David A. Pattison

Efficacy of Peptide Receptor Radionuclide Therapy for Functional Metastatic Paraganglioma and Pheochromocytoma

Purpose: Treatment options for unresectable paraganglioma (PGL)/pheochromocytoma (PCC), especially with uncontrolled secondary hypertension (HTN), are limited. Preliminary studies with peptide receptor radionuclide therapy (PRRT) suggest efficacy, but data on HTN control and survival are lacking. We assessed PRRT outcomes in such patients from two referral centers. Methods: Twenty consecutive patients (13 men; age range, 21 to 77 years) with high somatostatin receptor (SSTR) expression treated with 177Lu‐DOTA‐octreotate, nine with radiosensitizing chemotherapy, were retrospectively reviewed. Median cumulative activity was 22 GBq (median 4 cycles). Fourteen patients were treated for uncontrolled HTN and six for progressive or symptomatic metastatic disease or local recurrence. Results: Three months after PRRT, 8 of 14 patients treated for HTN required reduced medication doses, 5 had no change in anti‐HTN doses, and 1 was lost to follow‐up. Eighty‐six percent had serum chromogranin‐A reduction. Of the entire cohort, 36% had disease regression (29% partial and 7% minor response) on computed tomography, with stable findings in 50%. Three other patients had bony disease evaluable only on SSTR imaging (2 partial response and 1 stable). Median progression‐free survival was 39 months; median overall survival was not reached (5 deaths; median follow‐up, 28 months). Four patients had grade 3 lymphopenia; 2 had grade 3 thrombocytopenia. Renal impairment in 2 patients was attributed to underlying disease processes. Conclusions: PRRT achieves worthwhile clinical and biochemical responses with low toxicity and encouraging survival in PGL/PCC. Because PRRT has logistic and radiation‐safety advantages compared to 131I‐MIBG therapy, further prospective evaluation is warranted.

Role of Fluorodeoxyglucose PET/Computed Tomography in Targeted Radionuclide Therapy for Endocrine Malignancies.

This review provides practical guidance for clinicians involved in the management of endocrine malignancies, including endocrinologists, medical oncologists, surgeons and nuclear medicine specialists regarding the indications and use of 2-fluoro-2-deoxy-d-glucose F-18 (FDG) PET/computed tomography (CT), particularly with respect to targeted radionuclide therapy. Key principles of FDG PET/CT for radionuclide therapy are explored in detail using gastroenteropancreatic neuroendocrine tumors as a prototype endocrine malignancy. The relevant literature is reviewed, and practical application in this new and emerging field is highlighted with the use of case examples.

A New Theranostic Paradigm for Advanced Thyroid Cancer

The successful use of 131I as a systemic treatment of a patient with metastatic thyroid cancer was first reported in 1948 (1). This agent has subsequently become firmly established as part of the treatment of high-risk thyroid cancer and especially for metastatic disease. There has been an evolution in the quality of assessment of the distribution of radioactive iodine (RAI) within the body, progressing from Geiger–Müller counting to imaging, first with the rectilinear scanning and then with the g-camera. The physical characteristics of 123I as a diagnostic tracer compared with 131I further improved imaging by facilitating higher quality SPECT and SPECT/CT. More recently, use of 124I PET/CT has further increased the sensitivity for detection of differentiated thyroid carcinoma (DTC) and offers the promise of prospective dosimetry estimation (2). Uptake of all these forms of RAI relies on the presence of functional sodium-iodide symporters, which are required for efficacious treatment with 131I.

Letter: THYROPET study: is biology or technology the issue?

