Next Article in Journal
Specific Multiomic Profiling in Aortic Stenosis in Bicuspid Aortic Valve Disease
Previous Article in Journal
SRPK1 Promotes Glioma Proliferation, Migration, and Invasion through Activation of Wnt/β-Catenin and JAK-2/STAT-3 Signaling Pathways
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomedicines
Volume 12
Issue 2
10.3390/biomedicines12020379
biomedicines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Systematic Review

Diagnostic and Therapeutic Management of Primary Orbital Neuroendocrine Tumors (NETs): Systematic Literature Review and Clinical Case Presentation

by
Giulia Arrivi
1,2,*,
Monia Specchia
1,
Emanuela Pilozzi
3,
Maria Rinzivillo
4,
Damiano Caruso
5,
Curzio Santangeli
5,
Daniela Prosperi
6,
Anna Maria Ascolese
7,
Francesco Panzuto
4,8,† and
Federica Mazzuca
1,†
1
Oncology Unit, Department of Clinical and Molecular Medicine, Sant’Andrea University Hospital, Sapienza University of Rome, Grottarossa Street 1035-1039, 00189 Rome, Italy
2
Department of Medical and Surgical Sciences and Translational Medicine, Faculty of Medicine and Psychology, PhD School in Translational Medicine and Oncology, Sapienza University of Rome, 00189 Rome, Italy
3
Anatomia Patologica Unit, Department of Clinical and Molecular Medicine, Sant’Andrea University Hospital, Sapienza University of Rome, 00189 Rome, Italy
4
European Neuroendocrine Tumor Society (ENETS) Center of Excellence, Digestive Disease Unit, Sant’Andrea University Hospital, 00189 Rome, Italy
5
Radiology Unit, Department of Medical Surgical Sciences and Translational Medicine, Sant’Andrea University Hospital, Sapienza University of Rome, 00189 Rome, Italy
6
Nuclear Medicine Unit, Sant’Andrea University Hospital, 00189 Rome, Italy
7
Radiotherapy Oncology Unit, Department of Surgical Medical Sciences and Translational Medicine, Sant’Andrea University Hospital, Sapienza University of Rome, 00189 Rome, Italy
8
European Neuroendocrine Tumor Society (ENETS) Center of Excellence, Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, 00189 Rome, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Biomedicines 2024, 12(2), 379; https://doi.org/10.3390/biomedicines12020379
Submission received: 1 December 2023 / Revised: 25 January 2024 / Accepted: 30 January 2024 / Published: 6 February 2024
(This article belongs to the Special Issue Advances in the Pharmacology of Neuroendocrine Tumors)
Browse Figures
Review Reports Versions Notes

Abstract

:
Background: The ocular involvement of neuroendocrine neoplasms (NENs) is uncommon and mainly represented by metastases from gastrointestinal and lung neuroendocrine tumors. Primary orbital NENs are even less common and their diagnostic and therapeutic management is a challenge. Methods: A systematic review of the literature was conducted from 1966 to September 2023 on PubMed to identify articles on orbital NENs and to summarize their clinical–pathological features, diagnosis and therapeutic management. Furthermore, we presented a case of a locally advanced retro-orbital primary neuroendocrine tumor that was referred to the certified Center of Excellence of Sant’Andrea Hospital, La Sapienza University of Rome, Italy. Results: The final analysis included 63 records on orbital NENs and 11 records focused on primary orbital NENs. The localization was mostly unilateral and in the right orbit; proptosis or exophthalmos represented the initial symptoms. The diagnostic work-up and therapeutic management was discussed and a diagnostic algorithm for the suspicion of primary orbital NENs was proposed. Conclusions: A multidisciplinary approach is required for the management of primary orbital NENs, emphasizing the importance of early referral to dedicated centers for prompt differential diagnosis, tailored treatment, and an improved quality of life and survival.

1. Introduction

Neuroendocrine tumors are rare neoplasms that arise from Kulchitsky, chromaffin, argyrophil, or argentaffin cells, which are distributed throughout the body but are mostly located in the gastrointestinal mucosa, lungs, biliary tract, pancreas, ovaries, testes, and thyroid gland [1]. Due to its indolent evolution, most diagnoses (50–75%) occur with metastatic disease, mainly in the lymph nodes, liver, and bones [2,3]. Instead, neuroendocrine cells are rarely detected in other organs, such as the brain or the organs of the senses, the eyes, or the orbital cavity. The incidence of brain metastases from neuroendocrine neoplasms (NENs) is reported to be between 1.5% and 5% [4] and is more frequent in primary lung neuroendocrine tumors (NETs); meanwhile, only 0.18% of brain disease comes from gastrointestinal NENs (GI-NENs), with a significant increase in the metastatic rate in poorly differentiated or undifferentiated NENs [2]. The eye and the orbital cavity are even more rare sites of cancer metastasis: approximately 8–10% of patients affected by a neoplasm of any histology or origin develop ocular metastases [5] in their cancer history; meanwhile, NENs account for 14–15% of all cases of orbital metastatic disease [6,7]. Although some reports in the literature are available [8,9,10,11], systematic epidemiological and clinical–pathological information about ocular metastases from NENs is still lacking. The most common site of the metastatic involvement of NENs is the uveal tract; these NENs arise from lung and breast NETs [8,12]; meanwhile, orbital cavity metastases are usually found in primary GI-NETs [13,14,15]. Only a few cases in the literature [16,17] have investigated neuroendocrine primary lesions of the orbit, suggesting that they are mostly represented by small-cell neuroendocrine carcinomas (SC-NECs) [18,19,20]. We report a locally advanced retro-orbital primary neuroendocrine tumor case that was referred to the European Neuroendocrine Tumor Society (ENETS)-certified Center of Excellence (CoE) of Sant’Andrea Hospital, La Sapienza University of Rome, Italy. Given the rarity of the orbital primary localization of neuroendocrine tumors, a comprehensive and systematic literature review was performed in order to systematically report all the clinical data available in the literature and outline a possible diagnostic algorithm and strategy for the therapeutic management of primary orbital NENs.

2. Materials and Methods

We present the rare case of a 75-year-old woman diagnosed with a primary orbital NET, from diagnosis to treatment. A search of the literature, according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines [21] in PubMed, from 1966 to September 2023, was conducted to identify available articles on NENs of the orbit and their clinical management; retrospective studies, reviews, and case reports or case series restricted to the English language and human field were included. Comments or editorials and abstracts of congress were excluded from the analysis (PRISMA registration code: 490993). The search strategy was as follows: (“orbit” OR “orbital” OR “eye” OR “eyes”) AND (“Neuroendocrine Tumors” OR “Carcinoma, Neuroendocrine” OR “Carcinoid Tumor” OR “Neuroendocrine Tumor” OR “Tumor, Neuroendocrine” OR “Tumors, Neuroendocrine” OR “Neuroendocrine Carcinoma” OR “Neuroendocrine Carcinomas” OR “Carcinoid Tumors” OR “Tumor, Carcinoid” OR “Tumors, Carcinoid” OR “Carcinoid”). All the records were independently screened, via consultation and reading the abstracts, by two authors: G.A. and M.S. Other articles not comprising the initial search but relevant to our topic were included in our analysis. The PRISMA 2020 flow diagram for the search strategy was reported in Figure 1. Focusing on the primary neuroendocrine tumor of the orbit, the results regarding the demographic and clinical features, the diagnosis and treatment work-up are presented in tables and discussed.

3. Case Presentation: Clinical History and Findings

In May 2020, a 75-year-old woman was referred to the ENETS-certified Center of Excellence (CoE) of Sant’Andrea Hospital, La Sapienza University of Rome, after several ophthalmic evaluations of a newly onset orbital mass of unexplained origin was carried out. She had been experiencing symptoms for three months: sporadic facial paresthesia, difficulty with facial movements, dysgeusia, and a visual acuity deficit in the right eye, which had worsened in recent months until complete blindness.
Before the diagnosis, the patient enjoyed good general conditions and led a regular life, and no relevant pathologies were reported in her pathological history. Initially, she was treated with steroid medications by a team of ophthalmologists and neurologists at another clinical center, but within a few months, she had not improved. For this reason, the patient underwent instrumental investigations using Computed Tomography (CT) scans and Magnetic Resonance Imaging (MRI), which demonstrated the presence of solid tissue that engaged the optic foramen, was located at the level of the right orbital cavity, and was in contact with the optic nerve and medial rectus muscle (Figure 2 and Figure 3).
MRI showed a hypointense mass in the baseline condition, with a subsequent contrast enhancement measuring 4 × 2.15 cm, growing through the right retrobulbar fat at the apex of the orbit; this involved the inferior orbital fissure and the lateral wall of the sphenoid sinus until it contacted the ipsilateral cavernous sinus. The lesion was arranged along the floor of the right orbit to infiltrate the inferior and medial rectus muscles and engaged the inferior orbital fissure in the context of the pterygopalatine fossa.
An incisional biopsy of the solid tissue in the pterygoid palatine fossa was performed. The tumor was composed of small to medium-sized cells with a hyperchromic nucleus and eosinophilic cytoplasm, with a mixed solid and trabecular growth pattern. Focal pseudo-glandular and papillary-like aspects with rosettes were present. The immunohistochemistry showed the intense and diffuse positivity of CKAE1/AE3, S100, Synaptophysin, Chromogranin A, CD56, INSM1, and CDX2, negativity for CD99, Vimentin, CD20, CD3, p40, p62 smooth muscle actin, TTF1, prolactin, ACTH, GH, FSH, LH, TSH, MELAN-A, CEA, p16, and p53, and a Ki67 proliferation index of 6% (Figure 4). Focal areas of necrosis were observed with a mitotic rate of 0 mitoses/2 mm2; no figures of lympho-vascular and perineural invasion were reported. According to the 2019 WHO Classification [22,23], these findings suggested a diagnosis of well-differentiated neuroendocrine tumor (WD-NET G2), not excluding the possible diagnosis of ectopic hypophyseal adenoma (S100+) or a metastatic localization of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) (CDX2+) [24]. Indeed, transcription factors can indicate the site of a primary tumor in the setting of an unknown primary. Although not entirely specific, lung origin is favored by TTF-1, pancreatic origin by Isl1 and PAX8, and intestinal origin by CDX2 [1,25].
Positron emission tomography/computed tomography (PET/CT) with 68-Gallium-DOTA-NOC revealed (68-Ga DOTA-NOC) an increased uptake in the right orbital cavity, a finding indicative of a neoplastic pathology with the high expression of somatostatin receptors (Figure 5).
The patient presented to us for further investigations and management and was referred to the Neuroendocrine Tumors Multidisciplinary Team (MDT) of our Institution.
A baseline total-body CT scan was requested, which confirmed the findings of previous radiological exams, namely the contact of the solid tissue in the right orbital cavity with the optic nerve and the medial rectus muscle engaging the optic foramen. A histological review was carried out by an expert pathologist in the field of NEN features, considering the critical role of the central pathology review and the strict correlation between a valid pathological diagnosis and the pathologist’s expertise. The diagnosis of WD-NET G2 with a Ki67 proliferation index of 6% was confirmed. Immunohistochemical coloration showed CDX2 positivity; immunostaining for pituitary transcription factors was performed to exclude the possible pituitary origin of the tumor. With the aim of excluding a midgut carcinoid, according to the suggestions of the pathological review and the literature data, which reported that most neuroendocrine orbital localizations are metastases of midgut NENs [13,14], CT enterography was performed; this showed no evidence of tumors in the small bowel. Moreover, a F-18 fluoro-deoxy-glucose (F-18 FDG) PET/TC revealed no FDG hyperaccumulation images in the right retro-orbital region and in the ipsilateral pterygoid palatine fossa (Figure 4).
According to these findings, the patient was started on treatment with somatostatin analogues (SSA)—long-term Lanreotide 120 mg—administered every four weeks. Given the symptoms of right eye blindness and exophthalmos, along with tinnitus and partial hearing loss, the patient was referred by MDT to a radiotherapist for palliative radiotherapy. Due to the difficult anatomical site of the lesion and the risk of consequent adverse effects, we decided to postpone an upfront radiotherapy treatment and to evaluate her clinical and radiological response to medical therapy. Surgery was not considered feasible after a multidisciplinary discussion due to the locally advanced aspect of the mass and the infiltrating involvement of nearby anatomical structures.
Three years after diagnosis, radiological assessment—MRI and 68-Ga DOTA-NOC PET/CT—showed stable disease. The patient undergoes clinical follow-up visits every six months, and there have been marked improvements in her general condition, upward mobility of the right eye, exophthalmos, vision, and hearing.
Written informed consent was obtained from the patient to participate in this study and for the publication of any potentially identifiable images or data included in this article.

