Neuroendocrine neoplasms of the orbit: report of three cases and a literature review

Abstract

Neuroendocrine neoplasms (NENs) originate from neuroendocrine cells, and mainly occur in the gastrointestinal tract and lungs, rarely occurring in the orbit. Here, the clinicopathologic factors, treatments and prognosis of three cases of orbital NENs are described. The mean age of the three patients (two females and one male) was 59 years. Two cases exhibited ocular symptoms, including unilateral proptosis and eyelid mass, while the third case presented systemic symptoms exhibited as Cushing’s syndrome. The tumours were surgically resected in all three patients. Immunohistochemistry assays revealed positive expression for pan cytokeratin and epithelial membrane antigen in all cases. Additionally, neural cell adhesion molecule 1 (also known as CD56) and synaptophysin were positive in two cases. The pathological diagnosis for case 1 and 2 was ‘neuroendocrine carcinoma’ and both patients died three months after diagnosis. Case 3 was diagnosed with a neuroendocrine tumour and the symptoms of Cushing’s syndrome gradually improved following surgery. In addition, no recurrence was observed during the four-year follow-up period. These cases demonstrate that orbital neuroendocrine tumours show different clinical manifestations due to the different types. Pathology may clarify the diagnosis, classification and grading, and provide a reference value for treatment and prognosis.

Introduction

Neuroendocrine neoplasms (NENs) are a rare group of neoplasms that arise from neuroendocrine cells and account for less than 1% of all malignant tumours. ¹ NENs may occur in various organs and tissues, including the gastrointestinal tract, lungs, pancreas and bronchus. ² Orbital NENs are rare and exhibit atypical clinical and imaging manifestations, ³ which pose challenges in their diagnosis. Therefore, it is crucial for ophthalmologists and pathologists to be well-versed in the clinicopathological features of orbital NENs to facilitate early and accurate treatment interventions. In the present study, three cases of orbital NENs with unknown primary origin are reported, highlighting their diverse clinical profiles. Additionally, the PubMed and Web of Science databases were searched to identify and review previously published cases of orbital NENs.

Case reports

Three cases of orbital NENs, diagnosed between 2016 and 2021, were retrospectively identified by reviewing databases of the Departments of Ophthalmology and Pathology of the West China Hospital of Sichuan University, China. The clinical histories, manifestations and pathological findings of these patients were carefully evaluated. Written informed consent for publication was obtained from the patients or their next of kin, and all patient details have been de-identified. Prior to hospital admission, all patients provided written informed consent for treatment. Due to the case report study design, institutional review board approval was waived. The study adhered to the tenets of the Declaration of Helsinki, and the reporting of the three cases conforms to CARE guidelines. ⁴

Case 1

In February 2018, a 48-year-old Chinese male patient presented at the Department of Ophthalmology, West China Hospital of Sichuan University, with a 2-month history of progressive right eye proptosis. No history of ocular discharge or thyroid eye disease was recorded. Best-corrected visual acuity was assessed using logarithm of the minimum angle of resolution (LogMAR) and was found to be 2.47 cm in the right eye and 0.1 in the left eye. Clinical examinations revealed proptosis (Hertel’s exophthalmometry was asymmetric at 19 mm for the right eye and 14 mm for the left eye), conjunctival oedema with protrusion beyond the eyelid fissure (Figure 1a and 1b), sluggish pupillary reactions, and mild optic disc pallor observed through indirect ophthalmoscopy. Computed tomography (CT) imaging revealed a well-defined and heterogeneous density retrobulbar nodule measuring 3.3 ×3.0 × 2.8 cm in the posterior part of the right orbit, which surrounded the optic nerve and compressed extraocular muscles (Figure 1c). Eye surgery was performed through a lateral orbitotomy approach, during which a brittle red neoplasm was found in the intraconal space and lateral rectus muscle (Figure 1d). Histological examination of the tumour showed positive staining for pan cytokeratin, thyroid transcription factor-1, neural cell adhesion molecule 1 (also known as CD56), epithelial membrane antigen (EMA), chromogranin A, and a MIB-1 rate of 80% (Figure 1e–k). According to the 2015 World Health Organization (WHO) classification, the lesion was identified as a poorly differentiated neuroendocrine carcinoma. The patient was then referred for extensive systemic examination, including chest and abdominal CT, and bone marrow evaluation, which yielded unremarkable results. Due to financial constraints, the patient declined a treatment recommendation of chemotherapy, and no further therapy was administered. After a follow-up of 3 months, the patient died due to tumour recurrence.

