Keywords
adenoid cystic carcinoma - dacryoadenitis - carcinoma ex pleomorphic adenoma - lacrimal
gland mass - orbital lymphoma - orbital pseudotumor - pleomorphic adenoma - surgical
debulking of lacrimal gland
Introduction
Masses of the lacrimal gland are relatively uncommon, with an incidence of approximately
1.3 per 1 million people per year.[1] Lacrimal gland lesions account for approximately 9 to 10% of all biopsied orbital
masses and can be caused by inflammation, lymphoproliferative disorders, primary epithelial
neoplasms (benign or malignant), or metastatic disease.[2]
[3] These lesions may be difficult to differentiate based on clinical and radiographic
findings alone, and a tissue biopsy is often required for definitive histopathologic
diagnosis. We review the most common etiologies of lacrimal gland enlargement and
their clinical characteristics, imaging findings, indications for biopsy, medical
and surgical treatment options, and prognosis, with a focus on the surgeon's approach
to each condition.
General Diagnostic Considerations
General Diagnostic Considerations
The clinical presentation, including history and physical examination, provides the
initial clues toward the diagnosis of a lacrimal gland mass. A palpable mass in the
lateral upper eyelid, inferonasal globe displacement, proptosis, ptosis, diplopia,
extraocular motility deficits, and vision loss are all possible signs and symptoms
of lacrimal gland enlargement. Generally, an acute presentation is most likely due
to either an infectious or an inflammatory etiology. Both present acutely or subacutely
with periocular pain and tenderness, upper eyelid edema and erythema, and conjunctival
injection, but a subacute presentation is more likely to be inflammatory. A more rapid
presentation with regional lymphadenopathy, purulent discharge, and/or abscess formation
suggests an infection. Slower onset, known history or concurrent manifestations of
autoimmune disease, and/or lack of response to systemic antibiotics point toward a
noninfectious inflammatory disease. Inflammatory signs and symptoms are typically
absent in lacrimal gland neoplasia, which usually present subacutely or chronically
with proptosis, inferonasal globe displacement, upper eyelid swelling or palpable
mass, diplopia, and/or vision loss. Periorbital pain may also be present with neoplastic
lesions, particularly if malignant.
Inflammatory Lesions of the Lacrimal Gland
Inflammatory Lesions of the Lacrimal Gland
Dacryoadenitis, or inflammation of the lacrimal gland, is the most common etiology
of lacrimal gland enlargement and may be unilateral or bilateral.[1] This can be secondary to a viral or bacterial infection, autoimmune disease, or
idiopathic inflammation.
Infectious Dacryoadenitis
Viral dacryoadenitis is rare, but more commonly occurs in children and young adults.
An acute presentation with upper eyelid swelling, erythema, and pain or discomfort
in the superotemporal orbit accompanied by conjunctival injection, chemosis, preauricular/cervical
adenopathy, and/or constitutional symptoms raises the possibility of an infectious
etiology.[4] This is most frequently associated with Epstein–Barr virus, but can also be due
to adenovirus, mumps rubella virus, herpes simplex viruses, varicella zoster virus,
and cytomegalovirus.[5]
[6] Lacrimal gland swelling related to a viral infection is typically self-limited and
resolves within 4 to 6 weeks of symptom onset.
A bacterial infection of the lacrimal gland occurs even less commonly and may be secondary
to Staphylococcus aureus (including methicillin-resistant strains), Streptococcus pneumoniae, and Haemophilus influenzae.[6]
[7] Sources include an overlying skin infection, adjacent sinusitis, or hematogenous
spread.[6] There is typically suppurative discharge from the lacrimal ducts, which should be
sent for Gram stain and culture to guide antibiotic selection. Treatment includes
systemic antibiotics, with incision and drainage of any abscess. Bacterial dacryoadenitis
is often diagnosed clinically and does not require orbital imaging or lacrimal gland
biopsy unless the patient's presentation is atypical (e.g., older patient), there
is disease recurrence, or there is persistence of lacrimal gland enlargement and/or
symptoms despite seemingly appropriate treatment.[8]
Idiopathic and Autoimmune Dacryoadenitis
Dacryoadenitis is part of a spectrum of orbital inflammatory disorders that may also
involve inflammation of the sclera, extraocular muscles, orbital fat, and/or optic
nerve sheath. Presenting symptoms classically include unilateral upper eyelid swelling,
erythema, pain or discomfort in the superotemporal orbit, conjunctival injection,
and chemosis ([Fig. 1a]), but may also be bilateral (either simultaneous or sequential) in approximately
16% of patients.[9] Dacryoadenitis may be the sole presenting symptom of systemic autoimmune disease
(e.g., sarcoidosis, granulomatosis with polyangiitis [GPA, formerly known as Wegener's
granulomatosis], Graves' disease, Sjögren's syndrome, and IgG4-related disease) but
can also be idiopathic and isolated to the orbit.[6] Some patients can also experience dry eye symptoms, whereas others may develop this
over time, especially if associated with systemic autoimmune disease. Nonspecific
or idiopathic orbital inflammation (NSOI) is a diagnosis of exclusion and requires
a negative workup for autoimmune disease.
