Lacrimal gland tumors
Lacrimal gland tumors
Disease and distribution
Lacrimal gland tumors are very rare, representing only 10% of orbital space-occupying lesions.(1) They have an estimated incidence of 1 per 1 million people per year. (2) The incidence rate for malignant lacrimal gland tumors in the US is estimated to be at 0.43 per million person-years.(3)
Many tumours types may arise from the lacrimal gland. These neoplasms are generally classified into two types: epithelial and non epithelial. Non epithelial lesions are by far the most common, corresponding to 70-80% of solid lacrimal gland masses whereas only 20-25% are of epithelial origin (1)(4). Non epithelial tumors include lymphoid tumors, plasmacytoma, fibrous histiocytoma, orbital granulocytic sarcoma, hemangioma, solitary fibrous tumor, lipoma, neurofibroma, schwannoma, metastatic or secondary tumors, and inflammation (eg. sarcoidosis, orbital inflammatory pseudotumor, Sjogren syndrome, dacryoadenitis).(4)(5)(6) In a survey conducted by Shields et al. (7) the most common nonepithelial mass of the lacrimal gland was dacryoadenitis, in the form of orbital inflammatory pseudotumor confined to the lacrimal gland. Most orbital lymphomas are non Hodgkin of the B cell lineage and represent the most common malignant orbital tumor in older patients, almost 1/4 of all orbital malignancies in the group above 60.(7)(8)
Primary epithelial lesions of the lacrimal gland may be subdivided into benign and malignant lesions. 55% of reported epithelial tumors are benign and 45% are malignant (1), and the proportional difference may be even greater in Asian populations, with studies which have reported up 72-76% pertaining to benign epithelial tumors.(9)(10) Benign epithelial lesions include ductal epithelial cyst and pleomorphic adenoma (PA, also called benign mixed tumor), the latter being the most common benign epithelial tumor of the lacrimal gland (4)(5). Other less common benign epithelial tumors include oncocytoma, Warthin's tumor, myoepithelioma, and sialoblastoma.(5) Of the malignant epithelial lesions, 'adenoid cystic carcinoma (ACC) comprises approximately 60%, 20% are pleomorphic adenocarcinoma, 10% are primary (de novo) adenocarcinoma, 5% are mucoepidermoid carcinoma, and 5% are miscellaneous malignant epithelial neoplasms'.(1)
All lacrimal gland tumors can present at any age. Epithelial tumors are commonly diagnosed in middle aged adults, PA and ACC generally present in patients with an average age of 40 years. On the other hand, lacrimal gland lymphomas usually are diagnosed in older patients, with an average age of 70 years. (2)(4)(7) Most neoplasias occur as sporadic lesions and arise when the number of genetic changes at the cellular level overcome the cell's ability to revert these. (2) Both the salivary and lacrimal glands share the same embryology and morphology, therefore tumors that develop from them are considered to be highly similar in their genetic background.(12) According to Holstein et al. (11) and Mendoza (13), analysis of lacrimal gland tumor biopsies revealed several findings: adenoid cystic carcinoma expressed the MYB–NFIB oncogene fusion and overexpressed MYB, mucoepidermoid carcinoma expressed the CRTC1–MAML2 gene fusion, and pleomorphic adenoma and carcinoma-ex-pleomorphic adenoma had high overexpression of the PLAG1 oncogene. Secondary metastasis to the lacrimal gland are quite rare but are mostly found to be associated to primary breast and lung carcinomas.(6)
Dacryops is a benign lacrimal duct lesion characterized by lacrimal duct epithelium cysts .(5)
Pleomorphic adenoma (PA) is pseudoencapsulated and tends to be well-defined. It is characterized by epithelial and myoepithelial elements that form lumen and spindle structures that are mixed in with other mesenchymatous structures. (13)(14)
Histopathologically, the only orbital structure where epithelial cells are commonly encountered is the lacrimal gland; therefore, orbital primary carcinomas should be considered to have their origin in the lacrimal gland unless proven otherwise.(8)
Adenoid cystic carcinoma (ACC) is characterized by solid areas or cords of bland-appearing malignant epithelial cells. The infiltrative borders of the epithelial areas can be distinguished from the surrounding connective tissue and typically show perineural invasion.(1) Immunohistochemical staining may be used to identify perineural invasion by identifying neurofilaments.(13) Adenocarcinoma and PA present myoepithelial cells in the surrounding connective tissue.(1)(13) ACC can be further subdivided into histopathologic subtypes: cribriform or 'Swiss cheese', sclerosing, basaloid, comedocarcinoma, and tubular types.
