Adenoid Cystic Carcinoma of the Lacrimal Gland

Key Points at a Glance

Key Points of This Disease

• Lacrimal gland adenoid cystic carcinoma (LGACC) is a rare malignant epithelial tumor arising in the lacrimal gland, accounting for approximately 1.6% of all orbital tumors.
• Perineural invasion (45–85%) is frequently observed, and pain is an important distinguishing feature from benign tumors.
• From the early stage, it may infiltrate the brainstem via the lacrimal nerve, and even wide excision may not prevent this.
• The most common histological subtype is cribriform (39.8%), while the basaloid type (31.8%) has the worst prognosis.
• Standard treatment is surgery (eye-sparing or orbital exenteration) combined with postoperative radiotherapy.
• Reported 5-year survival rates are approximately 19–55%, and 10-year survival rates are 20–30%; about 50% develop distant metastases to the lungs, bones, etc.
• Molecular targeted therapies targeting the MYB-NFIB fusion gene and Notch signaling pathway are under investigation.

1. What is Lacrimal Gland Adenoid Cystic Carcinoma?

Adenoid cystic carcinoma (ACC) is a rare malignant tumor arising in secretory glands, with a worldwide incidence of 3–4 cases per million population ¹⁾. It accounts for about 1% of all head and neck cancers, and when it occurs in the lacrimal gland, it is called lacrimal gland adenoid cystic carcinoma ¹⁾.

Lacrimal gland adenoid cystic carcinoma accounts for approximately 1.6% of all orbital tumors ³⁾⁵⁾ and is the most common malignant epithelial tumor of the lacrimal gland, constituting about 13–40% of lacrimal gland carcinomas ⁵⁾. Lacrimal gland tumors account for about 10% of orbital space-occupying lesions; about 20% of solid lacrimal gland tumors are epithelial-derived, of which about 45% are malignant, and about 60% of malignant epithelial lacrimal gland tumors are adenoid cystic carcinoma.

Lacrimal gland adenoid cystic carcinoma was first described by Theodor Billroth and was initially named “cylindroma” based on its histological features ⁵⁾.

Epidemiological features are as follows.

• Mean age at diagnosis: 42.7 ± 12.5 years (range 9–76 years). Pediatric cases 5.9%, under 40 years 41.9%⁵⁾
• Sex difference: Large-scale data show a slight female predominance (female 53.8%, male 46.2%)⁵⁾. However, some reports indicate a male predominance, with variation across the literature.
• Laterality: Almost no difference (right 49.3%, left 50.5%). Bilateral cases are extremely rare⁵⁾
• Prognosis: 5-year survival rate 19.4–55.3% (large review of 806 cases)⁵⁾, 10-year survival rate 20–30%, indicating poor prognosis.
• Distant metastasis: About 50% develop distant metastases to the lungs, bones, etc.

Q How rare is adenoid cystic carcinoma of the lacrimal gland?

A

It accounts for approximately 1.6% of all orbital tumors, and the global incidence of adenoid cystic carcinoma is extremely rare at 3–4 cases per million population¹⁾⁵⁾. It is the most common histological type among malignant epithelial tumors of the lacrimal gland.

2. Main symptoms and clinical findings

Subjective symptoms

According to a large review of 806 cases, the frequency of initial symptoms is as follows⁵⁾.

Symptom	Frequency
Proptosis	27.4%
Pain	21.7%
Eyelid swelling	10.9%
Eye deviation	10.2%
Restricted eye movement	10.1%
Decreased vision	9.3%
Double vision	6.7%
Ptosis	4.1%

Pain is a characteristic symptom of adenoid cystic carcinoma, caused by perineural invasion (PNI). It is an important distinguishing feature from benign tumors. Since the lacrimal gland is located in the superolateral orbit, the eye often deviates inferomedially. Hypesthesia in the frontotemporal region or S-shaped ptosis may also occur. The time from symptom onset to diagnosis averages 11.1 ± 18.3 months (range 0.5–120 months) ⁵⁾.

The growth rate of the tumor is faster than that of pleomorphic adenoma, and it is more likely to be accompanied by pain, which is an important point for differentiation. Proptosis due to tumor enlargement, restriction of eye movement due to invasion of extraocular muscles and nerves, and decreased visual acuity due to optic nerve compression also progress relatively rapidly.

Q How can lacrimal gland adenoid cystic carcinoma be distinguished from benign lacrimal gland tumors?