Fig. 1 Nonspecific orbital inflammation (NSOI) involving the lacrimal gland. (a) A 36-year-old woman with chronic left-sided proptosis and recurrent bouts of inflammation
of the lacrimal gland and surrounding structures. Systemic workup was negative for
underlying autoimmune disease, and lacrimal gland biopsy confirmed the diagnosis of
NSOI. (b) T1-weighted contrast-enhanced magnetic resonance imaging of the orbits showed marked
and diffuse enhancement of the lacrimal gland, superior rectus muscle, and adjacent
connective tissues on the left.
In general, initial, mild, and/or unilateral presentations may be observed or treated
with nonsteroidal anti-inflammatory drugs (NSAIDs). However, bilateral, recurrent,
or more severe presentations should be thoroughly worked up and treated more aggressively.
Systemic workup includes complete blood count (CBC), complete metabolic panel (CMP),
angiotensin-converting enzyme (ACE), antineutrophil cytoplasmic antibodies (ANCA),
anti-Sjögren syndrome related antigen A (anti-SSA/Ro) antibodies, anti-Sjögren syndrome
related antigen B (anti-SSB/La) antibodies, antinuclear antibodies (ANAs), rheumatoid
factor (RF), chest radiograph, and orbital imaging.[6] On both computed tomography (CT) and magnetic resonance imaging (MRI), the lacrimal
gland is typically diffusely enlarged and brightly enhances with intravenous contrast
([Fig. 1b]).[10]
[11] The gland also characteristically molds to surrounding structures, without any changes
in the overlying bony architecture. Depending on the extent of involvement, diffuse
enhancement of sclera, extraocular muscles, orbital fat, and/or the optic nerve sheath
may also be observed. Other findings (e.g., sinus and midline disease in GPA, ipsilateral
sinus disease in IgG4-related disease) may also be seen on neuroimaging.[6]
Treatment often requires systemic corticosteroids (e.g., oral prednisone dosed at
1 mg/kg/d) with slow taper over weeks to months.[11] In severe, vision-threatening orbital inflammation, admission for high-dose intravenous
corticosteroids is indicated. Most patients respond well to systemic corticosteroids,
but up to 74% of patients have recurrence of symptoms when attempting to taper or
discontinue steroids.[12] Over a quarter of patients also ultimately develop steroid dependence and may require
steroid-sparing therapy (e.g., methotrexate, azathioprine, mycophenolate mofetil),
orbital radiation, or biologics (e.g., rituximab) to achieve remission.[12]
[13] Intra- or perilesional corticosteroid injection may also be considered, and sustained
results have been reported.[14] If autoimmune disease is present, systemic therapy is often required. Unlike other
autoimmune conditions, GPA should always be initially treated with high-dose systemic
corticosteroids and cytotoxic agents (e.g., cyclophosphamide); even if the disease
is localized to the lacrimal gland, any patient with suspected GPA should be co-managed
with a rheumatologist.[6]
Lacrimal gland biopsy is not absolutely necessary to diagnose inflammatory dacryoadenitis
because clinical response to treatment with NSAIDs and/or systemic corticosteroids
is typically sufficient.[6] However, lacrimal gland biopsy is indicated in recalcitrant cases or in those with
suspected systemic inflammatory conditions. This is performed on the orbital lobe
of the gland, via a lid crease incision, in order to protect the lacrimal ductules
passing through the smaller palpebral lobe. Surgical debulking or complete excision
of the orbital lobe may be considered for both diagnostic and therapeutic purposes.[12] For this procedure, any firm, white, abnormal-appearing tissue is excised for diagnostic
biopsy and therapeutic debulking. A large sample of tissue is required and should
be sent fresh in transport media in case flow cytometry is indicated. If a well-delineated
mass is present, the orbital lobe can be removed in its entirety, with the palpebral
lobe left intact. In a two-center study of 46 patients with idiopathic dacryoadenitis,
surgical debulking or complete excision of the orbital lobe of the lacrimal gland,
with or without concurrent local and/or systemic steroid, was effective in achieving
clinical remission in 80% of patients, with 8% recurrence.[12] Complete cure was achieved in 74% of all patients, some of whom previously exhibited
steroid dependence. Interestingly, surgical debulking did not lead to new or worsening
dry eye symptoms.
