Malignant Mixed Tumor of the Lacrimal Gland

Etiology

• Typically develops from malignant transformation of a pleomorphic adenoma (“benign mixed tumor”) of the lacrimal gland or arise de novo
• Most commonly arises after incomplete resection of a pleomorphic adenoma or degeneration of a chronic lacrimal gland lesion (ie, long-standing tumor with acute change
• Also termed “carcinoma ex pleomorphic adenoma” and “carcinoma in pleomorphic adenoma”

Epidemiology

• Represents 4–15% of epithelial neoplasms of the lacrimal gland (Shields 2009)
• When transformation occurs, it is typically 15–20 years after excision of pleomorphic adenoma
• Median age of 43 years in one series (Von Holstein 2014); mid 50s in a surgical sries (Tom 2020) and sixth or seventh decade in earlier reports (Shields 2004)
• No consistent sex predilection

History

• Enlarging mass in the lacrimal gland fossa
• Inferior or inferomedial displacement of globe
• Can be associated with discomfort, edema, and diplopia
• Duration of lesion and history of previous surgical interventions.

Clinical features

• Progressive inferior and inferolateral displacement of the globe
• Axial proptosis
• Long-standing symptoms
• Palpable mass, choroidal striae, increased resistance to retropulsion

Testing and evaluation for establishing the diagnosis

• Computed tomographic (CT) imaging will show both enlargement of the lacrimal gland fossa, of the pleomorphic adenoma, and bony destruction suggesting malignant transformation.
• Compare to previous studies when available.
• MRI helps define soft-tissue extent, perineural spread and apical extension.
• Radiographic features overlap between benign and malignant lesions can be inconsistent.
• Histopathology
• Observing malignant elements within a pleomorphic adenoma makes diagnosis.
• Can be malignant elements in what appears similar to a pleomorphic adenoma
• Atypia, necrosis, mitotic figures
• Molecular Pathology
  • PLAG1 and HMGA2 rearrangements are seen in pleomorphic adenoma retained through malignant transformation
  • Lacrimal gland pleomorphic adenoma and malignant mixed tumors share genetic profiles that frequently overexpress PLAG1 with 9p (NFIB) and 22q (PDGFB)_ gains implicated in progression (von Holstein 2014).

Testing for staging, fundamental impairment

• The sixth or seventh edition of the American Joint Committee on Cancer (AJCC) TNM definitions for carcinoma of the lacrimal gland can be used (see outline on Adenoid Cystic Carcinoma), but has not been validated for malignant mixed tumor.
• Histopathologic classifications might have prognostic value.
• Noninvasive (i.e., in situ disease) within the encapsulated tumor
• Minimally invasive (involvement < 1.5 mm distal from the capsule)
• Frankly invasive (involvement > 1.5 mm from the capsule)

Primary risk factor is a history of pleomorphic adenoma with incomplete excision, capsular violation, spillage.

• Benign mixed tumor (pleomorphic adenoma)
• Adenoid cystic carcinoma
• Adenocarcinoma
• Squamous cell carcinoma
• Mucoepidermoid carcinoma
• Lymphoproliferative lesion of the lacrimal gland
• Specific inflammatory process/rheumatologic disease/dacryoadenitis
• Nonspecific or idiopathic orbital inflammation
• Less common lacrimal gland lesions
• Oncocytoma
• Acinic cell carcinoma
• Myoepithelioma
• Solitary fibrous tumor
• Cystadenocarcinoma

Natural history

• Can behave like adenoid cystic carcinoma with intracranial and perineural invasion
• Can have tumor-related death when intervention is delayed.
• Usually identified relatively early in tumor progression because of the harbinger pleomorphic adenoma.

Overall treatment approach

• Contemporary management has shifted towards eye-sparing surgery followed by adjuvant radiotherapy, reserving orbital exenteration and cranio-orbital resection for extensive disease (Tom 2020).

Medical therapy

• There is no known effective chemotherapeutic or immunobiologic regimen for this tumor.

Radiation

• No studies have assessed the impact of radiation therapy on lacrimal gland malignant mixed tumor.
• For invasive parotid malignant mixed tumor, adjunctive radiation has been shown to improve local recurrence rates (Chen 2007).
• Adjuvant radiotherapy is recommended for invasive, high grade, large (T3-T4) tumors, close-positive margins, or perineural invasion (Tom 2020).
• IMRT or proton therapy can be considered (Tom 2020).

Surgery

• There has been no large case series. Complete excision with clear margins is the primary goal.
• For well-circumscribed lesions lacking aggressive radiographic features, gross total resection is often better given risk of seeding and recurrence with capsular violation (Esmaeli 2026).
• Outcomes are good for noninvasive and minimally invasive disease after surgery, even without adjuvant radiation (Bernardini 2008).
• Across lacrimal gland carcinoma cohorts, eye-sparing surgery plus radiation yields overall and disease-free survival compared to exenteration.
• Cranio-orbital resection has not demonstrated a survival advantage (Rose 208).

Common treatment responses, follow-up strategies

• With minimally invasive and in situ disease surgical cure can be achieved with wide excision.
• Early perineural invasion and bony involvement are not seen; this differs from adenoid cystic carcinoma.
• Local and distant spread can be seen with continued tumor progression beyond the encapsulated mass.

• Radiation-related toxicity
• Dry eye syndrome/ocular surface disease
• Radiation dermatitis
• Radiation retinopathy
• Radiation optic neuropathy

• Local recurrence can be managed with exenteration and/or radiotherapy.
• Regional lymph node metastasis can be managed with nodal dissection and/or radiotherapy.
• Distant metastasis has no known treatment.

• Godtfredsen in 1948 reported a case of malignant mixed among 10 lacrimal gland epithelial tumors in Denmark.
• Davies reported an additional 3 cases in 1954.
• Ten cases were reported from the AFIP in 1962, of which 4 died of metastatic disease, 3 of unrelated causes, and only 1 was living free of recurrence.

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