Figure 1.

Images from a 48-year-old male patient who presented with a 2-month history of progressive right eye proptosis: (a) right eye proptosis; (b) conjunctival congestion and oedema of the right eye; (c) preoperative axial computed tomography image showing the neoplasm surrounding the optic nerve and squeezed extraocular muscles; (d) gross image of resected specimen showing the red and brittle tumour mass. Histology findings: (e) tumour cells were closely arranged with a round or oval nucleus and no nucleolus, and no apparent cytoplasm (haematoxylin and eosin); (f) positive cytoplasmic pan cytokeratin immunostaining of tumour cells; (g) neural cell adhesion molecule 1 (CD56) immunostaining of tumour cells showing diffuse cytoplasmic immunoreactivity; (h) thyroid transcription factor-1 staining of tumour cells showing nuclear immunoreactivity; (i) positive cytoplasmic epithelial membrane antigen immunostaining of tumour cells; (j) positive cytoplasmic chromogranin immunostaining of tumour cells and (k) MIB-1 positive staining demonstrating strong nuclear immunoreactivity in about 80% of tumour cells. (All photomicrographs: original magnification, ×200).

Case 2

In June 2021, an 82-year-old Chinese female patient presented at the Department of Ophthalmology, West China Hospital of Sichuan University, due to a progressively increasing lower eyelid mass that had been noted 1 month previously. Best-corrected visual acuity was assessed using LogMAR and found to be 1.4 and 2.77 in the right and left eyes, respectively. Clinical examination revealed a red mass on the nasal side of the left lower eyelid (Figure 2a). Apart from lens opacity, no definite abnormalities were observed in the anterior and posterior segments of the left eye. In May 2021, a CT scan showed a well-defined peribulbar nodule measuring 2.2 × 1.9 × 2.1 cm in the area of the orbital muscle cone and nasolacrimal duct (Figure 2b and 2c). One month later, a magnetic resonance imaging (MRI) scan revealed a maximum cross-section of the lesion measuring 4.0 × 3.2 cm (Figure 2e [1–4]). The mass was surgically resected through a transcutaneous orbitotomy approach, revealing a large grey-white neoplasm with hard and brittle characteristics in the left orbit (Figure 2f). Immunohistochemistry results demonstrated positive pan cytokeratin, EMA, CD56, and synaptophysin staining, along with a Ki-67 proliferation index of 90% (Figure 2g–m), confirming a diagnosis of poorly differentiated neuroendocrine carcinoma. A subsequent comprehensive work-up, including total body CT and bone marrow evaluation, ruled out any occult internal malignancy. Despite the diagnosis, the patient declined further therapy due to her advanced age. During regular follow-up intervals, the patient's condition deteriorated, and she eventually died due to cachexia associated with the tumour after 3 months of follow-up.

Figure 2.