A

The presence or absence of pain is the most important differentiating point. Adenoid cystic carcinoma is accompanied by pain due to perineural invasion, whereas benign tumors (such as pleomorphic adenoma) are painless and progress slowly. If bone destruction is confirmed on CT, it can be judged as malignant, but there are also cases of adenoid cystic carcinoma without bone destruction, so if there is pain, actively consider biopsy.

Clinical Findings

T2-weighted MRI (axial and coronal) of lacrimal gland adenoid cystic carcinoma: a hyperintense mass in the superolateral left orbit with invasion of the orbital bone wall

Liang M, Yu Z, Wang F. A case report: An unusual presentation of adenoid cystic carcinoma of the lacrimal gland. Medicine (Baltimore). 2023;102(13):e33446. Figure 1. PMCID: PMC10063268. License: CC BY 4.0.

T2-weighted axial (A) and coronal (B) images show an ill-defined hyperintense mass in the lacrimal gland region of the superolateral left orbit, with invasion of the orbital bone wall but preservation of the periosteum. This corresponds to the MRI findings (lacrimal fossa mass, bone invasion) discussed in the section “2. Main Symptoms and Clinical Findings”.

• CT findings: An ill-defined oval soft tissue mass in the superolateral orbit. Bone erosion is seen in 35.3% of cases, and focal calcification in 2.2% ⁵⁾. If bone destruction is confirmed on CT, it can be judged as malignant, but there are also cases without bone destruction.
• MRI findings: Iso- to hyperintense on T1-weighted images, most commonly hyperintense on T2-weighted images. Shows diffuse enhancement after contrast ⁵⁾.
• Diffusion-weighted MRI: Low ADC values (reflecting high cellular density) are useful for differentiation from benign lesions ⁵⁾.

According to a report by Williams et al., histological evidence of lacrimal fossa invasion was confirmed in 82% of patients ¹⁾. If the tumor destroys the orbital bone on CT, it can be judged as malignant, but caution is needed because there are also cases of adenoid cystic carcinoma without bone destruction.

3. Causes and Risk Factors

The cause of adenoid cystic carcinoma is unknown, and no specific risk factors have been established. The tumor most commonly arises from the orbital lobe of the lacrimal gland and is an unencapsulated tumor.

The following pathological and clinical features are known as poor prognostic factors.

• Perineural invasion: Found in 45.3% of cases in a large review ⁵⁾, it is one of the most important poor prognostic factors. It can invade the brainstem through the lacrimal nerve and may occur early in the disease. Even with wide excision and radiotherapy, brainstem invasion may not be prevented.
• Basaloid variant: A histological type with poor prognosis ⁵⁾.
• High T stage: T3 or higher has significantly higher risk of recurrence and metastasis ⁵⁾
• Distant metastasis: Hematogenous, most commonly to lung (40.8%), brain (25%), bone (22.9%), and liver (17.4%) ⁵⁾. About 50% of all cases develop distant metastasis
• p53 and Bcl-2 abnormalities: Apoptosis impairment due to p53 downregulation and Bcl-2 upregulation is associated with worse prognosis

Specialist supplement

Adenoid cystic carcinoma is pathologically a well-differentiated, low-grade malignancy with relatively slow tumor growth. In young and middle-aged patients, long-term survival may occur even after metastasis is detected. However, eventually, outcomes may worsen due to cachexia from systemic metastasis or complications from intracranial invasion.

4. Diagnosis and examination methods

Definitive diagnosis is based on histopathological evaluation. If malignancy is suspected, excisional biopsy is recommended to prevent intraorbital seeding of tumor cells. Fine-needle aspiration biopsy may be appropriate for unresectable tumors, but only at facilities with experienced cytopathologists.

If a lacrimal gland tumor is suspected due to symptoms such as proptosis, ophthalmic examinations including visual acuity, visual field, and eye movement are performed, along with imaging studies using plain CT and plain/contrast MRI. If systemic evaluation is needed, PET-CT or contrast CT may also be performed. Definitive diagnosis is made by histopathological examination of a biopsy or the entire resected specimen.