TO THE EDITOR: We read with interest the results of the recently published THYROPET study (1), a prospective multicenter diagnostic cohort study testing the hypothesis that a recombinant human thyroid-stimulating hormone (rh-TSH)–stimulated 124I PET/ CT scan can identify patients with a negative thyroxine withdrawal (T4WD) posttherapy 131I scan and avoid futile treatment in patients with suspected recurrence of differentiated thyroid carcinoma. The trial was terminated prematurely because of a high number of falsenegative rh-TSH–stimulated 124I PET/CT scans, which would preclude potential therapeutic benefit from 131I therapy. Although this may be interpreted as a rebuttal of the theranostic approach and affirmation of the established practice of empiric 131I, we agree with the authors’ conclusion that “124I PET/CT remains the most rational strategy to reduce futile 131I therapies” despite this statement’s apparent conflict with their actual study findings. The explanation of this result will be critical to guide the use of 124I PET/CT for management of advanced thyroid cancer. In particular, we would like to focus on the very different clinical implications arising from the possible technical and biologic explanations for the false-negative rh-TSH–stimulated 124I results. Radioiodine imaging is a classic theranostic investigation, whereby the distribution of iodine uptake and retention within tumor is used to predict the response to a therapeutic administered activity of 131I. A key advantage of 124I PET/CT imaging is the opportunity to perform prospective dosimetry to more accurately predict this response (2). In this context, it is highly unlikely that a necessarily faint focus of uptake below the resolution of 124I PET but visible on post-131I imaging would deliver a clinically meaningful dose of radiation. Thus, if technical differences were the only explanation for the high false-negative rate of 124I PET/CT, then it remains an appropriate screening investigation for this indication as the risks of high-dose 131I therapy are likely to outweigh the modest benefits due to unfavorable radiation dosimetry. However, a recently published phantom study (3) confirms that there is no appreciable technical difference in detectability for even small spheres (,10 mm) at this administered activity (74 MBq of 124I) on scanners using point-spread function model-based resolution recovery and time-of-flight technology. We note that some but not all THYROPET study centers had time-of-flight technology, and thus, knowledge of the number of patients imaged using this protocol is necessary to better interpret the results of this study. Different imaging times are another potential technical explanation for uptake that was seen on delayed posttherapy scans (5 d) but missed on early (24 h) 124I imaging (4). However, this is unlikely to be relevant because of the dual-time-point 24and 96-h acquisitions utilized in the THYROPET study. In contrast, it remains plausible that the false-negative 124I PET/CT scans reflect different biologic tumor responses to TSH stimulation from rh-TSH and thyroxine withdrawal. The authors appropriately discuss this possibility with numerous published intrapatient case studies. We also note that in the subset of THYROPET cases, there was one patient who underwent 124I PET/CT after both rhTSH and T4WD, and this patient had 23 times greater 124I retention after T4WD. If this finding were confirmed in a large, prospective, intrapatient 124I study, there would be profound clinical implications for the management of metastatic thyroid cancer, given the widespread use of off-label rh-TSH stimulation for both diagnostic 124I and therapeutic 131I therapy in this setting. We believe it is more plausible that biologic differences between rh-TSH and T4WD stimulation of recurrent thyroid cancer explain the THYROPET results with significant clinical impact. To the extent that technical factors associated with 124I imaging explain the THYROPET study findings, we believe that they are unlikely to affect its role as a theranostic test in this setting.

Enhanced white adipose tissue metabolism in iatrogenic Cushing's syndrome with FDG PET/CT.

A 35-year-old man commenced high-dose dexamethasone (16 mg/d) at diagnosis of cerebral metastases from non-small cell lung carcinoma. F-fluorodeoxyglucose (F-FDG) positron emission tomography (PET)/ computed tomography (CT) performed 9 days later (Figure 1) was nondiagnostic due to widespread abnormally increased FDG-uptake in sc and visceral white adipose tissue (WAT). Comparison with baseline CT demonstrated rapid interval growth of ectopic WAT in a Cushingoid distribution (Figure 2). Prominent sc and visceral WAT FDG uptake was also evident in a 14-year-old boy with Hodgkin lymphoma imaged 6 days after commencement of high-dose prednisolone (75 mg/d). Glucocorticoids induce “catabolic” lipolysis, “anabolic” lipogenesis (adipocyte hypertrophy), and adipogenesis (adipocyte hyperplasia) to remodel WAT into the characteristic Cushingoid distribution (1). Dexamethasone-induced adipocyte differentiation (2) required for ectopic WAT remodeling requires increased glycolytic mitochondrial metabolism (3), and thus ectopic WAT FDG uptake. Increased lipogenesis utilizing glucose as a nonlipid substrate could also explain the widespread WAT FDG uptake in these cases (4). Dexamethasone also induces a proinflammatory milieu within WAT (including raised serum amyloid A) (5), potentially increasing WAT FDG uptake associated with macrophage recruitment. The reduced fasting myocardial and skeletal muscle uptake presumably reflects utilization of high circulating levels of free fatty acids and reduced insulin sensitivity. This is the first description of widespread FDG uptake in WAT after commencement of high-dose glucocorticoids, and it provides unique in vivo insight into the rapid developmentof iatrogenicCushing’s syndrome.However, this uncommon finding is potentially influenced by other factors including age, sex, dosage, and duration of glucocorticoid exposure. The potential utility of FDG PET/CT for assessing WAT metabolism warrants prospective clinical evaluation.

