Saudi Journal of Ophthalmology (2018) 32, 13–16

Orbital Pathology Update

Pleomorphic adenoma of the lacrimal gland: A review with

updates on malignant transformation and molecular genetics
William Harrison ⇑; Patricia Pittman; Thomas Cummings

Abstract

Pleomorphic adenoma (benign mixed tumor) is the most common epithelial neoplasm of the lacrimal gland. It is usually a slow
growing, well-circumscribed, mass that is identical to its salivary gland counterpart. Patients generally have an excellent prognosis
for vision and long-term survival after complete surgical excision. There is a tendency to reoccur, especially if there is an incom-
plete excision, and rarely, malignant transformation to carcinoma ex pleomorphic adenoma can occur, which has a much poorer
prognosis. The molecular genetics of lacrimal gland pleomorphic adenomas have only recently been studies, but appear to display
similar genetic aberration found in the salivary gland counterparts.

Keywords: Pleomorphic adenoma, Lacrimal gland, Malignant transformation, Molecular genetics

Ó 2018 The Authors. Production and hosting by Elsevier B.V. on behalf of Saudi Ophthalmological Society, King Saud University.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
https://doi.org/10.1016/j.sjopt.2018.02.014

Introduction benign, these epithelial tumors have a propensity to recur

and undergo malignant transformation if incompletely
The lacrimal gland, an almond shaped, bi-lobed, eccrine excised, leading to increased morbidity in these patients.5
secretory gland, approximately 2 cm long that lies in the lacri- The purpose of this review is to summarize in a multi-
mal fossa in the supero-lateral part of each orbit, secretes a faceted manner the data available in the literature regarding
watery physiologic fluid which lubricates and provides nutri- the clinicopathologic features, radiographic findings, treat-
ents for the eye and contains the bactericidal enzyme ment, malignant transformation, and advances in molecular
lysozyme.1 Many different types of neoplasms, including genetics in patients with lacrimal gland pleomorphic
metastases,2 can arise within the lacrimal gland, which adenomas.
account for 5% to 25% of all orbital neoplasms.3 Primary lacri-
mal gland neoplasms often arise in the orbital lobe where the Clinical features
gland attached to the orbital rim about the lacrimal fossa.
The most common is the benign mixed tumor or pleomorphic Pleomorphic adenomas (PA) are the most common
adenoma (PA), a benign mixed tumor consisting of epithelial epithelial tumor to arise within the lacrimal gland. They are
and mesenchymal components.2 These neoplasms character- usually slow growing and patients commonly present with
istically presents with slow, painless enlargement of the lat- slight fullness in the temporal upper lid, to those with frank
eral portion of the upper eyelid in the 3rd and 4th decades proptosis, diplopia, visual impairment, and eyeball
of life, with no clear gender predominance.4 Although displacement.6 Due to the location of the tumor, at or near

Received 19 November 2017; received in revised form 11 February 2018; accepted 17 February 2018; available online 2 March 2018.

Duke University Medical Center, Department of Pathology, United States

⇑ Corresponding author.
e-mail address: william.t.harrison@dm.duke.edu (W. Harrison).

Peer review under responsibility Access this article online:

of Saudi Ophthalmological Society, www.saudiophthaljournal.com
King Saud University Production and hosting by Elsevier www.sciencedirect.com
14 W. Harrison et al.