TNM classification (AJCC 8th edition)

T stage	Definition
T1	Maximum diameter ≤ 2 cm
T2	Maximum diameter > 2 cm to ≤ 4 cm
T3	>4 cm in greatest dimension or orbital soft tissue extension
T4	Invasion of paranasal sinuses, temporal fossa, pterygopalatine fossa, superior orbital fissure, cavernous sinus, or brain

Histologic Subtype Classification

HE-stained histopathology of lacrimal gland adenoid cystic carcinoma: cribriform, tubular, and solid basaloid patterns with orbital bone invasion and perineural invasion

Wu J, Cui H, Liang M, Wang F. Histological-pathological and clinical T stage of primary adenoid cystic carcinoma of the lacrimal gland in a Chinese population. BMC Cancer. 2025;26:110. Figure 1. PMCID: PMC12831414. License: CC BY 4.0.

Six-panel histopathology images with HE staining: A = solid basaloid type, B = tubular type, C = cribriform type, D = mixed tubular and cribriform, E = orbital bone invasion by tumor cells, F = perineural invasion of the orbital nerve sheath (scale bar 50–100 µm). Corresponds to the histologic subtype classification and perineural invasion discussed in section “4. Diagnosis and Examination Methods”.

The frequency of histologic subtypes based on an analysis of 515 cases is as follows⁵⁾.

Cribriform Type

Frequency: Most common (39.8%)

Features: Lobular structures with circular pools of mucin. “Swiss cheese” appearance. Intermediate prognosis.

Basaloid Type

Frequency: 31.8%

Features: Poorly differentiated. Large basophilic nuclei and scant cytoplasm. Worst prognosis.

Tubular Type

Frequency: 7.4%

Features: Epithelial tubules lined by 2–3 layers of cells. Most differentiated, best prognosis.

Other types include mixed (13.9%), undifferentiated (6.1%), and sclerosing (0.9%). A solid pattern exceeding 30% is considered poor prognosis¹⁾. Histologically, tumor cells are small with scant, basophilic cytoplasm and chromatin-rich nuclei. The border between tumor nests and stroma is distinct, clearly different from pleomorphic adenoma.

Differential Diagnosis

• Pleomorphic adenoma: Most common lacrimal gland tumor (benign). Painless, slow-growing. Potential for malignant transformation.
• Lymphoma/Chronic dacryoadenitis: Differentiation from inflammatory diseases is necessary.
• Reactive lymphoid hyperplasia, sarcoidosis, Sjögren syndrome: May present with bilateral lacrimal gland enlargement.
• Other malignant epithelial lacrimal gland tumors: Carcinoma ex pleomorphic adenoma (20%), primary adenocarcinoma (10%), mucoepidermoid carcinoma (5%).

5. Standard Treatment

Surgical Therapy

Surgery is the mainstay of treatment, and the surgical approach is determined by tumor stage and imaging findings³⁾⁵⁾.

• Eye-sparing surgery (excisional biopsy): Performed in 447 of 708 cases (63.1%). Recommended for T1–T2 tumors⁵⁾.
• Orbital exenteration: Performed in 245 of 708 cases (34.6%). Indicated for T3–T4 tumors or cases with orbital apex or extraorbital extension⁵⁾.

Kaplan-Meier analysis showed that eye-sparing surgery plus radiotherapy had better survival than orbital exenteration with or without radiotherapy (P<0.05)⁵⁾.

If imaging shows a small tumor that can be completely resected, aim for complete resection. If complete resection is deemed impossible, perform an incisional biopsy to confirm pathology, then consider wide excision or radiotherapy. For adenoid cystic carcinoma of the lacrimal gland confined to the orbit, orbital exenteration may be considered, but conservative treatment may be chosen based on cosmetic concerns, patient age, and preferences. Lymph node metastasis is rare (4–9%), and lymph node dissection is usually unnecessary⁶⁾.

Even after wide excision and radiation therapy, invasion into the brainstem through the lacrimal nerve may not be prevented. It is not always possible to prevent distant metastasis, and long-term follow-up is necessary.

Radiation Therapy

• Adjuvant radiation therapy: Performed in 519 cases. External beam radiation was the most common (76.3%)⁵⁾
• Standard dose: Conventional fractionation at 2 Gy/day, total dose 60–66 Gy (30–33 fractions)⁵⁾⁶⁾
• Local control rate: Radiation therapy alone achieves 5-year local control rates of 50–80%, but evidence for improved survival is limited⁶⁾
• After R1 resection: 66 Gy is recommended as postoperative radiation therapy⁶⁾
• In cases with perineural invasion: Radiation therapy is often indicated

For unresectable adenoid cystic carcinoma, heavy particle therapy is performed and is positioned as a promising treatment that can control the tumor while preserving the eyelid, eyeball, and orbit.