Images from an 82-year-old female patient who presented with an increasing lower eyelid mass from 1 month previously. In May 2021: (a) left lower eyelid red mass; (b) axial computed tomography (CT) Continued.image showing a well‑defined peribulbar nodule in the orbital muscle cone; (c) coronal CT image showing that the muscle and the eyeball were squeezed by the neoplasm. In June 2021: (d) the left lower eyelid mass was found to be rapidly growing; (e [1–4]) magnetic resonance imaging scans showing T1, fat-suppressed, post-contrast, axial T2, T1 and coronal images with a well‑defined mass squeezing the eyeball and muscle. A moderately hypointense region on T1 and mildly hyperintense region on T2 with heterogeneous contrast enhancement of fat suppression were also detected; (f) gross image of resected specimen showing hard, brittle and grey-white masses. Histology images, showing: (g) closely arranged tumour cells with dense chromatin staining, and fusiform or oval nucleus with no nucleolus (haematoxylin and eosin [H&E]; original magnification, ×200); (h) tumour cells invading the muscle (H&E; original magnification, ×200); (i) positive cytoplasmic epithelial membrane antigen immunostaining of tumour cells (original magnification, ×400); (j) positive cytoplasmic pan cytokeratin immunostaining of tumour cells (original magnification, ×400); (k) neural cell adhesion molecule 1 (CD56) immunostaining of tumour cells showing diffuse cytoplasmic immunoreactivity (original magnification, × 400); (l) positive cytoplasmic synaptophysin immunostaining of tumour cells (original magnification, ×400); and (m) Ki67 immunostaining demonstrating strong nuclear immunoreactivity in approximately 90% of tumour cells (original magnification, ×400).

Figure 3.

Images from a 48-year-old female patient who presented with fatigue, anasarca for 1 year, alopecia, and skin pigmentation for 5 months: (a) patient’s moon face appearance; (b1–4) preoperative orbital magnetic resonance images (MRIs) showing T1, fat-suppressed, post-contrast, axial T2, T1 and coronal images. A 1.5 ×2.6 cm lesion was detected and presented slightly high T1 and equal T2 signals.Continued.A well-circumscribed lesion in the orbit was detected with homogeneous contrast enhancement that surrounded the external rectus muscle and pushed the optic nerve; (c) gross image of resected specimen (2.5 cm, ovoid, well-circumscribed, glistening mass). Histology images, showing: (d) fusiform or round tumour cells with rare nucleolus and mitotic appearance, and punctate or dense chromatin detected in the nucleus (haematoxylin and eosin [H&E]; original magnification, ×200); (e) tumour cells invading the muscle (H&E; original magnification, ×200); (f) positive cytoplasmic pan cytokeratin immunostaining of tumour cells (original magnification, ×400); (g) positive cytoplasmic epithelial membrane antigen immunostaining of tumour cells (original magnification, ×400); (h) neural cell adhesion molecule 1 (CD56) immunostaining of tumour cells showing diffuse cytoplasmic immunoreactivity (original magnification, ×400); (i) positive cytoplasmic synaptophysin immunostaining of tumour cells (original magnification, ×400); (j1–4) postoperative orbital MRIs showing T1, fat-suppressed, post-contrast, axial T2, T1 and coronal images, respectively. The left extraocular rectus muscle was thickened with a blurred edge and the orbital fat was swollen; and (k) symptoms of Cushing’s syndrome disappeared after the operation, including moon face appearance.

Case 3

In July 2016, a 48-year-old female patient was admitted to the Endocrinology Department of West China Hospital of Sichuan University, with fatigue, anasarca for 1 year, alopecia, and skin pigmentation for the previous 5 months. Physical examination revealed mildly elevated blood pressure (150/79 mmHg), moon face (Figure 3a), central obesity, multiple purple striae on the abdomen, scattered bruises, and proximal muscle weakness. The patient had a history of an orbital mass 20 years ago, which was previously considered an inflammatory pseudotumor, and she was discharged without surgery as she was asymptomatic at that time. Laboratory tests showed abnormally elevated cortisol levels, and the 1-mg overnight dexamethasone suppression test confirmed Cushing’s syndrome. Subsequent adrenocorticotropic hormone (ACTH) measurement revealed a significant elevation in ACTH levels, but the failure to suppress plasma total cortisol with a high-dose dexamethasone suppression test suggested possible ectopic Cushing’s syndrome. Despite negative findings in the pituitary enhanced MRI, an enhancement was incidentally discovered in the lateral rectus muscle of the patient's left orbit. Subsequently, an orbital enhanced MRI was performed, and an enhanced orbital mass was found encompassing the left orbital lateral rectus muscle (Figure 3b [1–4]). Surgery was then performed through a lateral orbitotomy approach. After complete excision of the mass (Figure 3c), histopathological analysis confirmed a typical orbital carcinoid tumour. Immunohistochemistry showed positive staining for pan cytokeratin, EMA, CD56, and synaptophysin (Figure 3d–i). The patient underwent extensive systemic examination, with a normal chest CT and hyperplastic adrenal glands noted on abdominal CT. The patient appeared stable and her ACTH levels gradually returned to normal during follow-up. Subsequent MRIs showed no signs of recurrence (Figure 3j [1–4]). Notably, the patient's clinical manifestations, including moon face, purple striate and central obesity, disappeared (Figure 3k). Up to the latest follow-up (in July 2023), no recurrence had been observed.

