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Year : 2023  |  Volume : 66  |  Issue : 1  |  Page : 155-158
Small cell neuroendocrine carcinoma with primary orbital involvement – The unseen, and a review of literature

1 Oculoplasty and Paediatric Ophthalmology Services, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi, India
2 Department of Ocular Pathology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi, India
3 Department of Ophthalmology, Northern Railway Central Hospital, New Delhi, India

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Date of Submission24-Nov-2021
Date of Decision13-Jun-2022
Date of Acceptance11-Jul-2022
Date of Web Publication18-Jan-2023


Neuroendocrine neoplasms are derived from the epithelial lineages mainly of respiratory tract, with predominant neuroendocrine differentiation. There are only a handful of documented cases of paranasal small cell neuroendocrine carcinomas (SNEC) with primary orbital involvement. Here, the authors describe a 33-year-old male patient with rapidly progressive swelling of the right lower lid with proptosis since 4 weeks. On contrast-MRI orbit, an ill-defined multilobulated mass measuring 3.6 × 3.1 cm with intense homogenous enhancement was seen in the right retrobulbar space involving the right ethmoid sinus. On incisional biopsy, a poorly differentiated mass containing numerous small round blue cells and scanty intervening stroma with prominent necrosis and apoptosis was seen. Immunohistochemistry was strongly positive for synaptophysin. He was diagnosed as a case of SNEC and received chemotherapy, with good response till date of 9 months of follow up. The authors present a literature review and describe challenges in management of a primary orbital SNEC.

Keywords: Neuroendocrine carcinoma, paranasal sinus malignancy, proptosis, small cell tumour, sino-orbital malignancy

How to cite this article:
Agrawal S, Deora A, Sen S, Gupta S, Das D. Small cell neuroendocrine carcinoma with primary orbital involvement – The unseen, and a review of literature. Indian J Pathol Microbiol 2023;66:155-8

How to cite this URL:
Agrawal S, Deora A, Sen S, Gupta S, Das D. Small cell neuroendocrine carcinoma with primary orbital involvement – The unseen, and a review of literature. Indian J Pathol Microbiol [serial online] 2023 [cited 2023 May 27];66:155-8. Available from:

   Introduction Top

Neuroendocrine neoplasms are derived from the epithelial lineages with predominant neuroendocrine differentiation and characterized by the production of dense-core secretory granules.[1] These are very rare in the nasal cavity, paranasal sinuses, or the nasopharynx.[2] To the author's best knowledge, only five previous reports [Table 1] have documented cases of paranasal small cell neuroendocrine carcinomas (SNEC) with primary orbital involvement. This study adhered to the tenets of the Declaration of Helsinki.
Table 1: Review of cases of SNEC with primarily orbital involvement

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   Case Presentation Top

A 33-year-old male patient presented with complaints of watering in the right eye for the past 3 months and rapidly progressive swelling of right lower lid with protrusion of the right eyeball in the past 4 weeks. The patient gave no history of trauma or any other associated symptoms. The patient had a history of smoking since 22 years and has stopped smoking 3 months back. On ophthalmic examination, best corrected visual acuity in the right eye was 6/18 and 6/6 in the left eye. Right lower lid fullness with conjunctival prolapse was noted on the right side. Right eye was proptosed 8 mm on Hertel's exophthalmometry, with globe dystopia 22 mm lateral and 5 mm superiorly [Figure 1]a. The swelling was palpable laterally from beyond the lateral canthus and inferiorly 33 mm below the lid margin. The medial extent of the swelling could not be delineated. The mass was non-tender, soft to firm in consistency with no palpable pulsations or thrill. It displayed mild resistance to retropulsion with no increase on valsalva maneuver. Bony orbital margins were intact. Three palpable lymph nodes noted in cervical regions Ib and II. Extraocular movements were found to be reduced equally in all meridians. On slit lamp examination, conjunctival prolapse with crusted discharge was seen. Pupillary reactions were sluggish, and fundus examination using indirect ophthalmoscopy revealed mild disc pallor. Ophthalmic examination for the left eye revealed no abnormalities. Patient was referred for ENT examination that revealed significant left deviation of the nasal septum.
Figure 1: (a) Clinical photograph of the patient at presentation showing abaxial proptosis with supero-temporal dystopia (b) clinical photograph at 9 months follow-up post six cycles of chemotherapy showing with almost complete symptomatic improvement except for slight globe displacement and no signs of recurrence (c) axial and coronal sections (d) of contrast-enhanced MRI orbit with brain showing an ill-defined multilobulated mass, measuring 3.6 × 3.1 cm with intense homogenous enhancement on both T1 and T2 images in the right retrobulbar space involving the right ethmoid sinus (e) coronal section of whole-body PET-CT scan showing a large FDG avid lesion in the right orbit involving the right ethmoid sinus, with no intracranial extension (f) Syncytial arrangement of small round tumor cells with finely granular chromatin. (HandE ×200). (g) the tumor cells are surrounded by a richvascular network. Frequent mitotic figures are seen (arrow) (HandE ×200)(h) tumor cells demonstrate strong cytoplasmic staining for cytokeratin AE1/AE3 and synaptophysin, and (i) Avidin Biotin ×400