Neoadjuvant Intra-arterial Chemotherapy (NIAC)

NIAC was first reported by Meldrum et al. in 1998, using a combination of intra-arterial cisplatin (100 mg/m²) and intravenous doxorubicin³⁾²⁾.

In a study of 19 cases by Tse et al. (2013), a 10-year disease-free survival rate of 100% was reported in 8 cases where the lacrimal artery was preserved and the protocol was followed²⁾³⁾.

The combination of NIAC + resection/orbital exenteration + radiation therapy shows favorable outcomes compared to other treatments, with recurrence rate 10.8%, metastasis rate 14.9%, and mortality rate 18.9%⁵⁾. Major risks of NIAC include transient facial nerve palsy, vision loss, anterior ischemia, neutropenia, and thrombocytopenia³⁾.

Chemotherapy (Adjuvant/Neoadjuvant)

• Adjuvant chemotherapy: Performed in 135 of 806 cases (16.7%). Cisplatin (39.2%), doxorubicin (24.6%), and 5-FU (10.7%) were frequently used⁵⁾
• Neoadjuvant chemotherapy: Performed in 74 of 806 cases (9.2%)⁵⁾
• The addition of adjuvant chemotherapy, even in combination with radiotherapy, has not shown a statistically significant difference (P=0.40)⁵⁾

Treatment considerations

• Lacrimal gland adenoid cystic carcinoma has a high risk of recurrence and distant metastasis, requiring long-term follow-up.
• Orbital exenteration offers high curability but results in significant cosmetic loss. The surgical approach should be determined with careful consideration of the patient’s age, general condition, and wishes.
• NIAC must be performed at a specialized facility and carries risks of serious complications (vision loss, facial nerve palsy)³⁾.

Q Which is better: orbital exenteration or eye-sparing surgery?

A

Kaplan-Meier analysis showed that survival rates for eye-sparing surgery plus radiotherapy were better than for orbital exenteration with or without radiotherapy (P<0.05)⁵⁾. Eye-sparing surgery is recommended for T1–T2 tumors, while orbital exenteration is considered for T3–T4 tumors or cases with extraorbital extension. However, conservative treatment may be chosen due to cosmetic concerns or patient preference.

6. Pathophysiology and detailed pathogenesis

Histological features

Tumor cells are small with scant, bluish cytoplasm and chromatin-rich nuclei. Histologically, the boundary between tumor nests and stroma is clear, distinctly different from pleomorphic adenoma.

In the cribriform type, true lumens (derived from ductal cells) and pseudolumens (mucin-filled spaces formed by myoepithelial cells) coexist, giving a “Swiss cheese” appearance. The sclerotic type appears as epithelial cords with dense hyalinized stroma. A solid pattern exceeding 30% is associated with poor prognosis¹⁾.

Tumor growth patterns are classified into five types: cribriform, solid, sclerotic, comedocarcinomatous, and tubular. Multiple growth patterns can be observed within the same specimen.

Molecular biological mechanisms

Molecular abnormality	Description
MYB-NFIB fusion	t(6;9)(q23;p23) translocation. Present in over 70% of all adenoid cystic carcinomas1)
MYB overexpression	Promotes cell proliferation, differentiation, angiogenesis, and upregulation of growth factors1)
NOTCH1 activating mutation	Major driver of proliferation and invasion in metastatic adenoid cystic carcinoma1)2)
KRAS/NRAS/MET mutations	Reported in 46%, 8%, and 13% of cases, respectively. The EGFR-RAS-RAF cascade may be a therapeutic target1)5)

In lacrimal gland adenoid cystic carcinoma, MYB rearrangement is detected in 58% of cases (Mayo Clinic, 12 cases/25 years), and MYB-NFIB fusion is a highly specific diagnostic marker for adenoid cystic carcinoma¹⁾. MYB-NFIB fusion is regulated by AKT-dependent IGF1R signaling, and IGF1R inhibition is considered a promising therapeutic target¹⁾³⁾.

Mechanisms of perineural invasion

Perineural invasion is observed in 45.3% of cases, and tumor cells can spread even without vascular or lymphatic invasion¹⁾. There is a strong tendency to invade nerves and lymphatics, and infiltration to the brainstem through the lacrimal nerve can occur early in the disease. Perineural invasion is associated with apoptosis resistance due to Bcl-2 upregulation.