Pleomorphic adenocarcinoma or carcinoma-ex-PA is a neoplasm resulting from the malignant transformation of a PA. It is characterized by areas of malignant change in a PA with unequal proportions of myxoid and chondroid structures, the epithelial cells also show carcinomatous changes. In comparison with PA, pleomorphic adenocarcinoma contains less gland structures and the cells show less differentiation.
Primary adenocarcinoma also is characterized by glandular differentiation but does not have features that identify more specific carcinoma types.
Mucoepidermoid carcinoma contains different proportions of mucous, epidermoid, intermediate, columnar, and clear cells; a cystic component is almost always present.
Primary Squamous Cell Carcinoma (SCC) is characterized by proliferation of keratinizing malignant squamous cells that are well to moderately differentiated without any glandular structures being present.
Sebaceous gland carcinoma is rarely a primary lacrimal gland tumor, most cases are due to secondary involvement from the primary affectation in the eyelids. It is characterized by poorly differentiated cells with high mitoses, with positive staining for lipids contained in vacuoles in the cellular cytoplasm.
Benign lymphoepithelial lesion can undergo malignant transformation, resulting in B-cell lymphoma or lymphoepithelial carcinoma. Lymphoepithelial carcinoma is characterized by islands of undifferentiated carcinoma cells surrounded by a dense stroma made up of lymphocytes and macrophages.
Basal cell adenocarcinoma is characterized by uniform basaloid cells without the rest of the elements found in PA. negative Alcian blue stain and negative reaction to smooth muscle actin can help to distinguish this entity from ACC.(1)
As mentioned previously, the shared embriological origin of the salivary and lacrimal glands has led to the use of the salivary gland classification for lacrimal gland tumors. In 2006, the Armed Forces Institute of Pathology (AFIP) monograph on lacrimal gland tumors provided an expanded classification based on classification of salivary gland tumors from the World Health Organization in 1991. (15)
Reactive lymphoid hyperplasia generally involves bilateral lacrimal glands and affects them in a diffuse form, originating from the same surrounding lymphoid tissue. Lymphoma that affects the orbit usually is secondary to primary disease elsewhere in the body. Both entities tend to mold to the globe. The most common type of orbital lymphoma is the mucosa-associated lymphoid tissue (MALT) type, which carries a better prognosis compared to other types such as follicular lymphoma. Orbital granulocytic sarcoma or chloroma can also affect the lacrimal gland secondarily, originating either previous to or after the development of systemic leukemia. Primary sources include the uvea, retina, choroid, optic nerve, and the orbital fat and can spread secondarily to either lacrimal gland. (4)
Dacryops preferentially affect the palpebral lobe of the lacrimal gland, making them visible upon eversion the the eyelid. When the orbital lobe is affected, the consequent proptosis and "S shaped" ptosis may make it difficult to distinguish clinically from other malignant lesions. (5)
Pseudotumor, also called inflammatory dacryoadenitis or idiopathic orbital inflammation is an idiopathic fibroinflammatory process that is associated with autoimmune deregulation. Most patients have affectation of only one gland, with a chronic history of enlargement that may have an intermittent course. Biopsy rules out other causes, showing nongranulomatous inflammation.
