NETs with oncocytic features are rare. Only few studies have described the metastatic characteristics of these tumors, most of which were limited by the low number of cases. Our study summarized the clinicopathological characteristics of 32 low to intermediate grade oncocytic NETs that were diagnosed at our institution over the past 21 years.
Gastroenteropancreatic NETs (GEP-NETs)
Previous studies have shown that GEP-NETs account for approximately 60-70% of all NETs [3], with the most common site being the small intestine [19]. The symptoms at the time of presentation vary by tumor location; some patients are asymptomatic and the tumor is found incidentally on imaging studies. Advanced midgut NETs (jejunum, ileum, appendix, and ascending colon) with liver metastasis can cause carcinoid syndrome, as bioactive substances such as serotonin secreted by the NETs fail to be metabolized by liver. Common symptoms include cutaneous flushing, diarrhea, wheezing/dyspnea, and carcinoid heart disease [20]. Computed tomography (CT), magnetic resonance imaging (MRI), and somatostatin receptor (SSTR)-based integrated positron emission tomography (PET)/CT are the main diagnostic and staging imaging modalities [21]. Hepatobiliary-phase liver MRI was indicated to be more sensitive in detecting liver metastases than CT or SSTR-PET/CT [22-24]. Whole-body SSTR imaging with 68Ga/64Cu-PET/CT provides high sensitivity and is recommend to be part of the tumor staging [21]. Histologically, well-differentiated GEP-NETs are classified into G1 (< 2 mitoses/2 mm2 and < 3% Ki-67 index), G2 (2-20 mitoses/2 mm2 and 3-20% Ki-67 index), and G3 (> 20 mitoses/2 mm2 and > 20% Ki-67 index). Surgical resection is the mainstay therapy even in the presence of liver metastasis [21]. No data is present to support adjuvant therapy in G1 or G2 NETs. Somatostatin analogs (such as octreotide) are used to treat symptomatic carcinoid syndrome and can also be used as anti-proliferative therapy in metastatic GEP-NETs [25, 26]. The prognosis varies depending on site, tumor grade and tumor stage. Patients with NETs in the small intestine have better prognosis than in the pancreas or colon/rectum [21]. There is no consensus on post-operative surveillance. The European Society for Medical Oncology (ESMO) recommends resected G1 NETs and G2 NETs with Ki-67 <5% be followed up with imaging every 6 months, and G2 NETs with Ki-67 >5% be followed up every 3 months at least during the first 5 years, and then every 1-2 years for lifetime surveillance [21].
Lung NETs
Lung NETs account for 20-30% of all NETs [3]. They can be found incidentally as peripheral solitary nodules without any symptoms. More often, they grow in the central airways and cause symptoms by mass effect, such as cough, hemoptysis, chest pain, and recurrent pneumonia [27, 28]. Rarely, these tumors release bioactive amines/peptide hormones that result in paraneoplastic syndromes occur. These syndromes include carcinoid syndrome (due to serotonin, etc.), Cushing’s syndrome (due to ectopic adrenocorticotropic hormone), and acromegaly (due to ectopic growth hormone-releasing hormone or insulin-like growth factor 1). These bioactive substances can be used as serologic markers to monitor the response to treatment [27]. According to the Commonwealth NET Research Collaboration and the North American NET Guidelines for the Lung NETs, CT of the chest and bronchoscopy are the initial diagnostic tests for these tumors, and liver MRI should be used for detection of liver metastasis [29]. Histologically, well-differentiated lung/thymus NETs is classified into TC (< 2 mitoses/2 mm2 and lacking necrosis) and AC (2–10 mitoses/2 mm2 and/or foci of necrosis). TC and AC generally correspond to low grade (G1) NETs and intermediate grade (G2) NETs. So far, mitotic count and necrosis are routinely reported in pathological diagnosis to grade the tumor, and mitoses can predict the prognosis of TC and AC [30]. The metastatic rate for TC is less than 5%, while that for AC is 20-30% [31]. The prognosis for TC is very good after treatment, with 10 year survival rates ranging from 82-93%. The prognosis for AC is worse, with a 10 year survival rates ranging from 35-64% [32-36]. Surgical resection is the treatment of choice for both TC and AC even in the situation of lymph node metastases [37]. Adjuvant therapy is not recommended for either TC or AC [38-40]. Surveillance should be life-long and depends on if the histology is TC or AC, and if the tumor is resected or residual/metastases [28].
