Metastatic primary breast neuroendocrine neoplasms: a case series.

BACKGROUND: Breast neuroendocrine neoplasms represent a rare subtype of breast cancer which have not been well studied or characterised, particularly in the metastatic setting. AIM: To present clinicopathological characteristics, treatment and outcomes of a series of patients with metastatic neuroendocrine carcinoma of the breast and review the current literature. METHODS: We performed a retrospective review to identify and describe patients with metastatic neuroendocrine carcinoma of the breast at our centre between 2011 and 2021. Medical records, pathology and imaging results were examined to evaluate the clinical and histopathological features as well as the treatment pathways and prognosis of these patients. RESULTS: We present a series of seven female patients with metastatic neuroendocrine carcinoma of the breast, as defined by the World Health Organization classification, over a period of 10 years (2011-2021) from a single centre. Median age at diagnosis was 48 years (range 39-63). Six of seven tissue samples expressed synaptophysin and chromogranin and were also oestrogen and progesterone receptor positive; median Ki-67 index was 50% (range 20-90%). All seven patients had demonstrated avidity on 18 F-FDG PET imaging, and the six who underwent 68 Ga-DOTATATE PET all had significant avidity. Treatment modalities and sequencing varied, but all patients received chemotherapy during their disease course. Six patients received three or more lines of treatment. Median overall survival was 31.8 months (range 3.7-108.6). Median progression-free survival (PFS) with first-line therapy for metastatic disease was 5.8 months (range 1.8-37.8). CONCLUSIONS: This series shows the use of multiple modalities in treating this disease, with different sequencing in different patients. Despite multiple modalities used in the first-line setting, first-line PFS remains short. Larger series and further molecular characterisation are required to aid clinicians in managing this condition and to guide optimal treatment sequencing to improve outcomes in this rare patient group.

Routine Early 68Ga-DOTATATE Positron Emission Tomography Has Low Yield After Resection of Appendiceal Neuroendocrine Neoplasms.

OBJECTIVES: Appendiceal neuroendocrine neoplasms (appNEN) generally carry a low recurrence risk. Ga-DOTATATE positron emission tomography (DOTA PET) is increasingly used as it is more sensitive than cross-sectional imaging. We hypothesize that early DOTA PET is unlikely to detect recurrent disease in patients with low-risk resected appNEN because of the delayed pattern of recurrence. METHODS: Retrospective study (dual review) of patients undergoing DOTA PET 0 to 18 months after resected appNEN. The primary outcome was the proportion of scans demonstrating residual disease. RESULTS: Forty-one patients were included (median age, 29 years; 63% female), most with small, low-grade appNEN. No scans (0%) showed residual/distant disease. Eight (20%) of 41 scans showed indeterminate findings requiring follow-up. Five (12%) scans were recommended for follow-up with modalities other than DOTA PET (vertebra, 3; thyroid; bone, 1 each). Three (7%) were recommended for follow-up with DOTA PET (all with indeterminate abdominal uptake). These 3 patients had no recurrent disease on follow-up. CONCLUSIONS: The Ga-DOTATATE PET is of no value when performed in the first 18 months after resected appNEN. Although 20% of scans showed indeterminate findings, more than half did not require repeat DOTA PET. Despite advantages over cross-sectional imaging, DOTA PET is not recommended in staging after completely resected appNEN.

Quantifying the effects of absorbed dose from radioembolisation on healthy liver function with [99mTc]TcMebrofenin.