Discussion

Neuroendocrine neoplasms of the orbit are extremely rare, with most cases being metastases from a distant primary NEN. ⁵ The current study describes three cases of orbital NENs with unknown primary, as no primary lesion was detected upon thorough whole-body examination. A review of the published literature regarding studies on primary orbital NENs, or orbital NENs with unknown primary, identified a total of 12 previously reported cases (Table 1).^6–14

Table 1.

Summary of previously published cases and the present case of primary neuroendocrine tumour.

Author (publication year)	Patient age (years)	Sex	Presentation	CT/MRI scan	Immunohist	Classification	Treatment	Survival	Follow-up	Metastasis
Riddle (1982) 14	NM	M	Proptosis	NM	NM	Carcinoid	S	Alive	4 months	No
	NM	F	Proptosis	NM	NM	Carcinoid	S	Alive	4 months	No
Yang (2011) 13	54	M	Proptosis and decreased vision	A soft tissue mass in the superior orbit situated behind the globe	Syn	Carcinoid	S	Alive	NM	NM
	59	M	Proptosis	A mass in the right inferior rectus muscle	Syn	Carcinoid	S + RA	Alive	5 years	No
	78	F	Proptosis and upper lidptosis	A multi-lobulated mass in the right superior orbit measuring involving the superior rectus and levator palpebrae superioris complex	NM	Carcinoid	S	Alive	3.5 years	Yes
Zimmerman (1983) 12	71	F	Proptosis, decreased vision, carcinoid syndrome	A large mass in the right orbit	NM	Carcinoid	S	Alive	3 years	No
Di Maria (2000) 11	84	M	Nodular mass	Mass in the whole left upper lid and the orbital soft tissues around the eyeball, involvement at recurrence	EMA, CK, CgA, NSE	Carcinoma	S + RA	Alive	2.5 years	Yes
	79	F	Proptosis	–	EMA, CK, CgA, NSE	Carcinoma	S	Alive	1 year	No
Thyparampil (2018) 10	64	F	Proptosis, pain, swelling	A 2-cm intraconal lesion in the right orbit	CgA, Syn, CDX2, Ki-67 (3–5%)	Carcinoid	S	Alive	3 years	No
Mititelu (2008) 9	60	M	Diplopia, decreased vision	A 17 × 9-mm fusiform lesion along the expected course of the left supraorbital nerve	CK, Syn	Carcinoma	S + ChT	Dead	4 years	Yes
Atik (2013) 8	35	F	Pain	Inflammatory mass in the right orbit, ethmoid, and right frontal bone	Syn , CgA, CD56	Carcinoma	S + ChT	Dead	2 years	Yes
Mittal (2019) 7	25	F	Proptosis, orbital abscess	Large mass in left orbit, ethmoid, frontal sinus involvement at recurrence	Syn, NSE, CD56, Ki-67 (90%)	Carcinoma	S + ChT	Dead	2 years	Yes
Present study	48	M	Proptosis	A mass in the right orbit, surrounded the optic nerve and squeezed the extraocular muscles	PCK, CD56, EMA, CgA, MIB-1 (80%)	Carcinoma	S	Dead	3 months	Yes
	82	F	Proptosis	A mass in the left orbit, squeezed the eyeball	PCK, EMA, CD56, Syn, Ki-67 (90%)	Carcinoma	S	Dead	3 months	Yes
	48	F	Carcinoid syndrome	A mass surrounded the lateral rectus muscle of the left eye	PCK, EMA, CD56, Syn, CgA	Carcinoid	S	Alive	4 years	No