Lymphoproliferative Disorders
Lymphoproliferative tumors account for 14 to 38% of lacrimal gland biopsies, with
increasing incidence over the last 30 years.[1]
[2]
[15]
[16]
[17]
[18] The most common presenting sign is painless unilateral enlargement of the lacrimal
gland. Bilateral lacrimal gland enlargement occurs less frequently and is associated
with disseminated disease ([Fig. 2]).[19]
[20]
Fig. 2 Lymphoma. (a) A 73-year-old man with a history of hypothyroidism presented with significant enlargement
of right greater than left lacrimal glands. On examination, both lacrimal glands were
firm, immobile, and nontender. (b) Computed tomography of the orbits showed enlarged, homogeneous, moderately enhancing
lacrimal glands. Positron emission tomography revealed diffuse visceral disease. The
patient is currently being monitored without treatment for indolent disease by his
hematologist-oncologist.
Once the patient is diagnosed with malignant lymphoma of the lacrimal gland, the patient
should be referred to a hematologist-oncologist for staging (most often with positron
emission tomography [PET]) and treatment. Approximately 17 to 25% of patients have
concurrent systemic lymphoma at the time of diagnosis of the orbital mass.[19]
[21]
[22]
Current therapeutic options for malignant lacrimal gland lymphomas include radiation
(typically 28–36 Gy), chemotherapy, immunotherapy, and surgical excision.[23] The prognosis for most lacrimal gland lymphomas is good, with disease-specific survival
of 76% at 5 years and 56% at 10 years.[19] All patients require long-term surveillance for disease recurrence and progression,
regardless of tumor grade.
Epithelial Masses of the Lacrimal Gland
Epithelial Masses of the Lacrimal Gland
Pleomorphic Adenoma (Benign Mixed Tumor)
Pleomorphic adenomas are the most common epithelial tumors of the lacrimal gland and
usually present as slowly progressive, painless, unilateral proptosis in middle-aged
adults.[15]
[24] Symptoms are typically present for more than 12 months and may gradually result
in inferonasal displacement of the ipsilateral globe with limitation of extraocular
motility. The tumor nearly always involves the orbital lobe ([Fig. 3a,b]).[24] Pain and sensory loss are not classically seen with pleomorphic adenomas and, if
present, suggest malignancy.[24]
Fig. 3 Pleomorphic adenoma (benign mixed tumor). (a) A 32-year-old woman with no prior medical history presented with symptoms of progressive
proptosis, diplopia, and decreased vision on the right for over 5 years. (b) There was marked limitation of upgaze on the right. (c) T1-weighted magnetic resonance imaging of the orbits showed a large, round, heterogeneously
enhancing mass of the orbital lobe of the lacrimal gland, with inferonasal globe displacement.
The mass was removed en bloc by lateral orbitotomy.
On orbital imaging, the tumor appears as a well-defined, unilateral, homogeneous,
round or oval mass in the anterolateral orbit that moderately enhances on both CT
and MRI ([Fig. 3c]).[25] Depending on tumor cellularity and composition, larger masses may have heterogeneous
attenuation, but calcification is rare.[24]
[26] Smooth, shallow scalloping, or pressure-related expansion of the lacrimal gland
fossa, is frequently seen on CT, but no true bone breakdown is seen.