PURPOSE: To quantify the effects of absorbed radiation dose on healthy liver parenchyma following radioembolisation (RE) using [99mTc]TcMebrofenin to analyse both global and regional liver function. METHODS: Patients having RE to treat hepatic disease underwent a [99mTc]TcMebrofenin hepatobilliary scintigraphy (HBS) study at both baseline and 8 weeks following treatment. Changes in global liver uptake rate were compared with healthy liver absorbed dose measures derived from the post-treatment 90Y PET/CT, including average dose, minimum dose to 70% of the volume (D70) and volume receiving at least 50 Gy (V50). Changes in functional burden associated with treatment and spared liver volumes in patients receiving lobar RE were also assessed, as were changes experienced by regional volumes corresponding to various dose ranges. Standard liver function pathology tests (LFTs) (bilirubin, albumin, ALP, AST, ALT and GGT) were examined for changes between baseline and post-treatment. RESULTS: Thirty-five patients were included in the study, of which, 9 had lobar treatment. A significant linear correlation was found between both baseline global liver uptake rate (negative) and D70 with change in global liver uptake rate. Patients undergoing lobar treatments demonstrated a shift in functional burden, and a significant difference was seen between the mean dose corresponding to liver volumes that increased their functional burden (9 Gy) and those that decreased their functional burden (35 Gy). No baseline LFTs predicted a decrease in global liver function; however, D70 demonstrated a linear correlation with changes in bilirubin and GGT. CONCLUSIONS: Given the significant negative relationship between baseline and change in global liver uptake rate, baseline HBS studies should not be used alone to disqualify patients considered for RE. In terms of treatment planning and evaluation, D70 may be the most appropriate metric of dose, with values greater than 15 Gy indicative of a likely drop in global liver function. The evidence of increasing functional burden in spared liver volumes suggests that patients at risk of complications could benefit from a lobar approach to treatment.

High Metabolic Tumour Volume on 18-Fluorodeoxyglucose Positron Emission Tomography Predicts Poor Survival from Neuroendocrine Neoplasms.

INTRODUCTION: 18-Fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) avidity in neuroendocrine neoplasms (NENs) has been associated with higher-grade disease. 18F-FDG avidity and high SUVmax have been demonstrated to predict poor outcome. Quantitative metrics of 18F-FDG PET, specifically metabolic tumour volume (MTV) and total lesion glycolysis (TLG), have been shown to be prognostic factors in other malignancies, but these have not been investigated to date in NENs. METHODS: Patients with NEN undergoing 18F-FDG at Royal North Shore Hospital from 2012 to 2018 were included. Images were analysed with automated segmentation (SUV cut-off of 4) followed by contour verification by a nuclear medicine physician and manual segmentation where required. Variables collected included patient age, histological grade, MTV, TLG, and SUVmax/SUVmean. The primary outcome was overall survival (OS), and the secondary outcome was progression-free survival (PFS). Univariate (UV) and multivariate (MV) analyses were performed for OS and PFS for MTV and TLG separately. For UV analysis, the median MTV and TLG were used to dichotomise the cohort. MTV/TLG for NENs of different histological grade were compared using ANOVA. RESULTS: One hundred and ninety patients were included (median age 63.5, 49% female). Primary site: 42% small bowel, 32% pancreas, 15% other gastrointestinal, 6% lung, 6% other. Grade for gastroenteropancreatic NENs and bronchial NEN: G1/typical carcinoid 37%, G2/atypical carcinoid 40%, G3/large-cell/small-cell neuroendocrine carcinoma 16%, unknown 8%. Median MTV was 4.83 mL (range 0-3,161 mL) and median TLG was 29.22. Patients with high MTV had worse median OS compared to those with low MTV (29.7 months vs. not reached, HR 4.1, 95% CI 2.25-7.49, p < 0.00001). Considered as a continuous variable, MTV predicted for poorer OS on UV (p < 0.00001) and MV (p = 0.003) analyses. Whilst histological grade was significant on both UV and MV, SUVmax was significant on UV (p < 0.00001) but not MV (p = 0.76). Tumours of higher grade had higher MTV (mean MTV - G1: 39.6 mL, G2: 107 mL, G3: 337 mL; p = 0.0001 by ANOVA). CONCLUSIONS: Quantitative analysis of 18F-FDG PET in NEN is feasible. High MTV/TLG are predictors of poor prognosis in NEN. Further analyses are underway to investigate a larger cohort of NEN patients.

Feasibility and accuracy of single time point imaging for renal dosimetry following 177Lu-DOTATATE ('Lutate') therapy.

