Clinical Management of Acinic Cell Carcinoma of the Lacrimal Gland Open Access

Lacrimal pathologies arise from all the structures related to the gland: epithelial tissue, lymphoid tissue, nervous and vascular tissue. Inflammatory and lymphoid lesions are two to three times more common than epithelial tumors that account for only 20–30% of lesions. The normal lacrimal gland is clinically impalpable and is located behind the supero-temporal orbital rim, in a hollow of the frontal bone called lacrimal fossa. Space occupying lesions of the lacrimal gland and its fossa constitute approximately 5% to 25% of orbital masses upon biopsy [1].Epithelial tumors usually arise from the orbital lobe of the lacrimal gland and tend to spread posteriorly within the orbit, along its lateral margin. However, around 17% of epithelial tumors arise from the palpebral segment and may be clinically visible in the fornix of the conjunctiva [2].

The initial diagnosis is often wrong because these masses could be confused with a heterogeneous group of inflammatory lesions or benign neoplasms. The histopathologic classification of epithelial lacrimal gland tumors is identical to that used in salivary gland tumors, as originally proposed by Foote and Frazell [3]. Rootman et al. in 2009 proposed an histopathologic type classification of lacrimal tumors, dividing the tumors into low and high grade on the basis of the World Health Organization classification of salivary gland neoplasm, although some histopathologic type have been described only in case report series (Table 1) [4, 5]. In order of frequency, the most common epithelial tumors are: benign mixed tumor or pleomorphic adenoma, adenoid cystic carcinoma and adenocarcinoma. Other rare variants of carcinoma are also seen, such as mucoepidermoid carcinoma and squamous cell carcinoma of the lacrimal gland [6-8].

In this paper, we focused on clinical management of low grade malignant primary epithelial tumors of the lacrimal gland, in particular on acinic cell carcinoma (AcCC) and we presented a case report.

In January 2012 a 59-year-old man was referred to the ophthalmologist for a sudden blurring of vision and orbital swelling on the left eye; his medical history detailed a bilateral keratoconus and open angle glaucoma, well controlled with topical therapy. The best corrected visual acuity decreased from 8/20 till 1/50 in one week.A corneal edema in the left eye was detected by physical examination and the retina was not detectable. In order to investigate the disease, the physician required an orbital ultrasound scan, which showed an extraconal solid mass with round well-defined outline, situated in the superior lateral corner of the left orbit. The patient was then admitted to treat this intra-orbital tumor at Cranio-Maxillo-Facial Unit, University Hospital of Modena.

The patient had a proptosis of the left eye at the time of admission into the hospital (Fig. 1a). There was a swelling of the left upper eyelid. A hard and tender mass was palpated in the superior temporal left orbit. The patient complained of mild double vision in left and down directions of the gaze, with a pathologic Hess-Lancaster test. The horizontal separation of perceived images by the patient and the worsening of diplopia in left gaze suggested limitation of left lateral rectus movement, since double vision is often worse in the field of action of the weakened ocular muscle.

Computed tomography (CT) revealed a mass which was 2 × 2.5 cm in size, well circumscribed, of ovoid shape, within the left lacrimal fossa, with a central region hypodense to muscle and homogeneous soft tissue density border (Fig. 1a, e). The tumor displaced medially the lateral rectus muscle (Fig. 1c). The mass did not appear well separable from the lacrimal gland and a slight scalloping of the greater sphenoid wing was evident (Fig. 1a). MRI showed an oval mass in the left lacrimal fossa, about two centimeters in diameter that appeared within normal lacrimal gland tissue. Tumor was heterogeneous, with mild and irregular enhancement following administration of contrast medium (gadolinium) (Fig. 1c, d, f–h). Radiologist described a solid mass within the lacrimal gland, hypothesizing a pleomorphic adenoma. However, since imaging findings were not pathognomonic, we decided to proceed with complete excision of the mass, without a diagnostic incisional biopsy. Preoperative CT and MR imaging were consistent with a completely localized disease within the lacrimal gland. To approach this malignancy we chose a coronal approach to get an easy control of the lacrimal fossa and aesthetically and functionally preserve the eyelid and periorbital skin. After general anesthesia and local injection of lidocaine and epinephrine (lidocaine and epinephrine 1:200,000), a bicoronal skin incision was made a few millimeters behind the hairline and just anterior to the tragus of the left ear, extending approximately to the superior temporal line on the opposite side. The scalp flap was developed anteriorly to expose the orbital margin from the superior orbital rim to the zygomatic arch; so the facial nerve preservation was achieved [9]. Then, the temporalis muscle was dissected subperiosteally and retracted posteriorly to completely expose the lateral orbital rim and the outer surface of the great sphenoid wing. The periorbita was elevated from the inner surface of the lateral wall of the orbit. After preplating the lateral orbital rim with two titanium microplates, a lateral orbitotomy was performed using a piezoelectric osteotome (Piezosurgery® Medical; MT1–10 tip; Mectron Medical Technology, Carasco, Italy), because less traumatic for orbital content and to improve osteotomic bone healing [10-12]. The former osteotomy was made just above the zygomatic-frontal suture line and the latter approximately 1, 5 cm below. The lateral orbital rim was out-fractured with a rongeur, removed and preserved in saline solution. The periorbita was opened, showing a mass of approximately 2 cm, adherent to the lacrimal gland (Fig. 2a). The lesion was well demarcated within the lacrimal gland and enucleoresection was performed. The periorbital fascia was relocated and the lateral orbital rim was reinserted in its correct anatomic position and fixated with previous pre-platted two microplates and screws (Fig. 2b) [13], without the need for a bone substitute [14-21]. A drain tube was placed; the muscular fascia, subcutaneous tissue and skin suturing is performed without any local flaps [22]; a firm compressive dressing is applied for 48 hours and then removed.