Sjögren syndrome tends to affect both lacrimal glands with diffuse enlargement. The diagnosis includes rose Bengal staining, measurement of tear flow and biopsy of the lacrimal gland. (4)
All lacrimal gland tumors typically share the following symptoms(14)(6):
- Facial asymmetry due to displacement of the globe
- Limited ocular motility
- Enlargement of the lacrimal gland.
Epithelial lesions tend to develop mostly in the orbital lobe of the lacrimal gland and are principally unilateral.(4)
The initial sign is usually inferior and nasal displacement of the globe and proptosis, due to the superotemporal location of the lacrimal gland in the anterior aspect of the orbit. (1)(6)
Pain is uncommon in patients with benign tumors, with some causing mild pain on occasion. Patients with PA usually have a long history of painless proptosis. (5)(17) One of the exceptions is dacryoadenitis, which patients typically develop acutely and present with pain. (1) Otherwise, pain is often suggestive of malignancy and may be secondary to bone or orbital nerve involvement, particularly in patients with adenoid cystic carcinoma. (1)(14)
In up to 85% of cases of ACC, perineural invasion is found and indicates more aggressive behavior.(5)(18) The mean duration of symptoms before initial ophthalmic consultation is around 2 years for patients with pleomorphic adenoma and 6 months or less for patients with adenoid cystic carcinoma. (1)(14)
Other findings related to malignancy include blepharoptosis, abnormalities in ocular motility, "S shaped" ptosis, globe dystopia, and proptosis.(5) Pleomorphic adenomas have been reported in patients with concurrent thyroid eye disease.
A complete ocular exam needs to be done including inspection and palpation of the lacrimal gland, exophthalmometry, and evaluation for ocular displacement. Hypoesthesia in the area of the first and second divisions of the trigeminal nerve are highly suggestive of perineural invasion of orbital nerves. In all cases, an attempt should be made to do an excisional biopsy with complete remotion of the tumor, the diagnosis of a benign or malignant epithelial tumor of the lacrimal gland should be made histopathologically. Fine needle aspiration biopsy (FNAB) may be a viable option for an unresectable tumor in which primary or metastatic malignancy is suspected. (1)
Computed tomography (CT) and Magnetic resonance imaging (MRI) are the most important diagnostic imaging methods. On CT scan, the normal lacrimal gland has the same density as muscle. The normal glands show symmetric contrast enhancement. MRI scans permit better evaluation of glandular and periglandular involvement. Normal lacrimal glands have intermediate signal on T1 and T2 weighted imaging and enhance symmetrically after gadolinium administration. (4) Dacryops may present in imaging studies as cystic lesions filled with clear fluid.(5) In CT and MRI scans, PA normally appears as a solid, well defined, rounded lesion in the lacrimal fossa that may have calcifications on occasion and remodeling of adjacent bones. (5)(14) This contrasts with malignant tumors that may have irregular margins and signs of bony erosion even with relatively small lesions. Focal calcification is more suggestive of a malignant type tumor, especially ACC. (1)(14)(19)
The treatment of lacrimal gland lymphoma depends on its histologic classification (eg. follicular, mantle cell, etc.). Local radiotherapy is recommended for lesions confined to the orbit, whereas chemotherapy is used for systemic disease. The treatment of granulocytic sarcoma includes local disease control, chemotherapy, and bone marrow transplantation. The mainstay treatment for sarcoidosis and pseudotumor are corticosteroids, although more severe cases may require additional treatment with immunosuppressants. (4)
The primary treatment of lacrimal gland tumors is surgical removal. For masses in which imaging studies are highly suggestive of benign epithelial tumors, as well as for circumscribed lesions with smooth limits, a dacryoadenectomy and tumor excision should be performed. Diagnostic biopsies should be avoided in these cases due to the rate of recurrence of up to 30% over 5 years. (17) PA may degenerate into malignancy in up to 20% of cases, especially if there has been an incomplete excisional biopsy. Therefore, treatment must include complete surgical removal without rupturing the tumor capsule. If preoperative incisional biopsy is performed, subsequent treatment with complete surgical removal and excision of adjacent periorbital tissues may practically eliminate the chance of recurrence. (4)(19) For malignant tumors, surgery is generally followed by radiotherapy and/or chemotherapy. However, there is still controversy about what is the best course of treatment, particularly of the adenoid cystic type tumors. Globe-sparing surgery vs exenteration does not correlate all the time with the prognosis and the use of adjuvant treatments has also been debated.(14) There have been many nonsurgical treatment modalities tried for patients with advanced ACC of the lacrimal gland and for patients who wish to avoid surgical treatment. As adjuvant therapies, these include: external beam radiation therapy, plaque therapy, proton therapy, and neutron therapy. (18)