M, male; F, female; CgA, chromogranin A; ChT, chemotherapy; CD56, neural cell adhesion molecule 1; CDX2, caudal type homeobox transcription factor 2; CK, cytokeratin; CT, computed tomography; EMA, epithelial membrane antigen; Immunohist, immunohistochemistry; MRI, magnetic resonance imaging; NM, not mentioned; NSE, neuronal-specific enolase; PCK, pan cytokeratin; RA, radiotherapy; S, surgery; Syn, synaptophysin.

The 12 patients in the previously published cases demonstrated an equal distribution of sexes, with a mean age of 60 years. The present cases comprised two female and one male patient, with a mean age of 59 years. Among all 15 patients with available clinical information, the most commonly observed signs of orbital NENs were proptosis and visual disturbances, including blurry vision, diplopia, and ocular motility disturbances (Table 1). A minority of orbital NENs were found to secrete hormones, leading to the manifestation of typical carcinoid syndromes,^6,12 which was consistent with the present case 3.

Typical radiographic findings play a crucial role in diagnosing NENs. Orbital NENs often present as heterogeneous, well-circumscribed, and contrast-enhancing lesions on CT. ³ The masses are mostly confined to the extraocular muscles, with some cases extending into the adjacent orbital or lacrimal gland tissues. On MRIs, these lesions typically appear moderately hypointense or isointense on T1-weighted imaging, and isointense or mildly hyperintense on T2-weighted imaging. ¹⁵ In instances where the primary NENs are unknown, further systemic investigation is always warranted. Whole-body contrast-enhanced CT and MRI scans have been employed as the initial approach to localize the primary site and identify any metastatic disease. ³ Additionally, functional imaging modalities, such as metaiodobenzylguanidine (MIBG scan), somatostatin receptor scintigraphy (octreotide scan) and fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET scan) have proven to be useful in detecting an occult primary tumour, uncovering unsuspected metastatic disease, and monitoring the response to treatment. ¹⁶

Histopathological analysis of tissue samples serves as the gold standard for diagnosing NENs. According to the 5th edition of the WHO classification in 2021, NENs are categorized into well-differentiated epithelial neuroendocrine neoplasms (termed neuroendocrine tumour, NET) and poorly differentiated neuroendocrine neoplasms (termed neuroendocrine carcinoma, NEC). ¹⁷ This classification emphasizes the importance of diagnostic immunohistochemical biomarkers to confirm the neuroendocrine nature of a neoplasm. Positive immunohistochemical staining for epithelial markers (EMA and cytokeratin) and neuroendocrine markers, including chromogranin A, synaptophysin, neuron-specific enolase and neural cell adhesion molecule 1 (CD56), is used. ¹⁸ Mitotic count and Ki-67 proliferation index/MIB1 staining are employed to assess cell proliferation activity. ¹⁹ NETs are graded as G1 NET (no necrosis and < 2 mitoses per 2 mm²; Ki67 < 20%), G2 NET (necrosis or 2–10 mitoses per 2 mm², and Ki67 < 20%), and G3 NET (> 10 mitoses per 2 mm² or Ki67 > 20%, and absence of poorly differentiated cytomorphology). NEC (>10 mitoses per 2 mm², Ki67 > 20%, and often associated with a Ki67 > 55%) are further subtyped, based on cytomorphological characteristics, as small cell and large cell neuroendocrine carcinomas. The distinction between G3 NET and NEC is often challenging in clinical practice, despite potential differences in pathological features and chemotherapy response. ²⁰ Additional immunohistochemistry, including protein 53 (p53), retinoblastoma-associated protein (RB1), transcriptional regulator ATRX, delta-like protein 3 (DLL3) and outer dense fibre protein 1 (ODF1), may be helpful in differentiating the two conditions. ¹⁷