BACKGROUND: This study aims to assess both feasibility and accuracy of renal dosimetry imaging protocols in patients receiving Lutate therapy for neuroendocrine tumours (NETs), when data acquisition over multiple days is not possible on all cycles. METHOD: Patients who had received a full 4 cycles of Lutate therapy with complete imaging at each cycle were included. Imaging consisted of quantitative SPECT/CT of the kidneys at 4, 24 and 96-120 h post injection. Renal absorbed dose was calculated for each data set, and in addition, five alternative methods were explored for comparison. Method 1: a patient average clearance time (t1/2 average) derived from the first half of contributing patient data was used to estimate absorbed dose for subsequent patients based on 4 h imaging alone; method 2: t1/2 average was applied to subsequent patients on 24 h imaging alone; method 3: a patient-specific clearance rate (t1/2 patient) was determined from complete image data of cycle 1 and applied subsequently to remaining cycles using 4 h image data alone; method 4: t1/2 patient was applied to 24 h imaging alone in subsequent cycles; method 5: the 120 h data was estimated on subsequent cycles based on the cycle 1 fraction of injected activity (%IA) at 24 and 120 h. RESULTS: Twenty treatments from 18 patients, resulting in 80 cycles of therapy, were analysed. The measured average renal absorbed dose per cycle of treatment was 0.38 ± 0.19 Gy/GBq when derived from full imaging data. The use of t1/2 average applied to a single time point led to large deviations of dose estimates from true values (on average 59% and 30%, when using 4 h data and 24 h data, respectively). The use of complete image data on cycle 1 and the derivation of t1/2 patient led to improved dose estimates, with an average deviation from true values of 13% and 2% when using 4 h data only and 24 h data only, respectively. The use of a 120 h %IA derived from cycle 1 led to an average deviation from true dose estimates of 14%. CONCLUSION: In instances where demands on both patients and facilities make multiple time point data acquisition impractical, renal dosimetry is best derived through complete imaging at cycle 1 only followed by a single 24 h imaging time point on subsequent cycles, assuming no significant changes in renal function during the time course of therapy.

Changing Therapeutic Paradigms: Predicting mCRC Lesion Response to Selective Internal Radionuclide Therapy (SIRT) based on Critical Absorbed Dose Thresholds: A Case Study.

A 65 year old male with metastatic colorectal cancer (mCRC) in the liver was referred for selective internal radionuclide therapy (SIRT) following a history of extensive systemic chemotherapy. 90Y PET imaging was performed immediately after treatment and used to confirm lesion targeting and measure individual lesion absorbed doses. Lesion dosimetry was highly predictive of eventual response in the follow-up FDG PET performed 8 weeks after therapy. The derived radiation dose map was used to plan a second SIRT procedure aiming to protect healthy liver by keeping absorbed dose below the critical dose threshold, whilst targeting the remaining lesions that had received sub-critical dosing. Again, 90Y PET was performed immediately post-treatment and used to derive absorbed dose measures to both lesions and healthy parenchyma. Additional follow-up FDG PET imaging again confirmed the role of the 90Y PET dose map as an early predictor of response, and a tool for safe repeat treatment planning.

Clinical and imaging-based prognostic factors in radioembolisation of liver metastases from colorectal cancer: a retrospective exploratory analysis.

BACKGROUND: The aim of this study was to investigate the relationship between absorbed dose and response of colorectal cancer liver metastases treated with [90Y]-resin microspheres and to explore possible clinical and imaging derived prognostic factors. METHODS: FDG PET/CT was used to measure response of individual lesions to a measured absorbed dose, derived from post-treatment 90Y PET imaging. Predicted dose was also derived from planning [99mTc]-MAA SPECT data. Peak standardised uptake value and total lesion glycolysis (TLG) were explored as response measures, and compared to dose metrics including average dose (D avg), biologically effective dose, minimum dose to 70% of lesion volume and volume receiving at least 50 Gy. Prognostic factors examined included baseline TLG, RAS mutation status, FDG heterogeneity and dose heterogeneity. In an exploratory analysis, response and clinico-pathological variables were evaluated and compared to overall survival. RESULTS: Sixty-three lesions were analysed from 22 patients. Poor agreement was seen between predicted and measured dose values. TLG was a superior measure of response, and all dose metrics were significant prognostic factors, with a D avg of ~50 Gy derived as the critical threshold for a significant response (>50% reduction in TLG). No significant correlation was found between baseline TLG or RAS mutation status and response. Measured dose heterogeneity was a significant prognostic factor and when combined with D avg had a positive predictive value for response >80%. In the exploratory analysis for prognostic factors of survival, low hepatic tumour burden and mean reduction in TLG >65% were independently associated with improved overall survival. CONCLUSIONS: Lesions receiving an average dose greater than 50 Gy are likely to have a significant response. For lesions receiving less than 50 Gy, dose heterogeneity is a significant prognostic factor. Lesions receiving an average dose less than 20 Gy are unlikely to respond. A reduction in TLG may be associated with improved overall survival.

