Jacqueline R. Carrasco

BASICS

DESCRIPTION

• Lacrimal gland tumors include a wide variety of masses that may be epithelial or nonepithelial, benign or malignant, and primary or metastatic.

• Historically, ∼50% of lacrimal gland lesions were epithelial, and 50% benign. It seems that these numbers were subject to referral bias to tertiary care institutions. Rarer, interesting, and/or malignant lesions may be more likely to be reported. Further, reviews of these subjects reveal that some cases reported individually were also included in series.

• Current guidelines show the following (1):

– 10% of orbital lesions are in the lacrimal gland.

– 20% are epithelial, and 80% are nonepithelial.

– Of nonepithelial cases, idiopathic orbital inflammation seems most common, followed by non-Hodgkin’s B-cell lymphoma.

– Of epithelial cases, 55% are benign while 45% are malignant.

– Of benign epithelial tumors, dacryops (ductal cyst of the palpebral lobe) seems most common (37%).

– Of malignant epithelial tumors, adenoid cystic carcinoma is most common (∼60%).

– Thus, this chapter focuses on inflammatory, benign epithelial, and adenoid cystic etiologies with greatest detail.

EPIDEMIOLOGY

Varies widely based on tumor etiology

• Adenoid cystic carcinoma: Mean age at presentation is 40 years, with recognized cases historically presenting in the first two decades as well. Can occur in any age.

• Dacryops: Common (6%), usually in young or middle-aged patients, and rarely symptomatic (only around 21% in reported series require excision).

• Orbital lymphoma/reactive lymphoproliferative processes: Equal incidence of males and females, with age range including all ages, mean age 55 years.

• Idiopathic orbital inflammation (IOI): Wide age range, from teens to 70s in many series, with a mean age of 45 years and an even gender distribution.

• Sarcoidosis: Can occur in any age, but most common between 20 and 40 years, and rare after 50 years.

– Within the orbit, the lacrimal gland is most commonly involved (up to 61%).

– In North America, highest incidence amongst African Americans: 35.5 cases per 100,000

– In the world, highest incidence amongst Northern Europeans: up to 60 cases per 100,000

RISK FACTORS

• Malignant epithelial lesions: Incomplete resection of prior lesion, whether benign or malignant

• Lymphoma: Sjögren’s syndrome predisposes to orbital adnexal lymphoma.

• Idiopathic inflammation: Viral and environmental factors are proposed triggers.

• Sarcoidosis: Environmental triggers such as pesticides and pollutants have been postulated but are largely theoretical.

Genetics

• Lymphoma: Largely depends on the type of lymphoma. T(11;18)(q21;q21) may represent an important developmental event in marginal zone lymphomas, resulting in a gene fusion on chromosome 11 and the development of the MALT1 gene on chromosome 18.

• Idiopathic inflammation: Unknown.

• Sarcoidosis: Two genome-wide scans may be biased by population selection:

– White Germans – chromosomes 3p and 6p

– African Americans – chromosomes 5p and 5q.

GENERAL PREVENTION

Depends on the etiology of orbital tumor, but largely unknown in most cases.

PATHOPHYSIOLOGY

Varies widely based on tumor etiology. See the “Pathological findings” section for histologic detail of tumor entity.

ETIOLOGY

• Epithelial lesions (in order of decreasing incidence in patients warranting referral to an ophthalmic oncology service):

– Dacryops, adenoid cystic carcinoma, pleomorphic adenoma, pleomorphic adenocarcinoma, prolapsed lacrimal gland, mucoepidermoid carcinoma

• Nonepithelial lesions (in order of decreasing incidence in patients warranting referral to an ophthalmic oncology service):

– Dacryoadenitis (pseudotumor), non-Hodgkin’s lymphoma, benign reactive lymphoid hyperplasia, atypical lymphoid hyperplasia, plasmacytoma, lymphoepithelial hyperplasia

• Sarcoidosis: See previous epidemiology

• Leukemia, metastases, dermoids, lipomas, Wegener’s granulomatosis, and plasmacytomas

• Infectious: tuberculosis, syphilis, and mumps

• A recent review of patients with lacrimal gland enlargement referred to the Wills Eye Institute Oculoplastics and Orbital Surgery service shows that 43% of lacrimal gland lesions were nongranulomatous inflammation, 20% were sarcoidosis, 10% were reactive lymphoid hyperplasia, 6% were lymphoma, and 5% were atypical lymphoid hyperplasia.

COMMONLY ASSOCIATED CONDITIONS

• Salmon patch: Pink subconjunctival lesion may represent extension of orbital lymphoma.

