Lacrimal Gland Adenoid Cystic Carcinoma with High Grade Transformation: A Case Report and Current Concepts in Multi Modality Management

Abstract

Lacrimal gland adenoid cystic carcinoma (AdCC) is associated with an aggressive clinical course and grave prognosis. A high grade transformation within adenoid cystic carcinoma of lacrimal gland is a rare condition which is even more locally aggressive with frequent neck and distant metastasis. We present a case of left lacrimal gland adenoid cystic carcinoma with high grade transformation to adenocarcinoma NOS type presenting with orbital pain and proptosis. After thorough evaluation for locoregional and distant spread of the disease, the patient underwent left orbital exenteration with orbitectomy and neck dissection with free flap reconstruction. Patient received adjuvant radiation therapy and is presently disease free for last 6 months. A multi-modality management protocol involving surgery, radiotherapy and chemotherapy has been proposed for management of lacrimal gland AdCC with high grade transformation. We report the 4th case in the literature of lacrimal gland adenoid cystic carcinoma with high grade transformation.

Introduction

Lacrimal gland tumors are a kind of salivary gland tumors representing 6–12% of orbital space occupying lesions. Primary malignant epithelial tumors represent around 20–30% of all lacrimal gland tumors which are associated with significant morbidity and mortality [1–3].

Adenoid cystic carcinoma (AdCC) is the commonest malignant epithelial tumor of lacrimal gland associated with poor prognosis despite aggressive local treatment due to high rates of local recurrences and late distant metastasis [3, 4]. Classical AdCC may undergo high grade transformation (HGT) or dedifferentiation which is associated with even worse clinical outcome due to high incidence of nodal metastasis and distant metastasis [5–7].

Since first description of ‘dedifferentiated’ AdCC by Cheuk et al. in 1999 [8] around 49 cases of salivary gland AdCC with dedifferentiation/HGT have been described in literature till date—submandibular glands (13 cases), sino-nasal region (9 cases), parotid and palate (7 cases each), nasal cavity (3 cases), lacrimal gland (3 cases), tongue (2 cases), pterygopalatine, lip, pyriform and epipharynx (1 case each) [9] (Table 1). There are only 3 cases of high grade transformation in adenoid cystic carcinoma of lacrimal gland reported in literature. Here we report the 4^th case of adenoid cystic carcinoma in lacrimal gland malignancy with high grade transformation (Table 2).

Table 3.

Comparative immunohistochemical features of two components

IHC markers	Low grade area	High grade area
Pancytokeratin	+	+
EMA	+	+
CK7	+	+
CD117 (CKIT)	Weak +	Weak +
p53	Weak +	Strong +
Mib1 (Ki67)	Mildly increase (10%)	Strongly increase (95%)
p63	Focally +	Loss
SMA	Loss	Loss
S100	+	−
GDCFP15	−	−
GATA3	−	−
ER	−	−
CDX2	−	−
NAPSIN-A	−	−
Synaptophysin	−	−

Table 1.

Review of reported cases of adenoid cystic carcinoma with high grade transformation/dedifferentiation

Authors	Cases
Cheuk et al. [8]	3
Moles et al. [31]	1
Terasaki et al. [4]	1
Chau et al. [32]	1
Ide et al. [33]	1
Nago et al. [34]	6
Brackrock et al. [35]	1
Sato et al. [36]	1
Seethala et al. [6]	11
Handra-Luca et al. [37]	1
Malhotra et al. [38]	1
Bonfitto et al. [39]	7
Costa et al. [40]	1
Panarelli et al. [41]	1
Boland et al. [42]	1
Argyris et al. [9]	1
Bavle et al. [43]	1
Ly et al. [44]	1
Sayar et al. [45]	1
Kusafuka et al. [46]	1
Noda et al. [47]	1
Tando et al. [48]	1
Bhardwaj et al. [49]	1
Dutta et al. [50]	1

Table 2.

