Tomographic evaluation of [131I] 6beta-iodomethyl-norcholesterol standardised uptake trend in...

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Tomographic evaluationof [131I] 6ββ-iodomethyl-norcholesterol standardised uptake

trend in clinically silent monolateraland bilateral adrenocortical incidentalomas

A. IMPERIALE 1, C. OLIANTI 1, M. MANNELLI 2, G. LA CAVA 1, A. PUPI 1

Aim. The aim of this study was three-fold: 1) to quan-tify [131I]-6β-iodomethyl-norcholesterol ([131I]-NP-59)adrenal uptake trend in patients with incidentalo-mas, 2) to identify a specific uptake trend (TREND)capable of characterising pre-clinical Cushing syn-drome (PC-CS) patients, 3) to assess the clinical avail-ability of TREND as a prognostic factor of late clini-cal outcome in a cohort of patients with bilateraladrenal adenomas.Methods. Fifty-seven consecutive patients were exam-ined using three-head SPECT at 24, 48, 72 hours fol-lowing intravenous injection of [131I ]-NP-59. On thebasis of the absence or presence of hormonal abnor-malities, the selected population was classified asGR1 or GR2, respectively. Adrenal glands were clas-sified into 4 groups taking into account both thepatient group (GR1, GR2) and the presence (+) orabsence (-) of the adenoma (AD) on CT scan. UsingROI technique, adrenal-liver uptake ratio (A/L) wasestimated bilaterally at 24, 48 and 72 hours. For eachadrenal group, mean [131I]-NP-59 uptake trends werederived.Results. TREND was significantly different betweenGR1/AD+ and GR2/AD+. Among GR2/AD+ patients,TREND correctly identified PC-CS with a global accu-racy of 74%. Two patients with bilateral incidentalo-ma developed an overt CS. In both patients, TRENDcorrectly identified the hyperfunctioning adrenal,thus permitting an effective sparing adrenalectomy.Conclusion. TREND seems to be a parameter whichclosely reflects adrenal physiological behaviour, espe-cially in the case of bilateral adrenal involving. Thepossibility to quantify even contralateral adrenaluptake as standardised index provides additionaluseful information about normal adrenal parenchy-

1Nuclear Medicine UnitDepartment of Clinical Pathophysiology

University of Florence, Florence, Italy2Endocrinology Unit

Department of Clinical PathophysiologyUniversity of Florence, Florence, Italy

ma and, indirectly, about adenoma functional auton-omy.KEY WORDS: Tomography, emission computed, single pho-ton - 131I-NP-59 uptake - Adrenal gland neoplasms -Cushing syndrome.

The increasing number of adrenal lesions detectedby CT and MRI, performed for indications unre-

lated to the adrenals, is emerging as a clinical prob-lem.1, 2 These lesions, described as incidentalomas,have been noted in 0.35-4.4% of CT studies.3 Once dis-covered, their nature must be defined so as to excludemalignancy or hormonal dysfunction.

In this field, the availability of positron emissiontomography (PET), as an imaging tool capable ofexploring the different metabolic activity betweennormal and pathological tissues, offers bothresearchers and clinicians new prospects for patientmanagement. The wide spread clinical use of [18F]-2-fluoro-2-deoxy-D-glucose (FDG) PET is justified inoncologic patients by its high diagnostic accuracy andtherapeutic impact.4, 5 In consideration of the fact thatFDG is not a tissue-specific tracer,4 no evidence existsabout its use in characterising benign adrenal masseswith different functional degree. To this end, alter-

Vol. 49 - No. 3 THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 287

Address reprint requests to: G. La Cava, Nuclear Medicine Unit,Department of Clinical Pathophysiology, University of Florence, VialeMorgagni 85, 50134 Florence, Italy. E-mail: [email protected]

Q J NUCL MED MOL IMAGING 2005;49:287-96

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IMPERIALE STANDARDISED 131I-NP-59 UPTAKE TREND

288 THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING September 2005

native tracers were proposed for adrenal investiga-tions. With regard to the adrenal cortex, someresearchers have tested the diagnostic potentiality of11C-Metomidate (MTO), an inhibitor of 11β-hydroxi-lase the key-enzyme for adrenocortical hormonal pro-duction (cortisol and aldosterone), which is capableof distinguishing adrenocortical from nonadrenocor-tical neoplasms with excellent results.6, 7 Nevertheless,a significant overlap exists in MTO uptake kineticsand standard uptake value between normal adrenalcortex and adrenal neoplasms, thus preventing a cleardiscrimination of adrenal adenomas from adrenal car-cinomas.