• Sjögren’s syndrome: May precede lacrimal gland lymphoma or be associated with sarcoidosis infiltration of the lacrimal gland, parotid, and conjunctiva

• Lofgren’s syndrome: Arthritis, erythema nodosum, and bilateral hilar adenopathy with sarcoidosis

• Arthritis: Rheumatoid or juvenile rheumatoid with sarcoidosis

• Heerfordt syndrome: Parotid enlargement, anterior uveitis, and cranial nerve palsies with sarcoidosis.

• Blau’s syndrome (familial juvenile systemic granulomatosis): Children may present with granulomatous arthritis, skin and eye pathology with sarcoidosis.

DIAGNOSIS

HISTORY

• Careful history must be taken regarding previous malignancies, lacrimal gland biopsies, or surgeries.

• Epithelial and nonepithelial malignancies: Inferior and nasal globe displacement with proptosis. Lesions are typically painless, although pain may be seen with bony erosion or perineural involvement (typical of adenoid cystic carcinoma). Ptosis, motility disturbances, and diplopia may occur with lacrimal gland malignancies.

• Benign epithelial tumors: Typically a long history of painless proptosis ± globe displacement. “S-shaped” proptosis seen in orbital lobe involvement.

• IOI: Explosive onset of pain and swelling predominantly in the outer one-third of the upper eyelid. Tearing, injection, diplopia, and decreased vision. If previous episodes exist, rapid response to corticosteroids is the norm.

• Infectious: May appear similar to IOI, which exists along a spectrum of inflammation with scleritis, but with purulent discharge in bacterial cases or frequent bilateral involvement with preauricular nodal involvement with viral etiologies. Fevers, chills, sweats, and other systemic symptoms should be screened for but are nonspecific.

• Sarcoidosis: Systemic symptoms such as fevers, chills, sweats, and weight loss. Adnexal involvement marked by pain, proptosis, and lacrimal gland enlargement. Sarcoidosis most commonly affects the lungs, eyes, and skin, so history may be tailored toward a targeted review of systems accordingly.

PHYSICAL EXAM

• Physical exam should be a thorough ophthalmologic evaluation with consideration of all aforementioned potential etiologies.

• Visual acuity, intraocular pressure, visual fields, and extraocular motility should be evaluated in all patients.

• All cranial nerves should be evaluated, and the presence or absence of ptosis should be documented.

• Optic nerve involvement and infiltration should be evaluated with visual fields, color plates, and pupillary examination.

• Anterior slit lamp exam includes evaluation of conjunctival nodules, conjunctivitis, episcleritis, scleritis, dry eyes, corneal edema, keratic precipitates (may be granulomatous, particularly in a triangular distribution on the inferior corneal endothelium), anterior chamber cell and flare, peripheral anterior synechiae, and posterior synechiae given differential diagnosis including sarcoidosis and blood dyscrasias.

• Posterior slit lamp and indirect exam should evaluate for peripheral retinal neovascularization, periphlebitis and peripheral retinal vein sheathing, intermediate uveitis, and optic nerve edema.

• Full physical exam should evaluate for tachypnea, arthritis, lymphadenopathy, hepatosplenomegaly, erythema nodosum (most commonly found over shins), and skin rashes.

– Imaging and further evaluation as below.

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• Angiotensin converting enzyme (ACE): Elevated in 60–90% of patients with active sarcoidosis. Rates higher in those with active signs and symptoms

• CBC with differential and serum protein electrophoresis if malignancies suspected. Blood smear to further pursue etiology.

• PPD with anergy panel to evaluate tuberculosis, and to rule it out if steroid therapy anticipated.

• Antineutrophil cytoplasmic antibody (cANCA), ANA, RPR, FTA-Abs to evaluate for autoimmune and infectious causes as history and exam warrant.

Imaging

Initial approach

• Orbital CT with axial and coronal views. Look at the lacrimal gland fossa (superotemporal orbit) for the presence of any bony erosion.

• MRI if suspicion of intracranial extension

• Chest X-ray to evaluate for sarcoidosis, tuberculosis, primary malignancy, or metastases

• Chest CT if initial imaging nondiagnostic

Follow-up & special considerations

• Systemic evaluation and full medical examination should be performed by an internist as etiology or suspected etiology demands.

• Hematology/oncology evaluation when malignancy, both epithelial and nonepithelial, is diagnosed or suspected.

• Systemic or neurologic involvement should involve internal medicine, pulmonology, rheumatology, and/or neurologic referral as primary etiology calls for. Further evaluation and treatment, as below, is often performed in conjunction with healthcare practitioners in those fields.

Diagnostic Procedures/Other

• Note: Do not biopsy lesions suspected to be dermoids! Ruptured dermoids may cause dramatic inflammatory reactions.

• Note: Do not biopsy or incompletely excise benign mixed tumors! Incomplete excision may result in orbital seeding and recurrence with our without malignant transformation.

• Lacrimal gland biopsy is considered if lesions are accessible, diagnosis is uncertain, and malignancy is suspected. The orbital lobe of the lacrimal gland is the preferred site of biopsy, in order to preserve lacrimal ductules in the palpebral lobe.

