TABLE 1. Diseases of the Lacrimal Gland

  Isolated inflammations
  Idiopathic
  Orbital inflammatory disease (OID)
  Granulomatous
  Infectious
  Systemic inflammations
  Sarcoidosis
  Wegener's granulomatosis
  Graves' disease
  Sjo†gren's disease
  Systemic lupus erythematosus
  Lymphoproliferative
  Benign lymphoid hyperplasia
  Atypical lymphoid hyperplasia
  Malignant lymphoma
  Benign tumors
  Pleomorphic adenoma (benign mixed tumor)
  Myoepithelioma
  Oncocytoma
  Cavernous hemangioma
  Malignant tumors
  Adenoid cystic carcinoma
  Primary adenocarcinoma
  Pleomorphic adenocarcinoma (malignant mixed tumor)
  Mucoepidermoid carcinoma
  Squamous cell carcinoma
  Sebaceous cell carcinoma
  Miscellaneous diseases
  Congenital dermoid cysts
  Dacryops
  Amyloidosis

This chapter will review the anatomy and embryology of the main lacrimal gland, the presentation of lacrimal gland diseases, the appropriate clinical and radiologic evaluation, the specific inflammatory and infiltrative processes, and the appropriate management of such disorders. For organization of the diagnosis and treatment, lacrimal gland fossa masses will be divided into four major categories, including infectious and noninfectious inflammations, lymphoproliferative disorders, benign neoplasms of the lacrimal gland, and malignant neoplasms of the lacrimal gland.

The main lacrimal gland is a bilobed, flat, oval mass of approximately 78 g. It occupies the space between the globe and orbital roof in the superior temporal quadrant of the orbit.⁷ The lobulated, grayish pink surface of the lacrimal gland allows one to easily distinguish this gland from surrounding orbital tissue. In addition, a thin pseudocapsule covers the gland, which assists in surgically defining a tissue plane between some lacrimal gland neoplasms and normal orbital tissue.^8,9 The inferior surface of the lacrimal gland contours to the shape of the globe and is therefore slightly concave. The superior convex surface fills a shallow depression in the anterior lateral aspect of the frontal bone called the fossa glandulae lacrimalis, or lacrimal gland fossa. The lacrimal gland fossa may be seen on plain radiographs as a smooth line arching over the superior temporal orbital rim.

The lacrimal gland is divided into two lobes by the lateral edge of the levator palpebrae aponeurosis. The orbital lobe, which is situated in a posterosuperior position, is two to three times larger than the palpebral lobe, which is situated in an anteroinferior position. The posterior edge of the orbital lobe is in the approximate coronal plane of the posterior pole of the globe. The anterior margin of the orbital portion rests on the superior surface of the levator palpebrae aponeurosis and is covered by orbital septum, orbicularis oculi muscle, and skin. The medial edge of the orbital lobe is situated within the preaponeurotic fat pocket anteriorly and approximates the lateral margin of the superior rectus muscle posteriorly. The lateral edge of the orbital lobe extends inferiorly toward the superior margin of the lateral rectus muscle.¹⁰ The palpebral lobe is located under the levator aponeurosis and just above the superior lateral conjunctival fornix. It is this portion of the lacrimal gland that is often visible when the upper eyelid is everted.

The lacrimal gland is supported by four fascial structures, including Soemmering's ligaments, Whitnall's ligament, the inferior ligament of Schwalbe, and the lateral horn of the levator palpebrae aponeurosis.¹¹ The majority of fibers that make up Whitnall's ligament pass under and through the orbital lobe to insert on the orbital roof, providing the greatest support for the lacrimal gland.¹² The superior surface of the lacrimal gland is weakly adherent to the periosteum of the lacrimal gland fossa by fine trabecular ligaments known as Soemmering's ligaments. The lateral edge of the levator aponeurosis provides additional support as it divides the gland into two lobes. The inferior ligament of Schwalbe is a small band of fascia, associated with the lacrimal artery and nerve, that passes under the posterior lip of the lacrimal gland. The anterior margin of this ligament and the lateral margin of the levator aponeurosis define an oval opening referred to as the lacrimal foramen.¹¹ It is through this foramen that ductules of the orbital lobe pass into the palpebral lobe. These ductules intertwine with ductules of the palpebral lobe and penetrate the conjunctiva of the lateral superior fornix, approximately 4 to 5 mm above the superior tarsal margin.