Localisation of occult extra-pancreatic insulinoma using glucagon-like peptide-1 receptor molecular imaging

We report a case of an occult insulinoma and the use of glucagon-like peptide-1 (GLP1) receptor molecular imaging for tumour localisation. A 64-year-old woman with type 2 diabetes mellitus presented to emergency with frequent symptomatic hypoglycaemia. Her local doctor had previously advised cessation of metformin monotherapy and home blood glucose level (BGL) monitoring in the context of hypoglycaemia and improved glycaemic control (HbA1c 5.4%) despite 20 kg weight gain. However, she recommenced monitoring due to transient impaired conscious state and noted hypoglycaemia (1.7 mmol/L) prompting this admission. On examination the patient was obese (132 kg) with central adiposity (body mass index (BMI) 52 kg/m), Glasgow Coma Score 15 and BGL 9.4 mmol/L. She became diaphoretic and anxious 5 h after presentation. Investigations confirmed hypoglycaemia (2.0 mmol/L) concurrent with inappropriately elevated insulin (46 mIU/L), pro-insulin (99.9 pmol/L, reference range (RR) <13.3) and c-peptide (2.54 nmol/L, RR 0.30–2.30) with a suppressed β-hydroxybutyrate (0.3 mmol/L, RR <0.5), negative insulin antibodies and a negative sulfonylurea screen consistent with insulinoma. HbA1c was 4.4%, other biochemistry were normal. Contrast-enhanced abdominal computed tomography (CT) demonstrated a normal pancreas with a 1-cm splenic hilum nodule consistent with a splenunculus. The patient’s abdominal girth precluded further investigation with magnetic resonance imaging (MRI). Gaexendin-4 positron emission tomography (PET)/CT clearly identified a solitary insulinoma at the site of the reported splenunculus (Fig. 1). The patient underwent laparoscopic resection and histology revealed a 15 × 10 × 10 mm neuroendocrine tumour abutting the pancreatic margin. Immunohistochemistry stained positive for synaptophysin, chromogranin, insulin and Ki-67 proliferation index was <1%. Postoperative hyperglycaemia (15 mmol/L) was managed with metformin 2 g plus gliclazide MR 60 mg daily. Hypoglycaemia due to insulinoma in patients with diabetes is rare. The majority of insulinomas are solitary and intra-pancreatic; <1% are ectopic and <10% are malignant or multifocal. Surgical resection is required for cure and preoperative localisation is preferable, but limited by small tumour size. Reported accuracy varies widely, but a contemporary study demonstrates sensitivity of abdominal CT (64%) and MRI (75%). Endoscopic ultrasound (65%) and intra-arterial calcium stimulation testing (IACST, 63%) are highly operator dependent and the latter particularly invasive. Extra-pancreatic location and typical enhancement pattern of the apparent ‘splenunculus’ in this case confounds localisation by conventional imaging and IACST likely would have been misleading. Notably a similar insulinoma masquerading as a splenunculus was identified postmortem in a patient who died despite multiple localisation attempts by conventional imaging, venous sampling and repeat laparotomy. Sensitivity of somatostatin receptor (SSTR) imaging is limited by SSTR type 2 expression in 69% of insulinomas. However, dense GLP1 receptor expression is present in nearly all insulinomas and rapidly emerging experience with Ga-exendin-4 PET/CT demonstrates confident localisation of up to 97.7% insulinomas. GLP1 negative cases are typically avid on SSTR imaging. Halo reconstruction artefact (i.e. suppression of background activity adjacent to regions of intense uptake) is a known limitation of PET ‘scatter correction’ algorithms.

Diagnostic challenges in a patient with an occult insulinoma:68 Ga-DOTA-exendin-4 PET/CT and 68Ga-DOTATATE PET/CT

Despite growing evidence for GLP‐1R molecular‐based imaging, successful localization of insulinomas may require the use of multiple imaging modalities. Not all benign insulinomas express the GLP‐1R as expected. Our case demonstrates that there is a still an important role for traditional methods for the anatomical localization of an insulinoma.