the lacrimal fossa bone, the enlarging tumor characteristically findings are suggestive of PA, a diagnostic biopsy is not rec-
displaces the eye downward and nasally. The duration of ommended as it may result in tumor recurrence later. A recur-
symptoms is a very important clinical indicator of a PA. The rence rate of up to 30% over five years has been reported
vast majority of patients with lacrimal gland PAs have had when biopsy specimens had been taken.6 Fortunately, in
some degree of the aforementioned symptoms for over a recent years, the rate of inadvertent biopsy of PAs has dra-
year, which correlates with the usual slow growing nature of matically decreased as a result of improved radiologic
the tumor. The suspicion for malignancy increases when the evaluation.7,9
symptoms have been less than 10 months.6 Additionally, sen-
sory loss and pain are not common symptoms of lacrimal Treatment
gland PA and when present, should raise concern for a malig-
nant neoplasm such as adenoid cystic carcinoma or mucoepi- Surgical intervention by lateral orbitotomy is the mainstay
dermoid carcinoma.6,7 However, it should be noted that very of treatment with complete resection of an intact cap-
rare atypical presentations have been reported in the litera- sule.6,10,11 Incomplete capsule removal or defect in the cap-
ture and include patients with PAs having presenting symp- sule at the time of surgery can lead to significantly high
toms mimicking inflammatory lesions such as orbital rate of recurrence caused by the displacement of the myxoid
cellulitis or painful subcutaneous nodules.7,8 component of PA into the orbital cavity.2,12 Incisional or nee-
dle core biopsies are strictly contraindicated.12 Radiation,
Radiographic imaging while not commonly used, may be considered for rare pleo-
morphic adenomas that are inoperable or for recurrent/resid-
Diagnostic imaging is critical for the clinical diagnosis of ual lesions. The prognosis is excellent when the lesion is
lacrimal gland neoplasms. Computed tomography (CT) and completely excised with an intact capsule, with a less than
magnetic resonance imaging (MRI) scans are ideal, with 3% recurrence rate after 5 years. Recurrence is even more dif-
MRI as the preferred method for visualization of the sur- ficult to treat as they are often multiple and infiltrate normal
rounding bone and examination for intracranial infiltration.6 orbital structures, leaving orbital exenteration as the only
On MRI, pleomorphic adenomas appear as isointense lesions therapeutic option in some cases. In very rare instances recur-
with regular margins and angles.4 For a PA, a well circum- rence in the frontoparietal areas of the brain have been
scribed mass identified within the lacrimal fossa is usually reported in patients with incompletely resected PAs.13
seen (See Fig. 1A and 1B).6 Certain radiographic findings
may illicit concern for a more aggressive malignancy and Pathological findings
these include irregular shaped mass, bone invasion or ero-
sion, molding of the mass to the globe or lateral orbital wall, On gross examination, PAs typically have a pseudocapsule
and calcification.6,7 If the radiographic findings and clinical surrounding the mass lesion. It is imperative that the capsule

Fig. 1. Images A and B show T1-weighted MRI images demonstrating a well circumscribed superior orbital mass that has mass effect on the right eye.
Images C and D are photomicrographs which highlight the biphasic nature of the neoplasm with an epithelial component forming cord and tubules and a
chondromyxoid mesenchymal component.
Pleomorphic adenoma of the lacrimal gland 15

