncommon (8.0%), but showed high success rate (57.1%). Conclusion: This review is the most comprehensive analysis of sinonasal and ventral skull base inflammatory pseudotumor to date. Radiologic findings and histopathological analysis are essential for diagnosis. Corticosteroids are the most common treatment modality. Surgery, although uncommon, appears to be an efficacious treatment modality. Key Words: Inflammatory pseudotumor, sinonasal, ventral skull base, sinonasal skull base inflammatory pseudotumor, sinonasal skull base inflammatory myofibroblastic tumor, ventral skull base pseudotumor, skull base inflammatory myofibroblastic tumor, head and neck inflammatory pseudotumor, skull base surgery, endoscopic skull base surgery. Level of Evidence: N/A Laryngoscope, 00:000–000, 2014
INTRODUCTION Inflammatory pseudotumor (IPT), also previously referred to as inflammatory myofibroblastic tumor, is an idiopathic non-neoplastic inflammatory process. Clinically, the lesion bears a striking resemblance to malig-
Accepted for presentation at the 2015 Combined Sections Meeting of the Triological Society, San Diego, CA, January 22–24, 2015. The authors have no funding, financial relationships, or conflicts of interest to disclose. Editor’s Note: This Manuscript was accepted for publication on October 1, 2014. From the Department of Otolaryngology–Head and Neck Surgery (S.V.D., E.F.S., C.H.F., G.H., S.T., J.K.L., S.B., J.A.E.); the Department of Neurological Surgery (J.K.L., J.A.E.) and the Center for Skull Base and Pituitary Surgery, Neurological Institute of New Jersey (J.K.L., S.B., J.A.E.), Rutgers New Jersey Medical School, Newark, New Jersey, U.S.A Send correspondence to Jean Anderson Eloy, MD, FACS, Professor and Vice Chairman, Director, Rhinology and Sinus Surgery, Director, Otolaryngology Research, Co-Director, Endoscopic Skull Base Surgery Program, Department of Otolaryngology–Head and Neck Surgery, Rutgers New Jersey Medical School, 90 Bergen St., Suite 8100, Newark, NJ 07103. E-mail: [email protected] DOI: 10.1002/lary.24993
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nancy if not properly scrutinized, which frequently leads to delay in proper diagnosis and management.1 Inflammatory pseudotumor is relatively rare in the head and neck, where it most commonly affects the orbit.2,3 Sinonasal and ventral skull base involvement of IPT is uncommon; understanding its clinical presentation, imaging characteristics, and histopathology is crucial to proper diagnosis and management. These attributes of IPT of the paranasal sinuses and skull base are currently ill-defined, with an apparent lack of standard of treatment in the literature. This study is the first systematic review of reported cases of sinonasal and ventral skull base IPT aiming to determine trends in presentation, diagnostic modalities, treatment modalities, and patient outcome.
MATERIALS AND METHODS A systematic review of the published literature on sinonasal and ventral skull base IPT was performed, which qualified as “nonhuman subject research” as per protocol of the Institutional Review Board of Rutgers New Jersey Medical
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Patients were male in 53 cases (60.9%) and female in 34 cases (39.1%). Age and gender were reported for all 87 patients. Presenting symptoms were included in all 87 cases with an average duration of 19.0 months (ranging from 1 week to 10 years). Fifty-one patients (58.6%) presented with vision changes, of which 22 (43.1%) reported vision loss and 29 (56.9%) suffered from diplopia. The second most common presenting symptom was headache (39 cases, 44.8%). Facial pain (20 cases, 23.0%), ptosis (17 cases, 19.5%), proptosis (12 cases, 13.8%), hearing loss (11 cases, 12.6%), and facial numbness (11 cases, 12.6%) were also common presenting symptoms. Inflammatory pseudotumor of the ventral skull base was most commonly located in the cavernous sinus (40 cases, 46.0%) and the orbit (28 cases, 32.2%). The middle cranial fossa was also frequently affected (21 cases, 24.1%). Inflammatory pseudotumor extended into the brain in nine cases (10.3%). Cranial nerve (CN) palsy was one of the most prevalent presenting symptoms affecting 45 of 57 cases (78.9%), with CN VI (44.4%), CN V (42.2%), and CN III (37.8%) being the most affected. Further details of demographics and IPT specifics are presented in Table II. Although associated past medical conditions were reported in only 18 cases, the most common were diabetes mellitus (DM) (10 cases, 55.6%), chronic otitis media (4 cases, 22.2%), and chronic rhinosinusitis (2 cases, 11.1%) (Table II).
Fig. 1. Flow diagram of included and excluded studies. IPD 5 individual patient data; IPT 5 inflammatory pseudotumor. School, Newark, New Jersey, and did not require approval. A literature search was performed using the MEDLINE and PubMed search engines for the following keywords: “inflammatory pseudotumor skull base” and “inflammatory myofibroblastic tumor skull base.” Search results were confined to articles in the English language and articles whose full text was obtainable. Literature that did not pertain to IPT of the sinonasal and ventral skull base or did not disclose individual patient data was excluded (Fig. 1). For the purposes of this study, the sinonasal tract and ventral skull base were defined as areas of the skull base that can be accessed endoscopically. Figure 2 maps the regions of the skull base that were considered sinonasal and ventral skull base in this review. An attending pathologist, radiologist, and endoscopic skull base surgeon were consulted with questions regarding the inclusion or exclusion of cases based on anatomical location, histopathology, or radiology. Additional articles that did not appear in our original search were obtained from a screen of the bibliographies of the initial articles. A total of 33 relevant articles with 87 patient cases were reviewed (Table I). The following data were extracted: patient demographics, presentation, associated pathology, imaging, histopathology, treatment, follow-up, recurrence, and final outcome of disease. Data analysis was performed using Microsoft Excel (Microsoft Corporation, Redmond, WA).
RESULTS Patient Demographics The average age of the individual patients in this review was 46.7 years, with a range of 4 to 81 years. Laryngoscope 00: Month 2014
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Radiographic Imaging The use of imaging as a diagnostic tool was reported in 80 of 87 cases (92.0%). The most common imaging techniques used for radiologic analysis were magnetic resonance imaging (MRI) (68 of 80 cases, 85.0%) and computed tomography (CT) (56 of 80 patients, 70.0%). Intensity of signal on T1-weighted (T1w) and T2-weighted (T2-w) MRI was reported in 45 cases and 43 cases, respectively. Analysis shows that in 30 of 45 cases (66.7%), the IPT lesion appears as isointense on T1-w compared to gray matter; whereas it appears hypointense on T2-w in 39 of 43 cases (90.7%). Inflammatory pseudotumor was enhanced on T1-w images in 51 of 54 reported cases (94.4%), especially when located in the cavernous sinus (38 of 40 masses in the cavernous sinus enhanced, 95.0%). Eighteen cases reported the pattern of IPT enhancement on T1-w images, which was generally described as confluent and homogeneous (14 of 18 cases, 77.8%). Enhancement on T2-w images followed a similar pattern with 31 of 37 cases (83.8%) showing enhancement, which was also uniformly homogeneous in 13 of 18 cases (72.2%). Although density of the IPT on CT was reported in only 19 cases, it commonly appeared hyperdense (15 of 19 cases, 78.9%) compared to gray matter. Enhancement of the IPT on CT was observed in 33 of 39 cases (84.6%), and it was mostly homogeneous (5 of 7 cases, 71.4%) (Table III). Twenty-three cases reported bony changes, of which 20 cases (87.0%) were identified as bony erosion. Extension of IPT into the meninges and brain was observed in 26 of 87 (29.9%) and nine of 87 (10.3%) cases, respectively. Desai et al.: Skull Base Inflammatory Pseudotumor
Fig. 2. The outlined areas of the axial (A) and sagittal (B) scans and the coronal (C) CT scans refer to the regions of the skull base that were considered endoscopically accessible, and thus the sinonasal and ventral skull base for this study. The coronal CT (C) depicts a heat map for the areas of the ventral skull base most commonly affected by inflammatory pseudotumor.
Biopsy and Pathology Inflammatory pseudotumor was reported to have been biopsied in 79 of 87 cases (90.8%), with an average of 1.3 biopsies performed per patient. The type of biopsy was specified only in 54 of 79 cases (68.4%), and the predominantly chosen approach was transnasal (27 of 54 biopsies, 50.0%), followed by open (14 of 54 biopsies, 25.9%), transoral (8 of 54 biopsies, 14.8%), percutaneous (4 of 54 biopsies, 7.4%), and transorbital (1 of 54 cases, 1.9%). Histopathological data were reported only in 71 cases (89.9%); analysis revealed infiltration of inflammatory cells in 67 of 71 cases (94.4%) that was associated with fibrosis in 57 of 71 cases (80.3%). No biopsied lesions were positive for fungi or bacteria, and cellular mitosis/ cellular atypism was reported in two of 58 cases (3.4%). Serologic tests for Epstein-Barr Virus (EBV), herpes human virus-8 (HHV-8), and immunoglobulin G4 (IgG4) were performed in a minority of patients. A total of four patients were tested for EBV, and only one resulted positive. None of the two patients that were tested for HHV8 resulted positive and 11 of 13 patients (84.6%) tested for the presence of IgG4 resulted positive for the antibody.