Innervation of the lacrimal gland is quite complex (Fig. 1). Parasympathetic motor fibers originate from the lacrimal nucleus in the pons. From the nucleus, fibers exit the pons in the ventrolateral aspect of the cerebellopontine angle as the nervus intermedius. This fine nerve runs between the motor root of the seventh and eighth cranial nerves as they enter the internal auditory meatus. The fibers continue through the geniculate ganglion without synapsing and then course away from the seventh cranial nerve. Once the fibers leave the geniculate ganglion they are referred to as the greater superficial petrosal nerve. This nerve runs in a groove in front of the petrous temporal bone. Under the gasserian ganglion it joins the deep petrosal nerve (which consists of sympathetic fibers from the internal carotid plexus) and forms the vidian nerve in the cartilage over the foramen lacerum. The vidian nerve passes through the pterygoid canal to synapse in a ganglion within the pterygopalatine fossa known as the sphenopalatine ganglion, Meckel's ganglion, or pterygopalatine ganglion. The ganglion is attached to the maxillary nerve by several short pterygopalatine nerves that carry the postsynaptic parasympathetic lacrimal fibers. These fibers then enter the orbit via the zygomatic nerve. A branch from the zygomatic nerve leaves the infraorbital groove to join the lacrimal nerve, a branch of the first division of the trigeminal nerve. The lacrimal nerve bifurcates as it enters the posterior edge of the lacrimal gland. The branch containing fibers to the lacrimal gland penetrates to the hilus of the gland and then passes peripherally with the ductules to innervate individual lobules of acini. The other branch of the bifurcation passes forward to provide innervation to the upper eyelid and superior conjunctival fornix.

Sympathetic innervation is known to reach the lacrimal gland via the vidian nerve, described above, as well as via the ophthalmic artery and lacrimal artery. The role of sympathetic innervation in the control of lacrimal secretion remains uncertain.

The lacrimal gland receives its blood supply from the internal and external carotid system. The majority of blood is provided by the internal carotid system via the lacrimal artery, a branch of the ophthalmic artery. The lacrimal artery anastomoses with branches of the external carotid system at a minimum of two sites. The first anastomosis is at the distal tip of the superior orbital fissure with the anterior division of the middle meningeal artery. The second anastomosis is within the eyelids between the anterior deep temporal artery and the lacrimal artery. Occasionally, the infraorbital artery sends a branch to the lacrimal gland, thus establishing a third potential anastomosis between the internal and external carotid system to supply blood to the main lacrimal gland. Venous return from the lacrimal gland drains into the superior ophthalmic vein. Lymphatic drainage parallels the conjunctival system to the preauricular nodes.

Lacrimal gland fossa lesions usually present with fullness of soft-tissue structures in the area of lacrimal gland fossa. Typically, this appears as an “S-shaped” contour of the upper eyelid (Fig. 2A) or as asymmetry of the superior sulci. In addition, ipsilateral blepharoptosis may be present. Table 2 lists other findings associated with lacrimal fossa lesions.

TABLE 2. Signs and Symptomsdof Lacrimal Gland Disease

  Fullness
  S-shaped upper eyelid contour
  Ptosis
  Asymmetric superior sulci
  Pain
  Edema
  Erythema
  Conjunctival injection
  Chemosis
  Proptosis
  Diplopia/restricted ocular motility
  Decreased visual acuity
  Globe indentation
  Disc edema
  Choroidal striae
  Lymphadenopathy

Pain in the lacrimal gland fossa may be associated with inflammation or malignant epithelial neoplasms of the lacrimal gland. Pain usually accompanies inflammatory processes, and the lacrimal gland fossa is no exception. The pain of lacrimal gland inflammation usually occurs early in the course of the disease and is associated with other inflammatory signs, including conjunctival injection and chemosis. Sometimes the pain is accentuated by movement of the globe or eyelids because of inflammation of adjacent tissues. Pain associated with malignant epithelial neoplasms of the lacrimal gland is secondary to bone and/or perineural invasion. Pain of these malignant epithelial neoplasms occurs late in the disease process and is usually associated with proptosis or a palpable mass.

Enlargement of the lacrimal gland beyond its fossa will cause displacement of the globe. In these situations, there is proptosis with the globe displaced inferiorly and medially. In addition, there may be indentation of the globe that is visible during indirect ophthalmoscopy.

