Metastatic retroperitoneal tumor from a non-functional neuroendocrine neoplasia of the left ethmoid-nose-orbitary region: Case report and short review of literature

Highlights • NENs are rare tumors with extremely variable behavior: they are difficult to diagnose, especially if biologically inactive.• NENs can originate from any epithelial organ and present unusual metastases.• NEN surgery is a valid treatment and a necessary tool for correct diagnosis.• NEN classification is evolving and being discussed.• Careful collection of anamnestic data and a correct analysis of patients’ symptoms can be a valuable resource.


Introduction
NeuroEndocrine Neoplasms (NENs) are rare, accounting for 0.5 % of all new cancer cases [1]. They represent neoplasms that can originate from any epithelial organ, but most of them start from the gastrointestinal (70 %) and respiratory tracts (25 %) [2]. Today, the diagnosis of NEN is morphofunctional and is mainly entrusted to microscopic characteristics and immunohistochemical data in the presence of hormonal hypersecretion. In accordance with the World Health Organization (WHO) 2010 classification, we distinguished NeuroEndocrine Tumour (NET) G1 for well-differentiated endocrine tumors (including carcinoids), NET G2 for well-differentiated endocrine carcinomas, and Neu-roEndocrine Carcinoma (NEC) for poorly differentiated endocrine carcinomas/small cell carcinomas [3]. The clinical case considered herein concerns the onset of a voluminous retroperitoneal metastasis from a non-functioning neuroendocrine primary neoplasm of the left ethmoid-sinus-orbital region treated exclusively with chemotherapy and radiotherapy cycles.  focus on the various issues related to NENs, ranging from their nosological classification up to the most recent acquisitions in the diagnostic-therapeutic field, which condition the prognosis of these rare neoplasms. The work is described in line with SCARE criteria [4].

Case presentation
At our institute, a 58-year-old female patient in good health came to our attention. Access to our department was determined by a persistent abdominal pain localized in the right lumbar region. The collection of anamnestic data revealed a small cell type NEC, discovered two years before, with positivity to Synaptophysin and Neuron Specific Enolase (NSE) but not to Chromogranin A, of the left ethmoid-nasal-orbital region, treated with chemo-and radiotherapy cycles. In our department the patient underwent a total body Computed Tomography (CT) scan ( Fig. 1) which showed the presence of a voluminous mass in the right retroperitoneal area, with a maximum transverse diameter of 12 cm, presenting areas of necrotic colliquation in its context. This mass infiltrated the sixth and seventh hepatic segments, dislocated and infiltrated the inferior intrahepatic vena cava, dislocated the right kidney by infiltrating the superior pole and extended to the right lumbar region. This mass also infiltrated the anterior abdominal wall in the right lumbar region, determining an edema of the underlying subcutaneous adipose tissue, and dislocated, but did not infiltrate, the cephalic portion of the pancreas. Surgery was performed with total median laparotomic access. The mass was removed en bloc (Figs. 2, Fig. 33).
The final histological examination showed a NEC composed of small cells with immunohistochemical characters that were Synaptophysin-positive, NSE positive, but chromogranine negative (Fig. 6).
The post-operative course was satisfactory and the patient was released from the hospital on the 24th day in good condition and entrusted to oncologists for treatment of the case. The patient had a positive follow-up at 6 months and 12 months.

Discussion
The definition of neuro-endocrine cells has been changing over the years owing to improved knowledge and acquisition of mod-   ern research techniques. From the proposal put forward by Pearse in the 1960s and the introduction of the Amine Precursor Uptake Decarboxylation (APUD) system, which led to a common embryological histogenesis of these cells that showed their derivation  from the neural crest, to the studies by Le Dourein, which highlighted that this was in part untrue, since the endocrine cells of the digestive tract, pancreas and lung are of endodermal origin [5]. NENs are rare neoplasms, representing about 0.5% of all newly diagnosed malignancies. Their distribution in general is: appendix 30%, colon-rectum 16%, stomach 14%, small intestine 9%, pancreas 6%, and medullary thyroid 5%. 20.8% of patients present with metastases [6]. NENs are a very heterogeneous group and originate from neuro-endocrine cells. They include carcinoids, noncarcinoid gastroenteropancreatic tumors, catacolamine-secreting tumors (pheochromocytomas, paragangliomas, gaglioneuromas, ganglioblastomas, sympathoblastoma, neuroblastoma), medullary thyroid carcinomas, pituitary tumors, small cell lung tumors and tumors of Merkel cells.