Some authors propose that fine-needle aspiration biopsy (FNAB) or incisional biopsy
should be considered for all epithelial tumors of the lacrimal gland because definitive
histopathologic diagnosis can guide subsequent therapeutic decision-making without
increased risk of recurrence or malignant change.[27]
[28] If preoperative incisional biopsy is performed, then a transcutaneous approach through
the lateral upper eyelid and septum is strongly recommended. Later surgical resection
should then excise the entire biopsy tract to ensure complete tumor removal because
residual tumor cells have the potential to proliferate and may undergo malignant transformation,
with patients presenting with recurrent disease years later.[29] If complete excision with an intact pseudocapsule is achieved, the 5-year recurrence
rate can be as low as 3%, compared to 32% among cases where there was history of prior
biopsy or incomplete excision.[24]
In cases of recurrence, a local resection can again be performed if the recurrent
mass is well circumscribed. However, if there is histopathologic evidence of orbital
invasion or there is concern for multifocal recurrence, then orbital exenteration
with removal of any involved bone is recommended. It is possible for the tumor to
invade the apex of the orbit and surrounding bone to the point where surgical resection
is no longer a viable option. In such cases, orbital radiation can be offered as palliative
therapy, but pleomorphic adenomas are considered to be fairly radioresistant.[30]
[31]
Pleomorphic Adenocarcinoma (Carcinoma Ex Pleomorphic Adenoma or Malignant Mixed Tumor)
Carcinoma ex pleomorphic adenoma arises from the malignant transformation of pleomorphic
adenoma and comprises approximately 8% of all epithelial lacrimal gland tumors.[1]
[2] Adenoid cystic carcinoma (ACC), mucoepidermoid carcinoma, carcinosarcoma, squamous
cell carcinoma, and sebaceous cell carcinoma have all been previously described as
histologic subtypes of carcinoma ex pleomorphic adenoma, although poorly differentiated
adenocarcinomas are the most common.[32]
[33]
[34]
[35]
[36] Generally, patients have a known history of pleomorphic adenoma that was either
biopsied or incompletely excised years or decades previously, though carcinoma may
also arise de novo from a primary pleomorphic adenoma with no prior surgical history.[29]
[37] Classic symptoms and signs include recent rapid progression of lateral upper eyelid
swelling and/or proptosis, the presence of pain, and evidence of bony erosion on orbital
imaging.[33] Malignant mixed tumors also typically have ill-defined margins and are more likely
to be heterogeneous, have calcifications, and show evidence of orbital spread with
or without bony invasion than pleomorphic adenomas on CT.[38]
A transcutaneous biopsy is generally recommended to confirm the diagnosis of malignant
mixed tumor. Once a histopathologic diagnosis is obtained, operability is determined.
Occasionally, a malignant mixed tumor may be well circumscribed and noninvasive, for
which local resection may be sufficient.[28]
[33]
[36]
[39] In more infiltrative cases, however, orbital exenteration with or without bone removal
should be performed, if possible.[33]
[40] Regional and cervical lymph node dissection should also be considered because there
can be early lymphatic dissemination.[33] Adjuvant radiotherapy may also be useful, but it will not improve outcomes if surgical
resection is incomplete.[31] Approximately 4 to 6 months after exenteration, the patient can be fitted for an
orbital prosthesis ([Fig. 4]).
Fig. 4 An orbital prosthesis, as seen on the patient's left, can be attached to the exenterated
socket by adhesives, magnets, or osseointegrated implants. Broad-rimmed spectacles
can help conceal the edges of the orbital prosthesis.
Despite aggressive surgical resection, prognosis is poor in patients whose histology
reveals poorly differentiated, invasive carcinoma.[28] Intracranial spread and metastasis to the lung, chest, and bones have all been reported.[32]
[33] Of note, patients with carcinoma ex pleomorphic adenoma and known history of pleomorphic
adenoma may live longer (median: 12.0 years) than those whose tumor arose de novo
(median: 3.5 years).[41]
Adenoid Cystic Carcinoma
ACC is the most common primary epithelial malignant tumor of the lacrimal gland.[1]
[2] Patients typically present with a less than 12-month history of symptoms and signs
similar to those with benign lacrimal gland masses, and also classically have periorbital
pain associated with paresthesias, suggesting perineural invasion.[39]
[42]
On orbital imaging, ACC is typically heterogeneous, is isodense or isointense to extraocular
muscle, and moderately enhances, but can either be well circumscribed or ill defined
with infiltration of adjacent tissues.[25]
[38] Bony invasion and intralesional calcification may also be seen. A “tail” or “wedge”
sign (extension of lacrimal gland tissue in the shape of a triangle between the neighboring
superior or lateral rectus muscle and respective orbital wall, without evidence of
intraconal involvement) is indicative of posterior extension and strongly suggests
a malignant rather than a benign tumor ([Fig. 5]).[38]
[43] Contrast-enhanced MRI is most useful in detecting perineural invasion, intracranial
extension, cavernous sinus involvement, and/or bone marrow replacement in ACC.[25]
[39]
Fig. 5 Adenoid cystic carcinoma. An axial view on T1-weighted magnetic resonance imaging
of the orbits shows a large, enhancing superolateral mass causing 5 mm of proptosis
and displacing the globe downward, with a positive tail sign (arrowhead). The patient underwent exenteration alone, but developed a pulmonary nodule a year
later, for which she was treated with carboplatin and paclitaxel. Approximately 7.5
years after diagnosis, she is alive with stable pulmonary nodules.