The patient's age and duration of symptoms may help distinguish between the various disorders of the lacrimal gland fossa. Primary lacrimal gland tumors are rare in the pediatric population. Masses within the lacrimal gland fossa at this age are often congenital dermoid cysts, although benign and malignant lacrimal gland tumors in pediatric patients have been reported.^9,13–18 Epithelial tumors of the lacrimal gland often present in the fifth or sixth decade of life, whereas malignant lymphoproliferative disorders of the lacrimal gland are common in patients aged 60 to 80 years. If the signs or symptoms have been present for more than a year, this suggests a slow-growing, benign epithelial neoplasm (less often a lymphoproliferative disorder). If signs and symptoms have been present for less than a year, then a malignant epithelial neoplasm or lymphoproliferative disease is more likely. Pain is common in the malignant epithelial neoplasms but rare in other tumors. Acute symptoms are suggestive of inflammatory disease, especially if associated with pain and erythematous swelling.

Review of constitutional symptoms, including fever, chills, anorexia, weight loss, and rheumatologic complaints, may reveal an underlying systemic condition. Systemic disease that affects the lacrimal gland ranges from relatively benign conditions like infectious mononucleosis to serious diseases such as malignant lymphoma. Laboratory evaluation is not routine but is indicated if the history or examination suggests a systemic disorder. For example, the white blood cell count may help confirm the clinical diagnosis of bacterial dacryoadenitis. Likewise, if one suspects sarcoidosis, Wegener's granulomatosis, or Sjögren's syndrome as a cause for dacryoadenitis, then the appropriate serology is indicated to confirm the diagnosis.

Plain-film radiographic studies are obsolete in the evaluation of lacrimal gland fossa lesions and have been surpassed by high-quality thin-section axial and direct coronal computed tomography (CT) imaging. Contour analysis of lacrimal gland lesions, along with careful evaluation of the surrounding structures, helps separate lacrimal gland masses into various categories, including inflammations, lymphoproliferative disorders, cystic lesions, and epithelial tumors.⁹ For example, contrast enhancement of an oblong mass in the lacrimal gland fossa without bone abnormalities that is associated with thickening of adjacent soft tissues and irregular opacification of orbital fat indicates an inflammatory process. Posterior extension of the mass, enlargement of extraocular muscles, or scleral thickening may also be seen with orbital inflammatory disease. Lymphoproliferative disorders may also have an oblong appearance on CT images and show contrast enhancement. However, lymphoproliferative disorders conform to surrounding structures and usually have a sharp demarcation between the mass and normal adjacent tissues. If the mass is round in shape rather than oblong, this is typical of epithelial tumors. If significantly large, these lesions will cause globe indentation and displacement. Smoothly contoured depression of the bone surface in the lacrimal fossa, without destruction of bone, is sometimes called pressure modeling and is characteristic of chronic, slowly enlarging masses of the lacrimal gland, including epithelial tumors. Actual bone destruction or invasion into the surrounding orbital structures is more typical of malignant epithelial tumors rather than benign tumors. Magnetic resonance imaging (MRI) is occasionally necessary to detect intracranial extension of the tumor. Orbital echography may be useful in differentiating lesions of the lacrimal gland fossa.¹⁹

Noninfectious dacryoadenitis may be associated with systemic diseases such as sarcoidosis,^9,16 Sjögren's syndrome,²¹ Graves' disease,^22,23 systemic lupus erythematosus,²⁴ Wegener's granulomatosis,²⁵ or other autoimmune diseases. Lacrimal gland enlargement in a patient with a history or symptoms of these diseases is often bilateral and the diagnosis readily apparent. Treatment is directed toward stabilization of the underlying condition and usually involves corticosteroids or other immunosuppressive agents under direction of an internist or rheumatologist. If prompt resolution of the inflammation does not occur, then a transcutaneous, transseptal biopsy of the abnormal lacrimal gland is recommended.