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On gadolinium-enhanced MRI orbit with brain, an ill-defined multilobulated mass, measuring 3.6 × 3.1 cm with intense homogenous enhancement on both T1 and T2 images, was seen in the right retrobulbar space involving the right ethmoid sinus [Figure 1]c and [Figure 1]d. The mass was indenting the posterior aspect of the right eyeball and causing superior displacement of the optic nerve, without any intracranial extensions.

An incisional biopsy was done through a transconjunctival orbitotomy approach. On histopathological examination, it was a poorly differentiated mass made up of sheets of numerous small round blue cells with scanty intervening stroma [Figure 1]f. Necrosis and apoptosis were prominent with the cells displaying atypical mitoses and high nuclear-cytoplasmic ratio. The nuclei exhibited a characteristic finely stippled (“salt and pepper”) chromatin without a conspicuous nucleolus indicative of a neuroendocrine or neuroblastic cell line [Figure 1]g. On immunostaining, cells were strongly positive for synaptophysin [Figure 1]h and [Figure 1]i. Further stains for LCA, CD34, CD68, mic-2, desmin, MPO, and TTF-1 were found to be negative. A diagnosis of high-grade SNEC was made.

A whole-body Positron Emission Tomography - Computed Tomography (PET-CT) scan revealed a large FDG avid in the right orbit with FDG avid metastatic right cervical lymphadenopathy [Figure 1]e. The patient was advised for six cycles of cisplatin and etoposide. He showed marked reduction in tumor size, proptosis, and lower eyelid swelling after two cycles of chemotherapy. 131 Iodine - Meta-Iodo-Benzyl-Guanidine (131I-MIBG) whole-body scan after two cycles showed soft tissue density in right orbit with no significant uptake and no evidence of MIBG concentrating tumor/lesions in the body. Gallium-68 (DOTA0-Phe1-Tyr3) octreotide (68Ga-DOTANOC) whole-body PET-CT study revealed somatostatin receptor expressing residual primary disease in right orbit with metastasis to cervical lymph nodes. There was a reduction in size and uptake of primary and right cervical lymph nodes suggestive of partial response.

Till 9 months follow up, patient had completed six cycles of chemotherapy with almost complete symptomatic improvement except for slight globe displacement and no signs of recurrence or distant metastasis [Figure 1]b. Patient had been advised radiotherapy thereafter.

   Discussion Top

SNEC are primarily tumors of the respiratory system comprising around 20% of malignant lung tumors.[1] Extrapulmonary SNEC accounts for 2–4% of all SNECs.[2] SNEC of the head and neck is an even rarer disease that accounts for approximately 0.3% of all SNECs.[3]