4. Results

From a search of the literature with the aforementioned search strategy on PubMed, 348 records were identified. We excluded 275 records for irrelevant content after they were screened by two authors independently. Of the remaining 73 potentially eligible studies, one duplicate, one comment, one letter to the Editor, two with insufficient information, and five in a non-English language were excluded (Figure 1).
We included, in the final analysis, 63 records on orbital neuroendocrine tumors published between 1966 and September 2023, which comprised 52 case reports or case series, 5 reviews, and 6 retrospective studies (Table 1). In the majority of cases, the gastrointestinal tract was the primary tumor’s location (n = 38 records), while the respiratory tract (n = 16 records) was the second most represented location. Furthermore, although infrequent, neuroendocrine orbital metastases originating from kidney (n = 6), ovary or testicular (n = 3), and breast (n = 1) primary tumors were described. Thirteen articles did not specify the primary site of tumor or reported tumors of “unknown origin”.
Table 2 lists all the studies investigating exclusively ocular primary NETs that were reported in the literature. Including our report, a total of 16 patients presented with primary orbital NENs, including nine females and seven males, with a median age of 56.5 years (range 25–82) at diagnosis. The laterality of ocular involvement was right and left in 11 and 5 cases, respectively, and the initial symptoms were mostly represented by proptosis or exophthalmos (n = 11.69%), ocular pain (n = 3.19%) and the loss of or reduction/alteration in vision (n = 5.31%). Neurological symptoms [26,27] and Cushing’s syndrome [28,29] were described in only two cases, respectively. The histological diagnosis was available for all patients, according to the histopathological classification used at the time of publication of the different cases: “carcinoid” was described in five cases, well-differentiated NETs in two, and NEC/poorly differentiated carcinoma/small-cell NEC in the remaining nine.
In all patients, the mass was diagnosed with an MRI or CT scan; a visual acuity exam was performed in the seven patients with loss or blurred vision. The use of 68-Ga and (F-18) FDG PET/CT was reported only in two case reports, including our patient [18]. Surgery represented the backbone of treatment in twelve patients, of whom five also received post-operative radiotherapy and two received chemotherapy. In one case, it was proposed that CT and RT treatment be combined [18], while two patients, including ours, were treated with exclusive medical treatment [30]. No data about the therapeutic algorithm proposed was available in one report.
Table 1. Literature data on orbital NETs published from 1966 to September 2023.
Table 1. Literature data on orbital NETs published from 1966 to September 2023.
First Author, Year
of Publication		Type of the StudyPatients (n)Age or Median AgeSite of Primary TumorHistotypes of Primary Tumor (WHO)TreatmentOutcomes
Font, R.L., 1966 [31] case report174LungNENSurgeryNA
Rush, J.A., 1980 [32]case report158ColonNENSurgery, radiotherapyNA
Harris, A.L., 1981 [33]case report1NANANANANA
Riddle, P.J., 1982 [17]retrospective1553LUNG (53.3%), GI (26.6%), NA (20%)NETsSurgery (80%), Chemotherapy (6.6%), Radiation (13.3)OS 5.2 y
Zimmerman, L.E., 1983
[16]		case report171OrbitMixture of the histologic patternsNANA
Shields, C.L., 1987 [15]case report163IleumNENSurgeryNA
Harris, G.J., 1989
[34]		reviewNANAGINANANA
Shetlar, D.J., 1990 [8]case report353.3GI (33.3%); Liver (33.3%); Unknown (33.3%)NETs (66.6%); Unknown (33.3%)Surgery (100%)OS 4 y (33.3%), PFS 7.5y (33.3%); NA (33.3%)
Nida, T.Y., 1992 [35]case report163Respiratory TractNECsurgeryNA
Aburn, N.S., 1995 [36]case report164LungACLocal radiotherapy, chemotherapyOS 1 y
Fan, J.T., 1995
[9]		case series759Bronchus (42.8%); Ileum (28.6%); Colon (14.3%); Unknown (14.3%)NENs (100%)Iodine 125 brachytherapy (28.6%); Chemotherapy (71.4%); Ruthenium brachytherapy (14.3%); Enucleation (14.3%); External beam irradiation (42.8%)FU 7–8 y (57.1%); FU 1–2 y (42.9%)
El-Toukhy, E., 1996 [37]case report145GINETSurgery, RadiotherapyNA
Hanson, M.W., 1998 [38]case report176IleumCarcinoid tumor from Kulchitsky cellsNANA
Couch, D.A., 2000 [39]case report250Pancreas; ileocecal tumourCarcinoid tumorRadiotherapy; SurgeryOS 2 mo;
disappearance of symptoms after surgery
Khaw, P., 2001
[40]		case report258Mediastinum (50%); Kidney (50%)AC (50%), NEN (50%)Radiotherapy (100%)No symptoms after treatment
Takemoto, Y., 2003 [41]case report139DuodenumNENSurgeryNA
Sivagnanavel, V., 2004
[42]		case report170NANETOcreotide therapy,NA
Borota, O.C., 2005 [43]case report161GINENSurgery, Interferon/SandostatinNA
Mehta, J.S., 2005 [11]case series1365.3Ileal (53.8%); Colon (30.7%); Bronchus (7.6%); Breast (7.6%)NENExenteration (30.7%); Radiotherapy after tumor debulking (38.4%); Radiotherapy alone (15.3%); Local radiotherapy with receptor-targeted chemotherapy (15.3%).5 y OS 72%
Kiratli, H., 2008 [44]case report174LungACCisplatin/EtoposideNA
Mititelu, M., 2008 [23]case report160OrbitNETChemotherapyOS 4 y
Bohman, E., 2009 [45]case report169MidgutNENSandostatinNA
Matsuo, T., 2010 [46]case report172RetroperitoneumWD-NETRadiationNA
Sira, M., 2010 [7]case report178NANETOctreotide therapyOS 1 y
Gupta, A., 2011 [47]case report461.9Pancreas (14.3%); Unknown (85.7%)NETs (100%)Chemotherapy (14.3%), Unknown (85.7%)NA
Turaka, K., 2011 [48]case series458–66GI (50%); lung (25%); testicle (25%).NETsSurgery (75%); external beam radiotherapy (50%)FU 39 mo
Yang, M., 2011
[49]		case series363GI (33.3%), NA (66.6%)NETs (66.6%), NEC (33.3%)Surgery (100%), Radiotherapy (66.6%)FU 3.5 y
Mehta, P., 2012 [50]case series250Unspecified, with bone metastases; ileal carcinoid tumourNENsOctreotide therapyIn the first case, it was necessary to use occlusive lenses to control diplopia; in the second case, complete resolution of ptosis after treatment
Atik, A., 2013
[20]		case report135Right orbitNECSurgery, Chemotherapy and RadiotherapyOS 2 y
Dobson, R., 2013 [51]case report165MidgutNETPRRT using Lu-DOTATATEFU 14 mo
Peixoto, R.D., 2013 [52]case report179GINETOctreotide therapy, radiotherapy and Capecitabine/TemozolamideNA
Kiratli, H., 2015 [53]case report157KidneyNETOctreotide therapy, Capecitabine/TemozolomideFU 24 mo
MacIntosh, P.W., 2015 [54]review135Antrum and OrbitSNECSurgery, chemotherapy and radiotherapyNA
Parikh, D., 2015 [55]case report170KidneyNENOctreotide therapy, everolimusFU 6 mo (stable proptosis without diplopia)
Makis, W., 2016 [56]retrospective467GI (75%), LUNG (25%)NETs (100%)Lu-DOTATATE (50%); I-MIBG (50%)PFS 27.75 mo
Matějka, V.M., 2016 [57]review150AppendixGCCSurgery, ChemotherapyDeath a few months after diagnosis
Ruiz, J.B., 2016
[58]		case report153Thyroidmedullary thyroid carcinomaSurgery, External radiation4 mo later: morphological stability and reduction in calcitonin levels.
Warren, C.C., 2016 [59]case report170GICarcinoid tumorResection, chemotherapyNA
Kamaleshwaran, K.K., 2017
[60]		case report145Respiratory TractNETLU_DOTATATENA
Chen, Y.J., 2018 [61]case report169PancreasNETSurgery, Octreotide therapyNA
Das, S., 2018
[62]		case series567.2Ileal (100%)NETsChemotherapy (20%); Radiation Therapy (IGRT) (40%;) 177Lu-DOTATATE (PRRT) (20%); surveillance (20%)NA
Guo, Y., 2018
[63]		case report186BronchialNENOctreotide acetate, dacarbazine, carboplatin, etoposideNA
Rasmussen, J.Ø., 2018
[64]		case report171LiverNECSurgery, radiotherapy, IntronA/Sandostatin/Nexavar/Dotatoc, Temodal, etoposide monotherapyFU 15 y