Noninfectious dacryoadenitis may be limited to the lacrimal gland fossa or involve adjacent orbital structures. Idiopathic, noninfectious dacryoadenitis is a specific example of the spectrum of orbital inflammatory disease (inflammatory pseudotumor). “Orbital pseudotumor” is a popular but confusing designation for benign orbital inflammation of unknown etiology. We prefer the general term “orbital inflammatory disease” (OID) to describe this spectrum of diseases. In other words, idiopathic, nongranulomatous, noninfectious inflammation of the lacrimal gland is merely a subset of OID. This condition is usually but not always unilateral. The clinical presentation of OID of the lacrimal gland is similar to that of other inflammatory conditions and includes pain, tenderness, erythema, and edema. OID of the lacrimal gland occurs more frequently in females than in males.^9,16 Computed tomographic imaging usually demonstrates a poorly demarcated mass in the lacrimal fossa area with a surrounding haze, suggesting inflammation of adjacent orbital tissue.²⁰ Radiographic signs of diffuse OID include enlarged ocular muscles and tendons, thickened Tenon's tissue and sclera, and diffuse irregular opacification of orbital fat.²⁶ The presence of bone abnormalities on CT makes the diagnosis of OID unlikely. Signs and symptoms associated with OID of the lacrimal gland should rapidly resolve with corticosteroid treatment. If symptoms do not abate, the clinical diagnosis should be reconsidered and a lacrimal gland biopsy specimen obtained. Pathologic features of OID include mature lymphocytes, plasma cells, histiocytes, and scattered follicles separated by a dense fibrous stroma. It is the absence of the sheetlike hyperplasia of lymphocytes and the presence of the dense stroma that histopathologically separate OID from lymphoma.²⁷ Radiotherapy can be used if there are contraindications to corticosteroid treatment. Occasionally, an orbital dermoid cyst of the frontal-zygomatic suture may rupture, mimicking a similar clinical appearance.

Infectious dacryoadenitis may be secondary to viral, bacterial, or fungal pathogens. Patients may have preauricular adenopathy, conjunctival chemosis, fever, malaise, and an elevated white cell count. It is important to reiterate that a complete ophthalmic examination is required to determine the extent of infection. A review of constitutional symptoms and systemic disorders is essential to discover any possible predisposing systemic conditions. Viral dacryoadenitis may be associated with systemic infections, including mononucleosis, mumps, or herpes zoster. In fact, many patients with dacryoadenitis suffer flulike symptoms prior to involvement of the lacrimal gland.²² Ascending dacryoadenitis results when the causative organism ascends through the ductules to infect the lacrimal gland, and it is usually secondary to staphylococcal organisms.²⁸ Occasionally, streptococcal and Neisseria species have been isolated from such infections.²⁸

Bacterial infections of the lacrimal gland require systemic antibiotics. If a viral etiology is suspected, then treatment may be limited to supportive measures such as maintaining hydration. Total resolution of symptoms occurs between 1 and 4 weeks.²² Therefore, if symptoms progress or incompletely resolve, a transcutaneous, transseptal biopsy is indicated. Sequelae from infectious dacryoadenitis are rare. Complications include external cutaneous fistulas, dacryops, and keratitis sicca secondary to atrophy of the lacrimal gland acini.²³ Meningitis secondary to cavernous sinus spread from bacterial dacryoadenitis was reported in the preantibiotic era.²⁹

In patients with lymphoproliferative infiltration of the lacrimal gland, a firm, rubbery mass is often palpable in the lacrimal gland fossa. In contrast to inflammatory lesions, lymphoid lesions are usually not tender. Lymphoid lesions contour to the shape of the fossa and surrounding structures, producing a well-demarcated, oblong mass on computed tomography (see Figs. 2B and 2C).^9,31 Prominent enhancement after intravenous administration of contrast material is typical for lymphoid lesions.³¹ The amount of enhancement is similar to enhancement of extraocular muscles. Anterior extension beyond the orbital rim indicates palpebral lobe involvement, which is more typical of lymphomatous lesions and very rare for epithelial tumors of the lacrimal gland.³⁰ In addition, destruction of bone is rare with lymphomatous lesions and therefore is useful in distinguishing lymphomatous lesions from malignant epithelial tumors.⁹

Lymphoproliferative disorders of the lacrimal gland include a spectrum of diseases ranging from benign inflammation to malignant lymphoma. It is difficult to distinguish between benign and malignant lymphoproliferative disorders on a clinical basis. Benign disorders are usually acute or subacute in presentation and are occasionally associated with inflammatory signs. In contrast, malignant lymphomas usually have a chronic presentation without pain. In addition, bilateral and recurrent lesions may also suggest a malignant lymphoma.^31,32 It is important to remember that these are not strict guidelines for diagnosis but rather clinical findings that may be associated with an increased risk of malignancy. The final diagnosis is established from an adequate biopsy specimen with the use of routine histopathology, flow cytometry, and possibly immunohistochemistry and electron microscopy.

