Abstract
Primary malignant tumors of the lacrimal gland are very rare. The standard treatment typically involves wide surgical excision, which may include orbital bone resection and enucleation of the eyeball, followed by adjuvant radiotherapy. Recent advancements in hadron therapy, particularly carbon-ion radiotherapy, enable highly precise dose delivery to the tumor while minimizing exposure to surrounding healthy tissues, which could reduce toxicity. We report the case of a 70-year-old man diagnosed with asymptomatic primary ductal adenocarcinoma of the lacrimal gland. After a conservative microsurgical excision, residual disease remained, prompting the patient to undergo carbon-ion radiotherapy, which resulted in complete resolution of the tumor with minimal toxicity.
Keywords: Primary ductal adenocarcinoma of the lacrimal gland (PDACL), Lacrimal gland neoplasm, Carbon-ion radiotherapy (CIRT), Hadrontherapy, Orbital tumor management, Organ-preserving therapy
Introduction
Primary ductal adenocarcinomas of the lacrimal gland (PDACL) are extremely rare, representing only 5%-7% of epithelial tumors of the lacrimal gland [1,2]. Since their first description in 1996 [1], only a limited number of cases have been reported. PDACLs are characterized by aggressive clinical behavior and poor prognosis [3,4].
Histologically and immunohistochemically, PDACL resembles high-grade salivary duct carcinoma and can be classified as low- or high-grade tumors [2]. The lacrimal gland is composed of lobular acini and ducts, similar to major salivary glands [3].
Standard management involves complete gland excision, orbital bone resection, lymph node dissection, and adjuvant radiotherapy. However, due to the rarity of PDACL, long-term prognosis and treatment response remain uncertain [4,5].
Imaging plays a critical role in diagnosis and staging. Orbital magnetic resonance imaging (MRI) is preferred for its superior soft tissue resolution, allowing detailed assessment of glandular, peri-glandular, and perineural involvement. Computed tomography (CT) is primarily used to detect bone erosion, while positron emission tomography/computed tomography (PET/CT) provides sensitive detection of distant metastases.
Case report
A 70-year-old man underwent brain MRI for dizziness, which incidentally revealed a solid, expansive lesion in the superolateral extraconal compartment of the right orbit, measuring 22 × 16 × 15 mm.
The study protocol was performed on a 1.5 Tesla MRI scanner. T1-weighted SE sequence (4 mm thickness), T1-weighted 3D GRE fat-saturation sequence (1 and 6 mm thickness), T2-weighted TSE MultiVane sequence (4 mm thickness), T2-weighted FFE sequence (5 mm thickness), STIR TSE sequence (3 mm thickness), EPI DWI sequence with b0 and b1000 values (4 mm thickness) and calculated Apparent Diffusion Coefficient map (ADC) were used.
T1-weighted 3D GRE fat-sat sequences were obtained after intravenous administration of 7.5 ml of Gadobutrol.
The lesion, which showed an oval shape and mildly irregular margins, demonstrated a heterogeneous hyper-intense signal on T2-weighted sequences, a hypointense signal on T1-weighted sequences and a peripheral restriction of water diffusivity on DWI sequences.
The mass compressed and displaced the lateral rectus muscle and appeared inseparable from the inferior pole of the lacrimal gland. The optic nerves were intact.
Postcontrast images showed heterogeneous enhancement. Signal heterogeneity and bone remodeling of the greater wing of the sphenoid raised suspicion for possible permeation vs reactive sclerosis (Fig. 1).
Fig. 1.
Axial GE contrast-enhanced T1W fat-suppressed (A) and axial T2-w (B) scans, coronal T2-w STIR (C) and contrast-enhanced GE T1-W fat-suppressed (D) coronal scans show a solid, expansive lesion in the superolateral extraconal compart of the right orbit, measuring 22 × 16 × 15 mm (arrows). The mass appeared inseparable from the inferior pole of the lacrimal gland, compressed and displaced the lateral rectus muscle (asterisks in B and C). The optic nerves were intact (arrowheads).
To more accurately assess the bone infiltration, it was decided to supplement the study with a non-contrast CT scan with a 0.625 mm bone reconstruction algorithm.
The CT revealed swelling and diffuse osteosclerotic alteration of the greater wing of the sphenoid and presence of intralesional microcalcifications (Fig. 2).
Fig. 2.
Axial noncontrast enhanced CT scan reveals intralesional microcalcifications (arrowhead), swelling and diffuse osteosclerotic alteration of the greater wing of the sphenoid (arrow).
To determine both local tumor extent and distant spread, the patient underwent F18-FDG PET/CT, using a 3D mode extending from the vertex to the proximal third of the thighs (with arms adducted), through acquisitions obtained approximately after 60 minutes from radiotracer administration.