Thyparampil, P.J., 2018
[24]		case report164OrbitNETSurgeryNA
Beam, A.S., 2019 [65]case report186GINETOctreotide therapyNA
Hafiz, A.A., 2019 [66]case report150Small bowelNETSurgery. Octreotide therapyNA
Kozubowska, K., 2019
[67]		case report173GINETSurgeryNA
Mittal, R., 2019 [19]case report125Left orbitNECChemotherapyOS 21 mo
Parghane, R.V., 2019
[68]		case report153KidneyNETRadiotherapy, Octreotide therapy, (Lu)—DOTATATE PRRTPFS 18 mo
Bacorn, C., 2020 [69]case report165GINETRadiotherapy, octreotide therapyFU 1 y
Kamieniarz, L., 2020
[70]		retrospective2753Small bowel (66.4%); Pancreas (14.8%). Hepatic with or without concomitant skeletal metastases (85%)NENExternal bema radiotherapy (45.4%)5 y OS 84.1%
La Salvia, A., 2020 [13]review64NALung (43.7%); Iileum (21.8%); Unknown (21.8%); Colon (4.6%); Rectum (1.5%); Esophagus (1.5%); Thymus (1.5%); Testicle (1.5%); Liver (1.5%)NETs (39%)Surgery (7.8%); External bema radiotherapy (29.6%); brachytherapy (7.8%); Photocoaugulation (1.5%)NA
Mustak, H., 2021 [71]observational cross-sectional cohort, retrospective2858.8Gastrointestinal tract (GI) (50%); lung (7.1%); kidney (7.1%) and ovary (3.6%)NETsObservation (14.3%); Radiation (35.7%); Octreotide (39.3%); Chemotherapy (32.1%); Steroids (10.7%); Surgery (60.7%)5 y OS 81.8%
Albanese, G., 2022 [14]case report and review9563.8GI (62–85%)NETs NA
Isidori, A.M., 2002 [72]case series652.8Bronchial (50%), Ileum (16.6%), Unknown (33.3%)NENs (83.3%), NA (16.6%)External Beam Radiotherapy (16.6%), 200 mCi I[MIBG] (16.6%); Surgery (16.6%); Radiotherapy (33.3%); Chemotherapy (50%)OS 1 y (16.6%), FU 3 y (16.6%); FU 6 y (16.6%); NA (50%)
Matsuo, S., 2022 [73]case report171GINETSurgeryNA
Meinhardt A, 2022
[74]		case report147ExtrapulmonaryNECCisplatin/Etoposide, radiotherapyOS 1–2 y
Morland, D., 2022 [75]retrospective4NAGI (100%)NETs (100%)NANA
Ryan, T.G., 2022 [76]retrospective953Bowel (33%), kidney (22%) pancreas (11%)NETsChemotherapy and RadiotherapyDied after diagnosis
Shen, A., 2022
[10]		case series229.5GI (100%)NET (50%), SNEC (50%)Capecitabine/Temozolamide (50%); Cisplatin/Etoposide, radiotherapy, Topotecan, Paclitaxel and Nivolumab (50%)NA
Agrawal, S., 2023 [18]case report133Respiratory TractSNECChemotherapyNA
Woods, M.D., 2023 [77]case report179GIcarcinoidSomatostatin analogueOS 6 y
Zhang, Y.S., 2023 [27]case report170Without a systemic primary siteNECChemotherapyOS 1 mo
Abbreviations: NETs: neuroendocrine tumors; WD: well differentiated; NEC: neuroendocrine carcinoma; NENs: neuroendocrine neoplasms; SNEC: small-cell neuroendocrine carcinoma; GCC: global cell carcinoid; AC: atypical carcinoid; PRRT: peptide receptor radiolabeled therapy; NOS: no other specified; GI: gastrointestinal; OS: overall survival; y: year; mo: months; NA: not available; FU: follow-up; PFS: progression free survival
Table 2. Characteristics of patients with ocular primary NETs analyzed in the present study.
Table 2. Characteristics of patients with ocular primary NETs analyzed in the present study.
Study, YearAge/SexClinical PresentationExams at DiagnosisHistotypes
(WHO) *		Histological PatternLateralityTreatmentsOutcomes
Zimmerman et al., 1983 [16]71/FExophthalmos; loss of vision5-HIAA levels; CT scanCarcinoid
1/70 HPF		Mixture of basaloid, trabecular, tubular and rosetted histologic patterns, positive argentaffin reaction, foci of PASS positive; Neurosecretory granulesRight OrbitNANA
El-Toukhy et al., 1996
[37]		45/MProptosis, increased tearing, painless swellingVisual field, CT scan; arteriogramCarcinoidPositive argentaffin and argyrophilic reactionsRight OrbitSurgery; radiation1976 first orbital tumor; 1979 orbital relapse; 1982 ileal carcinoid; 1986 orbital tumor
(pt alive in 1996)
OS 20 y
Mititelu et al., 2008
[26]		60/MCranial neuropathies, pupillary abnormalities, ptosis, ocular motility disturbanceMRI brain, MRI venography, MRI angiography, cerebral angiogram, CT chest/abdomen,
cerebrospinal fluid cytology		Poorly differentiated neuroendocrine carcinomaSynaptophysin, positive perinuclear distribution, negative for Cam 5.2, chromogranin, CD56, neuron-specific enolase, S100 protein, thyroid transcription factor-1Left OrbitSurgery and CT (CBDCA VP-16)OS 4 y (dead for meningitis spread)
Yang et al., 2011
[49]
  • 54/M
Proptosis, loss of vision, abdominal pain MRI imaging; best-corrected visual acuity (BCVA) Low grade carcinoid Ovoid monomorphic cells with “salt and pepper” chromatin and nucleoli Right Orbit Surgery NA
  • 59/M
 Proptosis BVCA, MRIPoorly differentiated carcinoma Epithelioid cells with pleomorphic nuclei Right Orbit Surgery + adjuvant radiotherapy (60 Gy in 30 fractions OS 5 y
  • 78/F **
AsyntomaticBVCA, MRIPoorly differentiatedCells with hyperchromatic, angulated, nuclei and scanty cytoplasm. Mitotic figures were readily found.Right OrbitSurgery + radiotherapyOS 3.5 y **
Atik et al., 2013
[20]		35/FPeriorbital pain, progressive swelling and blurred visionVisual acuity exam, MRI, CT scan,
PET		Small-cell neuroendocrine carcinoma (SCNEC)Small blue cells arranged in broad sheets, nests and
cords		Right OrbitCT (CCDP 5FU) followed by surgery, adjuvant CT CDDP-based + RTOS 2 y
Thyparampil et al., 2018 [27]64/FProptosis, orbital pain, eyelid swelling after several weeks of ipsilateral headachesMRI, chest/abdomen/pelvis CT scan,
octreoscan		WD-NET
(KI67 3–5%)		Cells with abundant cytoplasm, fine granular (salt and pepper) chromatin, rare mitosesRight OrbitSurgeryOS 1 y
Mittal et al., 2019
[19]		25/FPain, proptosis, swellingVisual acuity exam, CT scanSmall-cell neuroendocrine carcinoma
(Ki67 90%)		Small round blue cells with scant cytoplasm, and dense nuclei amidst necrotic debrisLeft OrbitSurgery + CT (CDDP VP-16) +RTOS 21 mo
Tan, H. et al.,
2020
[29]		48/FCushing’s syndromeACTH test, MRITypical Carcinoidpositive staining of ACTH, chromogranin A, Syn, PCK and
EMA		Left OrbitSurgeryNA
Agrawal et al., 2023
[18]		33/MProptosis, swellingPET-CT Ga-68, PET-CT 18-F,
MRI		High grade SCNECSmall round blue cells with scanty intervening stroma, abundant necrosis and apoptosisRight OrbitCT 6 cycles + RTNA
Jun, Y.Q.,
2023
[28]
  • 48/M
 ProptosisAbdominal CT and bone marrow evaluation Carcinoma (Ki67 80%) Poorly differentiated Right Orbit Surgery OS 3 mo
  • 82/F
Progressive mass on the lower eyelid Total body CT, bone marrow evaluation Carcinoma (Ki67 90%) Poorly differentiated Left Orbit Surgery OS 3 mo
  • 48/F
Cushing syndromeCortisol/ACTH levels, pituitary/orbital MRI, abdominal CTCarcinoidCarcinoidLeft Orbit SurgeryOS 4 y
Zhang, Y.S., 2023
[30]		70/Mpainless bilateral eyelid oedema and vertical diplopiaMRI, chest X-ray, Total body CT,
PET-CT 18-F		Carcinoma
(Ki67 70%)		Poorly differentiated high-grade neuroendocrine carcinomaRight OrbitCT
(CBDCA VP-16)		OS 1 mo
Arrivi et al., 2023
(our case)		77/FProptosis, loss of visionPET-CT Ga-68
PET-CT 18-F,
MRI, total body CT, CT Enterography
Visual acuity exam		WD-NET G2
(Ki-67 6%)		WD-NETRight OrbitLanreotide OS 3 y
Abbreviations: F: female; M: male; CT scan: Computed Tomography scan; OS: overall survival; NA: not available; HPF: high-power fields; 5-HIAA: 5-hydroxyindoleacetic acid; MRI: magnetic resonance imaging; pt/pts: patient/patients; Cam 5.2: low molecular weight cytokeratin; CT: chemotherapy; RT: radiotherapy; CBDCA: carboplatin; VP-16: etoposide; PET-CT: positron emission tomography/computed tomography; CCDP: cisplatin; 5FU:5 fluorouracil; WD-NET: well-differentiated neuroendocrine neoplasia; G: grading. * WHO Classification was reported according to paper’s publication year. ** pt developed a colon neuroendocrine tumor one-year post orbitotomy.