On gross examination the lesion appeared nodular, brownish, measuring about 2 × 1.5 cm. Histopathological examination demonstrated a monomorphic epithelial tumor, composed of basophilic cells with prominent nucleoli and granular cytoplasm. Microcystic and focal papillary areas were present (Fig. 3a). Melanin pigment deposition was occasionally revealed (Fig. 3b). Immunohistochemistry revealed positivity for cytokeratin 7. Immunohistochemical analyses using S-100 protein, p63 (transformation-related protein 63), CD34 (cluster of designation 34), TTF1 (thyroid transcription factor-1), CD 10 (cluster of designation 10) and muscle actin antibodies were negative. Histopathological findings were consistent with acinic cell carcinoma (AcCC) with a microcystic, focally papillary-cystic growth of pattern. The mass appeared well-circumscribed, and did not involve the margins of resection. There was no evidence of vascular nor perineural invasion. Neither mitosis nor necrosis was observed. Proliferation rate was 2–4%, according to MIB-1 (antibody against Ki-67 protein) proliferation index. According to American Joint Committee on Cancer (AJCC) Eight Edition Staging System for lacrimal gland carcinomas, the staging of this AcCC is T1N0M0 [23].

The postoperative course was uneventful, exophthalmos and ocular pain slowly subsided. Acuity vision improved and the patient was discharged 3 days after the operation. Early postoperative head CT scan showed complete removal; contrast chest CT scan and ultrasound scan of the liver were performed to assess pulmonary or liver metastases, which resulted respectively normal. The patient’s case was debated at our local head & neck cancer multidisciplinary team meeting. Given the low grade malignancy of this tumor and the apparent radical excision of the mass, the meeting decided for no other postoperative treatment and to carry out a careful follow-up in order to notice any eventual recurrence. MRI at 6 months showed an area of solid tissue of about 1.5 cm characterized by a low enhancement in the left lacrimal fossa. The patient did not present any clinical signs of disease. Considering the lack of specificity of MRI in detecting a low grade malignancy recurrence, we decided to perform the complete removal of the residual lacrimal gland under general anesthesia through the previous coronal access. Histological examination of the surgical specimen revealed normal lacrimal gland and fibrous tissue free from cancer.

Visual acuity was 8/20 fifteen months after surgery; the keratoconus did not get worse and no corneal edema and flare were present in anterior chamber. Intraocular pressure was 14 mm Hg without changes in topical therapy. The patient did not refer diplopia. Hess-Lancaster test showed recovery of extraocular muscles action. The patient is now free from disease at 7-year follow-up. Hyaluronic acid eye drops (Xailin HA, Visufarma, s.p.a., Rome, Italy) were provided in the post-operative period for the left eye, to compensate for the reduced lacrimation that would now affect that eye. As time goes by tears from accessory lacrimal glands were sufficient to maintain a stable tear layer on the cornea, and artificial tears use have come to be not regular. No tumor recurrences where detected at 7-year follow-up.

AcCC is very rare in lacrimal gland and exceptional in the sinonasal tract [24]. The imaging characteristics of lacrimal gland tumors are nonspecific, with most lesions having a generally benign appearance, often appearing on CT and on MRI as a pleomorphic adenoma [25]. No papers are present in the English literature about positron emission tomography/computed tomography (PET/CT) for AcCC of the lacrimal gland, whereas PET/CT may identify primary adenoid cystic carcinoma of the lacrimal gland [26].

The initial management of low grade malignant primary epithelial tumors of the lacrimal gland is complete surgical resection with tumor-free margins, given the difficulty in preoperatively differentiating malignant from benign lesions. Incisional biopsy for diagnosis is often avoided because this procedure is occasionally associated with local recurrences [27, 28]. The histological examination of surgical specimen remains the only method for a correct diagnosis. For small tumors of lacrimal apparatus Skinner et al. (2011) in a large study recommended evaluating eye-preserving surgery; adenoid cystic carcinoma was present in nearly half of these group of patients, histotype characterized by the worst prognosis between malignant neoplasia. Although the mainstay of treatment for malignant lacrimal gland tumors is surgery, the option among orbital sparing conservative surgery followed by postoperative radiation and orbital exenteration/cranio-facial approaches is debated [29-31]. Major evidences on postoperative radiotherapy effectiveness in local control of disease in lacrimal gland malignancies come from adenoid cystic carcinoma cases retrospective analysis [8], and are not appropriate to low grade malignancies.