Treatment options for orbital NENs include surgery, chemotherapy and radiotherapy, either alone or in combination. Among these, surgery is the most common intervention. ²¹ Depending on the specific location of the tumour within the orbit, different surgical approaches are chosen to achieve the most radical resection of the mass, ²² aiming for curative intent. However, for the treatment of NEC, ²³ orbital surgery is mainly reserved for diagnostic purposes, and subsequent chemotherapy (platinum–etoposide-based regimens), or radiotherapy (external beam radiotherapy) plays a crucial role. ²⁴ Somatostatin analogues (SSAs) are the primary treatment for functional tumours, aiming to control symptoms related to hormone excess. Additionally, SSAs are considered a first-line therapy for the low-grade NETs with a Ki-67 tumour index of 10% or less, or for unresectable locally advanced or metastatic NETs. ²⁵ Peptide receptor radionuclide therapy with radiolabelled SSAs has emerged as a promising systemic treatment modality for patients with inoperable or metastatic NETs. ²⁶ In the present review of the literature, all cases underwent surgical intervention, and patients with orbital NEC received a combination of radiotherapy and/or chemotherapy.

The prognosis of orbital NENs is reported to be better than other systemic metastatic diseases. In a study of orbital metastatic NETs, ²⁷ the median survival was found to be 11.3 years and the 10-year survival was estimated at 71%. ²¹ Among cases included in the present review, five patients with NEC died during a follow-up of 3 months to 4 years, whereas seven patients with confirmed diagnosis of carcinoids were reported to be alive with no metastasis during follow-up of between 4 months and 5 years (Table 1).^6–14

Discussion surrounding the primary origins of the three cases in the present case series is intriguing. The patients in case 1 and case 2 deteriorated and died within 3 months without further treatment. This raises the question of whether the orbital lesions were metastases from occult primary tumours elsewhere, or if they originated as primary lesions in the orbit. NECs are known to exhibit a high propensity for metastasis. ¹⁶ In particular, small cell neuroendocrine carcinomas (SNECs) are characterized by rapid local invasion, metastasis and a median survival time for untreated patients of only 2–3 months. In the head and neck region, the prognosis of SNECs is even poorer than that of lung NEC, with a survival rate of only about 13 months. ²⁸ If the present two cases indeed represent metastatic tumours, there may be a greater inclination towards head and neck NECs, particularly paranasal small cell neuroendocrine carcinomas, due to their closer anatomical proximity. Moreover, there have been a few documented cases of paranasal SNECs with primary orbital involvement. ²⁰ To date, the patient in case 3 has been followed-up for 4 years without identification of the primary site. However, it is essential to consider that even in cases where well-differentiated NETs demonstrate distant metastases, patients may still achieve longer survival, as reported in cases with survival rates of 5 years or even 10 years after radical resection. In a review of 102 cases of orbital NENs conducted by Mustak et al., ²¹ among the remaining five cases without an identified primary tumour, only orbital disease was observed. Within this subgroup, one death from the disease occurred during a 105-month follow-up period. Therefore, extended follow-up is required for the patient in the present case 3.

In conclusion, orbital NENs may manifest as increased eye proptosis or rapid-onset orbital masses. Therefore, it is crucial to conduct imaging examinations and seek histopathological evaluation of all orbital lesions. Additionally, it should be noted that some patients may not initially present to the ophthalmology department, due to systemic symptoms. Hence, proactive efforts are required to identify potential primary lesions. Surgical intervention remains the optimal treatment approach for orbital NENs, either as a standalone option or in combination with radiotherapy and chemotherapy. The selection of treatment strategy depends on the tumour classification and grading, and the patient's overall condition. Regular re-examination is necessary to monitor and detect any potential tumour metastasis.