5. Discussion

In the natural history of neoplasms of any origin and histological type, ocular involvement is a rare occurrence. This finding is even more uncommon in NENs, which account for about 14–15% of all orbital metastatic disease [6,7], mainly involving the uvea, the orbital cavity, and the extraocular muscles [13,14,78].
Ocular metastases, with no substantial gender predominance, occur mostly in GI-NENs (range 62–69%) and in the lung (range 7–23%), but primary testicular/ovarian, breast, and renal tumors are also described in the literature [13,14].
Although several reviews and cases in the literature have been published about neuroendocrine orbital metastases [13,14,34,57], the management of NENs ocular metastases still appears difficult and not well defined by algorithms and guidelines. Even more unexplored is the issue of primary orbital NENs, and according to our knowledge, this is the first systematic review to focus on primary orbital NENs and present a proposal for diagnostic and therapeutic work-up in the ENETs CoE.
Only 15 cases of primary orbital NENs, excluding our case, have been described in the literature since the 1980s. The median age at diagnosis was 56.5 years (range 25–82), with a slight prevalence of female sex and right orbit involvement. Unlike what was observed for metastatic sites—12.5% of metastases are bilateral [13]—no ocular bilateral involvement was described in primary tumors. Only one case showed an initial involvement of the right eye, a subsequent involvement of homolateral cervical nodes, and further disease progression with tumor spread in the contralateral left orbit [20].
The clinical presentation is often characterized by a progressive orbital mass with proptosis, swelling, and visual disturbances such as diplopia, unilateral blindness, and blurry vision, while only a few cases are associated with pain and neurological symptoms such as headaches or neuropathy [26,27]. A small number of orbital primary neoplasms can secrete hormones, leading to carcinoid syndrome with the ectopic release of adrenocorticotropic hormone (ACTH) [28,29]. Therefore, although Cushing’s Syndrome is mainly associated with neuroendocrine lung cancers [79,80], it should be taken account of as an uncommon but described clinical occurrence of this rare NEN localization. The diagnosis of Cushing’s syndrome is important but challenging, and a complete physical examination to identify alopecia, skin pigmentation, moon face, central obesity, multiple purple striae on the abdomen, scattered bruises, and proximal muscle weakness could help the physician achieve a timely differential diagnosis. We propose that the algorithm used to diagnose Cushing’s Syndrome is proceeded with in cases of suggestive symptoms [81].
The 5-hydroxyindolacetic acid (5-HIAA) urinary levels of patients should be evaluated in the presence of chronic diarrhea, flushing, and/or bronchospasm, even though the classic form of carcinoid syndrome was not described in orbital NENs; however, it was predominantly encountered in patients with WD-NENs of intestinal origin and lung NETs [82].
Blood tests and neurological examinations with assessments of peripheral and central nerve function can be useful to exclude endocrinological or neurological disorders. In cases of visual disturbances, an ophthalmologist consultation with visual acuity and visual field tests should be pursued. Given the limited accuracy of physical or ophthalmologic examination findings for a differential diagnosis, facial and brain MRI or CT scans should be mandatory in the diagnostic work-up of orbital NENs. Metastatic lesions appear as well-circumscribed, fusiform, or round masses in extra-ocular muscle, do not show uniform hypervascularity on MRI and have both homogeneous and heterogeneous density on CT scans [47,76]. Instead, primary orbital NENs show highly variable imaging characteristics such as intense enhancement [18,20,29] or heterogeneous aspects, with patchy or mild enhancement on MRI [26,49]. It must be considered that MRI is superior to CT for the imaging of the bones and the brain [83,84]; therefore, it may be advisable to use MRI when orbital NENs are suspected. To exclude a different primary site than the orbit, a CT scan of the abdomen and thorax is suggested. Given that the majority of orbital localizations originate from primary intestinal NENs [13,70], the use of CT enterography (CTE) or MR enterography (MRE) can be useful to detect small bowel lesions, especially if the signs and symptoms of carcinoid syndrome are noted [85,86]. El-Toukhy described a case of orbital carcinoid with several local recurrences that was diagnosed six years before the detection of ileal NEN. This case suggests the possibility that the orbital NEN was not the primary neoplasm, but rather the metastasis of an occult small intestine tumor [37]. For this reason, we advise integrating CTE, MRE or functional methods in the diagnostic work-up of these NENs from the first diagnosis.
The sensitivity required to detect NENs by 68-Ga somatostatin analogs PET/CT is 92% (range 64–100%) and the specificity is 95% (range 83–100%) [87]. Indeed, 68-Ga PET/CT could help to detect additional or unknown lesions compared to conventional radiological methods such as CT or MRI [62,83,88] and play a central role in therapy selection, identifying patients eligible for peptide receptor radionuclide therapy and monitoring their response to treatment [89,90]. The use of (F-18) FDG PET/CT, due to its prognostic role and according to guidelines [84], is optional and suggested in G2/G3 NETs, which generally have a higher glucose metabolism and a lower somatostatin receptor expression [91,92,93]; meanwhile, it represents the main functional method used for investigation in the study of NECs [83]. When using functional imaging techniques in the diagnostic work-up of orbital NENs, we must consider that somatostatin receptors are expressed in several normal human tissues, including the brain [94,95,96], and that (F-18) FDG is accumulated in the brain with a very high uptake. Despite the use of PET/CT, as recommended by European guidelines from 2017 [83], only three patients, including our case [18,30], underwent functional studies, and only two underwent double-tracer PET/CT.
The histopathological analysis of tissue samples remains the gold standard for diagnosis and can be performed through incisional biopsy or the surgery of the whole lesion if resectable. The histomorphological growth pattern and cytology evidenced on hematoxylin eosin (HE)-stained tissue suggest the diagnosis of NENs, but the neuroendocrine phenotype is proven by the immunohistochemical detection of the neuroendocrine markers synaptophysin and chromogranin A [84]. A comprehensive immunohistochemical analysis for transcription factors is very helpful in the identification of tumor differentiation and the site of origin of a metastatic tumor [97]. Furthermore, considering the strict correlation between the correct pathological diagnosis of NENs and the pathologist’s expertise, a central pathology review is always recommended when feasible. The most represented pathologic features of primary orbital neoplasms are those of poorly differentiated neuroendocrine carcinomas (n = 9); meanwhile, only two cases were described as well-differentiated NETs, and the other five cases were reported with a generic term of “carcinoid”. Over time, there has been an evolution of the nomenclature in NEN classification [97], so we must carefully consider the histopathological definitions of the cases, especially due to the different times of publication and the lack of a central pathology review. Despite the low strength of evidence in the literature in this field, a proposal of the diagnostic algorithm to be used if a primary orbital NEN is suspected is presented in Figure 6.
The combination of histopathological characteristics and functional imaging represents the possibility of acquiring a more comprehensive understanding of individual patients’ disease biology and prognostic aspects, leading to a proper diagnostic and therapeutic algorithm. In this field, a dedicated MDT appears crucial in ensuring the quality of the clinical management of NENs [98]. Therapeutic decision making should always be discussed with the components of the MDT, and even more so in these rare primary site tumors.
The backbone of therapeutic management has been surgery since the first cases were reported in 1996; meanwhile, subsequent or concomitant treatments have been proposed according to histology. Surgery should be always offered in resectable disease, irrespective of histology, although retrospective series indicate that it is rarely curative alone in NECs [99]. Given the high risk of relapse, adjuvant platinum-based chemotherapy or radiotherapy could be considered. Radiotherapy should also be proposed in localized unresectable disease with or without chemotherapy, or lastly as palliative treatment for the control of symptoms. Although some patients have been treated with cytoreductive chemotherapy [18,20], currently, there are insufficient data to recommend this treatment. The management of advanced disease is currently based on evidence in the literature regarding gastrointestinal and lung NECs [100,101,102,103]; consequently, cisplatin or carboplatin plus etoposide represented the most commonly used chemotherapy regimen. Evidence for salvage therapy in patients progressing on first-line platinum-based chemotherapy is still lacking regarding orbital NECs; only in one case of relapse was intra-arterial chemotherapy used, with disease progression after three months [20]. In metastatic WD-NETs, the therapeutic decision making should be essentially based on the grading, functionality, somatostatin receptor status, tumor extent, and hepatic tumor burden if metastatic disease, and should refer to consensus guidelines [84,99,104].
The median OS of primary orbital NENs was 2.5 years (range: 1 month—20 years), and the outcome was not reported in four cases. This is except for one patient who presented with leptomeningeal spreading four years after the first diagnosis; the typical attitude of these neoplasms is of locoregional involvement with no distant metastases described. Currently, we are unable to produce a clear recommendation regarding follow up-management, but we suggest that clinical and radiological evaluations with MRI and PET/CT are performed for at least 5 years, according to national and international oncological guidelines [84,105,106].

6. Conclusions

Primary orbital NENs represent a rare disease, and the lack of comprehensive epidemiological and clinical–pathological data makes their management difficult. Due to this complexity, a multidisciplinary approach is widely encouraged in order to guarantee the best diagnostic and therapeutic work-up for our patients [107]. In this context, this review aims to be useful as a guide for our colleagues who are dealing with primary orbital neuroendocrine tumors, summarizing the most typical symptoms at diagnosis, with a focus on the diagnostic examinations that must be performed to promptly differentiate between orbital primary neoplasms and metastases.
Our case emphasizes the importance of early referral to NEN-dedicated centers and the important role of the MDT in prompt differential diagnosis; this would provide the patient with tailored treatment and an improvement in their quality of life and survival [108,109].

Author Contributions

Conceptualization, G.A.; methodology, G.A.; formal analysis, G.A. and M.S.; investigation, G.A. and M.S.; data curation, G.A.; writing—original draft preparation, G.A., M.S., C.S., E.P. and D.P.; writing—review and editing, G.A. and F.M.; visualization, E.P., M.R., D.C., C.S., D.P., A.M.A., F.P. and F.M.; supervision, F.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Informed Consent Statement

Written informed consent has been obtained from the patient to publish this paper.