Approximately one third to one half of patients with lymphoma of the lacrimal gland have or will develop systemic lymphoma.^20,31 Therefore, once the diagnosis of orbital lymphoma is suspected, evaluation for systemic involvement is mandatory. Complete physical examination, hematologic evaluation, liver function tests, chest radiographs, and CT evaluation of the abdomen, retroperitoneum, and liver are indicated. Neurologic symptoms require appropriate imaging studies and cerebrospinal fluid analysis to rule out central nervous system involvement.

Radiation therapy is the mainstay of treatment for orbital lymphoproliferative disorders, including lesions involving the lacrimal gland.^22,30,33,34 Benign lesions usually require 1000 to 2500 rads, whereas malignant lesions require 1500 to 3500 rads. Systemic corticosteroids and antineoplastic agents are usually required for systemic disease and are administered under the direction of an oncologist.

Even after initial successful treatment, yearly examination for local and systemic disease is required.³¹ If local recurrence develops, the initial specimen should be reviewed. If atypical, a repeat biopsy should be considered because recurrences may suggest malignancy.^31,32

The incidence of pleomorphic adenomas is equal for both genders, and these neoplasms usually present in the fifth decade of life.^15,16 Symptoms may vary depending on the location of the tumor within the lacrimal gland.^15,36,37 Pleomorphic adenomas usually involve the orbital lobe and present with symptoms of painless, progressive, nonaxial proptosis and restricted ocular motility (Fig. 4A). These symptoms are typically present for more than 1 year.^9,13–15,22 A round or oval mass is present within the lacrimal gland fossa. Smooth erosion (bone modeling) without invasion or destruction of bone is almost always visualized on computed tomography^9,15,22 and indicates the slow growth of this disorder (see Fig. 4B).

In Rose and Wright's series of 78 patients with pleomorphic adenoma, the tumor was isolated to the palpebral lobe in 8 patients (10%).¹⁵ These eight patients presented with a painless, palpable, mobile lump in the lacrimal gland fossa. Symptoms were present for a shorter duration, averaging less than 1 year, when compared with similar lesions of the orbital lobe. However, other reports indicate that pleomorphic adenomas of the palpebral lobe are rare and may have a longer duration of symptoms, ranging from 1 to 21 years.^9,36–39 If the tumor is confined to the palpebral lobe of the lacrimal gland, isolated dacryoadenectomy of this lobe may be indicated.^15,36,37

Histopathologic review of benign pleomorphic adenomas reveals a mixture of epithelial and mesenchymal elements.³⁵ The epithelial component consists of benign epithelial cells arranged in a double layer forming lumina. Various tissue degenerations may be seen within the stroma and include myxoid changes, cartilaginous changes, and bone formation.⁴⁰

Radiographic evidence of calcification of the lacrimal fossa mass usually indicates a malignant process.¹⁸ However, calcification with a benign pleomorphic adenoma has also been reported.^15,41 Therefore, the presence of calcification on CT images must be taken in context with other clinical and radiologic features, such as pain, duration of symptoms, and bone destruction, to avoid clinically mislabeling benign lesions as malignant.

The generally accepted treatment protocol recommends lateral orbitotomy and complete en bloc excision of the suspected benign tumor without a preliminary biopsy.^{8,15,22,38,42} In fact, several authors state that an incisional biopsy is CONTRAINDICATED if a benign pleomorphic adenoma is suspected. This aggressive treatment plan is based on Font and Gamel's series from 1978, documenting an increased rate of recurrence of incompletely excised pleomorphic adenomas.¹³ In this study, the 5-year recurrence rate was 3% for completely excised lesions and 32% for incompletely excised tumors. However, it remains unknown if recurrence is more likely after complete excision of the tumor immediately after incisional biopsy. In fact, seven patients (10%) in Rose and Wright's series of benign pleomorphic adenomas of the lacrimal gland had a prior biopsy.¹⁵ All seven patients have remained tumor free following complete excision after initial biopsy at follow-up intervals of 5 years (4 patients), 10 years (2 patients), and 20 years (1 patient). However, because late recurrence is not uncommon with pleomorphic adenomas, a longer follow-up interval will be needed.