Clinicopathologic features of lacrimal gland AdCCs with high grade transformation case

Case	Author	Year	Age	Sex	Tumor site	Size (cm)	Histology
							AdCC-LG	HG
1	Terasaki et al. [4]	2000	49	F	Orbit and middle fossa (R)	No details	Cribriform	Solid with necrosis Panarelli
2	Panarelli et al. [41]	2011	52	M	Extraconal comp. (R)	3.2 × 3.2x2.9	Cribriform	Myoepithelial sarcomatoid
3	Argyris et al. [9]	2012	39	F	Extraconal comp. (L)	3 × 2.2x2	Cribriform	Myoepithelial comedo-carcinomatous
4	Present case	2020	42	M	Extra conal and extra orbital. (L)	5 × 4 × 1	Solid (predominantly) + cribriform pattern	Adenocarcinoma NOS type

Management of lacrimal gland adenoid cystic carcinoma involves a multimodality treatment. Surgery remains the main stay of the treatment with radiation therapy as adjuvant. The role of systemic therapy either in neoadjuvant or concurrent adjuvant form is still unclear.

Case Details

History

A young healthy 42 years male patient with no major medical or family history and no history of previous treatment had presented to an ophthalmologist with complaint of left eye redness and increasing swelling associated with pain. He was initially managed conservatively for around 2 months. With increasing symptoms and later proptosis, a contrast enhanced CT (CECT) scan was done which suggested a mass originating from left lacrimal gland. An external approach excision biopsy was done which suggested high grade lacrimal carcinoma, hybrid adenoid cystic and adeno carcinoma NOS type. Patient was later referred to our surgical oncology department for further management.

On clinical examination, the left eye had proptosis with scar of biopsy over left upper lid. There was exposure keratitis, chemosis with congestion and fullness in left temporal fossa region. Eye movements were partly restricted and patient had only light perception. The other eye was normal with normal vision and movements. No other significant neck node enlargement seen.

Imaging Findings

As this was a case of high grade tumor of lacrimal gland, PET-CT scan was done for locoregional extension and to evaluate nodal and distant metastasis. PET-CT showed a large metabolically active heterogeneously enhancing tumor superolateral extraconal compartment of left orbit, lacrimal gland was not seen separately. It has an intraconal and retro-orbital extension, closely adherent to superior and lateral rectus muscle as well as abutting retrobulbar portion of left optic nerve without infiltration. Reformatted bone algorithm showed thinning and erosion of roof and lateral orbital wall with lesion in close proximity to anterior cranial fossa on left side (Fig. 1a). No cervical or parotid nodes or distant metastasis seen.

Fig. 1.

Radiological images (MRI and PET CT). a Coronal and axial PECT-CT images show metabolically active left lacrimal gland tumor (large arrow) and it is abutting and minimally displacing retrobulbar portion of left optic nerve (arrowhead). b Coronal T2WFS and Post contrast T1WFS images show large heterogeneously enhancing left lacrimal gland tumor (large arrow) causing erosion of roof of orbit and adherent to dura of left anteroinferior aspect of frontal lobe (arrowhead)

Contrast enhanced MRI of orbit and brain was also done additionally to exclude any dural or intradural involvement. MRI confirmed the findings of PET-CT and additionally showed adherence of the tumor to dura of anteroinferior aspect of left frontal lobe (Fig. 1b). No intradural extension. Optic chiasma and right orbit appear normal.

Surgical Details

Surgery was planned after all necessary covid workup. As the tumor was high grade, locally aggressive with extra orbital involvement and abutting intra orbital contents, a radical surgical excision involving total orbital exenteration and orbitectomy was planned. The parotid region was explored for any suspicious nodes. Left selective neck dissection (Ib–III) was done.The defect was reconstructed with anterolateral thigh flap which was anastomosed with facial artery and internal jugular vein (IJV) (Fig. 2).

Fig. 2.

Clinical and surgical profile of the patient. a Clinical picture, b Surgical Specimen, c Surgical Defect, d post operative period

Final Biopsy Report

Tumor size was 5.0 × 4.0 × 1.0 cm arising from lacrimal gland involving periorbital fat, muscle (temporalis), soft tissue and periorbital fascia. Perineural invasion was present intra-tumoral without lympho-vascular invasion. The eye ball and optic nerve were close but free. Overlying skin was free. All margins and dissected nodes were free. Histologically there were two distinct tumor areas without any clear demarcation. The first predominant area is high grade component arranged in solid,trabecular and glandular component with marked nuclear enlargement (2–3 times) with desmoplastic stroma, prominent nucleoli and focal comedo necrosis seen. suggesting a high grade carcinomatous component. The second component was a classical adenoid cystic carcinoma predominantly solid area and focal cribriform pattern.