Acknowledgments

The authors thank all the members of the neuroendocrine MDT of Sant ‘Andrea University Hospital, ENETS Center of Excellence, Rome, Italy.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Klimstra, D.S.; Modlin, I.R.; Coppola, D.; Lloyd, R.V.; Suster, S. The Pathologic Classification of Neuroendocrine Tumors: A Review of Nomenclature, Grading, and Staging Systems. Pancreas 2010, 39, 707–712. [Google Scholar] [CrossRef]
  2. Zheng, Z.; Chen, C.; Jiang, L.; Zhou, X.; Dai, X.; Song, Y.; Li, Y. Incidence and Risk Factors of Gastrointestinal Neuroendocrine Neoplasm Metastasis in Liver, Lung, Bone, and Brain: A Population-based Study. Cancer Med. 2019, 8, 7288–7298. [Google Scholar] [CrossRef] [PubMed]
  3. Seifter, E.J. Cancer: Principles and Practice of Oncology, 5th ed.; DeVita, V.T., Jr., Hellman, S., Rosenberg, S.A., Eds.; Lippincott-Raven Publishers, 1997.3125 pp., Illus. $199. ISBN 0-397-51573-4. JNCI J. Natl. Cancer Inst. 1997, 89, 353. [Google Scholar] [CrossRef]
  4. Pavel, M.; Grossman, A.; Arnold, R.; Perren, A.; Kaltsas, G.; Steinmüller, T.; De Herder, W.; Nikou, G.; Plöckinger, U.; Lopes, J.M.; et al. ENETS Consensus Guidelines for the Management of Brain, Cardiac and Ovarian Metastases from Neuroendocrine Tumors. Neuroendocrinology 2010, 91, 326–332. [Google Scholar] [CrossRef]
  5. Eliassi-Rad, B.; Albert, D.M.; Green, W.R. Frequency of Ocular Metastases in Patients Dying of Cancer in Eye Bank Populations. Br. J. Ophthalmol. 1996, 80, 125–128. [Google Scholar] [CrossRef] [PubMed]
  6. Leung, V.; Wei, M.; Roberts, T.V. Metastasis to the Extraocular Muscles: A Case Report, Literature Review and Pooled Data Analysis. Clin. Experiment. Ophthalmol. 2018, 46, 687–694. [Google Scholar] [CrossRef] [PubMed]
  7. Sira, M.; Clauss, R.P.; Maclean, C.; Rose, G.E. Orbital Metastases from Neuroendocrine Carcinoma, Masquerading as Graves Orbitopathy. Orbit 2010, 29, 94–96. [Google Scholar] [CrossRef]
  8. Shetlar, D.J.; Font, R.L.; Ordóñez, N.; El-Naggar, A.; Boniuk, M. A Clinicopathologic Study of Three Carcinoid Tumors Metastatic to the Orbit. Ophthalmology 1990, 97, 257–264. [Google Scholar] [CrossRef]
  9. Fan, J.T.; Buettner, H.; Bartley, G.B.; Bolling, J.P. Clinical Features and Treatment of Seven Patients with Carcinoid Tumor Metastatic to the Eye and Orbit. Am. J. Ophthalmol. 1995, 119, 211–218. [Google Scholar] [CrossRef]
  10. Shen, A.; Haghighi, A.; Liang, T.; Lee, O.-T.; Gange, W.; DeBoer, C.; Akhter, M.; Saber, M.S.; Patel, V.R.; Berry, J.L.; et al. Metastatic Neuroendocrine Tumors Mimicking as Primary Ocular Disease. Am. J. Ophthalmol. Case Rep. 2022, 26, 101425. [Google Scholar] [CrossRef]
  11. Mehta, J.S.; Abou-Rayyah, Y.; Rose, G.E. Orbital Carcinoid Metastases. Ophthalmology 2006, 113, 466–472. [Google Scholar] [CrossRef]
  12. Demirci, H.; Shields, C.L.; Chao, A.-N.; Shields, J.A. Uveal Metastasis from Breast Cancer in 264 Patients. Am. J. Ophthalmol. 2003, 136, 264–271. [Google Scholar] [CrossRef]
  13. La Salvia, A.; Persano, I.; Trevisi, E.; Parlagreco, E.; Muratori, L.; Scagliotti, G.V.; Brizzi, M.P. Ocular Metastases from Neuroendocrine Tumors: A Literature Review. Semin. Oncol. 2020, 47, 144–147. [Google Scholar] [CrossRef] [PubMed]
  14. Albanese, G.; Harieaswar, S.; Sampath, R. Orbital Metastasis from Neuroendocrine Tumour: Case Report and Literature Review. Eur. J. Ophthalmol. 2022, 32, 2498–2504. [Google Scholar] [CrossRef] [PubMed]
  15. Shields, J.A.; Shields, C.L.; Brotman, H.K.; Carvalho, C.; Perez, N.; Eagle, R.C. Cancer Metastatic to the Orbit: The 2000 Robert M. Curts Lecture. Ophthal. Plast. Reconstr. Surg. 2001, 17, 346–354. [Google Scholar] [CrossRef]
  16. Zimmerman, L.E. Primary Carcinoid Tumor of the Orbit: A Clinicopathologic Study with Histochemical and Electron Microscopic Observations. Arch. Ophthalmol. 1983, 101, 1395. [Google Scholar] [CrossRef] [PubMed]
  17. Riddle, P.J.; Font, R.L.; Zimmerman, L.E. Carcinoid Tumors of the Eyeand Orbit: A Clinicopathologic Study of 15 Cases, with Histochemical and Electron Microscopic Observations. Hum. Pathol. 1982, 13, 459–469. [Google Scholar] [CrossRef] [PubMed]
  18. 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. [Google Scholar] [CrossRef]
  19. 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, 308–311. [Google Scholar] [CrossRef]
  20. Atik, A.; Krilis, M.; Shannon, K. Small Cell Neuroendocrine Carcinoma Masquerading as Cellulitis and Causing Blindness via Bilateral Orbital Involvement. Orbit 2013, 32, 197–199. [Google Scholar] [CrossRef]
  21. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G.; for the PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. BMJ 2009, 339, b2535. [Google Scholar] [CrossRef] [PubMed]
  22. Organisation Mondiale de la Santé e Centre International de Recherche sur le Cancer. Digestive system tumours. In World Health Organization Classification of Tumours, No. 1, 5th ed.; International Agency for Research on Cancer: Lyon, France, 2019. [Google Scholar]
  23. Rindi, G.; Klimstra, D.S.; Abedi-Ardekani, B.; Asa, S.L.; Bosman, F.T.; Brambilla, E.; Busam, K.J.; De Krijger, R.R.; Dietel, M.; El-Naggar, A.K.; et al. A common classification framework for neuroendocrine neoplasms: An International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod. Pathol. 2018, 31, 1770–1786. [Google Scholar] [CrossRef] [PubMed]
  24. Zee, S.Y.; Hochwald, S.N.; Conlon, K.C.; Brennan, M.F.; Klimstra, D.S. Pleomorphic Pancreatic Endocrine Neoplasms: A Variant Commonly Confused with Adenocarcinoma. Am. J. Surg. Pathol. 2005, 29, 1194–1200. [Google Scholar] [CrossRef] [PubMed]
  25. Koo, J.; Mertens, R.B.; Mirocha, J.M.; Wang, H.L.; Dhall, D. Value of Islet 1 and PAX8 in identifying metastatic neuroendocrine tumors of pancreatic origin. Mod. Pathol. 2012, 25, 893–901. [Google Scholar] [CrossRef]
  26. Mititelu, M.; Stanton, C.A.; Yeatts, R.P. Primary Neuroendocrine Tumor of the Orbit Progressing to Neoplastic Meningitis. Ophthal. Plast. Reconstr. Surg. 2008, 24, 231–233. [Google Scholar] [CrossRef] [PubMed]
  27. Thyparampil, P.J.; Yen, M.T.; Dhingra, S.; Shetlar, D.J.; Zarrin-Khameh, N.; Musher, B.L. Primary Neuroendocrine Tumor of the Orbit Presenting with Acute Proptosis. Ophthal. Plast. Reconstr. Surg. 2018, 34, e17–e19. [Google Scholar] [CrossRef] [PubMed]
  28. Qiao, J.; Wang, Y.; He, W. Neuroendocrine Neoplasms of the Orbit: Report of Three Cases and a Literature Review. J. Int. Med. Res. 2023, 51, 03000605231199762. [Google Scholar] [CrossRef]
  29. Tan, H.; Chen, D.; Yu, Y.; Yu, K.; He, W.; Cai, B.; Jiang, S.; Tang, Y.; Tong, N.; An, Z. Unusual Ectopic ACTH Syndrome in a Patient with Orbital Neuroendocrine Tumor, Resulted False-Positive Outcome of BIPSS: A Case Report. BMC Endocr. Disord. 2020, 20, 116. [Google Scholar] [CrossRef]
  30. Zhang, Y.S.; Jiro, M.; Pekmezci, M.; Winn, B. Poorly Differentiated Orbital Neuroendocrine Carcinoma. BMJ Case Rep. 2023, 16, e254844. [Google Scholar] [CrossRef]
  31. Font, R.L.; Kaufer, G.; Winstanley, R.A. Metastasis of Bronchial Carcinoid Tumor to the Eye. Am. J. Ophthalmol. 1966, 62, 723–727. [Google Scholar] [CrossRef]
  32. Rush, J.A.; Waller, R.R.; Campbell, R.J. Orbital Carcinoid Tumor Metastatic from the Colon. Am. J. Ophthalmol. 1980, 89, 636–640. [Google Scholar] [CrossRef] [PubMed]
  33. Harris, A.L.; Montgomery, A.; Reyes, R.R.; Gazet, J.C.; Smith, I.E. Carcinoid Tumour Presenting as an Orbital Metastasis. Clin. Oncol. 1981, 7, 365–372. [Google Scholar] [PubMed]
  34. Harris, G.J.; Urdaneta, L.F.; Mitros, F.A. Gastrointestinal Carcinoid Tumor Metastatic to the Orbit. South Med. J. 1989, 82, 1549–1551. [Google Scholar] [CrossRef] [PubMed]
  35. Nida, T.Y.; Hall, W.A.; Glantz, M.J.; Clark, H.B. Metastatic Carcinoid Tumor to the Orbit and Brain. Neurosurgery 1992, 31, 949–954. [Google Scholar] [CrossRef] [PubMed]
  36. Aburn, N.S.; Whitehead, K.; Sullivan, T.J. Bronchopulmonary Atypical Carcinoid Tumour Metastatic to the Orbit. Aust. N. Z. J. Ophthalmol. 1995, 23, 241–244. [Google Scholar] [CrossRef] [PubMed]