A clinical diagnosis of benign pleomorphic adenoma, based on presentation and radiographic analysis as outlined above, correlates with the histopathologic diagnosis in 80% to 87% of cases.^15,22 Some authors consider a planned transseptal incisional biopsy as appropriate initial management for most patients with lacrimal fossa masses, especially if symptoms are subacute (less than 10 months) and there is no evidence of inflammation.⁴³ The preliminary biopsy for frozen-section analysis can be performed through an incision that can be extended for a lateral orbitotomy with en bloc resection, or the incision can be included in the en bloc resection if a diagnosis of pleomorphic adenoma is confirmed. Frozen-section review should distinguish between epithelial tumors, lymphoproliferative disorders, and chronic inflammation and should allow appropriate management. For example, if results indicate another infiltrative or inflammatory process, the patient will be spared unnecessary surgery, allowing appropriate nonsurgical treatment to be initiated. Similarly, if results indicate a malignant epithelial neoplasm of the lacrimal gland, exenteration with postoperative radiation can be offered.^43–45 If clinical and radiographic evidence demonstrates isolation of the benign tumor to the orbital lobe, then the palpebral lobe may be spared by use of the dacryoadenectomy technique described by Rose and Wright.¹⁵

Other benign tumors of the lacrimal gland fossa are uncommon and include case reports of oncocytoma,⁴⁶ myoepithelioma,^47,48 cavernous hemangioma,^49,50 congenital dermoid cysts, and dacryops.^16,51 Of these disorders, the most common are probably dermoid cysts and dacryops. However, the true incidence of these two cystic disorders remains unknown because they are usually easily diagnosed and not included in reports of lacrimal fossa masses at tertiary care centers.

Dacryops is a cystic dilation within the lacrimal gland. It presents as a slowly enlarging, painless bluish mass within the superotemporal conjunctival fornix, corresponding to the opening of the lacrimal gland ducts. Transillumination of the mass usually allows one to clinically differentiate cystic from solid tumors of the lacrimal gland. In addition, ultrasonography and radiographic studies reveal a characteristic cystic appearance. Pathogenesis of dacryops is related to chronic inflammation and scarring of the lacrimal gland ducts and appears unrelated to dacryolithiasis of the lacrimal gland.^51,52 Shields and colleagues reported lacrimal gland dacryops in 8 of 142 specimens (6%) from lacrimal gland fossa biopsies.¹⁶ Six of the eight cases occurred in females. The average age at time of biopsy was 38 years. Observation is appropriate management for asymptomatic patients with dacryops. However, if the patient is symptomatic, marsupialization or excision of the cyst is possible.^53–55 Simple puncture or incision and drainage is only temporizing and therefore not recommended, because recurrence is almost guaranteed.

Another cystic lesion within the area of the lacrimal gland fossa is the congenital dermoid cyst (Fig. 5). These benign lesions develop from inclusion of epithelial structures during embryogenesis. Although they are not primary lesions of the lacrimal gland per se, their proximity to the lacrimal gland fossa places them in the differential diagnosis of lacrimal gland masses. Dermoid cysts usually present within the first decade of life as a cosmetic concern to the patient or family. Clinically, these cystic lesions can usually be defined by palpation, although deep orbital involvement has been reported.⁵⁶ Spontaneous or post-traumatic rupture of a dermoid cyst may cause leakage of its contents and elicit an intense inflammatory reaction. This usually prompts the patient to seek medical attention, and he or she may therefore present to the physician with inflammatory symptoms similar to those of acute dacryoadenitis. CT images of the orbit will reveal a cystic lesion within the superotemporal orbit with or without pressure modeling of the adjacent orbital bone (see Fig. 5B).

Malignant tumors of the lacrimal gland affect males more commonly than females,^9,18,43 and the majority (70%) of patients complain of pain.¹⁸ Palpable mass, soft-tissue fullness, globe displacement, and/or abnormal ocular motility are all common findings.¹⁸ Other less common findings include decreased visual acuity, optic disc swelling, choroidal folds, and diminished trigeminal nerve function. Compared with patients with benign epithelial tumors of the lacrimal gland, patients with malignant epithelial tumors have a higher incidence of pain, a shorter duration of symptoms, and a higher incidence of bone abnormalities evident on CT imaging.^{9,15,16,18,22,43,58}

Adenoid cystic carcinoma (ACC) is the most common primary epithelial malignancy of the lacrimal gland^13,14,18 and has the worst prognosis.^14,45 Compared with the other malignancies of the lacrimal gland, ACC tends to affect younger patients.^13,16,18 In the series by Wright and associates concerning 50 patients with primary malignancies of the lacrimal gland, 38 (76%) developed ACC at an average age of 41 years (range, 8–79 years).¹⁸ All patients in this series younger than age 30 had ACC. In addition, there are several reports of ACC in teenage patients.^{9,13,14,16,18} In the 38 patients in the series by Wright and colleagues, CT abnormalities consisted of bone erosion (75%), bone destruction (39%), and soft-tissue calcification (22%). The overall prognosis for ACC is grim.^13,18,45 In the review by Wright and associates, nearly half of all patients with ACC had recurrence of their disease, usually within 2 years (range, 2 months to 9 years).¹⁸ In the review by Lee and colleagues, of 26 patients with ACC, only half survived 2.5 years after the diagnosis of ACC.⁴⁵ The major cause of death from ACC is intracranial extension.^14,45