Only four other cases of acinic cell carcinoma in the lacrimal gland have been reported in patients from 18 to 78 years of age (Table 2, Table 3) [32-35] and one case was present in case series of Verdijk et al. [36]. Two of these lesions showed a benign clinical behavior, while two proved to be aggressive, characterized by histopathological infiltrative comportment: bone involvement, intracranial extensions and local recurrence (Table 2, Table 3). In our case the mass was completely situated within the orbital lobe of the gland in the lacrimal fossa, without bone erosion. At the time of diagnosis no lymph nodal localization or distant metastasis were detected. Our patient was treated through an eye-sparing surgery that is excision of the mass together with a cuff of normal gland tissue around the lesion, followed 6 months later by residual gland removal for suspicion of recurrence. Considering the favorable prognostic factor (the malignancy is completely localized within normal lacrimal gland tissue, the lack of perineural and vascular invasion, the low mitotic index, the absence of mitosis and necrosis, and the integrity of the cortical bone and the surrounding soft tissue) and the disabling complications of more postoperative treatments, nor more therapies had been applied. Expected survival and freedom of metastasis for this patient is good, according to the state of low grade malignancy for AcCC and the staging (≤T2) [31].

TNM classification for primary carcinomas of the lacrimal gland is significantly changed from the AJCC Cancer Staging Manual, 7th Edition staging system. Comparing seventh and eighth edition of the AJCC staging system, we can note that the attention for bone involvement has gained importance [5, 23]. Broadly speaking, local extent of cancer contribute in determining appropriate treatment [37], and for carcinoma high T number often relates to more extensive surgery. In orbital pathology extensive and demolitive surgery corresponds to exenteration orbitae, while more and more authors recommend globe-preserving surgery, based on similar survival outcomes to those in patients treated with an orbital exenteration [31].

T1 or T2 – a mild score – can indifferently correspond to orbital sparing surgery or orbital exenteration in seventh and eighth edition of AJCC Staging Manual, lacrimal gland carcinoma staging system (Table 2, Table 3). In clinical practice the following factors determine the surgical extent in lacrimal gland malignancies: infiltrated orbital tissue beyond lacrimal capsule, sphenoid bone involvement, intracranial extension, dura involvement suspicion, high grade carcinoma, treatment of recurrence [31, 38, 39]. According to us the correlation between high T score and wide surgical excision (exenteration orbitae) is not strong for AcCC (Table 2, Table 3) and for other low grade carcinomas of the lacrimal gland, in both last two editions of the AJCC staging system manual, lacrimal gland carcinoma staging system. However, it is important to remember that changes undertaken by the authors of the AJCC Cancer Staging Manual, 8th Edition lacrimal gland carcinoma staging system are aimed to determining which factor—tumor size or periosteal or bone invasion – is the most important factor in defining outcome for these malignancies [23].

In our opinion, considering the limited literature inherent lacrimal gland AcCC, the clinical care of low grade malignancy should considerate some aspects. Diffusion of the malignancy outside of lacrimal gland, history of recurrences, periosteal involvement, bone erosion, dural infiltration, high mitotic index, and presence of perineural and vascular invasion can predict a poor outcome: in this situation radical surgery even or without eye-preserving is necessary; adjuvant radiation therapy is mandatory or consider neutron therapy, if available. We recommend eye-preserving surgery for a new onset of a localized low grade malignancy of lacrimal gland, to be carried out by an entire en bloc removal of the lacrimal gland through a lateral orbitotomy for wide exposure in large lesions [39]. A close follow up through MR imaging is advisable. However, as the imaging characteristics of AcCC are nonspecific, a suspicion of recurrence disclosed during imaging follow-up requires a surgical biopsy. More studies for low grade malignancies of the lacrimal gland supported by large numbers of patients are needed.

Due to the retrospective nature of this study, it was granted an exemption by the Institutional Review Board of the University Hospital of Modena, Italy. All procedures performed involving human participant were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

The patient consented to publication of this report and clinical photographs.

The authors have no conflicts of interest to declare.

No funding was received for this work.

Conceptualization: Alexandre Anesi; Lorenzo Trevisiol.

Methodology: Donatella Luchetti, Alexandre Anesi.

Data curation: Giuseppe Pollastri, Andrea Lazzerini, Licia Badiali.

Writing original draft preparation: Alexandre Anesi; Sara Negrello.

Writing review and editing: Alexandre Anesi; Luigi Chiarini; Gian Maria Cavallini.

Gian Maria Cavallini and Luigi Chiarini share last authorship.