  37. El-Toukhy, E.; Levine, M.R.; Abdul-Karim, F.W.; Larson, D.W. Carcinoid Tumors of the Orbit: A Dilemma of Diagnosis and Treatment. Ophthal. Plast. Reconstr. Surg. 1996, 12, 279–283. [Google Scholar] [CrossRef]
  38. Hanson, M.W.; Schneider, A.M.; Enterline, D.S.; Feldman, J.M.; Gockerman, J.P. Iodine-131-Metaiodobenzylguanidine Uptake in Metastatic Carcinoid Tumor to the Orbit. J. Nucl. Med. Off. Publ. Soc. Nucl. Med. 1998, 39, 647–650. [Google Scholar]
  39. Couch, D.A.; O’Halloran, H.S.; Hainsworth, K.M.; Cowen, D.E.; Baker, R.S. Carcinoid Metastasis to Extraocular Muscles: Case Reports and Review of the Literature. Orbit 2000, 19, 263–269. [Google Scholar] [CrossRef]
  40. Khaw, P.; Ball, D.; Duchesne, G. Carcinoid Tumour of the Orbital Muscles: A Rare Occurrence. Australas. Radiol. 2001, 45, 179–181. [Google Scholar] [CrossRef]
  41. Takemoto, Y.; Nishida, N.; Kojiro, S.; Jimi, A.; Kojiro, M. Metastatic Carcinoid Tumor in the Orbit. Kurume Med. J. 2003, 50, 165–167. [Google Scholar] [CrossRef]
  42. Sivagnanavel, V.; Riordan-Eva, P.; Jarosz, J.; Portmann, B.; Buxton-Thomas, M. Bilateral Orbital Metastases from a Neuroendocrine Tumor. J. Neuroophthalmol. 2004, 24, 240–242. [Google Scholar] [CrossRef]
  43. Borota, O.C.; Kloster, R.; Lindal, S. Carcinoid Tumour Metastatic to the Orbit with Infiltration to the Extraocular Orbital Muscle: Case Report. APMIS 2005, 113, 135–139. [Google Scholar] [CrossRef] [PubMed]
  44. Kiratli, H.; Yilmaz, P.T.; Yildiz, Z.I. Metastatic Atypical Carcinoid Tumor of the Inferior Rectus Muscle. Ophthal. Plast. Reconstr. Surg. 2008, 24, 482–484. [Google Scholar] [CrossRef] [PubMed]
  45. Bohman, E.; Sahlin, S.; Seregard, S. Carcinoid Presenting as Extrinsic Eye Muscle Metastasis. Acta Ophthalmol. 2009, 87, 916–917. [Google Scholar] [CrossRef] [PubMed]
  46. Matsuo, T.; Ichimura, K.; Tanaka, T.; Takenaka, T.; Nakayama, T. Neuroendocrine Tumor (Carcinoid) Metastatic to Orbital Extraocular Muscle: Case Report and Literature Review. Strabismus 2010, 18, 123–128. [Google Scholar] [CrossRef] [PubMed]
  47. Gupta, A.; Chazen, J.L.; Phillips, C.D. Carcinoid Tumor Metastases to the Extraocular Muscles: MR Imaging and CT Findings and Review of the Literature. Am. J. Neuroradiol. 2011, 32, 1208–1211. [Google Scholar] [CrossRef] [PubMed]
  48. Turaka, K.; Mashayekhi, A.; Shields, C.; Lally, S.; Kligman, B.; Shields, J. A Case Series of Neuroendocrine (Carcinoid) Tumor Metastasis to the Orbit. Oman J. Ophthalmol. 2011, 4, 125. [Google Scholar] [CrossRef] [PubMed]
  49. Yang, M.; Loh, A.; Seah, L.L.; Jajeh, I.A.; Looi, A. Neuroendocrine Tumors of the Orbit—Clinicopathological Findings in 3 More Cases of This Rare Entity and Review of the Literature. Orbit 2011, 30, 145–149. [Google Scholar] [CrossRef] [PubMed]
  50. Mehta, P.; Malik, S.; Adesanya, O.; Snead, D.; Ahluwalia, H. Orbital Carcinoid Metastasis: Diverse Presentations and Value of Indium-Octreotide Imaging. Orbit 2012, 31, 379–382. [Google Scholar] [CrossRef]
  51. Dobson, R.; Vinjamuri, S.; Hsuan, J.; Banks, M.; Terlizzo, M.; Wieshmann, H.; Daousi, C.; Poston, G.P.; Cuthbertson, D.J. Treatment of Orbital Metastases from a Primary Midgut Neuroendocrine Tumor with Peptide-Receptor Radiolabeled Therapy Using 177 Lutetium-DOTATATE. J. Clin. Oncol. 2013, 31, e272–e275. [Google Scholar] [CrossRef]
  52. Peixoto, R.D. Neuroendocrine Tumor Metastatic to the Orbit Treated with Radiotherapy. World J. Gastrointest. Oncol. 2013, 5, 177. [Google Scholar] [CrossRef] [PubMed]
  53. Kiratli, H.; Uzun, S.; Tarlan, B.; Ateş, D.; Baydar, D.E.; Söylemezoğlu, F. Renal Carcinoid Tumor Metastatic to the Uvea, Medial Rectus Muscle, and the Contralateral Lacrimal Gland. Ophthal. Plast. Reconstr. Surg. 2015, 31, e91–e93. [Google Scholar] [CrossRef] [PubMed]
  54. MacIntosh, P.W.; Jakobiec, F.A.; Stagner, A.M.; Gilani, S.; Fay, A. High Grade Neuroendocrine Neoplasm of the Antrum and Orbit. Surv. Ophthalmol. 2015, 60, 486–494. [Google Scholar] [CrossRef] [PubMed]
  55. Parikh, D.; Shinder, R. Primary Renal Carcinoid Metastatic to the Orbit. Ophthal. Plast. Reconstr. Surg. 2015, 31, e37–e38. [Google Scholar] [CrossRef] [PubMed]
  56. Makis, W.; McCann, K.; McEwan, A.J.B. Orbital Metastases of Neuroendocrine Tumors Treated with 177Lu-DOTATATE PRRT or 131I-MIBG Therapies. Clin. Nucl. Med. 2016, 41, 137–141. [Google Scholar] [CrossRef] [PubMed]
  57. Matějka, V.M.; Mukenšnabl, P.; Tupý, R.; Fiala, O.; Fínek, J. Carcinoid of the Appendix Goblet Cells Metastasize to the Orbit—A Clinical Case Report and Review of the Literature. Klin. Onkol. 2016, 29, 220–223. [Google Scholar] [CrossRef] [PubMed]
  58. Ruiz, J.-B.; Orré, M.; Cazeau, A.-L.; De Figueiredo, B.H.; Godbert, Y. 18F-DOPA PET/CT in Orbital Metastasis from Medullary Thyroid Carcinoma. Clin. Nucl. Med. 2016, 41, e296–e297. [Google Scholar] [CrossRef]
  59. Warren, C.C.; Liao, J.C.; Griepentrog, G.J. Bilateral Extraocular Muscle Metastases from a Gastrointestinal Carcinoid Tumor. JAMA Ophthalmol. 2016, 134, e153651. [Google Scholar] [CrossRef]
  60. Kamaleshwaran, K.; Joseph, J.; Upadhya, I.; Shinto, A. Image Findings of a Rare Case of Neuroendocrine Tumor Metastatic to Orbital Extraocular Muscle in Gallium-68 DOTANOC Positron Emission Tomography/Computed Tomography and Therapy with Lutetium-177 DOTATATE. Indian J. Nucl. Med. 2017, 32, 125. [Google Scholar] [CrossRef]
  61. Chen, Y.J.; Farwell, M.D. Incidental Orbital Neuroendocrine Metastases on 111In-OctreoScan and MRI. Clin. Nucl. Med. 2018, 43, 864–866. [Google Scholar] [CrossRef]
  62. Das, S.; Pineda, G.; Goff, L.; Sobel, R.; Berlin, J.; Fisher, G. The Eye of the Beholder: Orbital Metastases from Midgut Neuroendocrine Tumors, a Two Institution Experience. Cancer Imaging 2018, 18, 47. [Google Scholar] [CrossRef]
  63. Guo, Y.; Shao, C.; Blau, T.; Tannapfel, A.; Koch, K.R.; Heindl, L.M. Ocular Metastasis of Bronchial Typical Carcinoid. J. Thorac. Oncol. 2018, 13, 1422–1423. [Google Scholar] [CrossRef] [PubMed]
  64. Rasmussen, J.Ø.; Von Holstein, S.L.; Prause, J.U.; Vainer, B.; Hansen, A.B.; Fehr, A.; Stenman, G.; Heegaard, S. Genetic Analysis of an Orbital Metastasis from a Primary Hepatic Neuroendocrine Carcinoma. Oncol. Rep. 2014, 32, 1447–1450. [Google Scholar] [CrossRef] [PubMed]
  65. Beam, A.S.; Moore, K.G.; Stephens, C.P.; West, S.J.; Barfield, J.; Dean, C.; Eldridge, T.; Green, J.; Vijayakumar, V. Rare Orbital Metastasis Originating from a Neuroendocrine Tumor. Radiol. Technol. 2019, 91, 112–119. [Google Scholar] [PubMed]
  66. Hafiz, A.A.; Ali, S.M.; Sidahmed, S.M.; Al-Hassan, A.; El-Naggar, N.M.M. Mid-Gut Carcinoid Tumour Presenting as Suspected Orbital Metastasis. Sultan Qaboos Univ. Med. J. SQUMJ 2019, 19, 253. [Google Scholar] [CrossRef] [PubMed]
  67. Kozubowska, K.; Skorek, A.; Pęksa, R. Neuroendocrine Tumour Metastasis to the Orbit. Endokrynol. Pol. 2019, 70, 455–456. [Google Scholar] [CrossRef] [PubMed]
  68. Parghane, R.V.; Basu, S. Bilateral Orbital Soft-Tissue Metastases from Renal Neuroendocrine Tumor: Successful Theranostic Application of 68 Ga/177 Lu-DOTATATE with Improvement of Vision. J. Nucl. Med. Technol. 2019, 47, 171–172. [Google Scholar] [CrossRef] [PubMed]
  69. Bacorn, C.; Kim, E.; Borowsky, A.D.; Lin, L.K. Previously Undiagnosed Neuroendocrine Tumour Mimicking Breast Cancer Metastasis to the Orbit. BMJ Case Rep. 2020, 13, e234629. [Google Scholar] [CrossRef] [PubMed]
  70. Kamieniarz, L.; Armeni, E.; O’Mahony, L.F.; Leigh, C.; Miah, L.; Narayan, A.; Bhatt, A.; Cox, N.; Mandair, D.; Navalkissoor, S.; et al. Orbital Metastases from Neuroendocrine Neoplasms: Clinical Implications and Outcomes. Endocrine 2020, 67, 485–493. [Google Scholar] [CrossRef]
  71. Mustak, H.; Liu, W.; Murta, F.; Ozgur, O.; Couch, S.; Garrity, J.; Shinder, R.; Kazim, M.; Callahan, A.; Hayek, B.; et al. Carcinoid Tumors of the Orbit and Ocular Adnexa. Ophthal. Plast. Reconstr. Surg. 2021, 37, 217–225. [Google Scholar] [CrossRef]