On the other hand, [131I]-6β-iodomethyl-norcholes-terol ([131I]-NP-59) adrenocortical scintigraphy is ahighly specific tracer for the morpho-functional char-acterisation of the adrenals. Different patterns of adren-al radiocholesterol uptake, related to adrenal massnature and functional status, are widely reported.8-10

However, the conventional planar [131I]-NP-59 adren-al scintigraphy suffers from low sensitivity in the detec-tion of small masses especially when physiologicalgallbladder and bowel radiotracer accumulation aresuperimposed.11, 12

Tomographic acquisition improves image resolu-tion by permitting a quantitative analysis of adreno-cortical uptake. The uptake in target tissues, nor-malised to those in a reference region, may be usedin clinical practice as an indicator of biological behav-iour in time.

Recently, our group tested the clinical availability ofSPECT semiquantitative [131I]-NP-59 adrenal uptakeevaluation in a cohort of patients with unilateral inci-dentaloma.13 The proposed index (UPT%), as a mea-sure of adrenal relative uptake, was utilised to strati-fy SC- and PC-CS patients.13

With these considerations in mind, we decided toaddress a specific problem in the differential diagno-sis of adrenal incidentalomas. Indeed, even thoughmost of the incidentalomas are non-functional adreno-cortical adenomas,14 quite a percentage of them maybe liable for clinically silent glucocorticoid hyper-production, shaping the so-called pre-clinical Cushingsyndrome (PC-CS).15 PC-CS is related to biochemicalabnormalities with a general progression to overt CS,even if long-term prospective studies which evaluatethe outcome of PC-CS patients, are still lacking.15, 16 InPC-CS patients a high prevalence of obesity, arterialhypertension and non insulin-dependent diabetesmellitus (NIDDM) is frequently observed while the

classical pattern of hypercortisolism is missing.15

Considering the clinical improvement obtained as aresult of the adrenalectomy,17, 18 surgery should beconsidered in PC-CS patients, before a complete con-tralateral adrenal atrophy occurs in order to avoid apost-surgical acute adrenal insufficiency.15

In this study we propose a new application of thesemiquantitative analysis of 131I-NP-59 adrenocorticaluptake in an attempt to parameterise a biological phe-nomenon for clinical purposes.

The aim of this study is three-fold:1. investigate [131I]-NP-59 early adrenal uptake trend

(TREND) from the 24th to the 72nd hour following trac-er injection in patients with incidentalomas,

2. identify a specific uptake trend capable of char-acterising PC-CS patients, and hence, compare UPT%and TREND index diagnostic accuracy,

3. assess the clinical availability of TREND as aprognostic factor of late clinical outcome in a cohortof patients with bilateral adrenal adenomas.

Materials and methods

Patient population

Fifty-seven consecutive patients (27 men, 30women; mean age±SD, 56±9 y), examined in ourinstitution for CT-discovered adrenal incidentaloma,were included in this study. Of these, 53 showed uni-lateral and 4 bilateral incidentalomas, respectively.Exclusion criteria were severe or paroxysmal hyper-tension, hypokaliemia, clinical signs of overt hyper-cortisolism or hyper-androgenism, previous or con-current malignancies, or a scintigraphic discordantuptake pattern. Only incidentalomas with CT char-acteristics suggestive of benign adrenocortical ade-noma were included:19 tumor size of less than 5 cmwith an oval shape, hypodense and homogeneouspattern with well-defined margins, no or mild homo-geneous enhancement after contrast i.v. administration.