On immunohistochemistry, the conventional adenoid cystic carcinoma component was positive for cytokeratin, CD117 (C-Kit) and EMA. Immunostains for p63 highlighted myoepithelial cells in this area. High Grade carcinomatous area was diffusely positive for cytokeratin, EMA with loss of p63 in this areas. The Mib1 labelling index was approximately 95% in high grade areas while is about 10–12% in adenoid cystic component (Fig. 3; Table 3).

Fig. 3.

Histopathological and IHC findings. a H&E slide showing high and low grade area. b Mib1 index higher (95%) in high grade area as compared to 10% in low grade area

Adjuvant Therapy

Patient received adjuvant radiotherapy to primary and neck.

Discussion

Lacrimal gland tumors are rare tumors with an occurrence of less than 1 per 1 000 000 population yearly. Adenoid Cystic Carcinoma is the commonest (60%) primary epithelial malignancy of the lacrimal gland characterized by prolonged clinical course, frequent local recurrences (due to peri-neural extension) and late distant metastasis with fatal outcome [2, 3]. Lacrimal gland AdCC is very aggressive and has poor prognosis with medial overall survival of 7.6 years. Age, tumor extent, histopathologic type, perineural invasion and bone invasion affect the patient prognosis [10].

AdCC-HGT is a tumor of sixth decade (32–88 years) with a slight male predominance of 1.4:1 as against conventional AdCC which has a female predominance [6] AdCC-HGT has a more aggressive clinical course than conventional AdCC being locally aggressive with bone erosion, extra glandular involvement, higher chances of margin positivity and nodal metastasis (43–57%) [6]. A size of > 2.5 cm and solid pattern are negative prognostic factors for AdCC of lacrimal gland [2].

The present case is a male patient of 42 years with tumor size > 3 cm having extra-glandular extension (involving intra-conal structures) and bone erosion of lateral, medial and superior orbital wall (into temporal fossa, medial orbital wall and skull base erosion) without any nodal or distant metastasis.

Seethla et al. [6] gave distinctive criteria to report high grade transformation in adenoid cystic carcinoma—(a) poorly differentiated carcinoma component arranged in solid confluent nests, (b) presence of desmoplastic stroma,(c) larger pleomorphic nuclei (at least 2–3 times the size of grades I–II AdCC nuclei), (d) loss of abluminal cell layer as highlighted by p63 and (e) diffusely and strongly positive for p53. The present case fulfilled all the criteria of high grade transformation as illustrated by Seethla.

Management of lacrimal gland AdCC is controversial and involves multidisciplinary approach mainly aimed at local control and prevention of distant metastasis. Surgery is considered as the main modality of treatment for loco regional control. The extent of the surgery is largely influenced by the extent of local involvement. Traditionally orbital exenteration has been the most common surgery for lacrimal gland adenoid cystic carcinoma. Orbitectomy with bone removal may be indicated for achieving local and regional control of advanced cases of AdCC [11]. Radical surgery is indicated in patients with severe symptoms (pain, hygiene issues, severe disfigurement caused by progressive proptosis, severe exposure keratopathy), gross tumor at orbital apex, extra orbital extension into PNS and brain parenchyma irrespective of long term outcomes [11, 12]. However, Yang et al in their review pointed out that radical surgical approach did not benefit in rate of recurrence, metastasis and mortality but reduced patients quality of life because of functional disability and disfigurement [13].

Eye-sparing surgery with adjuvant radiation therapy (RT) have shown favourable local control and long-term survival outcomes in patients with orbit confined lacrimal gland AdCC (AJCC 8th T1-T2) [14, 15]. For stages T3 (AJCC 8^th edition) and above eye sparing surgeries were associated with poor outcomes even with post-operative RT likely due to distant metastasis [16]. Ahmad et al. assessed the efficacy of AJCC to predict the outcomes at initial stage of diagnosis of lacrimal gland adenoid cystic carcinoma and concluded that the traditional approach of orbital exenteration with bone removal and postoperative adjuvant RT is appropriate for tumors ≥ T3 while for < T3 tumors (orbit confined) an eye sparing en bloc tumor excision followed by RT may achieve similar loco-regional control rates [12].

Hung et al. reported 5 and 10 year overall survival rates for eye sparing surgery with adjuvant radiation therapy for < T3 tumors as 81.8% and 68.2%respectively [17]. Han et al. reported a local control rate of 90% and overall survival of 90% at 89.5 months follow up period [15]. Woo et al. reported 5-year recurrence-free, disease-free and overall survival rates were 44.8%, 72.9%, and 87.4% respectively [15–17]. However, according to Yang et al. < T3 tumors of adenoid cystic carcinoma of lacrimal gland, 5 years local recurrences (83.3%), distant metastasis (35%) and mortality (20%) for eye sparing surgery followed by adjuvant radiation therapy were reported [13].