Dual Somatostatin Receptor/FDG PET/CT Imaging in Metastatic Neuroendocrine Tumours: Proposal for a Novel Grading Scheme with Prognostic Significance.

Background: PET scans using FDG and somatostatin receptor imaging agents have both been used to study neuroendocrine tumours. Most reports have documented the sensitivity and specificity of each radiopharmaceutical independently, and even suggested the superiority of one over the other for different grades of disease. Aim: The aim of this work was to develop a grading scheme that describes the joint results of both the FDG and somatostatin receptor imaging PET scans in staging subjects with neuroendocrine tumours in a single combined parameter. The grading scheme that has been developed is referred to as the NETPET grade. Methods: This is a retrospective study which assessed subjects who had both FDG and somatostatin receptor PET imaging at our institution within 31 days of each other. The NETPET grade was assigned by experienced nuclear medicine physicians and compared with other clinical data such as WHO grade and overall survival. Results: In the period 2011-2015 we were able to recruit 62 subjects with histologically proven metastatic neuroendocrine tumour for review. The NETPET grade incorporating both the FDG and somatostatin receptor imaging results was significantly correlated with overall survival by univariate analysis (p=0.0018), whereas in this cohort the WHO grade at the time of diagnosis did not correlate with survival. Conclusions: The NETPET grade has promise as a prognostic imaging biomarker in neuroendocrine tumours. It permits the capturing of the complexity of dual radiotracer imaging in a single parameter which describes the subjects' disease and is readily amenable to use in patient management and further research.

Dramatic response to selective internal radiation therapy for unresectable hepatocellular carcinoma.

A 54-year-old woman with a known history of multifocal hepatocellular carcinoma was treated with selective internal radiation therapy (SIRT) using yttrium-90 ((90)Y) microspheres, despite disease relapses after surgical resection and transarterial chemoembolization. She developed a dramatic clinical, radiological and metabolic response after 9 weeks. This case provides visual illustration of the potential roles of SIRT in the treatment of hepatocellular carcinoma.

Comparison of pinhole and SPECT 99mTc-MIBI imaging in primary hyperparathyroidism.

OBJECTIVE: This study aims to compare dual tracer, dual phase pinhole technetium-99m labelled 2-methoxyisobutylisonitrile (Tc-MIBI) imaging (including oblique imaging), with single photon emission computed tomography (SPECT) and dual phase planar Tc-MIBI images, and combined SPECT, dual phase planar Tc-MIBI images and anterior pinhole thyroid images for the localization of parathyroid adenomas in the neck in primary hyperparathyroidism. METHODS: Sixty-two patients underwent Tc-MIBI dual phase, anterior and anterior oblique pinhole images of the neck, anterior planar images of the neck and chest and early phase neck/chest SPECT followed by [Tc] pertechnetate anterior and anterior oblique pinhole thyroid images. Images were reviewed by consensus in three combinations - dual phase anterior and anterior oblique pinhole Tc-MIBI images and pinhole thyroid images; SPECT and dual phase planar Tc-MIBI images and combined SPECT, dual phase planar Tc-MIBI images and anterior pinhole thyroid images. RESULTS: For 52 parathyroid adenomas in 50 patients, the sensitivity of dual phase anterior and anterior oblique pinhole Tc-images and pinhole thyroid images was 81%. Significantly lower sensitivities were observed with SPECT and dual phase planar Tc-MIBI images (54%, P=0.0005) and combined SPECT, dual phase planar Tc-MIBI images and anterior pinhole thyroid images (65%, P=0.0209). The positive predictive value for all imaging combinations was 88-92%. CONCLUSION: Dual phase anterior and anterior oblique pinhole Tc-MIBI images and pinhole thyroid images are significantly more sensitive than imaging combinations that included SPECT and remains the optimal imaging protocol for the localization of parathyroid adenomas in the neck in primary hyperparathyroidism.