5) Hyperplastic and preneoplastic lesions.
This classification is highly relevant to the prognosis and treatment of choice. The diagnosis of NEN is therefore morphofunctional and based essentially on microscopic features and immunohistochemical data: positive to Synaptophysin, to NSE and to Chromogranin. It is to be noted that well-differentiated NENs are intensely positive to the latter marker. This is true only in 10-15% of NENs in small cells are [7]. The study of genetic predisposition in the oncological diagnosis of NETs was possible thanks to the fundamental contribution of genetic analysis; these tumors occur in family groups carrying Multiple Endocrine Neoplasia (MEN) 1 and MEN2. These neoplasms are divided into Biologically Inactive Neuroendocrine Tumors (BINTs) forms and active forms. BINTs present clinical manifestations related to the size and location of the neoplasm. Signs and symptoms depend on the mechanical or mass effect of the tumor. A small cell NEC of the ethmoid-nose-orbital region is an extremely rare occurrence. It is divided into epithelial and neural, based on the presence of keratin or neurofilaments. Although rare, NECs and the olfactory neuroblastomas represent the most common neoplasia of the rhinosinusal tract [8]. The most frequent metastatic localization is the larynx, but other metastases can be found at the level of the cervical lymph nodes, lungs, liver, bone marrow and vertebrae [9]. Synaptophysin positivity also represents an extremely rare occurrence [10]. Less than 100 cases are reported in the literature and NEC is the most common in the ethmoid region [11]. It must be said that patients who have been treated with radiotherapy have an increased risk of developing secondary neuroendocrine cancers, and only two cases are reported in the literature [12]. The differential diagnosis with neuroblastoma, a tumor more easily found in this anatomical region, may present difficulties and only immunohistochemistry is decisive, even in controversial cases. These neoplasms have characteristics morphologically similar to those of small cell anaplastic tumors of lung cancer (Koss) [13]. The instrumental diagnosis makes use of ultrasound, depending on the primary lesion, biopsy samples, CT, CT angiography, Magnetic Resonance Imaging (MRI), immunoscintigraphy, Positrone Emission Tomography (PET), and a specific metabolic tracer (labeled 5-hydroxy tryptophan) which is able to selectively bind to NENs in 90% of cases showing lesions not visible on CT and MRI. The search for specific markers is very important. The therapy is multidisciplinary: surgery plays a fundamental role and must be as radical as possible, even using extensive demolitions, preceded when necessary by adjuvant and post-operative chemo-and radiotherapy. For the prognosis it is now established that the use of FluoroDeoxyGlucose (FDG)-PET is an excellent choice, with new research on 3 -deosoxy 3 -18F-FLuoroThymidine (18F-FLT), but it is not yet clear if it is useful for the choice of a specific treatment [14]. In the case that came to our attention, there was an interval that was free of disease, similar to the average survival in these cases, but in absence of surgery for removing the primary lesion. It is to be considered unusual that the resumption of the disease occurred through a voluminous retroperitoneal metastasis that required debulking, with sacrifice of the many organs involved, in absence of local recurrence of the primary tumor, thus representing the only case of retroperitoneal metastasis from NEC of the ethmoid-nose-orbital region described worldwide, although this region represents one of the most frequent locations of NECs of unknown origin [15].

Conclusion
NENs represent a chapter of oncology whose systematization remains difficult. Classification, study and research on these neoplasms entails complex knowledge involving all branches of medical science. The rarity of most NENs necessitates multicenter studies that allow histopathological classification. The non-active forms usually have a paucisintomatic symptomatology that is revealed only when the tumors occupy space. However, they are very aggressive neoplasms, especially in their poorly differentiated form. The diagnostic procedure includes ultrasonography, CT scan, immunoscintigraphy and PET. Immunohistochemical findings, and even those of genetic mutations, should not be overlooked for prognostic purposes. From a therapeutic point of view, surgery plays a fundamental role: it must be radical, with extensive lymphectomies and aggression of any metastases. The discovery of new biomarkers may open up new possibilities for classification, diagnosis and type of treatment. Ultimately, the clinical case presented herein highlights all the contradictions and problems typical of NETs and only new scientific acquisitions in the histopathological field will open new and more comforting scenarios in biological and therapeutic behavior.

Sources of funding
This study did not receive any funding.

Ethical approval
The study not require ethical approval.

Consent
Written informed consent was obtained from the patient.

Registration of research studies
This study does not require registration.

Provenance and peer review
Not commissioned, externally peer-reviewed.

Declaration of Competing Interest
The authors declare that they have no financial conflict of interest related to this paper.