In order to establish the adenoma functional status,the selected population underwent an endocrinolog-ical evaluation based on baseline measurements ofplasmatic cortisol at 08:00 h, morning adrenocorti-cotropin (ACTH), dehydroepiandrosterone sulphate(DHEA-S), 17-hydroxyprogesterone (17-OHP), 24 hurinary-free cortisol (UFC), supine and upright plas-matic renin activity (PRA) and aldosterone, and 24 hurinary aldosterone. Measurement of the above select-

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STANDARDISED 131I-NP-59 UPTAKE TREND IMPERIALE


ed hormonal variables were performed in a referencelaboratory by immunoassays using commercially avail-able kits. The normal range for serum cortisol andACTH concentrations at 08:00 h was 140-690 nmol/Land 9-52 ng/L, respectively. The normal value for 24h UFC was less than 275 nmol/24 h. The normal rangefor serum DHEAS and 17-OHP concentrations was1.3-6.7 mmol/L and 0.2-9 nmol/L, respectively. In allpatients, plasmatic cholesterol concentration was with-in the range of normality (160-220 mg/dl).20

On the basis of endocrine features, 53 patients withunilateral incidentaloma were classified into 2 groupsas follows: 1) Group 1 (GR1): subjects showing no hor-monal abnormalities (EA), suggesting silent hyper-cortisolism (21 subjects: 10 M, 11 F, mean age±SD,

59± 6 y); 2) Group 2 (GR2): subjects with almost sup-pressed baseline ACTH, as an index of hypothala-mus-pituitary-adrenal (HPA) axis alteration, havingpreviously excluded any potential pharmacologicalinterference (32 subjects: 15 M, 17 F, mean age±SD,54±10 y). Table I summarises patient population clin-ical features. Subsequently, the 106 adrenal glandsexamined were classified into 4 groups taking intoaccount both the patient group (GR1, GR2) and thepresence (+) or absence (-) of the adenoma (AD) onCT scan: a total of 21, 21, 32 and 32 adrenals weregrouped GR1/AD+, GR1/AD-, GR2/AD+ and GR2/AD-, respectively (Figure 1).

According to Reincke classification 15 and on thebasis of both clinical and endocrine features at thestaging, the same 53 patients previously considered,were classified into 3 groups as follows (Table II): 1)no functioning adenoma (NF): subjects showing nei-ther endocrine abnormalities (EA) nor typical signs orsymptoms (SS) of overt CS (moon face, central obe-sity, irsutism, buffalo hump, strie rubrae) 15 nor nonspecific signs or symptoms of CS (edema, arterialhypertension, diffuse obesity, NIDDM or glucose intol-erance) (total 19 subjects: 9 M, 10 F, mean age±SD,58±7 years); 2) sub-clinical CS (SC-CS): subjects show-ing EA but no typical or non specific signs or symp-toms of CS (total 11 subjects: 6 M, 5 F, mean age±SD,58±6 years); 3) PC-CS: subjects showing EA, no SS, butat least 2 of the non specific clinical signs (total 23 sub-

TABLE I.—Patients with unilateral adrenocortical adenoma: hor-monal and radiological evaluation at staging.

Characteristics GR1 p GR2(No.=21) (No.=32)

Sex (F/M) 11/10 NS 17/15Age (y) 59±6 NS 54±10ACTH at 0800 (ng/L) 21±8 <0.0002 7.5±1.7Cortisol at 0800 (nmol/L) 354±148 <0.0002 549±181UFC (nmol/24 h) 178±59 <0.01 479±586CT adenoma size (cm) 2.2±0.74 <0.01 2.8±0.87

GR1: subjects without hormonal abnormalities; GR2: subjects with almostsuppressed baseline ACTH; ACTH: adrenocorticotropin; UFC: 24-h urinaryfree cortisol; ns: not significant

53 patients with CT monolateral incidentaloma(106 adrenals)

32 patients with almost ACTH<9 ng/LGR2

(64 adrenals)

GR2/AD-GR2/AD+

Adrenals with CT incidentalomaAD+

(32 adrenals)

Contralateral adrenalsAD-

(32 adrenals)

21 patients with ACTH ≥9 ng/LGR2

(42 adrenals)

GR1/AD-GR1/AD+

Adrenals with CT incidentalomaAD+

(21 adrenals)

Contralateral adrenalsAD-

(21 adrenals)

Figure 1.—Adopted criteria for patients and adrenals classification. HA=hormonal alterations; ACTH=baseline adrenocorticotropin.