Five histopathologic patterns of ACC of the lacrimal gland have been described and include cribriform (“Swiss cheese”), sclerosing, basaloid (“solid”), comedocarcinomatous, and tubular (“ductal”).^45,59 The most common variety is the cribriform pattern.¹⁸ Although there is not uniform agreement, patients with cribriform pattern lesions tend to have longer survival, whereas patients with basaloid patterns tend to have the worst prognosis.^18,45,59

Optimal treatment of patients with adenoid cystic carcinoma of the lacrimal gland has yet to be determined. A combination of tumor resection with radiotherapy is the most commonly employed treatment.^18,45 Techniques of tumor excision include en bloc resection, exenteration, and cranio-orbital resection.^18,45,60 Because adenoid cystic carcinoma is a relatively rare tumor and the prognosis is poor, comparison of different treatment approaches is difficult. There is no definitive evidence that any treatment prolongs survival.^18,45 Therefore, treatment plans should be tailored to each individual patient based on clinical and radiographic evidence of tumor extension.

Other malignant epithelial neoplasms of the lacrimal gland are rare, and the terminology to describe them is confusing. We prefer to designate malignant carcinoma arising within a pleomorphic adenoma as “pleomorphic adenocarcinoma” (rather than malignant mixed tumor or adenocarcinoma of the lacrimal gland). If there is no prior history, then the term “primary adenocarcinoma” may be used to indicate a de novo occurrence of the tumor. These neoplasms present in the same manner as other epithelial malignancies. It is rare for primary or pleomorphic adenocarcinomas to occur in patients younger than 30 years of age.^14,18,43 Erosion of bone was present in all 10 patients described by Wright and colleagues.¹⁸ Calcification was present in 3 of 5 patients with primary adenocarcinoma and 4 of 5 patients with pleomorphic adenocarcinoma.

Recurrence of primary adenocarcinoma is very common,¹³ as reported in 9 of 13 patients in the series by Heaps and colleagues⁴³ and in all patients in the series by Wright and co-workers.¹⁸ Optimal treatment for primary adenocarcinoma of the lacrimal gland appears to be orbital exenteration with postoperative radiotherapy.⁴³ This protocol is based on the report by Heaps and colleagues in which only the four surviving patients without tumor recurrence received this method of treatment.⁴³ These four patients have been tumor free after treatment for 1 year, 3.5 years, 14 years, and 16 years, respectively.

Similar grim statistics are true for pleomorphic adenocarcinoma.^13,14,18 The dismal prognosis of pleomorphic adenocarcinoma relates to its propensity for early lymphatic dissemination.⁴⁰ Treatment is often limited to surgically debulking the tumor followed by postoperative radiotherapy.^18,40 Parotid and cervical lymph node dissection at the time of radical orbital surgery has also been advised.⁴⁰

Mucoepidermoid carcinoma (MEC) is a rare malignancy of the lacrimal gland^17,40,44,61 but may account for 10% to 15% of salivary gland tumors.^62,63 The largest series of lacrimal gland involvement by MEC was compiled by Eviatar and Hornblass.⁴⁴ These authors divided MEC into two categories, high- and low-grade tumors, based on histopathologic features. Clinically, patients with low-grade tumors tend to do well, with seven of eight patients alive without tumor recurrence at an average follow-up interval of 3 years (range, 1–10 years). Conversely, patients with high-grade lesions do poorly, with seven of nine patients having tumor-related deaths 3 weeks to 3 years after treatment. Eviatar and Hornblass recommend exenteration with radiotherapy for patients with high-grade MEC of the lacrimal gland. For patients with low-grade lesions, simple extirpation of the lesion with or without radiation appears appropriate.