When there is high clinical suspicion for ACC, a direct transcutaneous biopsy should
be performed. Once a histopathologic diagnosis is obtained, staging by the American
Joint Committee on Cancer (AJCC) classification system is recommended to assess the
extent of disease and determine treatment options.[44]
[45] Often, there is already evidence of local and perineural spread; a majority of patients
have ≥T3 tumors on presentation.[44]
[46]
Traditionally, orbital exenteration with or without bony removal, followed by adjuvant
radiotherapy, is recommended to achieve locoregional control, but recent studies have
shown that globe-preserving surgery with or without bony removal, followed by postoperative
radiotherapy, may be appropriate for patients with <T3 disease.[44]
[47]
[48] However, if the tumor is >2.5 cm in its greatest dimension or there is radiographic
evidence of posterior extension, then orbital exenteration should be performed, with
removal of all radiologically and/or clinically involved bone.[44] Adjuvant radiotherapy is recommended for nearly all patients, given the propensity
for early perineural invasion.[44]
[49] Postoperative chemotherapy may also be considered in certain patients.[50]
In recent years, a treatment protocol consisting of neoadjuvant intra-arterial cytoreductive
chemotherapy (IACC), followed by orbital exenteration, postoperative chemoradiation,
and adjuvant chemotherapy, has been proposed to achieve locoregional control and improve
disease-specific survival in patients with ACC.[51] However, strict adherence to protocol and an intact lacrimal artery, without significant
prior tissue manipulation (other than transcutaneous biopsy for histopathologic diagnosis),
are required for success of this treatment plan. Although reported results have been
promising, prospective randomized multicenter clinical trials with long-term follow-up
have been very difficult to carry out.[52]
Despite aggressive treatment, prognosis is very poor for patients with ACC. According
to a review of patients with ACC in the Surveillance, Epidemiology, and End Results
(SEER) Registry, those with localized tumors at the time of diagnosis have nearly
89% disease-specific survival at 5 years, 59% at 10 years, 52% at 15 years, and 45%
at 20 and 25 years.[46] Although 5-year disease-specific survival is similar at 85% for patients with regional
spread at diagnosis, only 37% are living at 10 years, and few live after 15 years.[46] Long-term surveillance is required for all patients with ACC, as late relapse, intracranial
spread, and distant metastasis are not uncommon.
Metastasis to the Lacrimal Gland
Metastasis to the Lacrimal Gland
There are several reports of tumors metastasizing to the lacrimal gland in the literature.
Metastatic tumors to the lacrimal gland are most commonly breast carcinomas.[1]
[53]
[54]
[55]
[56] Neuroendocrine or carcinoid tumors,[57] gestational choriocarcinoma,[58] esophageal carcinoma,[59] hepatocellular carcinoma,[60] renal cell carcinoma,[61] gastrointestinal stromal tumors,[62] osteosarcoma,[63] and pleural mesothelioma[64] have all been reported. Biopsy yields a histopathologic diagnosis, with subsequent
systemic evaluation performed for staging. Treatment depends on tumor type, grade,
and stage, and is directed by either a surgical or medical oncologist.
Conclusion
Masses of the lacrimal gland encompass a broad range of pathologies, and a good working
knowledge of common clinical characteristics and radiographic imaging findings is
essential in differentiating between inflammatory lesions, benign and malignant lacrimal
gland neoplasms, and metastatic disease. Inflammatory lesions are the most common
causes of lacrimal gland enlargement, followed by lymphoproliferative disorders. Epithelial
lacrimal gland masses tend to be unilateral and involve the orbital lobe. Periorbital
pain and rapid symptom onset (i.e., <10 months) are strongly suggestive of malignancy.
A histopathologic specimen is often required for diagnosis. Depending on the suspected
diagnosis, an anterior transcutaneous tissue biopsy or FNAB may be advised in order
to preserve normal tissue barriers, such as the periosteum.
Once a diagnosis is obtained, treatment often involves multidisciplinary care, with
involvement of rheumatology and oncology in addition to the skull base team. All patients
with history of an epithelial lacrimal gland tumor (i.e., benign or malignant) or
lymphoproliferative disease involving the lacrimal gland require long-term surveillance
for disease recurrence and progression, regardless of tumor grade, given the propensity
for late locoregional recurrence and systemic disease.