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jects: 12 M, 11 F, mean age±SD, 53±11 years). Thefinal clinical diagnosis was confirmed in all patientsincluded in the study by 1 year follow-up data.Nobody developed an overt CS during this observa-tion period.

Finally, the remaining 4 patients with bilateral inci-dentaloma were retrospectively evaluated after a meanendocrinological and radiological follow-up of 31months (mean age±SD follow-up: 31±9 months, fol-low-up range: 23-43 months) starting with the staging[131I]-NP-59 scan.

Adrenocortical scintigraphy

Abdominal SPECT was performed by using three-head SPECT (IRIX 3000; PIKER International) at 24,48 and 72 hours following 37 MBq [131I]-NP-59 (NOR-CHOL-131‚ CIS Bio International Paris; Schering S.A.)i.v. injection in accordance with our usual proto-col.13 In a feasibility study, the first 20 patients under-went delayed scan until 120 h. To block thyroidaluptake of free [131-I], 10 drops of Lugol solutionwere given daily for a period of 1 week, beginning3 days prior to [131I]-NP-59 injection. To decrease theenterohepatic circulation of radiocholesterol whichresults in the intestinal background, a mild laxativewas given throughout the examination beginning 2days prior to the 1st day of image acquisition.21 Highenergy collimators were employed. The 15% energywindow was centred at 364 KeV. 4.4×4.4 mm pixelsize 128×128 matrices were obtained by using a step-and-shoot 360° acquisition arc, and 120 projections(40 per head). The images, acquired for 60 secondsper projection for a total imaging time of 40 min-utes, were reconstructed from projection data byusing the filtered back-projection algorithm; aButterworth filter with an order of 9, and a cut-off fre-quency of 0.3.

Semiquantitative uptake measurement

The tomographic images at the above specifiedtimes (24, 48 and 72 h following tracer injection) wereanalysed as follows. To obtain the total activity in theadrenal regions, 10 transaxial slices, beginning fromthe first in which the adrenal gland appeared, wereadded in the caudal direction. In all the cases exam-ined, 10 slices comprised both adrenal glands for theirentire length. Standard elliptical regions of interest(ROIs) were drawn on the resulting transaxial imageconnected with adrenals and the liver, taking care toavoid the gallbladder region. Next a ratio betweeneach adrenal and the liver (A/LT) was estimated as fol-lows:

A/LT = (AdrROI)cntT / (LivROI)cntT

where (AdrROI)cntT and (LivROI)cntT are the ROIuptake measurements of the adrenal and liver respec-tively, and T is the acquisition time in hours.

A/L values, derived from each single adrenal dur-ing the different acquisition times (24, 48 and 72hours), were plotted against time in hours and sub-sequently interpolated applying a linear fitting (Figures2, 3). Hence, from the 106 regression lines obtained,both linear regression angular coefficients (TREND)and intercepts were determined. Mean TREND, foreach adrenal group (GR1/AD+, GR1/AD-, GR2/AD+and GR2/AD-), were derived.

The adrenal ROI integral count, obtained by sum-ming the 24, 48, and 72 h A/L values, was normalizedto the hepatic integral one (nUPTint). Subsequently,the adrenal percentage of relative uptake (UPT%) wascomputed as follows:13

UPT%=(nUPTint)adenoma/[(nUPTint)adenoma+(nUPTint)normofunctional]

where (nUPTint)adenoma is the normalized integral counton the adenomatous gland and (nUPTint)normofunctional

TABLE II.—Results of semiquantitative analysis of 131I-NP-59 adrenocortical uptake obtained from 53 patients with unilateral inci-dentaloma.

GR 1 GR 2

A/LT AD+ p AD- AD+ p AD- p 1-3 p 2-4

A/L 24 0.63±0.18 <0.04 0.52-0.17 0.66±0.16 <0.0001 0.44±0.08 NS NSA/L 48 0.85±0.18 <0.003 0.66-0.19 0.99±0.25 <0.0001 0.60±0.14 <0.03 NSA/L 72 1-0.24 <0.01 0.79-0.24 1.48±0.26 <0.0001 0.75±0.15 <0.0001 NS

AD+: adenomatous adrenal; AD-: controlateral morphologically normal adrenal; A/L: adrenal/liver ratio; T: SPECT acquisition time in hours; p 1-3: GR1/AD+vs GR2/AD+; p 2-4: GR1/AD- vs GR2/AD-

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is the normalized integral count on the other adren-al gland.