AdCC is considered as a radioresistant tumor due to its indolent growth pattern irrespective of the gland involved and requires a dose escalation for curative irradiation [3, 18]. For adjuvant radiation therapy various types including external beam photon radiation therapy—3D conformal radiation therapy (CRT) [19] or intensity modulated radiation therapy (IMRT) [20], neutron radiation therapy [21] and proton beam therapy [18] have been reported with the goal to achieve local control.[13] Adjuvant radiation therapy helps reduces the risk of recurrence (61% vs. 20%) [12]. However, ocular toxic effects of radiation therapy include dry eye, radiation retinopathy, cataract, severe corneal and conjunctival damage requiring enucleation and brain radionecrosis have to be considered [13, 15–17].

For locally advanced inoperable primary or recurrent lacrimal gland AdCC, carbon-ion radiation therapy have shown better local control with 3 year OS and LR 82.2% and 79% respectively^.[22, 23] IMRT combined with raster-scanned carbon ion boost showed superior locoregional control and overall survival for advanced AdCC of head and neck [24].

Neo-adjuvant intra-arterial cytoreductive chemotherapy (IACC) have shown improved overall survival and reduced disease recurrence [25] but with substantial toxicity like myelosuppression, nausea, vomiting, fever, sepsis, renal dysfunction, ototoxicity and catheter related thrombotic/vascular compromise that limits its routine application [26]. For metastatic disease or not amenable to surgery or radiotherapy, chemotherapy has modest efficacy even in non-lacrimal AdCC [26].

Neo-adjuvant intra-venous chemotherapy with 5-Fluorouracil and cisplatin have shown cytoreduction in lacrimal gland AdCC and can be considered prior to eye sparing surgery. Although it is better tolerated, easier to deliver and associated with fewer potential serious side effects, its survival benefit is questionable [3, 13]. Concomitant platinum-based chemotherapy may be considered with radiation therapy in an attempt to enhance radio-sensitivity [26, 27].

The newer insights into molecular abnormalities underlying lacrimal gland carcinogenesis have opened up potentials for targeted therapy in extensive and metastatic lacrimal gland AdCC. Lacrimal gland AdCC have shown KRAS, NRAS, and MET gene mutations suggesting possibility of targeted therapy aimed at EGFR-RAS-RAF cascade [28].

Recent studies have shown that AdCC cells of lacrimal gland express high levels of anti-apoptosis proteins like survivin, and TNF-α. Arsenic Trioxide (As₂O₃) have been found to be significantly increasing the apoptosis rate in in vitro studies by inhibition of these anti-apoptotic genes [29, 30].

Conclusion

The present case report is the 4th case in literature reporting high grade transformation in lacrimal gland AdCC. High grade transformation in lacrimal gland AdCC has been associated with worse clinical outcomes owing to local aggressiveness, increased incidence of nodal and distant metastasis. Surgery for local disease and elective neck dissection with adjuvant radiation therapy is at present the most preferred treatment modality. Newer radiation therapy techniques (photon, carbon ion) significantly reduce the radiation morbidity and allow better local control enabling conservative surgical resections. Chemotherapy in the neoadjuvant settings may help reduce the tumor burden while planning for eye preserving surgery or in the adjuvant settings to enhance radio sensitivity. Understanding of molecular pathogenesis will allow development of newer targeted therapy for management of metastatic and resistant AdCC.

Abbreviations

AdCC

Adenoid cystic carcinoma

HGT

High grade transformation

AdCC-HGT

Adenoid cystic carcinoma with high grade transformation

CECT

Contrast enhanced computed tomography

RT

Radiation therapy

3D CRT

3 Dimensional conformal radiation therapy

IMRT

Intensity modulated radiation therapy

AJCC

American Joint Committee on Cancer

IJV

Internal jugular vein

IACC

Intra-arterial cytoreductive chemotherapy

As₂O₃

Arsenic Trioxide

TNF-α

Tumor necrosis factor

Author’s Contribution

RS—have helped with the surgical reconstruction and providing the post-operative images, JB—have helped with the surgical reconstruction and providing the post-operative images. RG—have helped in data collection and formatting.

Funding

None.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.