Introduction
Neuroendocrine tumors’ (NETs) incidence of 35/100,000 cases is increasing [1] with tumors noted in all anatomic sites, particularly the lungs, gastrointestinal tract, rectum, and pancreas [2]. Surgical resection can be curative with a corresponding increase in survival [3] due to earlier detection of disease.
Octreotide, a synthetic peptide somatostatin analog, utilizing Indium-111 radiolabeling [4], has a high affinity to somatostatin receptors SSTR2 and SSTR5, low affinity for SSTR3, and minimal affinity for the SSTR1 or SSTR4 subtypes [5]. A limitation of utilizing octreotide for imaging has been its affinity for SSTR2 and SSTR5, but not the other subtypes. In comparison, Gallium-68 DOTATATE (68Ga-DOTOTATE) has a much higher affinity to SSTR2 (10×) and an affinity to SSTR4 and SSTR5 [6], with superior sensitivity, allowing for better detection of smaller NETs and those that express fewer SSTR2 receptor subtypes.
Previously reported studies demonstrated 68Ga-DOTOTATE exhibited a sensitivity of 80%–100% for primary or metastatic lesions [1] and 82%–90% specificity when compared to pathology as the diagnostic gold standard [1]. The Food and Drug Association approved the use of 68Ga-DOTOTATE PET/computed tomography (CT) in 2016. 68Ga-DOTOTATE PET/CT showed a 100% sensitivity in the neck and thoracic regions, with the lowest sensitivity in the liver and pancreas regions (83.3%) [7]. This sensitivity is notably higher than Octreotide’s 25% sensitivity for the neck and thoracic regions and 83.3% in the pancreatic region. Octreotide was also only positive in 50% of abdominal lymph nodes. 68Ga-DOTOTATE had an overall 90% specificity, with other studies reporting specificity as high as 100% when compared to CT or magnetic resonance imaging (MRI) imaging [8–10]. The use of 68Ga-DOTOTATE PET/CT has changed management in 20% and 24% of patients referred for re-evaluation or re-staging from previous CT/MRI or Octreotide imaging, respectively [7]. This is primarily due to the increased physiological uptake from the approximate 10-fold increased affinity 68Ga-DOTOTATE has with the SSTR2 receptor leading to higher and more detailed image quality, especially for the smaller lesions [7].
This report presents and discusses a patient who underwent 68Ga-DOTOTATE PET/CT imaging with avidity for a small bowel mesenteric lesion suggesting a NET regional lymph node disease. The surgical evaluation demonstrated a finding inconsistent with NET, as confirmed by histological analysis. Given the reported high specificity and sensitivity of 68Ga-DOTOTATE, we report inconsistency in avidity for a necrotic and non-NET lesion and present a comprehensive literature review evaluating other false positives.
Case Report
This report has been approved by the institutional review board and the need for written informed consent was waived. A 68-year-old male was referred to surgical oncology for a second opinion concerning a mass in the proximal small bowel mesentery. The patient had presented a month earlier to his primary care physician with symptoms of small bowel obstruction and was admitted to an outside facility for evaluation. Intravenous and oral contrast-enhanced CT of the abdomen and pelvis was obtained. CT findings included a normal hepatic morphology without intrahepatic biliary dilation or mass. A mesenteric mass was noted in the proximal small bowel measuring 5 × 3.1 cm (Fig. 1a and b); mildly dilatated contrast-filled loops of the small bowel were noted with a gradual transition into normal caliber distal loops, suggesting an ileus versus partial obstruction.
The differential diagnosis included metastatic adenopathy, nodal NET disease, or lymphoma. Biopsy via laparoscopy was recommended, at which point the patient sought a second opinion.
A review of the outside films noted the incidental abdominal mass. Due to proximity to the root of the mesentery and the entire small bowel vasculature, laparoscopic resection would be difficult. The solid nature in the mesentery suggested a neuroendocrine tumor with regional nodal disease. The patient underwent a 68Ga-DOTOTATE PET/CT. Heterogeneous tracer accumulation within the mesenteric mass was noted (Fig. 1c and d), suggestive of somatostatin avidity. A couple of small tracer avid lymph nodes were present immediately cephalad to the mass. There was also intense uptake within an enlarged mesenteric lymph node or nodal cluster within the more proximal mesentery. No distant disease was noted.