Statistical analysis

Results are expressed as mean±SD. Analysis of vari-ance (ANOVA) using the Tukey posthoc test was usedfor between- and within-group comparisons while t-test for depending samples was used to comparedTREND values obtained from 72 h until 120 h.Correlations were examined using linear regressionanalysis. Univariate discriminant analysis was per-formed on TREND and UPT% data (belonging frompatients with unilateral incidentaloma) to determinethe cut-off values of both considered variables, whichare able to linearly discriminate best between the SC-CS and PC-CS groups. This procedure involves thecomputation of a linear function which yields the

optimal possible classification of the observationshaving as its reference a grouping factor.

In the present study the reference grouping factorwas the staging clinical diagnosis of SC-CS and PC-CS,confirmed after almost 1 year patient follow-up. Theachieved classification, after cross-validation, was sub-mitted to a jack-knife validation procedure to limitbias in the number of patients correctly classified.Pair Receiver operating characteristic curve (PairROC)analysis was used for tests (UPT% and TREND) com-parison.

STATISTICA (Statsoft) software packages were usedfor statistical data analysis. CMDT (computationalmethods for diagnostic tests, provided by FreieUniversitat Berlin, Institute for Parasitology andTropical Veterinary Medicine, [email protected]) soft-ware was used for PairROC analysis. A p value lessthan 0.05 was considered statistically significant.

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Time (hours)

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GR1/AD+ MEANGR1/AD+ +SDGR1/AD+ -SDGR1/AD- MEANGR1/AD- +SDGR1/AD- -SD

y2=0.43+0.008 xy1=0.22+0.017 x

y2=0.35+0.006 xy1=0.43+0.008 x

Figure 2.—Radiocholesterol uptake mean trends of adrenals with functioning (2.A) and no-functioning (2.B) adenomas versus the contrala-teral morphologically normal glands.

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GR1/AD- MEANGR1/AD- +SDGR1/AD- -SDGR2/AD- MEANGR2/AD- +SDGR2/AD- -SD

y2=0.43+0.008 xy1=0.22+0.017 x

y2=0.39+0.006 xy1=0.30+0.006 x

Figure 3.—Radiocholesterol uptake mean trends of adrenals with functioning versus no-functioning adenomas (3.A) and GR1 versus GR2 con-tralateral glands (3.B).

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Results

Feasibility study

In order to assess whether or not the hepatic activi-ty was available to standardise UPT% and TREND, wetested the variability of liver activity trend in the wholepopulation. To this end, hepatic activity expressed as 24hour activity percent was plotted against the time inhours. The linear and exponential fit of the liver uptakedata showed a close agreement in the whole population.Both intercept and slope were very similar among allsubjects examined, yielding the follow mean±SD values:1.2±0.5 and -0.012±0.001 for linear fit and 1.5±0.1 and-0.02±0.003 for exponential fit. On the basis of these data,no significant differences were found among the patientsexamined as regards hepatic activity trend.

In order to optimise [131I]-NP-59 scan acquisition tim-ing, the first 20 consecutive patients, independently ofadenoma functional degree and dimension, were stud-ied until 120 hours. Subsequently, TREND valuesobtained until both 72 h (0.0090±0.008) and 120 h(0.0088±0.005) were derived and compared using thet-test for depending samples. No significant differencewas observed (p=0.25). A strong correlation (p<0.00001)between 72 and 120 h TREND was found (r=0.92).

Hence, by using early acquisitions (24-72 h), it ispossible to obtain reliable clinical results withoutextending the duration of each SPECT, an essentialrequirement in case of late scans (5-7 day after trac-er injection) in order to reduce the statistical errorrelated to the measurement. With regard to A/L mea-surements reproducibility, as reported in our previouswork,18 there was no significant A/L determinationinterobserver difference (p=0.57).