Treatment Treatment approach was reported in all cases and included surgery, corticosteroids, antibiotics, other immunosuppressive therapy, or a combination of these Laryngoscope 00: Month 2014
modalities. The predominant treatment strategy was high-dose corticosteroids alone (48 of 87 cases, 55.2%). Corticosteroids in combination with radiotherapy were the second most common treatment modality, applied to eight of 87 cases (9.2%). Surgical treatment alone was used in seven of 87 cases (8.0%) or in combination with other treatment modalities in nine of 87 cases (10.3%). Immunosuppressive treatment alone was comprised of cyclophosphamide and/or a-interferon and applied to two of 87 patients (2.3% of cases), sometimes in conjunction with corticosteroids (3 patients, 3.4%) (Table IV). The average follow-up among reported cases was 17.6 months. Only 59 of 87 cases reported patient progress at first follow-up. Twenty-two of 59 patients (37.3%) were asymptomatic, and 18 of 59 patients (30.5%) showed improvement at first follow-up. Recurrence of disease at first follow-up was observed in five of 59 patients (8.5%), four of whom were treated initially with corticosteroids alone. Four of 59 patients (6.8%) showed stable symptoms, and two of 29 patients (6.8%) were dead of disease. Of the 62 patients whose first follow-up was reported, only 13 had a documented second follow-up after a mean time of 12.1 months from their first visit. Whereas most of the patients were reported as stable, improved, or asymptomatic (9 of 13 cases, 69.2%), two of the 13 patients (15.4%) showed worsening of symptoms, and another two patients showed recurrence of disease (15.4%). Desai et al.: Skull Base Inflammatory Pseudotumor
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TABLE I. Studies Meeting Criteria for Systematic Review. Number of Cases
Oxford CEBM
2007 Case report
6
5
2009 Case report 2007 Case report
1 1
5 5
Chen et al.10
1994 Case Series
3
4
Cho et al.11 Chwang et al.12
2001 Case report 2012 Case series
1 4
5 4
Dwarakanath et al.13 2004 Case report
1
5
Garcia et al.14 Garg et al.2
2012 Case report 2010 Case series
1 4
5 4
Hadi et al.15
2001 Case report
1
5
Han et al.16 Huang et al.17
1996 Case series 2011 Case report
5 1
4 5
Kahairi et al.18
2012 Case report
1
5
Kasliwal et al.19 Katsura et al.20
2008 Case report 2011 Case report
1 1
5 5
Lee DK et al.21
2006 Case series
8
4
Lee EJ et al.22 Lee JH et al.23
2005 Case series 2001 Case report
5 1
4 5
Li et al.24
2013 Case series
8
4
Lu et al.25 Maire et al.26
2010 Case series 2013 Case report
7 1
4 5
Mangiardi et al.5
2007 Case series
6
4
McCall et al.1 McKinney et al.3
2006 Case report 2006 Case report
1 1
5 5
Moss et al.27
2012 Case series
2
4
Nelson et al.28 Nishio et al.29
2012 Case report 2014 Case report
1 1
5 5
Pallini et al.30
2002 Case report
2
5
Patel PC et al.31 Seol et al.32
1998 Case series 2009 Case report
1 1
4 5
Strasnick et al.33
2008 Case report
1
5
Sung et al.34 Ulivieri et al.35
1997 Case series 2010 Case report
7 1
4 5
Author
Year
Agir et al.7 Allona et al.8 Battineni et al.9
Study Type
Aggregate: 3b CEBM 5 Centre for Evidence-Based Medicine.
Patient outcome was reported in all 87 cases and was classified as alive with no evidence of disease (ANED), alive with disease (AWD), dead of disease (DOD), or died of other causes (DOC). Fifty-four of 87 patients (62.1%) were AWD, 24 of 87 patients (27.6%) were ANED, five of 87 (5.7%) were DOD, and the outcomes of four of 87 patients (4.6%) were not reported (Table II). Analysis of patient outcome according to treatment modality shows that 34 of 48 patients (70.8%) who were treated with corticosteroids alone resulted AWD, and 11 of 48 (22.9%) were ANED. Although corticosteroids and radiotherapy was the second most common chosen treatment modality, it showed to be the most unsuccessful with four of eight patients (50.0%) Laryngoscope 00: Month 2014
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resulting DOD. In contrast, surgical removal alone was the chosen intervention in only seven of 87 cases (8.0%), but showed a high success rate (4 of 7 cases, 57.1%) (Table IV).
DISCUSSION Busse and Hochheim first described IPT in 1903, after which it was characterized as a unique pathological entity by Birch-Hirschfield in 1905.4 Characterized as a benign inflammatory process mimicking a neoplastic lesion, the most common involvement of IPT in the head and neck is the orbit. Skull base IPT sparing the orbit is rare.5 This review of 87 sinonasal and ventral skull base IPT cases showed involvement of all age groups.
Patient Demographics In this analysis, the clinical presentation of sinonasal and ventral skull base IPT is related to lesion location. The most common presenting symptoms observed were vision changes and headache, which correlated with the most common lesion locations, the cavernous sinus, and the orbit. Because the cavernous sinus was the most frequently involved skull base site, the most commonly affected cranial nerves were CN VI, CN V, and CN III, all of which run through the cavernous sinus. Extension of sinonasal and ventral skull base IPT into the meninges and brain was rare. Patients presented with a variety of additional symptoms, including facial numbness, facial pain, facial paralysis, otalgia, proptosis, and ptosis, which again appeared to be related to the location of the lesion. This widespread symptomatic presentation of sinonasal and ventral skull base IPT appears to contribute to its diagnostic challenge. It was not uncommon for the lesion to initially be mistaken for a neoplasm prior to thorough evaluation. The most common associated pathology with sinonasal and ventral skull base IPT was DM. Patients with DM and IPT may pose a treatment challenge because high-dose corticosteroids often are the initial treatment of choice for this lesion. Although the specific details of treatment were not disclosed for the majority of patients, Garg et al.2 reported a diabetic patient who required having her initial corticosteroid dosage tapered down to a low dose due to poor glycemic control. It is unclear from this data pool whether DM may be correlated with the occurrence of IPT.
Radiographic Imaging Imaging findings of ventral skull base IPT commonly resemble malignancy. Magnetic resonance imaging and CT were the most preferred imaging tools. The majority of sinonasal and ventral skull base IPT appeared isointense on T1-w imaging and hypointense on T2-w imaging as compared to gray matter. CT scans showed IPT to be predominantly hyperdense compared to gray matter. The lesion was frequently enhancing on T1-w and T2-w images and, as disease progressed, focal bony erosion was common. Enhancement was also commonly seen in MRIs of patients with cavernous sinus Desai et al.: Skull Base Inflammatory Pseudotumor
TABLE II. Summary of Presentation and Overall Outcome. Characteristic
Number of Subjects
Totals
n 5 87
TABLE II. (Continued) Characteristic
Totals
V
19 (42.2%) 20 (44.4%) 6 (13.3%)
Demographics Age in years, mean (range)
46.7 (4–81)
VI VII
Sex, male/female (ratio)
53/34 (1.56:1)
VIII
4 (8.9%)
n 5 87 39 (44.8%)
IX X
5 (11.1%) 6 (13.3%)
29 (33.3%)
XI
Presenting Symptoms, No. (%) Headache Diplopia
1 (2.2%)
XII Associated Findings, No. (%)
8 (17.8%) n 5 18
Vision loss Facial pain
22 (25.3%) 20 (23.0%)
Ptosis
17 (19.5%)
Diabetes mellitus
10 (55.6%)
Proptosis Hearing loss
12 (13.8%) 11 (12.6%)
Chronic otitis media Chronic rhinosinusitis
4 (22.2%) 2 (11.1%)
Facial numbness
11 (12.6%)
Adenoidectomy
2 (11.1%)
Otalgia Eye pain
9 (10.3%) 8 (9.2%)
Outcome, No. (%) AWD
n 5 87 54 (62.1%)
Facial paralysis
7 (8.0%)
ANED
24 (27.6%)
Dysphagia Hoarseness
6 (6.9%) 5 (5.7%)
DOD DOC
5 (57.5%) 0 (0%)
Aural fullness
4 (4.6%)
Unknown
4 (4.6%)
Middle ear effusion Vomiting
4 (4.6%) 4 (4.6%)
Trismus
3 (3.4%)
Otorrhea Neck pain
2 (2.3%) 2 (2.3%)
Weight loss
2 (2.3%)
Vertigo Photophobia
1 (1.1%) 1 (1.1%)
Tinnitus
1 (1.1%)
AMS Sore throat
1 (1.1%) 1 (1.1%)
AMS 5 altered mental status; ANED 5 alive with no evidence of disease; AWD 5 alive with disease; DOC 5 dead of other cause; DOD 5 dead of disease; n 5 number of cases.
involvement. Most cases reviewed used both MRI and CT as diagnostic tools, although MRI may be preferred to allow for better soft tissue definition and differentiation of intracranial contents. Computed tomography imaging is typically useful for bony architecture. Magnetic resonance imaging seems to be preferred for characterization of the soft tissue mass.