18F-fluorodeoxyglycose-avid thyroid incidentalomas: the importance of contextual interpretation

18F-FDG–avid thyroid incidentaloma (TI) is seen in approximately 2.5% of patients imaged for staging or response assessment of malignancy and represents thyroid cancer in approximately 35% of cases. Consequently, the 2015 American Thyroid Association guidelines strongly recommend investigation of all 18F-FDG–avid nodules 1 cm or larger with ultrasound and fine-needle aspiration cytology (FNA). This study aimed to assess the overall and thyroid cancer–specific survival in a large cohort of patients with 18F-FDG–avid TI with long-term follow-up to assess the validity of this approach. Methods: Retrospective review of 45,680 PET/CT scans performed at a comprehensive cancer center from January 2007 to January 2015 identified 2,588 18F-FDG PET/CT reports referring to the thyroid. After exclusion of nonavid thyroid nodules, diffuse 18F-FDG uptake, known thyroid cancer, abnormalities adjacent to the thyroid, and repeat studies, 500 patients (1.1%) with TI were identified, of whom 362 had confirmed death or more than 12 mo of clinical follow-up. Variables including age, sex, primary malignancy, overall survival, thyroid cancer–specific survival, FNA, and histopathology were collected until January 2016. Multivariate logistic regression and survival analysis were performed. Results: The 362 analyzed patients (65% female) had a median age of 65 y (range, 19–96 y) and follow-up of 24 mo (range, 1–103 mo). Lymphoid, lung, and colorectal malignancy were the most common staging indications. Median overall survival was 20 mo (interquartile range, 9.5–39 mo). Most of the 180 observed deaths were due to the primary malignancy under investigation (92.2%) or to causes not related to cancer (7.2%); one patient (0.6%) died from incidentally detected medullary thyroid cancer. 18F-FDG avidity in the index malignancy, an advanced stage for that malignancy, and a clinician decision not to investigate 18F-FDG–avid TI were all predictors of mortality, with hazard ratios of 8.5, 3.0, and 3.3, respectively, and 95% confidence intervals of 4.6–15.8, 2.3–3.9, and 2.0–5.0, respectively (P < 0.001). Of 131 patients suitable for cytologic or histopathologic evaluation, 47 (36%) had incidental thyroid cancer (24 papillary, 11 malignant FNA, 5 oncocytic/Hürthle cell, 2 medullary, 1 follicular, and 4 metastases from underlying malignancy). Conclusion: Overall survival with 18F-FDG–avid TI was poor because of the prognosis associated with underlying malignancy, which must be considered before investigation of 18F-FDG–avid TI and certainly before aggressive treatment. Active surveillance should be considered in this group of patients.

Intense focal pituitary FDG uptake due to Intravascular Large B‐Cell Lymphoma in Pyrexia of Unknown Origin

Intravascular large B-Cell lymphoma (IVLBCL) is a rare extranodal lymphoma characterized by the presence of neoplastic lymphocytes in the lumina of small vessels [1]. Diagnostic delay (often made post-mortem) is at least in part responsible for its poor prognosis. We present two cases with pyrexia of unknown origin (PUO) despite exhaustive prior investigation (repeated radiologic, serological, and bone marrow biopsy) and prolonged inpatient admission referred for F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT). Intense pituitary uptake (SUVmax5 9.9) without abnormality on co-registered CT was the dominant finding in Case 1 (Image 1A), a 58-year-old man with nine-month history of fevers, 20 kg weight loss, raised inflammatory markers, and pancytopenia. Magnetic resonance imaging (MRI) excluded pituitary macroadenoma and transphenoidal-surgical biopsy was diagnostic for IVLBCL with CD201 ve staining in small arterioles (Image 1B) but complicated by panhypopituitarism. Case 2 is a 63-year-old man hospitalized with a six-week history of fever, weight loss, raised inflammatory markers, anemia, and thrombocytopenia. A similar finding of focal pituitary FDG uptake (SUVmax5 7.1, Image 1C), raised suspicion of IVLBCL that was subsequently confirmed by CD201 ve staining of bone marrow biopsy (Image 1D). MRI pituitary was unremarkable and repeat FDG PET/CT after 5 cycles of R-CHOP demonstrated complete resolution of previously intense pituitary uptake. Both patients remain in complete remission at 68 months and 31 months following diagnosis, respectively. IVLBCL demonstrates highly varied clinical presentation and end-organ involvement with FDG uptake abnormalities described in bone (focal or diffuse), kidneys, spleen, liver, meninges, or stomach [2,3]; however isolated focal pituitary uptake has not been reported. It is critical that referring Image 1. A,C: Sagittal fused FDG PET/CT and FDG PET images demonstrate focal intense pituitary uptake. B: Transphenoidal pituitary biopsy, with CD201 ve immunohistochemical staining of small vessels. D: Bone marrow trephine, CD201 ve immunohistochemical staining associated with small vessels.