be carefully examined for any evidence of disruption. Histo- tion.16,21 As aforementioned, 17p loss is common in Ca-ex-
logically, PAs demonstrate significant histologic heterogene- PAs, indicating the tumor suppressor gene, p53, is thereby
ity with varying proportions of epithelial and mesenchymal commonly lost in the late carcinogenesis of CA-ex-PA.16
components (See Fig. 1C and 1D). The epithelial cells form Additionally, many genes that regulate tumor angiogenesis,
characteristic double-layer ductal structures, acini, irregular growth factors, and cell-cell adhesion also play a role in the
tubules, strands, and sheets with surrounding myoepithelial development and progression of Ca-ex-PA.
cells. The elements are typically dispersed within a back- While the molecular genetics of salivary gland PAs have
ground of loose myxoid tissue containing chondroid and been more extensively studied, very little has been published
rarely, foci of bone.3,8,14,15 Islands of squamous metaplasia on the genetic alterations in lacrimal gland PAs. High-
may also be present and in most cases there is no evidence resolution array-based comparative genomic hybridization
of dysplasia or elevated mitotic activity.8,15 No apparent dif- has been used to study the genomic profiles of a series of
ference in biological behavior has been reported between lacrimal gland PAs and Ca-ex-PAs.5 This analysis showed that
tumors composed largely of epithelial elements and those lacrimal gland PAs have no or few copy number alterations
composed entirely of mesenchymal elements.15 and that losses involving 1p, 6q, 8q, and 13q and gains of
9p are recurrent alterations. The average number of genomic
imbalances per tumor was 3.25 in primary and recurrent PAs
Malignant transformation
compared with 7.7 in CA-ex-PAs. Overall, these findings sup-
port the notion that PAs are genetically stable tumors. The
A carcinoma arising in a pleomorphic adenoma is referred
only recurrent copy number alteration identified in CA-ex-
to as a carcinoma ex pleomorphic adenoma (Ca-ex-PA) or a
PAs was a gain of 22q12.3-qter. A detailed analysis of their
malignant mixed tumor and conveys a poor prognosis.3,5,12,15
array data identified 2 major candidate target genes, NFIB
The incidence of malignant transformation is increased with
and PDGFB, which may be activated as a result of copy num-
the duration of the tumor and accounts for approximately
ber gains involving 9p and 22q. It was also shown that the
10% of all malignant lacrimal gland tumors.6,16 The longest
translocation target gene PLAG1 was frequently overex-
interval reported in the literature for metastatic transforma-
pressed in PAs and less frequently in Ca-ex-PAs and HMGA2
tion of a PA is 60 years.17 Seventy-five percent of the trans-
is overexpressed in a small subset of PAs. No genomic imbal-
formed carcinomatous component is to adenocarcinoma,2
ances with break points in PLAG1 were found but this was
but can have a variety of morphologies including mucoepi-
thought to be due to balanced translocations which is a
dermoid carcinoma, adenoid cystic carcinoma, salivary duct
well-known genetic phenomenon in PAs. Immunohistochem-
carcinoma, and adenocarcinoma not otherwise specified
istry for PLAG1 showed strong staining in approximately half
(NOS).16 Older literature reports approximately up to 10%
of the PAs studied. These findings support previous studies
of pleomorphic adenomas undergo malignant change within
showing that PLAG1 is frequently activated and overex-
20 years after first treatment and 20% by the end of 30
pressed in PAs.19 PLAG1 activation is thought to be a key
years.6 This number is significantly increased if the PA was
event in the development of both salivary and lacrimal gland
not completely excised during initial resection.2,12 With
PAs. Overall, their findings showed that lacrimal gland PAs
recent advances in therapy the prognosis appears to have
have similar genetic profiles to salivary PAs.
improved. In a 2009 review of 118 lacrimal gland tumors,
including 57 pleomorphic adenomas, it was shown that only
3 of the pleomorphic adenomas recurred and none under-
went malignant transformation.18 A case of malignant trans-
Conclusion
formation of a lacrimal pleomorphic adenoma to squamous
While lacrimal tumors are overall rare, pleomorphic ade-
cell carcinoma 19 years after the initial surgical resection with
noma is the most common epithelial tumor found to arise
metastases to the lungs has been reported.19 Another inter-
in this gland. Accurate clinical diagnosis followed by appro-
esting case was reported in which a patient developed ade-
priate surgical excision leads to an excellent prognosis in
nocarcinoma with recurrent nodules of recognizable
the vast majority of cases. Local recurrence, which is often a
pleomorphic adenoma 32 years after the initial resection.18
result of incomplete excision and malignant transformation
Unfortunately, no biomarkers currently exist to help predict
to carcinoma-ex pleomorphic adenoma, are associated with
the risk of malignant transformation of PA.
increased morbidity and mortality. The molecular genetics
of pleomorphic adenoma and carcinoma-ex pleomorphic
Molecular genetics adenoma are beginning to be better understood and current
studies suggest that they harbor similar aberrations seen in
Molecular studies on salivary gland PAs revealed that the their salivary gland counterparts.
development of CA-ex-PA follows a multi-step model of car-
cinogenesis, with the progressive loss of heterozygosity at
8q, then 12q, and finally 17p.16 Early alterations of chromoso- Conflict of interest
mal arm 8q often involve PLAG1 (8q12.1), an adenoma asso-
ciated gene, and MYC (8q22.1-q24.1) a known oncogene, The authors declared that there are no conflicts of interest.
resulting in overexpression. The PLAG1 gene translocation t
(5;8)(p13;q12) has been found to be highly specific for
PAs20, potentially making it a powerful diagnostic marker. Acknowledgement
Alterations including amplification, gene fusion, and
translocations, in 12q genes such as HMGIC, HMGA2, and We would like to acknowledge Mr. Steve Conlon for his
MDM2 are thought to play a role in malignant transforma- help with photography.
16 W. Harrison et al.

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