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7. Latest research and future perspectives (reports at research stage)

For patients: Please read carefully

The following content is currently at the research stage or under clinical trial and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Molecular Targeted Therapy

Currently, no molecular targeted drugs are approved for lacrimal gland adenoid cystic carcinoma. The following targets are being investigated in research stages¹⁾³⁾.

• EGFR-TKI (erlotinib): Efficacy for 14 months has been reported in one case of metastatic lacrimal gland adenoid cystic carcinoma³⁾
• IGF1R inhibition: Stable disease for 1.5 years was reported in one case treated with figitumumab (IGF1R monoclonal antibody) plus dacomitinib (pan-EGFR inhibitor)³⁾
• FGFR1 inhibitor AZD4547 + cisplatin: FGFR1 signaling increased after NIAC, and the combination showed enhanced tumoricidal effect³⁾
• Survivin inhibition: Survivin is highly expressed in adenoid cystic carcinoma. Arsenic trioxide (As₂O₃) suppresses survivin mRNA expression and induces apoptosis³⁾

Results from phase II clinical trials have reported dovitinib (ORR 6%, mPFS 8.2 months), lenvatinib (ORR 16%, mPFS 17.5 months), and axitinib (ORR 9%, mPFS 5.7 months)³⁾.

Immunotherapy and Vaccines

• TetMYB vaccine + anti-PD1 antibody: A phase I clinical trial is ongoing¹⁾
• Notch1 inhibitor (AL101): A phase II ACCURACY trial of a gamma-secretase inhibitor is ongoing¹⁾

Genomic Analysis for Treatment Response Assessment

Yu et al. (2022) reported an assessment combining pre- and post-treatment genomic sequencing with apoptosis markers (cCas3, PARP) analysis²⁾. The variant allele frequency (VAF) of NOTCH1 mutation after NIAC decreased from 18.07% before treatment to 11.34% after treatment (37% reduction), suggesting it may be a predictive marker for cisplatin sensitivity.

New Radiotherapy Approaches

• Proton beam therapy (PRT): Performed after eye-sparing surgery in 7 cases. No local recurrence at a median follow-up of 27.1 months³⁾
• Carbon ion radiotherapy (CIRT): A study of 24 cases reported 2-year local control rate of 93%, overall survival of 96%, and disease-free survival of 87%³⁾
• VMAT (Volumetric Modulated Arc Therapy): In cases treated with 66 Gy in 33 fractions, acute toxicity was mild (Grade 1 dermatitis). No recurrence has been confirmed for 24 months or more⁶⁾

Q Is molecular targeted therapy available for lacrimal gland adenoid cystic carcinoma?

A

Currently, no molecular targeted drugs are approved for lacrimal gland adenoid cystic carcinoma. MYB-NFIB fusion, Notch signaling pathway, EGFR-RAS-RAF cascade, and others are being investigated as therapeutic targets in research, and several phase II clinical trials are ongoing¹⁾³⁾. For those seeking standard treatment, the combination of surgery and radiation therapy is the current option.

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8. References

1. Powell SK, Kulakova K, Kennedy S. A Review of the Molecular Landscape of Adenoid Cystic Carcinoma of the Lacrimal Gland. Int J Mol Sci. 2023;24(18):13755.
2. Yu MD, Men CJ, Do H, et al. Genome Sequencing and Apoptotic Markers to Assess Treatment Response of Lacrimal Gland Adenoid Cystic Carcinoma to Intra-Arterial Cytoreductive Chemotherapy. Ophthalmic Plast Reconstr Surg. 2022;38(2):e44-e47.
3. Wang X, Ma H, Chen Y, et al. Treatment strategies and prognostic insights for lacrimal gland adenoid cystic carcinoma: a review. Discover Oncology. 2025;16:858.
4. （統合済み：PMC11567613はPMC12098222と同一論文と判断し引用3に統合）
5. Pal SS, Alam MS, Manikantan K, Honavar S. Adenoid cystic carcinoma of the lacrimal gland - A major review. Indian J Ophthalmol. 2025;73:1399-1411.
6. Benali K, Benmessaoud H, Aarab J, et al. Lacrimal gland adenoid cystic carcinoma: report of an unusual case with literature review. Radiat Oncol J. 2021;39(2):152-158.