  72. Isidori, A.M.; Kaltsas, G.; Frajese, V.; Kola, B.; Whitelocke, R.A.F.; Plowman, P.N.; Britton, K.E.; Monson, J.P.; Grossman, A.B.; Besser, G.M. Ocular Metastases Secondary to Carcinoid Tumors: The Utility of Imaging with [123I]Meta-Iodobenzylguanidine and [111In]DTPA Pentetreotide. J. Clin. Endocrinol. Metab. 2002, 87, 1627–1633. [Google Scholar] [CrossRef] [PubMed]
  73. Matsuo, S.; Amano, T.; Miyamatsu, Y.; Hayashi, D.; Yamashita, S.; Momosaki, S.; Kawabe, K.; Nakamizo, A. Discrepancy in the Ki67 Labeling Index of Brain and Orbital Metastatic Lesions from Gastrointestinal Neuroendocrine Tumors: A Case Report. Neurocir. Engl. Ed. 2022, 33, 345–349. [Google Scholar] [CrossRef]
  74. Meinhardt, A.-L.; Uppuluri, A.; Shkolnik, E.; Chang, V.T. Extrapulmonary Small Cell Carcinoma Presenting as an Orbital Mass: A Case Report. Cureus 2022, 14, e26012. [Google Scholar] [CrossRef] [PubMed]
  75. Morland, D.; Jallet, L.; Deguelte, S.; Cadiot, G.; Papathanassiou, D. Orbital Metastasis: A Rare but Typical Location of Small Intestine Neuroendocrine Tumor on 18F-FDOPA PET/CT. Clin. Nucl. Med. 2022, 47, 717–718. [Google Scholar] [CrossRef] [PubMed]
  76. Ryan, T.G.; Juniat, V.; Stewart, C.; Malhotra, R.; Hardy, T.G.; McNab, A.A.; Davis, G.; Selva, D. Clinico-Radiological Findings of Neuroendocrine Tumour Metastases to the Orbit. Orbit 2022, 41, 44–52. [Google Scholar] [CrossRef]
  77. Woods, M.D.; Afkhamnejad, E.; Pakravan, M.; Charoenkijkajorn, C.; Lee, A.G. Optic Neuropathy as the Presenting Manifestation of Carcinoid. Can. J. Ophthalmol. 2023, 58, e255–e257. [Google Scholar] [CrossRef] [PubMed]
  78. Roth, M. Eyelid, Conjunctival, and Orbital Tumors: An Atlas and Textbook. Clin. Exp. Optom. 2018, 101, 618–619. [Google Scholar] [CrossRef]
  79. Ilias, I.; Torpy, D.J.; Pacak, K.; Mullen, N.; Wesley, R.A.; Nieman, L.K. Cushing’s Syndrome Due to Ectopic Corticotropin Secretion: Twenty Years’ Experience at the National Institutes of Health. J. Clin. Endocrinol. Metab. 2005, 90, 4955–4962. [Google Scholar] [CrossRef]
  80. Morton, A. Ectopic Adrenocorticotropin Syndrome. Intern. Med. J. 2017, 47, 1328–1329. [Google Scholar] [CrossRef]
  81. Fleseriu, M.; Auchus, R.; Bancos, I.; Ben-Shlomo, A.; Bertherat, J.; Biermasz, N.R.; Boguszewski, C.L.; Bronstein, M.D.; Buchfelder, M.; Carmichael, J.D.; et al. Consensus on Diagnosis and Management of Cushing’s Disease: A Guideline Update. Lancet Diabetes Endocrinol. 2021, 9, 847–875. [Google Scholar] [CrossRef]
  82. Grozinsky-Glasberg, S.; Davar, J.; Hofland, J.; Dobson, R.; Prasad, V.; Pascher, A.; Denecke, T.; Tesselaar, M.E.T.; Panzuto, F.; Albåge, A.; et al. European Neuroendocrine Tumor Society (ENETS) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease. J. Neuroendocrinol. 2022, 34, e13146. [Google Scholar] [CrossRef] [PubMed]
  83. Sundin, A.; Arnold, R.; Baudin, E.; Cwikla, J.B.; Eriksson, B.; Fanti, S.; Fazio, N.; Giammarile, F.; Hicks, R.J.; Kjaer, A.; et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Radiological, Nuclear Medicine and Hybrid Imaging. Neuroendocrinology 2017, 105, 212–244. [Google Scholar] [CrossRef]
  84. Pavel, M.; Öberg, K.; Falconi, M.; Krenning, E.P.; Sundin, A.; Perren, A.; Berruti, A. Gastroenteropancreatic Neuroendocrine Neoplasms: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up. Ann. Oncol. 2020, 31, 844–860. [Google Scholar] [CrossRef] [PubMed]
  85. Martin, S.; Iravani, A.; Shetty, A.S.; Zulfiqar, M.; Morani, A.; Yano, M.; Bhosale, P.R.; Itani, M. Neuroendocrine Neoplasm Imaging: Protocols by Site of Origin. Abdom. Radiol. 2022, 47, 4081–4095. [Google Scholar] [CrossRef]
  86. Vlachou, E.; Koffas, A.; Toumpanakis, C.; Keuchel, M. Updates in the Diagnosis and Management of Small-Bowel Tumors. Best Pract. Res. Clin. Gastroenterol. 2023, 64–65, 101860. [Google Scholar] [CrossRef] [PubMed]
  87. Geijer, H.; Breimer, L.H. Somatostatin Receptor PET/CT in Neuroendocrine Tumours: Update on Systematic Review and Meta-Analysis. Eur. J. Nucl. Med. Mol. Imaging 2013, 40, 1770–1780. [Google Scholar] [CrossRef] [PubMed]
  88. Chen, D.; Yang, S.; Chen, J.; Li, T.; Liu, Y.; Zhao, X.; Zhang, T.; Xu, M.; Wang, H.; Zhao, K.; et al. Comparison of [18F]-OC PET/CT and Contrast-Enhanced CT/MRI in the Detection and Evaluation of Neuroendocrine Neoplasms. Eur. J. Nucl. Med. Mol. Imaging 2023, 50, 2420–2431. [Google Scholar] [CrossRef]
  89. Bozkurt, M.F.; Virgolini, I.; Balogova, S.; Beheshti, M.; Rubello, D.; Decristoforo, C.; Ambrosini, V.; Kjaer, A.; Delgado-Bolton, R.; Kunikowska, J.; et al. Guideline for PET/CT Imaging of Neuroendocrine Neoplasms with 68Ga-DOTA-Conjugated Somatostatin Receptor Targeting Peptides and 18F–DOPA. Eur. J. Nucl. Med. Mol. Imaging 2017, 44, 1588–1601. [Google Scholar] [CrossRef]
  90. Sadowski, S.M.; Neychev, V.; Millo, C.; Shih, J.; Nilubol, N.; Herscovitch, P.; Pacak, K.; Marx, S.J.; Kebebew, E. Prospective Study of 68 Ga-DOTATATE Positron Emission Tomography/Computed Tomography for Detecting Gastro-Entero-Pancreatic Neuroendocrine Tumors and Unknown Primary Sites. J. Clin. Oncol. 2016, 34, 588–596. [Google Scholar] [CrossRef]
  91. Binderup, T.; Knigge, U.; Loft, A.; Federspiel, B.; Kjaer, A. 18F-Fluorodeoxyglucose Positron Emission Tomography Predicts Survival of Patients with Neuroendocrine Tumors. Clin. Cancer Res. 2010, 16, 978–985. [Google Scholar] [CrossRef]
  92. Simsek, D.H.; Kuyumcu, S.; Turkmen, C.; Sanlı, Y.; Aykan, F.; Unal, S.; Adalet, I. Can Complementary 68 Ga-DOTATATE and 18 F-FDG PET/CT Establish the Missing Link Between Histopathology and Therapeutic Approach in Gastroenteropancreatic Neuroendocrine Tumors? J. Nucl. Med. 2014, 55, 1811–1817. [Google Scholar] [CrossRef] [PubMed]
  93. Naswa, N.; Sharma, P.; Gupta, S.K.; Karunanithi, S.; Reddy, R.M.; Patnecha, M.; Lata, S.; Kumar, R.; Malhotra, A.; Bal, C. Dual Tracer Functional Imaging of Gastroenteropancreatic Neuroendocrine Tumors Using 68Ga-DOTA-NOC PET-CT and 18F-FDG PET-CT: Competitive or Complimentary? Clin. Nucl. Med. 2014, 39, e27–e34. [Google Scholar] [CrossRef] [PubMed]
  94. Reubi, J.C.; Horisberger, U.; Waser, B.; Gebbers, J.O.; Laissue, J. Preferential Location of Somatostatin Receptors in Germinal Centers of Human Gut Lymphoid Tissue. Gastroenterology 1992, 103, 1207–1214. [Google Scholar] [CrossRef] [PubMed]
  95. Reubi, J.C.; Schaer, J.C.; Markwalder, R.; Waser, B.; Horisberger, U.; Laissue, J. Distribution of Somatostatin Receptors in Normal and Neoplastic Human Tissues: Recent Advances and Potential Relevance. Yale J. Biol. Med. 1997, 70, 471–479. [Google Scholar] [PubMed]
  96. Csaba, Z.; Dournaud, P. Cellular Biology of Somatostatin Receptors. Neuropeptides 2001, 35, 1–23. [Google Scholar] [CrossRef] [PubMed]
  97. Rindi, G.; Mete, O.; Uccella, S.; Basturk, O.; La Rosa, S.; Brosens, L.A.A.; Ezzat, S.; De Herder, W.W.; Klimstra, D.S.; Papotti, M.; et al. Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms. Endocr. Pathol. 2022, 33, 115–154. [Google Scholar] [CrossRef] [PubMed]
  98. Available online: https://www.enets.org/coe.html (accessed on 1 November 2023).
  99. Garcia-Carbonero, R.; Sorbye, H.; Baudin, E.; Raymond, E.; Wiedenmann, B.; Niederle, B.; Sedlackova, E.; Toumpanakis, C.; Anlauf, M.; Cwikla, J.B.; et al. ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas. Neuroendocrinology 2016, 103, 186–194. [Google Scholar] [CrossRef]
  100. Moertel, C.G.; Kvols, L.K.; O’Connell, M.J.; Rubin, J. Treatment of Neuroendocrine Carcinomas with Combined Etoposide and Cisplatin. Evidence of Major Therapeutic Activity in the Anaplastic Variants of These Neoplasms. Cancer 1991, 68, 227–232. [Google Scholar] [CrossRef]
  101. Mitry, E.; Baudin, E.; Ducreux, M.; Sabourin, J.-C.; Rufié, P.; Aparicio, T.; Lasser, P.; Elias, D.; Duvillard, P.; Schlumberger, M.; et al. Treatment of Poorly Differentiated Neuroendocrine Tumours with Etoposide and Cisplatin. Br. J. Cancer 1999, 81, 1351–1355. [Google Scholar] [CrossRef]
  102. Iwasa, S.; Morizane, C.; Okusaka, T.; Ueno, H.; Ikeda, M.; Kondo, S.; Tanaka, T.; Nakachi, K.; Mitsunaga, S.; Kojima, Y.; et al. Cisplatin and Etoposide as First-Line Chemotherapy for Poorly Differentiated Neuroendocrine Carcinoma of the Hepatobiliary Tract and Pancreas. Jpn. J. Clin. Oncol. 2010, 40, 313–318. [Google Scholar] [CrossRef]