Although treatment strategies need to be customized to the individual patient, some generalization can be made by separating patients with lacrimal gland disorders into four broad categories based on duration of symptoms as well as clinical and radiographic findings. These categories include:

1. ÌAcute presentation suggesting inflammation
   
2. Painless subacute (less than 1 year) presentation with clinical and radiographic evidence suggesting lymphoproliferative diseases
   
3. Subacute presentation with pain and radiographic evidence suggesting malignant epithelial neoplasms
   
4. Chronic presentation without pain associated with radiographic evidence suggesting benign lacrimal gland tumors (Table 3)
   

TABLE 3. Clinical and Radiographic Analysis of Lacrimal Gland Tumors

Group 1: When historical, clinical and radiographic analyses suggest acute inflammation isolated to the lacrimal gland, a diagnosis of dacryoadenitis is likely (see Table 3). If there are no other signs or symptoms of systemic disease, oral antibiotics (cephalexin) are administered. However, if the patient presents with bilateral disease or if systemic review indicates an underlying disease, evaluation for such a disease is necessary and treated accordingly. Acute dacryoadenitis should resolve within a few weeks. If the condition persists, a lacrimal gland biopsy must be performed to establish a pathologic diagnosis. The biopsy should be done via a percutaneous, transseptal approach to avoid damage to the lacrimal gland ductules. If the histopathologic evaluation reveals an inflammatory process, oral corticosteroids are initiated provided there are no contraindications. If the working diagnosis is nonspecific inflammation, a shorter course of treatment (2–6 weeks) is required. If the working diagnosis is orbital inflammatory disease, then a longer treatment regimen with a slower taper is indicated. If the patient fails to improve, the initial biopsy specimen should be re-evaluated. If there are any questions regarding the histopathologic diagnosis, a repeat biopsy might be required. However, if the clinical, radiographic, and pathologic review is otherwise consistent with inflammatory disease, radiotherapy may be an alternative method of treatment.

Group 2: When clinical and radiologic findings are consistent with lymphoproliferative disorders of the lacrimal gland (see Table 3), histopathologic diagnosis of benign or malignant disease is required. With use of the transseptal approach, a generous biopsy specimen should be obtained to provide adequate tissue for routine histopathology, immunohistology, and flow cytometry. In addition, evaluation for systemic involvement is necessary. The mainstay of treatment for this class of disorders is radiotherapy.

Group 3: Incisional biopsy of lacrimal gland lesions of short duration with bone destruction is recommended because these findings are highly suspicious of malignant epithelial neoplasms (see Table 3).^8,18,22,43 For this category of lacrimal gland disease, treatment options are not easy and often end in failure despite heroic efforts. Careful histopathologic evaluation of permanent sections will establish a firm diagnosis and therefore help determine the most appropriate intervention. For example, the only patients to survive primary adenocarcinoma of the lacrimal gland have been treated with exenteration and radiotherapy.⁴³ Patients with low-grade mucoepidermoid carcinoma may do well with local extirpation with or without radiotherapy, whereas patients with high-grade mucoepidermoid carcinoma require exenteration and radiotherapy.⁴⁴ If pathologic evaluation of the permanent sections of the lacrimal gland lesion reveals adenoid cystic carcinoma or pleomorphic adenocarcinoma, there is poor prognosis for survival. Treatment usually involves combined surgery and radiotherapy and is based on extent of the tumor and the desires of the patient.^18,45

Group 4: If the clinical history and radiographic findings reveal a painless, chronic lacrimal gland lesion associated with pressure modeling of the bone (see Table 3), a benign pleomorphic adenoma is presumed and a lateral orbitotomy is planned in anticipation of en bloc resection. An en bloc resection is planned to avoid the higher recurrence rate associated with incompletely excised or previously biopsied pleomorphic adenomas.¹³

Not all patients with lacrimal gland fossa masses conform exactly to one of the categories described above. Treatment remains controversial for patients whose clinical and radiologic features are not typical for a single diagnosis. In these atypical cases, an initial incisional biopsy may be appropriate, because clinical and radiographic findings of a painless expanding fossa mass without bone destruction are not limited to a benign pleomorphic adenoma of the lacrimal gland; they can also be seen in malignant epithelial tumors and other chronic benign tumors.^15,18,22,64 Frozen section should differentiate inflammatory lesions, lymphoproliferative disorders, and epithelial neoplasm, and possibly even benign and malignant epithelial tumors. If inflammatory or lymphoproliferative disease is diagnosed, the patient is spared aggressive orbital surgery. If a malignant epithelial neoplasm is discovered, further discussion with the patient after permanent section review is possible. If a pleomorphic adenoma is confirmed, the incision can be included in the definitive surgery of lateral orbitotomy with en bloc excision of the tumor.

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