• Typical granulomas need evaluation with special stains (methenamine-silver to rule out tuberculosis and fungal infections, and acid-fast to look for mycobacteria). In sarcoidosis, lacrimal gland biopsy has a 60% yield.

• Conjunctiva may be biopsied in sarcoidosis suspects: Yield of blind conjunctival biopsy is 66% in sarcoidosis patients, and 80% in those with conjunctival involvement.

• Skin lesions may be biopsied in sarcoidosis: The edges of lesions should be sampled. Erythema nodosum does not contain pathologic changes.

• Whole-body gallium scan, when combined with positive ACE, is up to 73% sensitive and 100% specific for sarcoidosis.

• Bronchoscopy with pulmonary biopsy may be performed with consideration from a pulmonologist and/or cardiothoracic surgeon in cases with pulmonary involvement by the primary etiology. Other distant organ system involvement, either metastatic or primary, warrants diagnostic evaluation by the appropriate subspecialist.

Pathological Findings

• Adenoid cystic carcinoma: Solid cords of bland-appearing malignant epithelial cells with well-defined borders of five subtypes, including basaloid, cribriform, sclerosing, tubular, and comedocarcinoma

• Benign epithelial neoplasms: Myoepithelial cells are present in adjacent tissue, as opposed to adenoid cystic carcinoma, which has clearly defined borders.

• Sarcoidosis: Noncaseating granulomas, or congregations of epithelioid cells and macrophages, with negative special stains as above

• IOI: Cellular infiltrate consisting of mature lymphocytes, plasma cells, neutrophils, eosinophils, macrophages, and occasionally histiocytes with stromal and vascular changes, fibrosis, and tissue edema

DIFFERENTIAL DIAGNOSIS

• See etiologies.

• Prolapsed retro-orbital fat in the anterior, superotemporal quadrant may simulate lacrimal gland enlargement.

• Perilacrimal gland tumors not involving the gland itself may simulate lacrimal gland masses.

TREATMENT

• Adenoid cystic carcinoma and other epithelial malignancies: Orbital exenteration is usually indicated, particularly in adenoid cystic carcinoma. Neoadjuvant intracarotid chemotherapy or systemic chemotherapy may improve prognosis, and postexenteration orbital irradiation (55–60 Gy) has been recommended, although long-term follow-up data are not available.

• Dacryops/benign epithelial tumors: Complete excision

• Lymphoid tumors: Initial biopsy with local radiation and corticosteroids in indolent cases if confined to the orbit; chemotherapy with subsequent irradiation for systemic involvement

• Sarcoidosis: Systemic immunosuppression with corticosteroids initially followed by steroid-sparing agents; however, high-dose NSAIDs standard of care in the UK. Systemic immunomodulators if steroids fail or are poorly tolerated. Surgical debulking or radiation therapy.

– Majority of sarcoidosis regresses spontaneously, but observation not recommended.

• IOI: Oral prednisone 80–100 mg daily with GI prophylaxis usually induces prompt response. Low-dose radiation may be used in nonresponders. Treatment refractory cases are atypical may warrant evaluation for other causes of lacrimal gland inflammation.

ADDITIONAL TREATMENT

Issues for Referral

• Neurology and neuro-ophthalmic consultation to evaluate for central neurologic involvement.

• Systemic or other organ involvement warrants referral for evaluation and management as stated previously.

IN-PATIENT CONSIDERATIONS

• As above, IOI not responding promptly to corticosteroids should prompt evaluation, including biopsy, for other etiologies of lacrimal gland inflammation/enlargement.

• Lacrimal gland malignancies warrant internal medicine/oncology subspecialist evaluation for metastatic work-up.

Admission Criteria

Compressive, inflammatory, or vascular optic neuropathies may warrant intravenous corticosteroids, orbital decompression, or other intervention necessitating admission and urgent management.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• Epithelial and nonepithelial malignancies must be followed as per recommendations by the hematology/oncology subspecialist for appropriate management.

• Inflammatory conditions: Follow-up intervals depend on severity of inflammation, and patients are usually followed every 1–7 days. Steroid doses, whether topical or oral, are adjusted according to response to treatment, and are tapered as clinical progress allows.

Patient Monitoring

• IOP and cataract development should be followed in patients treated with steroids.

• Patients treated with oral steroids should be seen by their primary care physicians every 3–6 weeks for general exams and blood work to evaluate blood pressures and blood sugars, for example.

PROGNOSIS

• Varies greatly based on the etiology of lacrimal gland mass

• Within epithelial lesions, adenoid cystic carcinoma carries worse prognosis than other lesions.

• Benign lesions completely excised usually do not recur.

• IOI and sarcoidosis often promptly respond to steroids, but may recur.

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