Congestion
1 (1.1%)
Biopsy and Pathology
Shoulder pain Oropharyngeal mass
1 (1.1%) 1 (1.1%)
Nasal mass
1 (1.1%)
Imaging alone cannot definitively diagnose IPT. Biopsy is the most important diagnostic modality. The transnasal approach was most common. The ventral
Nausea Gait disturbance
1 (1.1%) 1 (1.1%)
Nasal obstruction Anatomic Site, No. (%) Cranial nerve involvement
1 (1.1%) n 5 87 45 (51.7%)
Cavernous sinus
40 (46.0%)
Orbit involvement Middle cranial fossa
28 (32.2%) 21 (24.1%)
Brain involvement
9 (10.3%)
Extraocular muscle involvement Sphenoid sinus
5 (5.7%) 4 (4.6%)
Sigmoid sinus Cranial Nerve (CN) Involvement, No. (%) II
1 (1.1%) n 5 45 8 (17.8%)
III
17 (37.8%)
IV
12 (26.7)
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TABLE III. Imaging Findings Total Number of Patients Undergoing Imaging Analysis n 5 80 CT
MRI-T1w
MRI-T2w
Number of imaging studies
n 5 56
Density/intensity of signal Hypo-dense/intense
n 5 19 0
n 5 45 9
4
30
2
15 n 5 39
6 n 5 54
2 n 5 37
Iso-dense/intense Hyper-dense/intense Report of enhancement Enhancing Pattern of enhancement Homogeneous Heterogeneous
n 5 68 n 5 43 39
33
51
31
n57 5
n 5 18 14
n 5 18 13
2
4
5
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TABLE IV. Frequency and Treatment Outcomes of Various Treatment Modalities in Sinonasal and Ventral Skull Base IPT.
Treatment
Percent of Total Cases (no.)
Corticosteroids Alone
48 (55.2%)
ANED
11 (22.9%)
AWD DOD
34 (70.8%) 0 (0%)
DOC
0 (0%)
Unknown Corticosteroids and Radiotherapy ANED
3 (6.3%) 8 (9.2%) 1 (12.5%)
AWD
3 (37.5%)
DOD DOC
4 (50.0%) 0 (0%)
Unknown Surgery alone ANED
0 (0%) 7 (8.0%) 4 (57.1%)
AWD
3 (42.9%)
DOD DOC
0 (0%) 0 (0%)
Unknown
0 (0%)
Corticosteroids and Surgery ANED
6 (6.9%)
Percent of Total Cases (no.)
Treatment
No. Cases per Treatment Modality (%)
AWD
0 (0%)
DOD DOC
0 (0%) 0 (0%)
Unknown Radiation ANED
0 (0%) 1 (1.1%) 1 (100%)
AWD
0 (0%)
DOD DOC
0 (0%) 0 (0%)
Unknown Radiation and Surgery ANED
0 (0%) 1 (1.1%) 1 (100%)
AWD
0 (0%)
DOD DOC
0 (0%) 0 (0%)
Unknown Corticosteroids and Antibiotics ANED
0 (0%) 1 (1.1%) 0 (0%)
AWD
1 (100%)
DOD DOC
0 (0%) 0 (0%)
Unknown 2 (33.3%)
Surgery and Immunosuppressant
0 (0%) 1 (1.1%)
AWD
3 (50.0%)
DOD DOC
0 (0%) 0 (0%)
ANED AWD
0 (0%) 1 (100%)
1 (16.7%)
DOD
0 (0%)
DOC Unknown
0 (0%) 0 (0%)
Unknown No Treatment ANED
4 (4.6%) 0 (0%)
AWD
3 (75.0%)
DOD DOC
1 (25.0%) 0 (0%)
Unknown Corticosteroids and Other Immunosuppressant ANED
25.0 3 (3.4%) 0 (0%)
AWD
3 (100%)
DOD DOC
0 (0%) 0 (0%)
Unknown
0 (0%)
Corticosteroids, Immunosuppressant, and Surgery
2 (2.3%)
ANED AWD
0 (0%) 2 (100%)
DOD
0 (0%)
DOC Unknown
0 (0%) 0 (0%)
Immunosuppressant Alone ANED
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No. Cases per Treatment Modality (%)
TABLE IV. (Continued)
1 (1.1%) 1 (100%)
Corticosteroids and Hyperbaric Oxygen Therapy
1 (1.1%)
ANED AWD
0 (0%) 1 (100%)
DOD
0 (0%)
DOC Unknown
0 (0%) 0 (0%)
Corticosteroids, Antibiotics, and Surgery
1 (1.1%)
ANED
1 (100%)
AWD DOD
0 (0%) 0 (0%)
DOC
0 (0%)
Unknown Corticosteroids, Antibiotics, Immunosuppressant, and Surgery
0 (0%) 1 (1.1%)
ANED
1 (100%)
AWD DOD
0 (0%) 0 (0%)
DOC
0 (0%)
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TABLE IV. (Continued)
Treatment
Percent of Total Cases (no.)
Unknown Antibiotics, Hyperbaric Oxygen Therapy, Surgery ANED AWD
No. Cases per Treatment Modality (%)
0 (0%) 1 (1.1%)
0 (0%) 1 (100%)
DOD
0 (0%)
DOC Unknown
0 (0%) 0 (0%)
ANED 5 alive with no evidence of disease; AWD 5 alive with disease; DOC, dead of other cause; DOD 5 dead of disease; n 5 number of cases.
skull base often poses problematic access for biopsy, frequently requiring an open approach. Cases of lesions in the cavernous sinus were most associated with the open biopsy approach in this review. Histologically, the vast majority of biopsies showed fibrosis with infiltration of inflammatory cells, most commonly lymphocytes and plasma cells. There appears to be universal consensus that these are the defining histopath-
ological attributes of IPT. The presence of fungus and bacteria were absent on all biopsy samples reported, and only 3.4% of cases showed cellular atypism or mitotic activity. Of the few cases that disclosed inflammatory marker results, erythrocyte sedimentation rate (ESR) and Creactive protein (CRP) were most commonly elevated. Serologic tests for EBV and viruses proved unfruitful in this review. Thirteen cases reported IgG4 testing, 11 of which tested positive for the antibody. The presence of IgG4positive plasma cells is the hallmark of IgG4-related diseases in which patients suffer from fibrotic and lymphoplasmacytic tumor-like swellings of organs such as the liver and orbit.6 These lesions histologically resemble IPT and make the IgG4 cell marker a point of interest. It appears that a thorough investigation into the relationship between IgG4 and IPT has not yet been performed, but considering the data from this study, it may provide valuable insight into the clinical nature and management of IPT.
Treatment and Outcome Complete eradication of sinonasal and ventral skull base IPT is difficult. Of the 87 cases reviewed, only 24 were reported to be symptom-free at follow-up, but over half of the patients were AWD with symptomatic improvement and/or improvement of lesion on repeat imaging. There is no consensus on optimal treatment for
Fig. 3. (A) Diagrammatic representation of diagnostic algorithm. On the left, the inverted triangle emphasizes the refining process of differential diagnosis and characterization of IPT, as guided by results obtained from diagnostic imaging and histopathological findings on biopsy. (B) Flow chart of an optimized algorithm for the management of skull base IPT. *Probable inflammatory pseudotumor based on findings from this systematic review. AMS 5 altered mental status; IPT 5 inflammatory pseudotumor.
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sinonasal and ventral skull base IPT. Given this information, it is not surprising that the reviewed treatment plans varied case to case at the discretion of the clinicians. Fifteen treatment approaches were observed involving the combination or exclusive use of corticosteroids, surgery, radiotherapy, other immunosuppression, antibiotics, and hyperbaric oxygen therapy. This review found corticosteroids to be the treatment of choice for sinonasal and ventral skull base IPT. Although few cases disclosed treatment specifics, variable initial dosages of corticosteroids were observed to range from 30 mg to 100 mg daily. The treatment courses were in effect for varying lengths of time, with no obvious relationship between patient outcome and dosage strength or course length. Because corticosteroids are the most popular treatment modality for IPT, there appears to be a need for guidelines or a standardized approach to their dosage and course length for sinonasal and ventral skull base IPT. Nevertheless, corticosteroids were observed to be a very effective treatment for these lesions. The combination of corticosteroids and radiotherapy was one of the least successful treatment modalities noted in this review, with half of the eight subjects DOD. Apart from corticosteroids or surgical intervention, the advantage of one treatment modality over another against sinonasal and ventral skull base IPT is unclear. The combination of corticosteroids and surgery or surgical resection alone appears to be a rarely used treatment modality for sinonasal and ventral skull base IPT, although very successful at completely eliminating disease in this review. Treatment of sinonasal and ventral skull base IPT remains heavily reliant on corticosteroid therapy; yet it appears to be less successful at producing disease-free patients than surgical resection. The reasoning behind this may lie within the history of skull base surgery itself. The intricate sinonasal and ventral skull base anatomy poses high-risk surgical access that historically has been difficult for surgeons to approach with limited morbidity until the recent use of endoscopy. Corticosteroids have been the first-line treatment since the classification of IPT, so it is not surprising that this review shows corticosteroids treatment and nonsurgical intervention to be the treatment of choice over the past several decades. However, given the success rates of surgical resection in this review and the noninvasive endoscopic surgical technology available to rhinologists and endoscopic skull base surgeons, it may be beneficial to explore the possibility of surgery as a first-line treatment option for sinonasal and ventral skull base IPT in select cases. Corticosteroids may be a beneficial supplement to surgical intervention. In patients unable to be treated with high-dose corticosteroids (e.g., diabetics), surgery can reduce the potential drawbacks associated with high-dose corticosteroids. Other immunosuppressants were rarely used as initial treatment but were most commonly added to existing treatment regimens at the point of symptomatic or lesion recurrence. The use of mycophenolate mofetil, methotrexate, cyclophosphamide, a-interferon, Laryngoscope 00: Month 2014
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rituximab, and azathioprine was observed. The least popular treatment modalities appear to be antibiotics and radiotherapy. Radiotherapy was applied most commonly in combination with surgical resection. Antibiotics showed no benefit in this review, and radiotherapy appeared beneficial only in conjunction with surgical resection. When sinonasal or ventral skull base IPT is suspected, we recommend first ruling out true neoplasm or malignancy. Helpful laboratory tests include ESR and CRP, which tend to be elevated in the setting of IPT. MRI and CT are important complementary diagnostic tools. Biopsy and histopathological analysis are essential for definitive diagnosis and should be performed early to prevent treatment delay. Histological landmarks of IPT are fibrosis with inflammatory cell infiltrate, predominantly lymphocytes and plasma cells. IgG4 staining of plasma cells can be useful if there remains any diagnostic uncertainty after biopsy. This report showed the greatest success rate of treatment with corticosteroids or surgical resection alone. Other immunosuppressants may be useful for recurrences. Regardless of treatment modality, total eradication of sinonasal and ventral skull base IPT is difficult. Consequently, close follow-up is recommended (Fig. 3).
Limitations Intrinsic limitations to this study stemmed from the quality of data available. Inflammatory pseudotumor of the sinonasal and ventral skull base is a rare entity with relatively few cases reported in the literature. Additionally, according to the Oxford Centre for Evidence-Based Medicine, the level of evidence for the studies included in this review were poor and comprised of level 4 and 5 studies. The cases available also provided nonuniform reporting of the presentation, imaging, course of treatment, and patient outcome. Many cases did not disclose key data variables, and the overall quality of data from case to case was inconsistent. Because of the small sample size in this study, a meta-analysis was not performed, predisposing this study to selection bias.
CONCLUSION Sinonasal and ventral skull base IPT is a rare nonneoplastic inflammatory lesion with variable symptomatic presentation. Its clinical presentation and radiographic resemblance to malignancy often contribute to misdiagnosis and delay in appropriate treatment. Although MRI and CT are useful tools for differential diagnosis, biopsy and histopathological analysis are essential for conclusive diagnosis. Corticosteroids were the most common treatment modality used and were very successful at managing disease. Although surgical resection was rarely utilized, it appeared to have been the most successful treatment modality in achieving disease-free patient outcome. Improvement of symptoms and/or lesion is likely, regardless of treatment modality. Complete resolution of disease is uncommon with IPT of the sinonasal and ventral skull base. Desai et al.: Skull Base Inflammatory Pseudotumor
BIBLIOGRAPHY 1. McCall T, Fassett DR, Lyons G, Couldwell WT. Inflammatory pseudotumor of the cavernous sinus and skull base. Neurosurg Rev 2006;29:194–200. 2. Garg V, Temin N, Hildenbrand P, Silverman M, Catalano PJ. Inflammatory pseudotumor of the skull base. Otolaryngol Head Neck Surg 2010; 142:129–131. 3. McKinney AM, Short J, Lucato L, SantaCruz K, McKinney Z, Kim Y. Inflammatory myofibroblastic tumor of the orbit with associated enhancement of the meninges and multiple cranial nerves. AJNR Am J Neuroradiol 2006;27:2217–2220. 4. Kamili MA, G A, Dar IH, Dar SH, Wazir HS, Qureishi T. Orbital pseudotumor. Oman J Ophthalmol 2009;2:96–99. 5. Mangiardi JR, Har-El G. Extraorbital skull base idiopathic pseudotumor. Laryngoscope 2007;117:589–594. 6. Pieringer H, Parzer I, Wohrer A, Reis P, Oppl B, Zwerina J. IgG4- related disease: an orphan disease with many faces. Orphanet J Rare Dis 2014; 9:110. 7. Agir H, Aburn N, Davis C, MacKinnon C, Tan ST. W(h)ither orbital pseudotumor? J Craniofac Surg 2007;18:1148–1153. 8. Allona M, Royo A, Lassaletta L, Moreno P, Galindo J. Inflammatory pseudotumor of the petrous apex with spontaneous improvement of the lesion. Otol Neurotol 2009;30:245–247. 9. Battineni ML, Galetta SL, Oh J, et al. Idiopathic hypereosinophilic syndrome with skull base involvement. AJNR Am J Neuroradiol 2007;28: 971–973. 10. Chen JM, Moll C, Schotton JC, Fisch U. Inflammatory pseudotumors of the skull base. Skull Base Surg 1994;4:93–98. 11. Cho YS, Kim SM, Chung WH, Hong SH. Inflammatory pseudotumour involving the skull base and cervical spine. J Laryngol Otol 2001;115: 580–584. 12. Chwang WB, Jain R, Narayan A, et al. Inflammatory pseudotumor of the nasopharynx and skull base: mimicking an aggressive neoplasm or infection. Arch Otolaryngol Head Neck Surg 2012;138:765–769. 13. Dwarakanath S, Jaiswal AK, Ralte AM, Sharma MC, Mahapatra AK. Primary plasma cell granuloma of petrous bone. J Clin Neurosci 2004;11:552–555. 14. Garcia BA, Tinsley S, Schellenberger T, Bobustuc GC. Recurrent inflammatory pseudotumor of the jaw with perineural intracranial invasion demonstrating sustained response to Rituximab. Medical Med Oncol 2012;29:2452–2455. 15. Hadi U, el-Bitar M, Zaatari G. Post-adenoidectomy inflammatory pseudotumor. Rhinology 2001;39:176–179. 16. Han MH, Chi JG, Kim MS, et al. Fibrosing inflammatory pseudotumors involving the skull base: MR and CT manifestations with histopathologic comparison. AJNR Am J Neuroradiol 1996;17:515–521. 17. Huang B, Liu HJ, Liang CH. Inflammatory pseudotumor of the skull base involving fissura petrooccipitalis: a rare case with challenging diagnosis. Skull Base Rep 2011;1:105–110. 18. Kahairi A, Ahmad RL, Wan Ishlah L, Norra H. Inflammatory pseudotumour of skull base—diagnostic challenge and treatment outcome. Med J Malaysia 2012;67:526–528.
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19. Kasliwal MK, Suri A, Gupta DK, Suri V, Rishi A, Sharma BS. Sphenoid wing inflammatory pseudotumor mimicking a clinoidal meningioma: case report and review of the literature. Surg Neurol 2008;70:509–513; discussion 513. 20. Katsura M, Morita A, Horiuchi H, Ohtomo K, Machida T. IgG4-related inflammatory pseudotumor of the trigeminal nerve: another component of IgG4-related sclerosing disease? AJNR Am J Neuroradiol 2011;32: E150–152. 21. Lee DK, Cho YS, Hong SH, Chung WH, Ahn YC. Inflammatory pseudotumor involving the skull base: response to steroid and radiation therapy. Otolaryngol Head Neck Surg 2006;135:144–148. 22. Lee EJ, Jung SL, Kim BS, et al. MR imaging of orbital inflammatory pseudotumors with extraorbital extension. Korean journal of radiology : official journal of the Korean Radiological Society 2005; 6:82–88. 23. Lee JH, Kim K, Chung SW, Choi YC, Lee A. A case report of inflammatory pseudotumor involving the clivus: CT and MR findings. Korean J Radiol 2001;2:231–234. 24. Li Y, Lip G, Chong V, Yuan J, Ding Z. Idiopathic orbital inflammation syndrome with retro-orbital involvement: a retrospective study of eight patients. PloS One 2013;8:e57126. 25. Lu CH, Yang CY, Wang CP, Yang CC, Liu HM, Chen YF. Imaging of nasopharyngeal inflammatory pseudotumours: differential from nasopharyngeal carcinoma. Br J Radiol 2010;83:8–16. 26. Maire JP, Eimer S, San Galli F, et al. Inflammatory myofibroblastic tumour of the skull base. Case Rep Otolaryngol 2013;2013:103646. 27. Moss HE, Mejico LJ, de la Roza G, Coyne TM, Galetta SL, Liu GT. IgG4related inflammatory pseudotumor of the central nervous system responsive to mycophenolate mofetil. J Neurol Sci 2012;318:31–35. 28. Nelson JJ, Goyal P. Extraorbital pseudotumor of the petrous apex: biopsy via a transnasal endoscopic approach. Ear Nose Throat J 2012;91:E6– E9. 29. Nishio N, Fujimoto Y, Nakashima T. Inflammatory pseudotumor of the infratemporal fossa leading to orbital apex syndrome. J Craniofac Surg 2014;25:1324–1326. 30. Pallini R, Liverana L, Maria LL, Cesare C, Eduardo F, Babu R. Isolated inflammatory pseudotumor of the occipital condyle. Report of two cases. J Neurosurg 2002;97:248–251. 31. Patel PC, Pellitteri PK, Vrabec DP, Szymanski M. Tumefactive fibroinflammatory lesion of the head and neck originating in the infratemporal fossa. Am J Otolaryngol 1998;19:216–219. 32. Seol JG, Loevner LA, O’Malley BW Jr, Grady MS. Inflammatory pseudotumor of the trigeminal nerve: a neoplastic mimic you do not want to miss. AJNR Am J Neuroradiol 2009;30:1941–1943. 33. Strasnick B, Vaughan A. Inflammatory pseudotumor of the temporal bone: a case series. Skull Base 2008;18:49–52. 34. Sung MW, Kim KH, Lee CH, Moh JH, Kim WH, Han MH. Fibrosing inflammatory pseudotumors of the central skull base. Laryngoscope 1997;107:1651–1655. 35. Ulivieri S, Oliveri G, Cerase A, et al. Pterygomaxillary extension of orbital pseudotumor. Case report. G Chir 2010;31:159–161.
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Rhinological and Otological Society, Inc.
Systematic Review
Sinonasal and Ventral Skull Base Inflammatory Pseudotumor: A Systematic Review Stuti V. Desai, BA; Eleonora F. Spinazzi, BA; Christina H. Fang, BS; Grace Huang, BS; Senja Tomovic, MD; James K. Liu, MD, FACS; Soly Baredes, MD, FACS; Jean Anderson Eloy, MD, FACS Objectives/Hypothesis: Inflammatory pseudotumor is a benign idiopathic inflammatory process often misdiagnosed as an infection or neoplasm. This review analyzes all reported cases of sinonasal and ventral skull base inflammatory pseudotumor to date, and provides a framework for evaluation and management of this uncommon condition. Data Sources: MEDLINE/PubMed database. Review Methods: A search for articles related to sinonasal and ventral skull base inflammatory pseudotumor, along with bibliographies of those articles, was performed. Demographics, presentation, radiographic findings, treatment, follow-up, and outcome were analyzed. Results: Thirty-three articles were reviewed, including a total of 87 patients. The most common presenting symptom was vision change (58.6%). Sinonasal and ventral skull base inflammatory pseudotumor was found in the cavernous sinus in 46.0% of cases. The lesion appeared isointense (66.7% of cases) and homogeneously enhancing on T1-weighted magnetic resonance imaging (MRI), whereas it appeared hypointense on T2-weighted MRI in 90.7% of cases. Inflammatory pseudotumor appeared hyperdense on computed tomography in 78.9% of cases. Histopathological analysis of biopsied specimens revealed presence of inflammatory cells (94.4%) and fibrosis (80.3%). Corticosteroids alone were the most common treatment modality (55.2%), resulting in disease-free patients in 22.9% of cases over a median follow-up period of 17.6 months. Surgical management alone was uncommon (8.0%), but showed high success rate (57.1%). Conclusion: This review is the most comprehensive analysis of sinonasal and ventral skull base inflammatory pseudotumor to date. Radiologic findings and histopathological analysis are essential for diagnosis. Corticosteroids are the most common treatment modality. Surgery, although uncommon, appears to be an efficacious treatment modality. Key Words: Inflammatory pseudotumor, sinonasal, ventral skull base, sinonasal skull base inflammatory pseudotumor, sinonasal skull base inflammatory myofibroblastic tumor, ventral skull base pseudotumor, skull base inflammatory myofibroblastic tumor, head and neck inflammatory pseudotumor, skull base surgery, endoscopic skull base surgery. Level of Evidence: N/A Laryngoscope, 00:000–000, 2014
INTRODUCTION Inflammatory pseudotumor (IPT), also previously referred to as inflammatory myofibroblastic tumor, is an idiopathic non-neoplastic inflammatory process. Clinically, the lesion bears a striking resemblance to malig-
Accepted for presentation at the 2015 Combined Sections Meeting of the Triological Society, San Diego, CA, January 22–24, 2015. The authors have no funding, financial relationships, or conflicts of interest to disclose. Editor’s Note: This Manuscript was accepted for publication on October 1, 2014. From the Department of Otolaryngology–Head and Neck Surgery (S.V.D., E.F.S., C.H.F., G.H., S.T., J.K.L., S.B., J.A.E.); the Department of Neurological Surgery (J.K.L., J.A.E.) and the Center for Skull Base and Pituitary Surgery, Neurological Institute of New Jersey (J.K.L., S.B., J.A.E.), Rutgers New Jersey Medical School, Newark, New Jersey, U.S.A Send correspondence to Jean Anderson Eloy, MD, FACS, Professor and Vice Chairman, Director, Rhinology and Sinus Surgery, Director, Otolaryngology Research, Co-Director, Endoscopic Skull Base Surgery Program, Department of Otolaryngology–Head and Neck Surgery, Rutgers New Jersey Medical School, 90 Bergen St., Suite 8100, Newark, NJ 07103. E-mail: [email protected] DOI: 10.1002/lary.24993
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nancy if not properly scrutinized, which frequently leads to delay in proper diagnosis and management.1 Inflammatory pseudotumor is relatively rare in the head and neck, where it most commonly affects the orbit.2,3 Sinonasal and ventral skull base involvement of IPT is uncommon; understanding its clinical presentation, imaging characteristics, and histopathology is crucial to proper diagnosis and management. These attributes of IPT of the paranasal sinuses and skull base are currently ill-defined, with an apparent lack of standard of treatment in the literature. This study is the first systematic review of reported cases of sinonasal and ventral skull base IPT aiming to determine trends in presentation, diagnostic modalities, treatment modalities, and patient outcome.
MATERIALS AND METHODS A systematic review of the published literature on sinonasal and ventral skull base IPT was performed, which qualified as “nonhuman subject research” as per protocol of the Institutional Review Board of Rutgers New Jersey Medical
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Patients were male in 53 cases (60.9%) and female in 34 cases (39.1%). Age and gender were reported for all 87 patients. Presenting symptoms were included in all 87 cases with an average duration of 19.0 months (ranging from 1 week to 10 years). Fifty-one patients (58.6%) presented with vision changes, of which 22 (43.1%) reported vision loss and 29 (56.9%) suffered from diplopia. The second most common presenting symptom was headache (39 cases, 44.8%). Facial pain (20 cases, 23.0%), ptosis (17 cases, 19.5%), proptosis (12 cases, 13.8%), hearing loss (11 cases, 12.6%), and facial numbness (11 cases, 12.6%) were also common presenting symptoms. Inflammatory pseudotumor of the ventral skull base was most commonly located in the cavernous sinus (40 cases, 46.0%) and the orbit (28 cases, 32.2%). The middle cranial fossa was also frequently affected (21 cases, 24.1%). Inflammatory pseudotumor extended into the brain in nine cases (10.3%). Cranial nerve (CN) palsy was one of the most prevalent presenting symptoms affecting 45 of 57 cases (78.9%), with CN VI (44.4%), CN V (42.2%), and CN III (37.8%) being the most affected. Further details of demographics and IPT specifics are presented in Table II. Although associated past medical conditions were reported in only 18 cases, the most common were diabetes mellitus (DM) (10 cases, 55.6%), chronic otitis media (4 cases, 22.2%), and chronic rhinosinusitis (2 cases, 11.1%) (Table II).
Fig. 1. Flow diagram of included and excluded studies. IPD 5 individual patient data; IPT 5 inflammatory pseudotumor. School, Newark, New Jersey, and did not require approval. A literature search was performed using the MEDLINE and PubMed search engines for the following keywords: “inflammatory pseudotumor skull base” and “inflammatory myofibroblastic tumor skull base.” Search results were confined to articles in the English language and articles whose full text was obtainable. Literature that did not pertain to IPT of the sinonasal and ventral skull base or did not disclose individual patient data was excluded (Fig. 1). For the purposes of this study, the sinonasal tract and ventral skull base were defined as areas of the skull base that can be accessed endoscopically. Figure 2 maps the regions of the skull base that were considered sinonasal and ventral skull base in this review. An attending pathologist, radiologist, and endoscopic skull base surgeon were consulted with questions regarding the inclusion or exclusion of cases based on anatomical location, histopathology, or radiology. Additional articles that did not appear in our original search were obtained from a screen of the bibliographies of the initial articles. A total of 33 relevant articles with 87 patient cases were reviewed (Table I). The following data were extracted: patient demographics, presentation, associated pathology, imaging, histopathology, treatment, follow-up, recurrence, and final outcome of disease. Data analysis was performed using Microsoft Excel (Microsoft Corporation, Redmond, WA).
RESULTS Patient Demographics The average age of the individual patients in this review was 46.7 years, with a range of 4 to 81 years. Laryngoscope 00: Month 2014
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Radiographic Imaging The use of imaging as a diagnostic tool was reported in 80 of 87 cases (92.0%). The most common imaging techniques used for radiologic analysis were magnetic resonance imaging (MRI) (68 of 80 cases, 85.0%) and computed tomography (CT) (56 of 80 patients, 70.0%). Intensity of signal on T1-weighted (T1w) and T2-weighted (T2-w) MRI was reported in 45 cases and 43 cases, respectively. Analysis shows that in 30 of 45 cases (66.7%), the IPT lesion appears as isointense on T1-w compared to gray matter; whereas it appears hypointense on T2-w in 39 of 43 cases (90.7%). Inflammatory pseudotumor was enhanced on T1-w images in 51 of 54 reported cases (94.4%), especially when located in the cavernous sinus (38 of 40 masses in the cavernous sinus enhanced, 95.0%). Eighteen cases reported the pattern of IPT enhancement on T1-w images, which was generally described as confluent and homogeneous (14 of 18 cases, 77.8%). Enhancement on T2-w images followed a similar pattern with 31 of 37 cases (83.8%) showing enhancement, which was also uniformly homogeneous in 13 of 18 cases (72.2%). Although density of the IPT on CT was reported in only 19 cases, it commonly appeared hyperdense (15 of 19 cases, 78.9%) compared to gray matter. Enhancement of the IPT on CT was observed in 33 of 39 cases (84.6%), and it was mostly homogeneous (5 of 7 cases, 71.4%) (Table III). Twenty-three cases reported bony changes, of which 20 cases (87.0%) were identified as bony erosion. Extension of IPT into the meninges and brain was observed in 26 of 87 (29.9%) and nine of 87 (10.3%) cases, respectively. Desai et al.: Skull Base Inflammatory Pseudotumor
Fig. 2. The outlined areas of the axial (A) and sagittal (B) scans and the coronal (C) CT scans refer to the regions of the skull base that were considered endoscopically accessible, and thus the sinonasal and ventral skull base for this study. The coronal CT (C) depicts a heat map for the areas of the ventral skull base most commonly affected by inflammatory pseudotumor.
Biopsy and Pathology Inflammatory pseudotumor was reported to have been biopsied in 79 of 87 cases (90.8%), with an average of 1.3 biopsies performed per patient. The type of biopsy was specified only in 54 of 79 cases (68.4%), and the predominantly chosen approach was transnasal (27 of 54 biopsies, 50.0%), followed by open (14 of 54 biopsies, 25.9%), transoral (8 of 54 biopsies, 14.8%), percutaneous (4 of 54 biopsies, 7.4%), and transorbital (1 of 54 cases, 1.9%). Histopathological data were reported only in 71 cases (89.9%); analysis revealed infiltration of inflammatory cells in 67 of 71 cases (94.4%) that was associated with fibrosis in 57 of 71 cases (80.3%). No biopsied lesions were positive for fungi or bacteria, and cellular mitosis/ cellular atypism was reported in two of 58 cases (3.4%). Serologic tests for Epstein-Barr Virus (EBV), herpes human virus-8 (HHV-8), and immunoglobulin G4 (IgG4) were performed in a minority of patients. A total of four patients were tested for EBV, and only one resulted positive. None of the two patients that were tested for HHV8 resulted positive and 11 of 13 patients (84.6%) tested for the presence of IgG4 resulted positive for the antibody.
Treatment Treatment approach was reported in all cases and included surgery, corticosteroids, antibiotics, other immunosuppressive therapy, or a combination of these Laryngoscope 00: Month 2014
modalities. The predominant treatment strategy was high-dose corticosteroids alone (48 of 87 cases, 55.2%). Corticosteroids in combination with radiotherapy were the second most common treatment modality, applied to eight of 87 cases (9.2%). Surgical treatment alone was used in seven of 87 cases (8.0%) or in combination with other treatment modalities in nine of 87 cases (10.3%). Immunosuppressive treatment alone was comprised of cyclophosphamide and/or a-interferon and applied to two of 87 patients (2.3% of cases), sometimes in conjunction with corticosteroids (3 patients, 3.4%) (Table IV). The average follow-up among reported cases was 17.6 months. Only 59 of 87 cases reported patient progress at first follow-up. Twenty-two of 59 patients (37.3%) were asymptomatic, and 18 of 59 patients (30.5%) showed improvement at first follow-up. Recurrence of disease at first follow-up was observed in five of 59 patients (8.5%), four of whom were treated initially with corticosteroids alone. Four of 59 patients (6.8%) showed stable symptoms, and two of 29 patients (6.8%) were dead of disease. Of the 62 patients whose first follow-up was reported, only 13 had a documented second follow-up after a mean time of 12.1 months from their first visit. Whereas most of the patients were reported as stable, improved, or asymptomatic (9 of 13 cases, 69.2%), two of the 13 patients (15.4%) showed worsening of symptoms, and another two patients showed recurrence of disease (15.4%). Desai et al.: Skull Base Inflammatory Pseudotumor
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TABLE I. Studies Meeting Criteria for Systematic Review. Number of Cases
Oxford CEBM
2007 Case report
6
5
2009 Case report 2007 Case report
1 1
5 5
Chen et al.10
1994 Case Series
3
4
Cho et al.11 Chwang et al.12
2001 Case report 2012 Case series
1 4
5 4
Dwarakanath et al.13 2004 Case report
1
5
Garcia et al.14 Garg et al.2
2012 Case report 2010 Case series
1 4
5 4
Hadi et al.15
2001 Case report
1
5
Han et al.16 Huang et al.17
1996 Case series 2011 Case report
5 1
4 5
Kahairi et al.18
2012 Case report
1
5
Kasliwal et al.19 Katsura et al.20
2008 Case report 2011 Case report
1 1
5 5
Lee DK et al.21
2006 Case series
8
4
Lee EJ et al.22 Lee JH et al.23
2005 Case series 2001 Case report
5 1
4 5
Li et al.24
2013 Case series
8
4
Lu et al.25 Maire et al.26
2010 Case series 2013 Case report
7 1
4 5
Mangiardi et al.5
2007 Case series
6
4
McCall et al.1 McKinney et al.3
2006 Case report 2006 Case report
1 1
5 5
Moss et al.27
2012 Case series
2
4
Nelson et al.28 Nishio et al.29
2012 Case report 2014 Case report
1 1
5 5
Pallini et al.30
2002 Case report
2
5
Patel PC et al.31 Seol et al.32
1998 Case series 2009 Case report
1 1
4 5
Strasnick et al.33
2008 Case report
1
5
Sung et al.34 Ulivieri et al.35
1997 Case series 2010 Case report
7 1
4 5
Author
Year
Agir et al.7 Allona et al.8 Battineni et al.9
Study Type
Aggregate: 3b CEBM 5 Centre for Evidence-Based Medicine.
Patient outcome was reported in all 87 cases and was classified as alive with no evidence of disease (ANED), alive with disease (AWD), dead of disease (DOD), or died of other causes (DOC). Fifty-four of 87 patients (62.1%) were AWD, 24 of 87 patients (27.6%) were ANED, five of 87 (5.7%) were DOD, and the outcomes of four of 87 patients (4.6%) were not reported (Table II). Analysis of patient outcome according to treatment modality shows that 34 of 48 patients (70.8%) who were treated with corticosteroids alone resulted AWD, and 11 of 48 (22.9%) were ANED. Although corticosteroids and radiotherapy was the second most common chosen treatment modality, it showed to be the most unsuccessful with four of eight patients (50.0%) Laryngoscope 00: Month 2014
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resulting DOD. In contrast, surgical removal alone was the chosen intervention in only seven of 87 cases (8.0%), but showed a high success rate (4 of 7 cases, 57.1%) (Table IV).
DISCUSSION Busse and Hochheim first described IPT in 1903, after which it was characterized as a unique pathological entity by Birch-Hirschfield in 1905.4 Characterized as a benign inflammatory process mimicking a neoplastic lesion, the most common involvement of IPT in the head and neck is the orbit. Skull base IPT sparing the orbit is rare.5 This review of 87 sinonasal and ventral skull base IPT cases showed involvement of all age groups.
Patient Demographics In this analysis, the clinical presentation of sinonasal and ventral skull base IPT is related to lesion location. The most common presenting symptoms observed were vision changes and headache, which correlated with the most common lesion locations, the cavernous sinus, and the orbit. Because the cavernous sinus was the most frequently involved skull base site, the most commonly affected cranial nerves were CN VI, CN V, and CN III, all of which run through the cavernous sinus. Extension of sinonasal and ventral skull base IPT into the meninges and brain was rare. Patients presented with a variety of additional symptoms, including facial numbness, facial pain, facial paralysis, otalgia, proptosis, and ptosis, which again appeared to be related to the location of the lesion. This widespread symptomatic presentation of sinonasal and ventral skull base IPT appears to contribute to its diagnostic challenge. It was not uncommon for the lesion to initially be mistaken for a neoplasm prior to thorough evaluation. The most common associated pathology with sinonasal and ventral skull base IPT was DM. Patients with DM and IPT may pose a treatment challenge because high-dose corticosteroids often are the initial treatment of choice for this lesion. Although the specific details of treatment were not disclosed for the majority of patients, Garg et al.2 reported a diabetic patient who required having her initial corticosteroid dosage tapered down to a low dose due to poor glycemic control. It is unclear from this data pool whether DM may be correlated with the occurrence of IPT.
Radiographic Imaging Imaging findings of ventral skull base IPT commonly resemble malignancy. Magnetic resonance imaging and CT were the most preferred imaging tools. The majority of sinonasal and ventral skull base IPT appeared isointense on T1-w imaging and hypointense on T2-w imaging as compared to gray matter. CT scans showed IPT to be predominantly hyperdense compared to gray matter. The lesion was frequently enhancing on T1-w and T2-w images and, as disease progressed, focal bony erosion was common. Enhancement was also commonly seen in MRIs of patients with cavernous sinus Desai et al.: Skull Base Inflammatory Pseudotumor
TABLE II. Summary of Presentation and Overall Outcome. Characteristic
Number of Subjects
Totals
n 5 87
TABLE II. (Continued) Characteristic
Totals
V
19 (42.2%) 20 (44.4%) 6 (13.3%)
Demographics Age in years, mean (range)
46.7 (4–81)
VI VII
Sex, male/female (ratio)
53/34 (1.56:1)
VIII
4 (8.9%)
n 5 87 39 (44.8%)
IX X
5 (11.1%) 6 (13.3%)
29 (33.3%)
XI
Presenting Symptoms, No. (%) Headache Diplopia
1 (2.2%)
XII Associated Findings, No. (%)
8 (17.8%) n 5 18
Vision loss Facial pain
22 (25.3%) 20 (23.0%)
Ptosis
17 (19.5%)
Diabetes mellitus
10 (55.6%)
Proptosis Hearing loss
12 (13.8%) 11 (12.6%)
Chronic otitis media Chronic rhinosinusitis
4 (22.2%) 2 (11.1%)
Facial numbness
11 (12.6%)
Adenoidectomy
2 (11.1%)
Otalgia Eye pain
9 (10.3%) 8 (9.2%)
Outcome, No. (%) AWD
n 5 87 54 (62.1%)
Facial paralysis
7 (8.0%)
ANED
24 (27.6%)
Dysphagia Hoarseness
6 (6.9%) 5 (5.7%)
DOD DOC
5 (57.5%) 0 (0%)
Aural fullness
4 (4.6%)
Unknown
4 (4.6%)
Middle ear effusion Vomiting
4 (4.6%) 4 (4.6%)
Trismus
3 (3.4%)
Otorrhea Neck pain
2 (2.3%) 2 (2.3%)
Weight loss
2 (2.3%)
Vertigo Photophobia
1 (1.1%) 1 (1.1%)
Tinnitus
1 (1.1%)
AMS Sore throat
1 (1.1%) 1 (1.1%)
AMS 5 altered mental status; ANED 5 alive with no evidence of disease; AWD 5 alive with disease; DOC 5 dead of other cause; DOD 5 dead of disease; n 5 number of cases.
involvement. Most cases reviewed used both MRI and CT as diagnostic tools, although MRI may be preferred to allow for better soft tissue definition and differentiation of intracranial contents. Computed tomography imaging is typically useful for bony architecture. Magnetic resonance imaging seems to be preferred for characterization of the soft tissue mass.
Congestion
1 (1.1%)
Biopsy and Pathology
Shoulder pain Oropharyngeal mass
1 (1.1%) 1 (1.1%)
Nasal mass
1 (1.1%)
Imaging alone cannot definitively diagnose IPT. Biopsy is the most important diagnostic modality. The transnasal approach was most common. The ventral
Nausea Gait disturbance
1 (1.1%) 1 (1.1%)
Nasal obstruction Anatomic Site, No. (%) Cranial nerve involvement
1 (1.1%) n 5 87 45 (51.7%)
Cavernous sinus
40 (46.0%)
Orbit involvement Middle cranial fossa
28 (32.2%) 21 (24.1%)
Brain involvement
9 (10.3%)
Extraocular muscle involvement Sphenoid sinus
5 (5.7%) 4 (4.6%)
Sigmoid sinus Cranial Nerve (CN) Involvement, No. (%) II
1 (1.1%) n 5 45 8 (17.8%)
III
17 (37.8%)
IV
12 (26.7)
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TABLE III. Imaging Findings Total Number of Patients Undergoing Imaging Analysis n 5 80 CT
MRI-T1w
MRI-T2w
Number of imaging studies
n 5 56
Density/intensity of signal Hypo-dense/intense
n 5 19 0
n 5 45 9
4
30
2
15 n 5 39
6 n 5 54
2 n 5 37
Iso-dense/intense Hyper-dense/intense Report of enhancement Enhancing Pattern of enhancement Homogeneous Heterogeneous
n 5 68 n 5 43 39
33
51
31
n57 5
n 5 18 14
n 5 18 13
2
4
5
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TABLE IV. Frequency and Treatment Outcomes of Various Treatment Modalities in Sinonasal and Ventral Skull Base IPT.
Treatment
Percent of Total Cases (no.)
Corticosteroids Alone
48 (55.2%)
ANED
11 (22.9%)
AWD DOD
34 (70.8%) 0 (0%)
DOC
0 (0%)
Unknown Corticosteroids and Radiotherapy ANED
3 (6.3%) 8 (9.2%) 1 (12.5%)
AWD
3 (37.5%)
DOD DOC
4 (50.0%) 0 (0%)
Unknown Surgery alone ANED
0 (0%) 7 (8.0%) 4 (57.1%)
AWD
3 (42.9%)
DOD DOC
0 (0%) 0 (0%)
Unknown
0 (0%)
Corticosteroids and Surgery ANED
6 (6.9%)
Percent of Total Cases (no.)
Treatment
No. Cases per Treatment Modality (%)
AWD
0 (0%)
DOD DOC
0 (0%) 0 (0%)
Unknown Radiation ANED
0 (0%) 1 (1.1%) 1 (100%)
AWD
0 (0%)
DOD DOC
0 (0%) 0 (0%)
Unknown Radiation and Surgery ANED
0 (0%) 1 (1.1%) 1 (100%)
AWD
0 (0%)
DOD DOC
0 (0%) 0 (0%)
Unknown Corticosteroids and Antibiotics ANED
0 (0%) 1 (1.1%) 0 (0%)
AWD
1 (100%)
DOD DOC
0 (0%) 0 (0%)
Unknown 2 (33.3%)
Surgery and Immunosuppressant
0 (0%) 1 (1.1%)
AWD
3 (50.0%)
DOD DOC
0 (0%) 0 (0%)
ANED AWD
0 (0%) 1 (100%)
1 (16.7%)
DOD
0 (0%)
DOC Unknown
0 (0%) 0 (0%)
Unknown No Treatment ANED
4 (4.6%) 0 (0%)
AWD
3 (75.0%)
DOD DOC
1 (25.0%) 0 (0%)
Unknown Corticosteroids and Other Immunosuppressant ANED
25.0 3 (3.4%) 0 (0%)
AWD
3 (100%)
DOD DOC
0 (0%) 0 (0%)
Unknown
0 (0%)
Corticosteroids, Immunosuppressant, and Surgery
2 (2.3%)
ANED AWD
0 (0%) 2 (100%)
DOD
0 (0%)
DOC Unknown
0 (0%) 0 (0%)
Immunosuppressant Alone ANED
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No. Cases per Treatment Modality (%)
TABLE IV. (Continued)
1 (1.1%) 1 (100%)
Corticosteroids and Hyperbaric Oxygen Therapy
1 (1.1%)
ANED AWD
0 (0%) 1 (100%)
DOD
0 (0%)
DOC Unknown
0 (0%) 0 (0%)
Corticosteroids, Antibiotics, and Surgery
1 (1.1%)
ANED
1 (100%)
AWD DOD
0 (0%) 0 (0%)
DOC
0 (0%)
Unknown Corticosteroids, Antibiotics, Immunosuppressant, and Surgery
0 (0%) 1 (1.1%)
ANED
1 (100%)
AWD DOD
0 (0%) 0 (0%)
DOC
0 (0%)
Desai et al.: Skull Base Inflammatory Pseudotumor
TABLE IV. (Continued)
Treatment
Percent of Total Cases (no.)
Unknown Antibiotics, Hyperbaric Oxygen Therapy, Surgery ANED AWD
No. Cases per Treatment Modality (%)
0 (0%) 1 (1.1%)
0 (0%) 1 (100%)
DOD
0 (0%)
DOC Unknown
0 (0%) 0 (0%)
ANED 5 alive with no evidence of disease; AWD 5 alive with disease; DOC, dead of other cause; DOD 5 dead of disease; n 5 number of cases.
skull base often poses problematic access for biopsy, frequently requiring an open approach. Cases of lesions in the cavernous sinus were most associated with the open biopsy approach in this review. Histologically, the vast majority of biopsies showed fibrosis with infiltration of inflammatory cells, most commonly lymphocytes and plasma cells. There appears to be universal consensus that these are the defining histopath-
ological attributes of IPT. The presence of fungus and bacteria were absent on all biopsy samples reported, and only 3.4% of cases showed cellular atypism or mitotic activity. Of the few cases that disclosed inflammatory marker results, erythrocyte sedimentation rate (ESR) and Creactive protein (CRP) were most commonly elevated. Serologic tests for EBV and viruses proved unfruitful in this review. Thirteen cases reported IgG4 testing, 11 of which tested positive for the antibody. The presence of IgG4positive plasma cells is the hallmark of IgG4-related diseases in which patients suffer from fibrotic and lymphoplasmacytic tumor-like swellings of organs such as the liver and orbit.6 These lesions histologically resemble IPT and make the IgG4 cell marker a point of interest. It appears that a thorough investigation into the relationship between IgG4 and IPT has not yet been performed, but considering the data from this study, it may provide valuable insight into the clinical nature and management of IPT.
Treatment and Outcome Complete eradication of sinonasal and ventral skull base IPT is difficult. Of the 87 cases reviewed, only 24 were reported to be symptom-free at follow-up, but over half of the patients were AWD with symptomatic improvement and/or improvement of lesion on repeat imaging. There is no consensus on optimal treatment for
Fig. 3. (A) Diagrammatic representation of diagnostic algorithm. On the left, the inverted triangle emphasizes the refining process of differential diagnosis and characterization of IPT, as guided by results obtained from diagnostic imaging and histopathological findings on biopsy. (B) Flow chart of an optimized algorithm for the management of skull base IPT. *Probable inflammatory pseudotumor based on findings from this systematic review. AMS 5 altered mental status; IPT 5 inflammatory pseudotumor.
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sinonasal and ventral skull base IPT. Given this information, it is not surprising that the reviewed treatment plans varied case to case at the discretion of the clinicians. Fifteen treatment approaches were observed involving the combination or exclusive use of corticosteroids, surgery, radiotherapy, other immunosuppression, antibiotics, and hyperbaric oxygen therapy. This review found corticosteroids to be the treatment of choice for sinonasal and ventral skull base IPT. Although few cases disclosed treatment specifics, variable initial dosages of corticosteroids were observed to range from 30 mg to 100 mg daily. The treatment courses were in effect for varying lengths of time, with no obvious relationship between patient outcome and dosage strength or course length. Because corticosteroids are the most popular treatment modality for IPT, there appears to be a need for guidelines or a standardized approach to their dosage and course length for sinonasal and ventral skull base IPT. Nevertheless, corticosteroids were observed to be a very effective treatment for these lesions. The combination of corticosteroids and radiotherapy was one of the least successful treatment modalities noted in this review, with half of the eight subjects DOD. Apart from corticosteroids or surgical intervention, the advantage of one treatment modality over another against sinonasal and ventral skull base IPT is unclear. The combination of corticosteroids and surgery or surgical resection alone appears to be a rarely used treatment modality for sinonasal and ventral skull base IPT, although very successful at completely eliminating disease in this review. Treatment of sinonasal and ventral skull base IPT remains heavily reliant on corticosteroid therapy; yet it appears to be less successful at producing disease-free patients than surgical resection. The reasoning behind this may lie within the history of skull base surgery itself. The intricate sinonasal and ventral skull base anatomy poses high-risk surgical access that historically has been difficult for surgeons to approach with limited morbidity until the recent use of endoscopy. Corticosteroids have been the first-line treatment since the classification of IPT, so it is not surprising that this review shows corticosteroids treatment and nonsurgical intervention to be the treatment of choice over the past several decades. However, given the success rates of surgical resection in this review and the noninvasive endoscopic surgical technology available to rhinologists and endoscopic skull base surgeons, it may be beneficial to explore the possibility of surgery as a first-line treatment option for sinonasal and ventral skull base IPT in select cases. Corticosteroids may be a beneficial supplement to surgical intervention. In patients unable to be treated with high-dose corticosteroids (e.g., diabetics), surgery can reduce the potential drawbacks associated with high-dose corticosteroids. Other immunosuppressants were rarely used as initial treatment but were most commonly added to existing treatment regimens at the point of symptomatic or lesion recurrence. The use of mycophenolate mofetil, methotrexate, cyclophosphamide, a-interferon, Laryngoscope 00: Month 2014
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rituximab, and azathioprine was observed. The least popular treatment modalities appear to be antibiotics and radiotherapy. Radiotherapy was applied most commonly in combination with surgical resection. Antibiotics showed no benefit in this review, and radiotherapy appeared beneficial only in conjunction with surgical resection. When sinonasal or ventral skull base IPT is suspected, we recommend first ruling out true neoplasm or malignancy. Helpful laboratory tests include ESR and CRP, which tend to be elevated in the setting of IPT. MRI and CT are important complementary diagnostic tools. Biopsy and histopathological analysis are essential for definitive diagnosis and should be performed early to prevent treatment delay. Histological landmarks of IPT are fibrosis with inflammatory cell infiltrate, predominantly lymphocytes and plasma cells. IgG4 staining of plasma cells can be useful if there remains any diagnostic uncertainty after biopsy. This report showed the greatest success rate of treatment with corticosteroids or surgical resection alone. Other immunosuppressants may be useful for recurrences. Regardless of treatment modality, total eradication of sinonasal and ventral skull base IPT is difficult. Consequently, close follow-up is recommended (Fig. 3).
Limitations Intrinsic limitations to this study stemmed from the quality of data available. Inflammatory pseudotumor of the sinonasal and ventral skull base is a rare entity with relatively few cases reported in the literature. Additionally, according to the Oxford Centre for Evidence-Based Medicine, the level of evidence for the studies included in this review were poor and comprised of level 4 and 5 studies. The cases available also provided nonuniform reporting of the presentation, imaging, course of treatment, and patient outcome. Many cases did not disclose key data variables, and the overall quality of data from case to case was inconsistent. Because of the small sample size in this study, a meta-analysis was not performed, predisposing this study to selection bias.
CONCLUSION Sinonasal and ventral skull base IPT is a rare nonneoplastic inflammatory lesion with variable symptomatic presentation. Its clinical presentation and radiographic resemblance to malignancy often contribute to misdiagnosis and delay in appropriate treatment. Although MRI and CT are useful tools for differential diagnosis, biopsy and histopathological analysis are essential for conclusive diagnosis. Corticosteroids were the most common treatment modality used and were very successful at managing disease. Although surgical resection was rarely utilized, it appeared to have been the most successful treatment modality in achieving disease-free patient outcome. Improvement of symptoms and/or lesion is likely, regardless of treatment modality. Complete resolution of disease is uncommon with IPT of the sinonasal and ventral skull base. Desai et al.: Skull Base Inflammatory Pseudotumor
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