Lacrimal gland enlargement is a common finding in TED and particularly in the active stage of the disease [4, 6, 7]. Asymmetric lacrimal gland enlargement on the background of thyroid eye disease is atypical and warrants further investigation given the possibility of malignancy and other inflammatory diseases. Ishikawa et al. presented a series of 16 patients with TED and asymmetrical lacrimal enlargement. Biopsies on 9 patients revealed disease entities other than thyroid eye disease such as IgG4-related disease, sarcoidosis and MALT lymphoma [3]. The potential for malignant and severe inflammatory disease means the threshold for biopsy should be low when faced with asymmetrical lacrimal gland enlargement.

Radiological findings may assist the decision-making regarding biopsy of the lacrimal gland. Epithelial neoplasms predominantly involve the orbital lobe whilst inflammatory and lymphoproliferative lesions tend to involve both the orbital and palpebral lobes [8]. Lymphoproliferative disease may also cause bony scalloping, which is generally not seen with inflammatory lesions [8]. Diffusion-weighted imaging (DWI) can be informative: typically the apparent diffusion coefficient (ADC) of the lacrimal gland is low in lymphoma but may be high in TED when compared to healthy controls [9, 10]. The ADC of the lacrimal gland also has a high predictive value to determine active compared to inactive TED. Lacrimal gland features on MRI may assist in staging TED. The signal intensity ratio of the lacrimal gland to the ipsilateral temporal muscle on fat suppressed T2 weighted MRI imaging has shown promise in staging active TED [11]. Patients with active TED demonstrate a higher signal intensity ratio (SIR) of the lacrimal gland to the ipsilateral temporal muscle compared against patients with inactive TED. Clinical features and a careful history may also aid the decision on whether to biopsy the lacrimal gland. Lacrimal gland prolapse is also more likely in active thyroid eye disease [6, 12]. However, the presence of a prolapsed lacrimal gland may make clinical judgement of an enlarged lacrimal gland more difficult clinically and therefore radiological measurements are required.

Previously reported lacrimal gland histopathological findings in TED have also shown nonspecific inflammatory cell infiltration with and without fibrosis [3, 13, 14]. Of the patients with nonspecific dacryoadenitis in the Ishikawa et al. series, inflammatory cells were present with a small amount of fibrotic change in all seven patients and two patients demonstrated germinal centres [3]. Yahalomi et al. described a case of asymmetric lacrimal gland enlargement in a patient with thyroid eye disease with histopathology demonstrating periacinar lymphocytic infiltration [13]. Khu et al. also presented a case report of asymmetric lacrimal gland enlargement in the setting of thyroid eye disease with biopsy showing a mild chronic inflammatory infiltrate composed of plasma cells [14]. The normal lacrimal gland becomes increasingly fibrotic with age [15]. The oldest patient at time of biopsy (68) in our series was the only biopsy specimen to demonstrate fibrosis; it is uncertain if this derives from age or TED chronicity. The residual inflammation present in the biopsies may be an indicator of grumbling inflammation despite all four patients being clinically inactive. Although not present in our series, germinal centres have previously been described in TED-related lacrimal gland enlargement [3]. This finding is also consistent with follicular type idiopathic orbital inflammation (IOI) [16, 17].

These nonspecific histological changes, to some extent, diagnoses thyroid eye disease by exclusion, given the lack of a specific histopathological marker, although there remains the possibility of other concurrent, non-specific, diseases such as idiopathic dacryoadenitis that tend to present unilaterally.

All four patients in the present study were hyperthyroid which contrasts with previous studies which have shown asymmetric TED clinical presentations predominantly in euthyroid or hypothyroid disease states [3, 14, 18, 19]. Fourteen of the sixteen patients analysed in the Ishikawa et al. series on asymmetrical lacrimal gland enlargement were euthyroid [3]. In Eckstein et al.’s study comparing TED clinical symptoms in hyperthyroid patients versus hypothyroid and euthyroid patients, the authors postulated that monosymptomatic and asymmetrical manifestations in euthyroid patients may lead to diagnostic difficulty, increasing the use of imaging by clinicians to confirm diagnosis. Sub-clinical enlargement of the lacrimal gland may therefore be revealed more often in euthyroid and hypothyroid patients through imaging [18].

There are several limitations to this study. Firstly, the retrospective and non-comparative design limit inferences that can be drawn. Secondly, a standard set of immunohistochemical testing was not undertaken due to the retrospective and multi-centre nature of the study. Finally, we have included a small number of patients, although this may reflect the relatively uncommon nature of TED-related, asymmetric lacrimal gland enlargement.