Figure 1.
Ga-68 DOTATATE Imaging. Axial (a) and coronal (b) intravenous and oral contrast enhanced CT of the abdomen demonstrates a central mesenteric mass (white arrow). (c) 68Ga-DOTOTATE PET-CT shows uptake within the mesenteric mass (white arrow). (d) 68Ga-DOTOTATE axial MIP demonstrating heterogeneous uptake and small focus of avidity (black arrow) greater than background and bowel.
Figure 2.
Histology. Fat necrosis (white arrow) surrounded by fibrosis and inflammation (black arrow; 100×).
Table 1.
Comprehensive literature review.*
| Author | Year | Age | Sex | Location | Symptoms/Hx | Imaging | Resection | Details/findings | Diagnosis | |
|---|---|---|---|---|---|---|---|---|---|---|
| Demirci | 2014 | 65 | F | Axillary, paraaortocavaland bilateral inguinal LN | Hx of pancreatic NETs | Increased uptake in LN as well as vertebrae and iliac bone | Excisional LN biopsy from axillary region; | Low grade follicular lymphoma, hemangiomas | ||
| Lancellotti | 2019 | 69 | M | Tail of pancreas | Sigmoid adenocarcinoma; colectomy and adjuvant chemo | MRI: 1.5 cm nodule pancreatic tail; EUS 1.5 cm anechoic nodule pancreatic tail; MRI/CT 2cm 8mo later; 68Ga-DOTOTATE focal uptake | distal spleno-pancreatectomy | Intrapancreatic accessory spleen (IPAS). | ||
| Schmidt | 2019 | 60 | M | Prostate | Hx metastatic NET; small bowel obstruction; elevated PSA | Uptake in prostate, liver, mesentery, peripancreatic LN | US guided bx | Prostate bx negative for malignancy | Prostate:inflammation; liver, mesentery, peripanacreatic LN NET | |
| Yilmaz† | 2019 | 66 | M | Prostate | Hx of midgut NET, elevated PSA | 68Ga-DOTOTATE uptake in prostate gland | Core bx of prostate | Chronic prostatitis | ||
| Chalmers | 2020 | 69 | M | Small bowel carcinoid; lymphadenopathy | Hx small bowel NET; octeotride;tx | 68Ga-DOTOTATE uptake in mediastinal/hilar LN | Bronchoscopy with FNA LN | Symptoms of new positive 68Ga-DOTOTATE improved after being treated with itraconazole | Non-necrotic granulomas; bronchial washing cryptococcus neoforman | |
| Lakhotia | 2020 | 78 | F | Pancreatic head | Yr long hx diarrhea; elevated VIP | CT; pancreatic uncinate lesion with 68Ga-DOTOTATE uptake | EUS with FNA | Presumed vipoma; symptoms resolved | Normal pancreatic tissue | |
| Zampetti† | 2020 | 75 | F | Interaortocaval | Hx kidney tumor; abn metanephrine level | 68Ga-DOTOTATE uptake abd/iliac crest | Suspected pheochromocytoma; abdominal resection;bone lesion bx:metastatic renal tumor | Resection of abdominal tumor | Interaortocaval PGL | |
| Filizoglu† | 2021 | 47 | M | Petrous apex stomach | Presumed stomach NET | 68Ga-DOTOTATE uptake in petrous apex | Cholesterol granuloma of temporal bone | |||
| Alruwaili† | 2021 | 52 | M | Palpitations, tachycardia, hot flashes, chest tightness | 68Ga-DOTOTATE avidity in thoracic and lumbar spine | MRI: atypical hemangioma; serum chromogranin A testing negative. | Hemangioma | |||
| Deng† | 2021 | 67 | F | Thyroid gland and cervical lymph nodes, bladder | Hx of thyroid cancer | 68Ga-DOTOTATE uptake in thyroid gland, cervical LN, and bladder | 68Ga-DOTOTATE uptake disappeared after urination | Bladder diverticulum | ||
| Civan† | 2021 | 50 | M | Cervical lesion in internal jugular chain | Suspicion of glomus jugular paraganglioma | 68Ga-DOTOTATE uptake from increased SSTR expression internal jugular chain | Bx of cervical LN | Met of squamous cell carcinoma | ||
| Xavier | 2021 | 68 | M | Small bowel mesentery | Symptoms of small bowel obstruction | Mass on abdominal CT in proximal small bowel mesentery, 68Ga-DOTOTATE uptake in mesenteric mass | Surgical resection | Inflammatory component upon evaluation of frozen section | Pancreatic fat necrosis | |
*Limited to complete reports, English only and those which the institution could obtain.