NETs of unknown primary site
NETs of unknown primary site account for approximately 10-14% of all NETs [41-43]. These cases are often discovered with liver metastases and most are from GEP origin [17]. The primary site is more likely to be in the small intestine if the patient presents with carcinoid syndrome associated symptoms. Although other primary sites such as lung NETs can also lead to carcinoid syndrome, the incidence is much lower [44]. For well differentiated NETs of unknown primary site, CT/MRI, SSTR imaging with 68Ga-DOTATATE PET/CT, and IHC stains on the tissue block can help to locate the origin of the tumor [45-47]. Liver is the most common site of metastasis regardless of the origin of the primary NETs [17]. Liver metastasis in neuroendocrine neoplasms has been reported to have a worse prognosis regardless of the primary sites or histology [48].
NETs with oncocytic features
The majority of the previously reported oncocytic NETs are from pancreas and lung origin. The incidence of oncocytic features in the lung and pancreas NETs is 8% and 4.85%, respectively [9, 10]. Only one oncocytic NET case from gastrointestinal (GI) origin has been reported [14]. In our 32 oncocytic NETs case series, 12 cases are from GI origin, 1 case from pancreas origin, 6 cases from lung origin, 3 cases from thymus origin, 1 case from kidney origin, and 9 cases from unknown origin. The oncocytic NETs of unknown primary site account for 28% of all oncocytic NETs in our experience, higher than the unknown primary rate in general NETs (10-14%) discussed above. Of the two pancreatic oncocytic NET case series, one reported 7 out of 11 cases (63.6%) demonstrated lymph node/liver metastasis at time of diagnosis, while the other one reported 5 out of 7 cases (71.4%) showed lymph node/distant metastasis at the time of surgery [8, 9]. In our cohort, there was one oncocytic pancreatic NET which had liver metastasis at the time of diagnosis. 5 out of 6 of our lung cases (83.3%) showed metastasis including during follow up; 1 case metastasized to lymph node, and 4 cases metastasized to the liver. The prior lung oncocytic NETs case series only reported 1 out of 15 cases as having lymph node metastasis, and distant metastasis was not mentioned [10]. The overall metastatic rate in our series is 84.4%, which is much higher than that of the G1/G2 NETs from Riihimaki’s study (25%), while similar to that of the G3 NETs from Heetfeld’s study (86.5%) and Lithgow’s study (80.8%). The most frequent metastatic site in our study is liver (63%), lower than that of the G1/G2 NETs from Riihimaki’s study (82%) and the G3 NETs from Heetfeld’s study (90.6%) and Lithgow’s study (95.2%). We did not observe a statistical significant difference of metastatic rate between low and intermediate grade NETs (80% vs 75%). Whether the proportion of oncocytic components and growth patterns of oncocytic NETs can correlate with the metastatic features is unknown. A larger number of cases with these histological details is needed for further study. PET with [18F]fluoro-deoxy-glucose (FDG) is recommended to be used in G3 NETs due to more avid uptake of 18FDG than low grade NETs [45, 49]. The treatment for G3 NETs is not well established [50]. The role of surgery and adjuvant therapy remains controversial [51]. Multiple cohort studies have suggested that G3 NETs do not respond well to the platinum-based chemotherapy, which is the first-line treatment for neuroendocrine carcinoma (NEC) [18, 52, 53]. Temozolomide, everolimus, and peptide receptor radionuclide therapy (PRRT) are potential treatment options for patients with G3 NETs [50]. According to the ESMO treatment guidelines for GEP-NET, chemotherapy may be effective in rapidly growing tumors or G2 NETs with higher Ki-67 index close to G3 NETs [21]. Our study showed metastatic rate of oncocytic G1/G2 NETs is much higher than that of the general G1/ G2 NETs while similar to that of general G3 NETs, indicating oncocytic features could potentially be characterized as a high risk feature in addition to high Ki-67 index, mitotic count, and necrosis. The application of 18FDG PET on patients with oncocytic G1/G2 NETs as well as the treatment response to chemotherapy in those patients need to be further studied.