PET imaging showed an increased uptake (SUVmax bw 11, 3) along the lateral aspect of the right orbit extending to the sphenoid wing (Fig. 3).
Fig. 3.
Coronal (A) and axial (B) FDG-PET imaging show increased uptake along the lateral aspect of the right orbit extending to the sphenoid wing (arrows).
However, there was no evidence of pathological lymph node uptake or distant metastasis.
Adenocarcinoma of the lacrimal gland ducts with bone involvement was proved at incisional biopsy. The periosteum of the lateral wall of the orbit and cancellous bone of the greater wing of the sphenoid presented widespread tumor infiltration.
Histology demonstrated cribriform and ductal growth patterns with clear to eosinophilic cytoplasm. Immunohistochemistry was positive for CK7 and androgen receptors, and negative for SOX10, DOG1, GATA3, 8100, p63, c-erbB2, and p53. No necrosis, vascular, lymphatic, or perineural invasion was observed.
The patient declined orbital exenteration and underwent conservative microsurgical excision of the lacrimal gland. Histopathology confirmed residual epithelial neoplastic tissue with moderate to severe cytologic atypia (pancytokeratin AE1/AE3+, CK7+, and CK20–) and a Ki-67 proliferative index of 60% (30% in the most proliferative areas).
Excisional biopsy, performed during the microsurgical excision, confirmed pan-cytokeratin-positive epithelial neoplasm on bone tissue fragments and periorbital tissues.
Follow-up MRI revealed residual tissue in the right extraconal orbital region (10 × 5 mm), inseparable from the lateral rectus muscle (Fig. 4).
Fig. 4.
MRI performed after conservative microsurgical excision of the lacrimal gland. Contrast-enhanced axial SE T1-w fat-suppressed (A) and axial STIR T2-w (B) scans show residual tissue in the right extraconal orbital region (10 × 5 mm) (arrows), inseparable from the lateral rectus muscle (asterisks).
F18-FDG PET/CT imaging showed metabolic hyper-uptake (SUVmax bw 10) in the same location. Given persistent disease and refusal of further surgery, the patient underwent carbon-ion radiotherapy, in a specialized hospital setting, using an active scanning system and intensity-modulated particle therapy to a total dose of 65.6 GyRBE (4.1 Gy[RBE]/fraction, 16 fractions, and 4 fractions/wk). Systemic therapy was not administered.
Three months after treatment, the MRI showed no visible lesions in the orbit. However, there was residual thickening and edema of the lateral rectus muscle, which were interpreted as reactive changes following treatment, along with partial fibrotic changes in the surrounding fat. The optic nerve appeared normal (see Fig. 5).
Fig. 5.
MRI performed 3 months after carbon-ion radiotherapy (CIRT). Contrast-enhanced SE T1-w fat-suppressed (A) and TSE T2-w (B) axial scans, coronal contrast-enhanced GE fat-suppressed T1-w (C) and coronal STIR T2-w (D) acquisitions show no visible lesions in the orbit (arrows). Reactive changes following treatment consisting in residual thickening and edema of the lateral rectus muscle are detectable (asterisk). The optic nerve appears normal (triangles).
During the clinical examination, mild right-sided neck edema, resolving erythema, mild upper eyelid swelling, and hyperemia of the right eye (without any discharge) were observed. Extrinsic ocular motility was intact, and there were no signs of nystagmus or diplopia. The functions of the trigeminal and facial nerves were normal. The patient’s mouth opening measured 2.5 cm, compared to a baseline of 4 cm.Treatment-related toxicity at 3 months:
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Xerostomia: Grade 1.
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Dysgeusia: Grade 1.
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Hyposmia: Grade 1.
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Edema: Grade 1.
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Ocular hyperemia: Grade 1.
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Xerophthalmia: Grade 1.
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Skin edema: Grade 2.
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Trismus: Grade 1.
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Neurological effects: None appreciable.
FDG PET/CT and orbital MRI, both performed approximately 1 year after carbon-ion radiotherapy, demonstrated no signs of loco-regional recurrence, no bilateral lymphadenopathies, although areas of cerebral radionecrosis occurred (Fig. 6).
Fig. 6.
MRI performed 1 year after carbon-ion radiotherapy. Axial TSE T2-w demonstrates complete remission from the disease (arrow) and normal signal intensity of the optic nerve (arrowhead). Nevertheless, hyperintensity of the right temporal lobe due to radionecrosis is appreciable (asterisk).
Indeed, no areas of pathological uptake were identified on FDG PET/CT.
Residual edematous thickening of the lateral rectus muscle remains unchanged.
The optic nerve is unremarkable. The osteosclerotic modification of the greater ipsilateral wing of the sphenoid remains stable.