  103. Sorbye, H.; Welin, S.; Langer, S.W.; Vestermark, L.W.; Holt, N.; Osterlund, P.; Dueland, S.; Hofsli, E.; Guren, M.G.; Ohrling, K.; et al. Predictive and Prognostic Factors for Treatment and Survival in 305 Patients with Advanced Gastrointestinal Neuroendocrine Carcinoma (WHO G3): The NORDIC NEC Study. Ann. Oncol. 2013, 24, 152–160. [Google Scholar] [CrossRef] [PubMed]
  104. Pavel, M.; O’Toole, D.; Costa, F.; Capdevila, J.; Gross, D.; Kianmanesh, R.; Krenning, E.; Knigge, U.; Salazar, R.; Pape, U.-F.; et al. ENETS Consensus Guidelines Update for the Management of Distant Metastatic Disease of Intestinal, Pancreatic, Bronchial Neuroendocrine Neoplasms (NEN) and NEN of Unknown Primary Site. Neuroendocrinology 2016, 103, 172–185. [Google Scholar] [CrossRef] [PubMed]
  105. Del Rivero, J.; Perez, K.; Kennedy, E.B.; Mittra, E.S.; Vijayvergia, N.; Arshad, J.; Basu, S.; Chauhan, A.; Dasari, A.N.; Bellizzi, A.M.; et al. Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline. J. Clin. Oncol. 2023, 41, 5049–5067. [Google Scholar] [CrossRef] [PubMed]
  106. Available online: https://www.aiom.it/Linee-Guida-Aiom-2021-Neoplasie-Neuroendocrine/ (accessed on 1 November 2023).
  107. Kunz, P.L.; Reidy-Lagunes, D.; Anthony, L.B.; Bertino, E.M.; Brendtro, K.; Chan, J.A.; Chen, H.; Jensen, R.T.; Kim, M.K.; Klimstra, D.S.; et al. Consensus Guidelines for the Management and Treatment of Neuroendocrine Tumors. Pancreas 2013, 42, 557–577. [Google Scholar] [CrossRef] [PubMed]
  108. Forrest, L.M.; McMillan, D.C.; McArdle, C.S.; Dunlop, D.J. An Evaluation of the Impact of a Multidisciplinary Team, in a Single Centre, on Treatment and Survival in Patients with Inoperable Non-Small-Cell Lung Cancer. Br. J. Cancer 2005, 93, 977–978. [Google Scholar] [CrossRef] [PubMed]
  109. Wright, F.C.; De Vito, C.; Langer, B.; Hunter, A. Multidisciplinary Cancer Conferences: A Systematic Review and Development of Practice Standards. Eur. J. Cancer 2007, 43, 1002–1010. [Google Scholar] [CrossRef]
Biomedicines 12 00379 g001
Figure 1. PRISMA 2020 flow diagram for the search strategy.
Figure 1. PRISMA 2020 flow diagram for the search strategy.
Biomedicines 12 00379 g001
Biomedicines 12 00379 g002
Figure 2. MRI sequences above show pathologic tissue (arrow) growing through the right retrobulbar fat at the apex of the orbit; this involves the inferior orbital fissure and the lateral wall of sphenoid sinus, until it contacts the ipsilateral cavernous sinus. (A) Axial T1 FSE: the lesion appears iso-intense to muscle. (B) Axial T2 weighted: the lesion shows a non-homogeneous signal intensity due to areas of cystic degeneration in the ventral part. (C) DWI: the lesion shows a restriction of the proton density. (D) Fat-saturated contrast-enhanced axial T1 weighted: the lesion shows high enhancement.
Figure 2. MRI sequences above show pathologic tissue (arrow) growing through the right retrobulbar fat at the apex of the orbit; this involves the inferior orbital fissure and the lateral wall of sphenoid sinus, until it contacts the ipsilateral cavernous sinus. (A) Axial T1 FSE: the lesion appears iso-intense to muscle. (B) Axial T2 weighted: the lesion shows a non-homogeneous signal intensity due to areas of cystic degeneration in the ventral part. (C) DWI: the lesion shows a restriction of the proton density. (D) Fat-saturated contrast-enhanced axial T1 weighted: the lesion shows high enhancement.
Biomedicines 12 00379 g002
Biomedicines 12 00379 g003
Figure 3. (A–D) Fat-saturated contrast-enhanced T1-weighted sequences, both axial and sagittal show, respectively, the lateral (*) and longitudinal (arrow) extension of the lesion. The pathological tissue is arranged along the floor of the right orbit to infiltrate the inferior and medial rectus muscles; this engages the inferior orbital fissure into the context of the pterygopalatine fossa.
Figure 3. (A–D) Fat-saturated contrast-enhanced T1-weighted sequences, both axial and sagittal show, respectively, the lateral (*) and longitudinal (arrow) extension of the lesion. The pathological tissue is arranged along the floor of the right orbit to infiltrate the inferior and medial rectus muscles; this engages the inferior orbital fissure into the context of the pterygopalatine fossa.
Biomedicines 12 00379 g003
Biomedicines 12 00379 g004
Figure 4. Photograph of orbital biopsy specimen. Hematoxylin and eosin (HE) stain of paraffin-embedded tumor tissue and immunochemistry with antibodies specific for Chromogranin A (CgA), CDX2, synaptophysin (Syn), S100; Ki67.
Figure 4. Photograph of orbital biopsy specimen. Hematoxylin and eosin (HE) stain of paraffin-embedded tumor tissue and immunochemistry with antibodies specific for Chromogranin A (CgA), CDX2, synaptophysin (Syn), S100; Ki67.
Biomedicines 12 00379 g004
Biomedicines 12 00379 g005
Figure 5. Baseline images of 68Ga-DOTA-NOC PET/CT (left) and (F-18) FDG PET/CT (right): the lesion shows a very high expression of somatostatin receptors, but is negative on (F-18) FDG PET/CT.
Figure 5. Baseline images of 68Ga-DOTA-NOC PET/CT (left) and (F-18) FDG PET/CT (right): the lesion shows a very high expression of somatostatin receptors, but is negative on (F-18) FDG PET/CT.
Biomedicines 12 00379 g005
Biomedicines 12 00379 g006
Figure 6. Diagnostic algorithm in the suspicion of primary orbital NENs. Abbreviations: PET/CT: Positron emission tomography/computed tomography; MRI: Magnetic Resonance Imaging; MRE: MR enterography; CTE: CT enterography (CTE); CDDP: cisplatin; CBDCA: carboplatin; NEC: neuroendocrine carcinoma; WD-NETs: well-differentiated neuroendocrine tumors; SSA: somatostatin analogues; TKIs: Tyrosine kinase inhibitors; RLT: radioligand therapy. * in the presence of diarrhea, flushing and/or bronchospasm. ** adjuvant treatment should be considered according to histology and risk factors (low-level evidence). # on the basis of available data in the literature, see GEP-NETs therapeutic algorithm.
Figure 6. Diagnostic algorithm in the suspicion of primary orbital NENs. Abbreviations: PET/CT: Positron emission tomography/computed tomography; MRI: Magnetic Resonance Imaging; MRE: MR enterography; CTE: CT enterography (CTE); CDDP: cisplatin; CBDCA: carboplatin; NEC: neuroendocrine carcinoma; WD-NETs: well-differentiated neuroendocrine tumors; SSA: somatostatin analogues; TKIs: Tyrosine kinase inhibitors; RLT: radioligand therapy. * in the presence of diarrhea, flushing and/or bronchospasm. ** adjuvant treatment should be considered according to histology and risk factors (low-level evidence). # on the basis of available data in the literature, see GEP-NETs therapeutic algorithm.
Biomedicines 12 00379 g006
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Arrivi, G.; Specchia, M.; Pilozzi, E.; Rinzivillo, M.; Caruso, D.; Santangeli, C.; Prosperi, D.; Ascolese, A.M.; Panzuto, F.; Mazzuca, F. Diagnostic and Therapeutic Management of Primary Orbital Neuroendocrine Tumors (NETs): Systematic Literature Review and Clinical Case Presentation. Biomedicines 2024, 12, 379. https://doi.org/10.3390/biomedicines12020379

AMA Style

Arrivi G, Specchia M, Pilozzi E, Rinzivillo M, Caruso D, Santangeli C, Prosperi D, Ascolese AM, Panzuto F, Mazzuca F. Diagnostic and Therapeutic Management of Primary Orbital Neuroendocrine Tumors (NETs): Systematic Literature Review and Clinical Case Presentation. Biomedicines. 2024; 12(2):379. https://doi.org/10.3390/biomedicines12020379

Chicago/Turabian Style

Arrivi, Giulia, Monia Specchia, Emanuela Pilozzi, Maria Rinzivillo, Damiano Caruso, Curzio Santangeli, Daniela Prosperi, Anna Maria Ascolese, Francesco Panzuto, and Federica Mazzuca. 2024. "Diagnostic and Therapeutic Management of Primary Orbital Neuroendocrine Tumors (NETs): Systematic Literature Review and Clinical Case Presentation" Biomedicines 12, no. 2: 379. https://doi.org/10.3390/biomedicines12020379

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop