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. 2023 Nov-Dec;39(6):588-593.
doi: 10.1097/IOP.0000000000002410. Epub 2023 Jun 6.

Inflammation and Fibrosis in Orbital Inflammatory Disease: A Histopathologic Analysis

Rohan Verma  1   2 , Allison J Chen  3 , Dongseok Choi  4   5 , David J Wilson  2 , Hans E Grossniklaus  6 , Roger A Dailey  1   2 , John D Ng  1   2 , Eric A Steele  1   2 , Stephen R Planck  2   7 , Craig N Czyz  8 , Bobby S Korn  3   9 , Don O Kikkawa  3   9 , Jill A Foster  10 , Michael Kazim  11 , Gerald J Harris  12 , Deepak P Edward  13   14 , Azza Al Maktabi  14 , James T Rosenbaum  2   4   7   15
Affiliations

Inflammation and Fibrosis in Orbital Inflammatory Disease: A Histopathologic Analysis

Rohan Verma et al. Ophthalmic Plast Reconstr Surg. 2023 Nov-Dec.

Abstract

Purpose: The purpose of this study was to compare the histopathologic inflammation and fibrosis of orbital adipose tissue in orbital inflammatory disease (OID) specimens.

Methods: In this retrospective cohort study, inflammation, and fibrosis in orbital adipose tissue from patients with thyroid-associated orbitopathy (TAO), granulomatosis with polyangiitis (GPA), sarcoidosis, nonspecific orbital inflammation (NSOI), and healthy controls were scored by 2 masked ocular pathologists. Both categories were scored on a scale of 0 to 3 with scoring criteria based on the percentage of specimens containing inflammation or fibrosis, respectively. Tissue specimens were collected from oculoplastic surgeons at 8 international centers representing 4 countries. Seventy-four specimens were included: 25 with TAO, 6 with orbital GPA, 7 with orbital sarcoidosis, 24 with NSOI, and 12 healthy controls.

Results: The mean inflammation and fibrosis scores for healthy controls were 0.0 and 1.1, respectively. Orbital inflammatory disease groups' inflammation (I) and fibrosis (F) scores, formatted [I, F] with respective p -values when compared to controls, were: TAO [0.2, 1.4] ( p = 1, 1), GPA [1.9, 2.6] ( p = 0.003, 0.009), sarcoidosis [2.4, 1.9] ( p = 0.001, 0.023), and NSOI [1.3, 1.8] ( p ≤ 0.001, 0.018). Sarcoidosis had the highest mean inflammation score. The pairwise analysis demonstrated that sarcoidosis had a significantly higher mean inflammation score than NSOI ( p = 0.036) and TAO ( p < 0.0001), but no difference when compared to GPA. GPA had the highest mean fibrosis score, with pairwise analysis demonstrating a significantly higher mean fibrosis score than TAO ( p = 0.048).

Conclusions: Mean inflammation and fibrosis scores in TAO orbital adipose tissue samples did not differ from healthy controls. In contrast, the more "intense" inflammatory diseases such as GPA, sarcoidosis, and NSOI did demonstrate higher histopathologic inflammation and fibrosis. This has implications in prognosis, therapeutic selection, and response monitoring in orbital inflammatory disease.

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Conflict of interest statement

J.T.R. has in the past consulted for Genentech/Roche and was a co-investigator on a study funded by Genentech to evaluate the use of rituximab for orbital inflammatory diseases. J.T.R., R.A.D., and D.O.K. are consultants, while G.J.H. and B.S.K. have in the past consulted for Horizon Pharmaceuticals, which manufactures teprotumumab. Other authors have no conflicts of interest to disclose.

Figures

Figure 1.
Figure 1.
Specimen grading examples. Representative images demonstrating the histologic variability of orbital fat in subjects diagnosed with TAO, GPA, sarcoidosis, and NSOI compared to heathy controls. Hematoxylin and eosin staining in paraffin embedded sections (20x). A. Control (center) Average inflammation score of 0 (DJW 0, HEG 0). Average fibrosis score of 0.5 (DJW 0, HEG 1). B. TAO (top left) 49-year-old female within 12 months of ocular onset. No history of steroid or steroid sparing agents or radiotherapy. Average inflammation score of 0 (DJW 0, HEG 0). Average fibrosis score of 2 (DJW 2, HEG 2). C. GPA (top right) 24-year-old male within 5 months of ocular onset. No history of steroid or steroid sparing agents or radiotherapy. Average inflammation score of 3 (DJW 3, HEG 3). Average fibrosis score of 2 (DJW 2, HEG 2). D. Sarcoidosis (bottom left) 60-year-old female within 8 months of ocular onset. On high dose steroids at time of biopsy without any history of steroid sparing agents or radiotherapy. Average inflammation score of 3 (DJW 3, HEG 3). Average fibrosis score of 2 (DJW 2, HEG 2). E. NSOI (bottom right) 83-year-old male within 1 month of ocular onset. On high dose steroids at time of biopsy without any history of steroid sparing agents or radiotherapy. Average inflammation score of 1 (DJW 1, HEG 1). Average fibrosis score of 1.5 (DJW 1, HEG 2).
Figure 2.
Figure 2.
Time in months from ocular symptom onset to biopsy in the OID groups. Asterisks indicate outlying data points: 1 sample in TAO: 432 months; 1 sample in NSOI: 444. All pairwise differences of median time of biopsy were statistically significant by the Mann-Whitney U test except between GPA and sarcoidosis. TAO = thyroid-associated orbitopathy; GPA = granulomatosis with polyangiitis; NSOI = nonspecific orbital inflammation.
Figure 3.
Figure 3.
Pathologist Grading Scale of inflammation and fibrosis in the OID groups with respect to time in months from ocular symptoms onset to biopsy. A. TAO. B. GPA. C. Sarcoidosis. D. NSOI. TAO = thyroid-associated orbitopathy; GPA = granulomatosis with polyangiitis; NSOI = nonspecific orbital inflammation.
See this image and copyright information in PMC

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