For ACC, aggressive treatment is usually done, consisting mainly of orbital exenteration and removal of adjacent orbital bone (radical orbitectomy) which may be combined with radiotherapy and/or chemotherapy. Improved imaging modalities have aided in the detection of ACC at much earlier stages than was previously possible, which also allows for more complete removal of the lesion. Therefore, it is more difficult to justify such radical surgery in patients who have scant or no evidence of residual tumor. Different reports have observed that radiotherapy may improve survival duration of patients with ACC and brachytherapy has been used in a few selected cases. Shields et al. (20) reported the use of a custom designed radioactive iodine-125 plaque which delivered radiation locally in patients who had minimal gross or microscopic residual tumor after surgery. None of their patients required exenteration of the diseased eye and they also did not present complications related to more extensive radiation (eg. external beam radiation therapy) such as cataract formation, radiation retinopathy, and keratopathy. Longer follow up in this report would be needed to confirm this initial findings. Noh and authors (21) also reported that gross residual tumor following surgery was a very important prognostic factor and that adjuvant radiotherapy was able to reduce local recurrence if there was no gross residual. Adding radiotherapy following R1 resection (complete resection with no gross residual tumor but positive for microscopic involvement of the margin on the pathology report) decreased the risk of progression but not if there was gross residual tumor present (R2). They also mentioned that globe-sparing surgery followed by radiotherapy was an appropriate treatment for patients with tumors <4 cm.
Neoadjuvant intracarotid chemotherapy, with cisplatin and doxorubicin, has also been used to try to improve the prognosis in patients with ACC and other types of malignant epidermoid tumors of the lacrimal gland. (2003 Shields) In a study conducted by Tse et al. (22), subjects studied did not have relapses after a median follow up of 10 years after the implementation of a neoadjuvant intraarterial cytoreductive chemotherapy protocol for patients whose tumor (ACC) had an intact lacrimal artery. The outcomes were significantly better than in the ACC patients who were treated with surgery and/or radiotherapy at the same institution. However, there were several patients in the study who presented chemotherapy-related, local, catheter-related, and neurologic adverse events which warrant further studies to minimize these types of treatment-related events. (18)
The prognosis of PA is generally good, but this type of tumors tend to recur locally. Multiple recurrences increase the risk of malignant transformation, especially in patients older than 45 years. (14)
Lacrimal gland carcinomas are often aggressive, with an average survival of only 36 months. ACC may recur and metastatize several years after the initial lesion is treated; the 10-year survival rate is only 20-30%. (14) Distant metastasis occur in about 50% of patients with ACC; factors that may contribute to local recurrence include: perineural invasion, microscopically positive resection margin, and a larger tumor size. (1)(18) A solid growth pattern or basaloid differentiation is associated with more aggressive tumors and a reduction in disease-free survival. (17) Preliminary exome sequencing studies of lacrimal gland ACC have demonstrated mutations in the NOTCH signally pathway and over-expression of Her-2 in adenocarcinomas. This knowledge may yield potential targets for future therapies. (24,25)
Improved resolution in current imaging studies of CT and MRI allows the earlier diagnosis and treatment of lacrimal gland tumors. Supplementary treatment modalities such as chemotherapy and radiotherapy have also evolved into being more specific and able to treat the affected area without causing more systemic complications. Therefore, increased survival rates are expected to continue in the future as these therapies are steadily refined.
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