†Full reports unavailable.
An open surgical resection was performed; during the procedure, the mesenteric mass was consistent with scarring rather than nodal tissue and inconsistent with a NET presentation, especially in light of no primary small bowel lesion noted. The small bowel was run from the ligament of Treitz to the ileocecal valve. No palpable lesions were noted, again, inconsistent with a NET presentation. An incisional biopsy of the nodular/scarred area in the mesentery was completed and sent for intraoperative diagnosis, which suggested an inflammatory component, including sclerosing mesenteritis and no evidence of NET disease. The operation was completed without incident or postoperative complications, and the patient was discharged on hospital day 3.
Final pathology revealed heterotopic necrotic pancreatic tissue (Fig. 2); IgG4-related inflammatory disease was negative. No further treatment was warranted; follow-up was scheduled for 6 months.
Discussion
Identification and staging of NETs are essential for appropriate therapy and optimal patient care. Staging is based on proliferation rate and regional/metastatic disease, which is optimized by imaging NETs that capitalizes on the sensitivity to the high SSTR2 expression [7] that is identified by 68Ga-DOTOTATE that hence, allows for differentiation from other cancerous processes. [11]. Additionally, the high SSTR2 expression of NETs has also been a target for specific therapy as the SSTRs have anti-secretory and apoptotic or anti-proliferative activity when bound with somatostatin analogs.
As NET expression of SSTR2 is high, 68Ga-DOTOTATE identification of these lesions has typically been specific; however, false-positive cases have been reported (Table 1). Overall, pancreatic tissue has had the highest incidence of false positives; pancreatic tissue is characterized by higher expression of SSTR2 in both cancerous and non-cancerous tissue [12]. Only one other report was noted in the small bowel mesentery (Table 1). Other intraoperative pathologic findings in the 68Ga-DOTOTATE false positive reports included non-necrotic granulomas, paraganglioma, inflammation, squamous cell carcinoma, a diverticulum, and hemangiomas.
To identify patterns in false-positive 68Ga-DOTOTATE uptake, we present a comprehensive literature review. Of the 11 patients reported, 7 were aged 65 or older, and 7 were male. The location of positivity was throughout the body: pancreas, prostate, small bowel, stomach, and bladder. Interestingly, four patients had a history of NET or a current diagnosis and demonstrated a false positive 68Ga-DOTOTATE uptake. In presenting our case and reviewing the literature, it is evident that 68Ga-DOTOTATE sensitivity and specificity are impressive; however, not 100%. Subjectively evaluating each patient based on criteria such as age, past medical history, and comorbidities should always be the cornerstone in correlating the imaging results with a possible NET diagnosis. In general, a less invasive approach to confirm the diagnosis before formal treatment, such as surgical resection, is advised.
Conclusion
The primary consideration in the management of patients with NETs is to define resectability. In this regard, imaging is critical in defining the extent of disease and what surgical approach may be considered or if the patient is unresectable. Our comprehensive review of the literature highlights the importance of confirming a diagnosis of NET prior to any major surgical resection. Percutaneous biopsies are ideal however, in the abdomen, this can be difficult. Therefore, if a solitary site of avidity is noted, this may require an intraoperative biopsy with a frozen section to confirm or refute the diagnosis: as was done in our case report.