Discussion
Adenocarcinoma accounts for approximately 7% of all epithelial tumors of the lacrimal gland. This type of cancer is known for its aggressive nature and is linked to decreased survival rates in patients. Common clinical symptoms include pseudoptosis, exophthalmos, displacement of the globe, reduced visual acuity, and pain [2].
CT and MRI are essential for characterizing intraorbital masses and evaluating the involvement of the lacrimal gland, extraocular muscles, and adjacent bone structures. FDG PET/CT offers high sensitivity for detecting distant metastases [10].
The primary goal of treatment is early locoregional disease control. Complete surgical excision followed by adjuvant radiotherapy is generally recommended [2].
Regional lymph node involvement should be assessed systematically, and lymph node dissection and/or radiotherapy are advised even in the absence of clinically evident lymphadenopathy [1]. Patients treated according to this approach tend to experience improved survival and lower recurrence rates [9,10]. Nevertheless, the optimal management strategy and overall prognosis remain uncertain and depend largely on tumor stage and early diagnosis.
This case highlights the potential of carbon-ion radiotherapy as an effective organ-preserving treatment option for lacrimal gland adenocarcinoma, particularly in patients who are medically unfit or unwilling to undergo orbital exenteration.
Carbon ions offer superior physical and biological properties, including a sharp Bragg peak and higher relative biological effectiveness (RBE ≈ 3), enabling precise dose delivery and enhanced tumor cell killing [6]. These characteristics make carbon ions especially useful in managing rare, radioresistant tumors such as PDACL.
Compared with conventional photon radiotherapy, carbon-ion therapy achieves better tumor control with reduced exposure to critical structures, minimizing both acute and late toxicities [6,7]. In rare head and neck malignancies, carbon-ion therapy has demonstrated encouraging local control and acceptable toxicity profiles [7,8].
Although orbital exenteration remains the standard for extensive disease, this case demonstrates that advanced hadron therapy can provide complete local control while preserving ocular function and quality of life.
However, the development of cerebral radiation necrosis (RN) following carbon-ion radiotherapy (C-ion RT) for tumors of the orbit or skull base is a well-documented phenomenon, strictly linked to the anatomical proximity between the target volume and the adjacent brain structures (primarily the temporal lobe and frontobasal regions) [11].
The aggressive radiobiology of heavy ions can concurrently trigger late-onset complications within the adjacent normal brain tissue exposed to boundary doses.
Neuroradiological data indicate that radiation-induced brain changes detectable via MRI occur in approximately 30%-60% of patients undergoing high-dose radiation near the skull base.
In most cases (exceeding 80%-90% of those who develop RN), the alteration is entirely asymptomatic and is identified through routine follow-up neuroimaging. In fact, only few patients (approx. 5%-7%) present clinical symptoms (e.g., headaches, dizziness, or focal seizures).
RN represents a late complication. The most frequent onset ranges between 12 and 22 months following completion of radiotherapy.
In our case, where PET and MRI both confirm no evidence of regional recurrence, it is assumed that the presence of radionecrosis is considered and expected result secondary to successful high-dose tumor exposition within a complex anatomical site.
Given the rarity of PDACL, accumulating additional case reports and prospective data will be essential to establish standardized protocols and evaluate long-term outcomes of carbon-ion radiotherapy in lacrimal gland malignancies.
Conclusion
Carbon-ion radiotherapy offers a promising organ-preserving treatment option for primary ductal adenocarcinoma of the lacrimal gland. It has demonstrated excellent local control with minimal toxicity. This case highlights the potential benefits of advanced hadron therapy for selected patients who are not candidates for radical surgery or who choose to refuse such treatment.
The development of cerebral radiation necrosis should not be interpreted as a therapeutic failure or disease progression. Rather it represents an adverse late-onset effect secondary to high-dose radiation therapy and could be recognized as a biological trade-off.
Further multicenter studies and long-term follow-up are needed to clarify the role of carbon-ion therapy in treating orbital epithelial malignancies and decrease complications. Additionally, efforts should be made to standardize the best treatment options available.
Author contributions
The conception and design of the study: CB and UB. Manuscript preparation and manuscript editing: GC and FI. Acquisition of data: CA and FG. Literature research and drafting the article: DC and GC. Revising it critically for important intellectual content: UB and CB. Final approval: All authors. guarantor: CB.
Ethics approval
This study was approved by the Institutional Review Board of (IRCCS Centro Neurolesi Bonino Pulejo).
Patient consent
Written informed consent for publication of this case report and associated images was obtained from the patient.
Footnotes
Acknowledgments: No funding was received for this study.
Competing Interests: The authors have declared that no competing interests exist.
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