Etiology

• Oncogenetic origin is unknown.
• Histology is characterized by involvement of epithelial and myoepithelial structures.
• Myoepithelial cells are contractile elements in the gland.
• Metallothionein is a cysteine-rich protein found in benign and malignant myoepithelial neoplasms; it might play a role in altering the pattern of apoptosis in these tumors (Viana 2013).

Epidemiology

• Most commonly presents in the fourth and fifth decade
• Pleomorphic adenoma is a head and neck tumor, and is the most common benign neoplasm of both the major and minor salivary glands.

History

• Slowly developing (> 1 year) proptosis or globe displacement
• Nonpainful enlargement of the lacrimal gland

Clinical features

• Globe displaced inferiorly and medially
• Tumors that arise in the palpebral lobe of the lacrimal gland present earlier than orbital tumors (Rose 1992).
• Pleomorphic adenoma has been reported in the eyebrow, upper eyelid, lateral and medial lower eyelid, lacrimal sac, and even intraocularly (Obi 2013).
• Recurrent benign pleomorphic adenoma can be multifocal and multinodular and can present multiple times after incomplete primary resection before developing malignant transformation (McNab 2011).
• Average time to malignant transformation is estimated to be 15–20 years (Font 1978).
• Recurrent pleomorphic adenoma, even without malignant transformation, can cause local morbidity such as compressive neuropathy (Benoit 2010).

Testing

• CT scan (Figure 1) and MRI demonstrate a well-circumscribed mass with pressure remodeling of the lacrimal fossa that can indent globe.
• In about a third of malignant lacrimal gland tumors, calcification is evident in a stippling patter; in benign tumors, calcification is less common and more localized and dense. Therefore, diffuse calcification raises the index of suspicion for malignancy and lowers the threshold for incisional biopsy (Wright 1992).
• Establishing a diagnosis of pleomorphic adenoma is unusual in that incisional biopsy is avoided to prevent possible tumor spillage and seeding, which can lead to recurrence after excision.
• Therefore the diagnosis is established on clinical grounds.
• After complete excision of an encapsulated mass, with the capsule intact, the diagnosis of pleomorphic adenoma can be confirmed by histopathology.
• Definitive management is complete surgical excision, which can be performed by anterior or lateral orbitotomy, depending on the size and location of the tumor.
• The cues that allow for clinical diagnosis include:
• Color: It is white versus pink, which would suggest a lymphoid tumor.
• Location: It can be seen as contiguous with and adjacent to the normal lacrimal gland
• Consistency: It is solid without a lobular gland-like appearance.
• Encapsulation (or pseudocapsule): It is surrounded by a glistening surface, which should not be violated.
• Definitive excision with the capsule intact is the goal of surgery even if the mass is fairly large.
• In the pre-CT era, John Wright proposed an approach to differentiating between benign and malignant lacrimal gland tumors based on duration of symptoms — benign tumors slowly enlarge over a period of at least one year — and presence of pain — painless growth implies benign tumor (Wright 1979).
• In a review of 78 patients treated at Moorfields Eye Hospital from 1968 to 1990 for pleomorphic adenoma, 89% (63 tumors) were correctly diagnosed prior to surgery, based on these clinical and radiographic characteristics (Rose 1992).
• Eight patients among those 78 had symptoms for less than 1 year and 4 had pain, leading to a misdiagnosis.
• Eight patients among those 78 had palpebral lobe tumors, and presented with clinical evidence of tumor for less than 1 year.
• Among six palpebral lobe lacrimal gland tumors treated at the University of British Columbia from 1982 to 1995, only 3 were pleomorphic adenomas. The malignant tumors included an adenoid cystic carcinoma and 2 malignant transformations of pleomorphic adenoma. The index of suspicion should be different for a palpebral lobe tumor (Vangveeravong 1996).
• Proponents of incisional biopsy assume that the risk of tumor seeding is outweighed by the advantage of establishing the diagnosis (Tse 1988).

Figure 1. Pleomorphic adenoma CT. Courtesy Robert G. Fante, MD, FACS.

Testing for staging, fundamental impairment

There is no staging needed for this benign tumor.

• Fourth to fifth decade
• No other known risk factors

• Inflammatory lesions of lacrimal gland
• Idiopathic orbital inflammation
• Sjögren syndrome
• Sarcoid
• Mumps
• Tuberculosis
• Lymphoid lesions
• Benign reactive lymphoid hyperplasia
• Atypical lymphoid hyperplasia
• Lymphoma
• Epithelial tumors
• Malignant mixed tumor of the lacrimal gland
• Adenoid cystic carcinoma

Natural history

This is a slow-growing tumor until malignant transformation occurs.

Medical therapy

• In the salivary gland, HER2/neu overactivity has been observed with malignant transformation carcinoma ex pleomorphic adenoma, therefore HER2 based therapy might be effective when medical treatment is needed (Sharon 2010). It has not yet been studied in orbital tumors.
• Trastuzumab (Herceptin) is a monoclonal antibody that competitively binds to the plasma membrane HER2 receptor.

Radiation

Cases of multinodular recurrent benign pleomorphic adenoma can be treated with radiotherapy, in addition to surgery or if surgical excision is impractical.

Surgery

Although excisional biopsy is the accepted standard of care there are advocates of limited preliminary biopsy prior to excision to confirm the diagnosis (Lai 2009).

• The theory behind incisional biopsy is that management can be changed by recognizing an alternative diagnosis.
• Incisional biopsy might be most appropriate when the lesion is not amenable to simple removal, without affecting tissues other than the lacrimal gland.

Figure 2. Bone flap for pleomorphic adenoma. Courtesy Robert G. Fante, MD, FACS.

Figure 3. Bone flap replaced. Courtesy Robert G. Fante, MD, FACS.

• Secondary excision if tumor has been left behind focuses similarly on dissection along the encapsulated surface
• Wide tumor free margins might be needed to assure complete excision and avoid malignant transformation.

Common treatment responses, follow-up strategies

Once complete excision has been accomplished with the capsule intact, there should be no risk of continued tumor growth.