Extrapulmonary SNEC of the sinonasal tract is a rare tumor with aggressive behavior. The first case of SNEC of the paranasal sinuses was reported by Raychowdhuri et al.[6] in 1965 following which a paucity in clinical and treatment data for the same remains to this date in literature. It is more prevalent between the fifth and sixth decades of life with a slight male preponderance.[4] A majority of malignant paranasal sinus tumors are squamous carcinomas and their variants (55%), nonepithelial neoplasms (20%), glandular tumors (15%), undifferentiated carcinomas (7%), and miscellaneous tumor (3%).[5] Whereas most of the other paranasal sinus carcinomas such as squamous cell carcinoma mostly arise from maxillary sinus, SNECs are more commonly seen in ethmoid sinus.[4] Initial clinical presentation is similar to other space-occupying lesions of paranasal sinuses that include unilateral nasal drainage, epistaxis, and obstruction. Advanced tumors may invade neighboring structures, such as skull base, brain, and the orbit. Primary orbital involvement is rare and such a case has been presented along with a review of similar presentations. Orbital spread can lead to pain, protrusion of the eyeball, decreased visual function as a consequence of optic nerve compression, diplopia, and strabismus as a result of extraocular muscle involvement, although such symptoms at presentation are uncommon.[6] Local pain, anosmia, and metastatic cervical nodes have also been described. The most frequent sites for distant metastases are the lungs, liver, and bone.[7]

Neuroendocrine malignancies share in common the production and storage of neurosecretory dense-core granules.[6] These may range from well-differentiated to poorly differentiated tumors with a high degree of cellular pleomorphisms, mitotic activity, and necrosis. Histologically, multiple small round blue cells can be seen arranged in sheets and ribbons with scanty intervening stroma. Lymphovascular, perineural and soft tissue invasion is not uncommon. Immunohistochemistry reveals positivity for an epithelial marker, namely, cytokeratin with diffuse positivity for markers of neuroendocrine differentiation, namely, synaptophysin, neuron-specific enolase, and chromogranin. The histologically recognizable types are typical carcinoid (well-differentiated), atypical carcinoid (moderately differentiated), and large cell neuroendocrine carcinomas and SNEC (poorly differentiated).[8]

A close differential diagnosis is Grade 3 (G3) Neuroendocrine Tumor (NET). The fiftth edition of the WHO classification of tumors of the digestive system avoids the confusion between these two clinically and molecularly distinct entities. From a clinical perspective, patients with neuroendocrine carcinomas (NECs) respond well to platinum-containing chemotherapy, whereas patients with G3 NETs fail to respond to this therapy.[3] Morphologically, NETs have organoid or nested architecture, uniform nuclear features, coarsely stippled chromatin, and minimal necrosis, whereas NECs often grow in sheets and show a less nested architectural pattern with abundant necrosis.[4]

Two more clinicopathological entities with neuroendocrine differentiation in the head and neck region are olfactory neuroblastoma and sinonasal undifferentiated carcinoma. Our case presented with rapidly growing right periorbital swelling extending medially into the ethmoid sinus with extensive infiltration and palpable draining lymph nodes, indicating a malignant nature of the tumor. Olfactory neuroblastomas have well-developed neuroendocrine differentiation, almost invariably arise from the olfactory mucosa, typically exhibit low-grade cytologic features, and may have protracted clinical course with an approximately 50% overall 5-year survival. In contrast, sinonasal undifferentiated carcinoma is a microscopically high-grade neoplasm with minimal abortive neuroendocrine features, a highly aggressive clinical course, and virtually 100% mortality. They can arise throughout the sinonasal region.[11] Also there was no evidence of a neutrophil, Homer Wright rosettes, or Flexner-Wintersteiner rosettes, which are characteristic features of olfactory neuroblastomas. Thus, based on characteristic histopathological presentation with immunohistochemical staining and supporting imagery of the tumor showing ill-defined infiltrative mass with minimal bony erosions confirmed the diagnosis of SNEC of the ethmoid sinus with orbital extension.

For staging of these tumors, Kadish et al.[5] staging system as well as 2002-American Joint Committee on Cancer Staging system of nasal cavity and paranasal sinus tumors can be employed (Kadish A: limited to nasal cavity, Kadish B: Limited to nasal cavity and paranasal sinuses, and Kadish C: Tumor extending beyond the nasal cavity and paranasal sinuses).

No consensus on treatment guidelines for NETs of paranasal sinuses has been reached mostly because of a paucity of cases in literature. Few recommendations do exist based on retrospective data. A multimodal approach comprising of chemotherapy, radiotherapy, and surgery is mostly necessary. Combined treatment based on surgery is associated with significantly better disease-free survival and overall survival compared to treatment without surgery irrespective of differentiation status of tumor.[12] However, as majority of patients have advanced disease at presentation with extensive involvement of orbit, skull, or brain, the benefit of surgery eludes these patients [Figure 2].
Figure 2: Flowchart showing treatment guidelines for neuroendocrine tumors

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The authors document this case with a view to present existing literature review and highlight the challenges in diagnosis and management of paranasal SNEC that has a high propensity to recur, invade surrounding structures, and metastasize to distant sites despite multimodal therapy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for the patient's images and other clinical information to be reported in the journal. The guardian understands that his name and initials will not be published, and due efforts will be made to conceal the identity of the patient, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

   References Top

American Cancer Society: Cancer Facts and Figures 2005. Atlanta, GA: American Cancer Society; 2005.  Back to cited text no. 1
Pointer KB, Ko HC, Brower JV, Witek ME, Kimple RJ, Lloyd RV, et al. Small cell carcinoma of the head and neck: An analysis of the National Cancer Database. Oral Oncol 2017;69:92-8.  Back to cited text no. 2
RaychowdhuriRN. Oat-cell carcinoma and paranasal sinuses. J LaryngolOtol 1965;79:253-5.  Back to cited text no. 3
Mitchell EH, Diaz A, Yilmaz T, Roberts D, Levine N, DeMonte F, et al. Multimodality treatment for sinonasal neuroendocrine carcinoma. Head Neck 2012;34:1372-6.  Back to cited text no. 4
Su SY, Bell D, Hanna EY. Esthesioneuroblastoma, neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma: Differentiation in diagnosis and treatment. Int Arch Otorhinolaryngol 2014;18(Suppl 2):S149-56.  Back to cited text no. 5
MacIntosh PW, Jakobiec FA, Stagner AM, Gilani S, Fay A. High grade neuroendocrine neoplasm of the antrum and orbit. SurvOphthalmol 2015;60:486-94.  Back to cited text no. 6
Silva EG, Butler JJ, Mackay B, Goepfert H. Neuroblastomas and neuroendocrine carcinomas of the nasal cavity: A proposed new classification. Cancer 1982;50:2388-405.  Back to cited text no. 7
Mills SE. Neuroendocrine tumors of the head and neck: A selected review with emphasis on terminology. EndocrPathol 1996;7:329-43.  Back to cited text no. 8
Strosberg JR, Coppola D, Klimstra DS, Phan AT, Kulke MH, Wiseman GA, et al. North American Neuroendocrine Tumor Society (NANETS). The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas. Pancreas 2010;39:799-800.  Back to cited text no. 9
Lokuhetty D, White V, Watanabe R, Cree I. WHO classification of tumours of the digestive system. Lyon: International agency for research on cancer; 2018.  Back to cited text no. 10
Kadish S, Goodman M, Wang CC. Olfactory neuroblastoma. A clinical analysis of 17 cases. Cancer 1976;37:1571-6.  Back to cited text no. 11
Chang CF, Li WY, Shu CH, Ho CY. Sino-nasal neuro-endocrine carcinoma. Acta Otolaryngol 2010;130:392-7.  Back to cited text no. 12
Renuka IV, Rao BS, Sasank R. Sinonasal neuro endocrine carcinoma extending into orbit - a case report. Ind J Otolaryngol Head Neck Surg. 2008;60:156-8.  Back to cited text no. 13
Han G, Wang Z, Guo X, Wang M, Wu H, Liu D. Extrapulmonary small cell neuroendocrine carcinoma of the paranasal sinuses: a case report and review of the literature. J Oral Maxillofac Surg. 2012;70:2347-51.  Back to cited text no. 14
Atik A, Krilis M, Shannon K. Small cell neuroendocrine carcinoma masquerading as cellulitis and causing blindness via bilateral orbital involvement. Orbit. 2013;32:197-9.  Back to cited text no. 15
Mittal R, Kaza H, Agarwal S, Rath S, Gowrishankar S. Small cell neuroendocrine carcinoma of the orbit presenting as an orbital abscess in a young female. Saudi J Ophthalmol 2019;33:308-11.  Back to cited text no. 16

Correspondence Address:
Deepsekhar Das
Oculoplasty and Pediatric Ophthalmology Services, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi –110 029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_1144_21

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