Experimental design

The derived A/L values for each adrenal groupswere summarized in Table II. The analysis of vari-

ance applied to A/L values showed a significant dif-ference for each timing of SPECT acquisition (24, 48,and 72 h) between GR1/AD+ and GR1/AD- (p<0.04,p<0.003 and p<0.01, respectively), as well asbetween GR2/AD+ and GR2/AD- (p<0.0001).Between GR1/AD+ and GR2/AD+ a significant dif-ference was shown for 48 h and 72 h A/L values(p<0.03, p<0.0001, respectively). On the contrary, theA/L values derived from GR1/AD- and GR2/AD-,for 24 h to 72 h SPECT study, were not significant-ly different.

A low correlation (p<0.0001) was found betweenA/L72 as well as for both ACTH values (r=-0.47) andCT adenoma dimension (r=0.30).

In Table III were summarised the mean values ofslope and intercept derived from each adrenal group(GR1/AD+, GR1/AD-, GR2/AD+ and GR2/AD-). TheANOVA applied on slope data showed significant dif-ferences between GR2/AD+ and GR2/AD- (p<0.0002)as well as between GR1/AD+ and GR2/AD+(p<0.0002). The only significant difference among theintercept values was found between GR2/AD+ andGR1/AD+ (p<0.01).

The existence of any relationship between TREND,CT dimensions and hormonal features was investi-gated by multiple regression analysis but no significantcorrelation was found.

UPT% and TREND indexes diagnostic accuracy com-parison

UPT% and TREND values derived from 131I-NP-59uptake analysis were submitted to univariate dis-criminant analysis and the classification matrix wasderived. The UPT% value of 61.8 best discriminatedSC-CS and PC-CS patients (p<0.0001), correctly iden-tifying 10/11 SC-CS and 21/23 PC-CS with a globaldiagnostic accuracy of 91%, a sensitivity and specificityof 91% and 91% respectively, together with a 95%positive and 83% negative predictive value. The

TABLE III.—Mean linear regression angular coefficient (slope) and mean intercept derived from each considered adrenal group in53 patients with unilateral incidentaloma.

GR 1 GR 2

AD+ p AD- AD+ p AD- p 1-3 p 2-4

Slope 0.008-0.004 NS 0.006-0.005 0.017-0.006 <0.0002 0.006-0.002 <0.0002 NSIntercept 0.43-0.28 NS 0.35-0.25 0.22-0.25 NS 0.30-0.12 <0.01 NS

AD+: adenomatous adrenal; AD-: controlateral morphologically normal adrenal; p 1-3: GR1/AD+ vs GR2/AD+; p 2-4: GR1/AD- vs GR2/AD-

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TREND value of 0.014 best discriminated SC-CS andPC-CS patients (p<0.001), correctly identifying 10/11SC-CS and 15/23 PC-CS with a global diagnostic accu-racy of 74%, a sensitivity and specificity of 65% and91% respectively, together with a 94% positive and56% negative predictive value.

Pair ROC analysis (Figure 4) applied in a matched-pair design for comparison the UPT% and TRENDdata showed a not significant difference between theROC curves derived from the 2 diagnostic tests con-sidered (p=0.35).

TREND in bilateral incidentaloma

Having tested the good clinical accuracy of TRENDto stratify patients with adrenal cortical functioningincidentaloma, we evaluated the clinical outcome of4 patients with bilateral adrenocortical adenoma aftera mean follow-up of 31±9 months. At staging nopatient showed classic clinical features of overt CS.Hypertension was present in patients 1 and 2, NIDDMin patient 2, obesity in patients 1, 2 and 3. The resultsof clinical, endocrinological, radiological and nuclearmedicine examinations at both staging and end follow-up, are resumed in Table IV. Patients 1 and 2 under-went complete left laparoscopic adrenalectomy 10and 5 months respectively following close endocrino-logic and radiological follow-up, showing overt hor-monal abnormalities, increase in CT mass diametertogether with exacerbation of clinical symptomatology.Histological examination confirmed the adenomatousnature of the excised cortical adrenal mass. At theend of follow-up, patients 3 and 4 did not show anyprogression of the disease in terms of CT mass dimen-sion (no mass enlargement was detected) and hor-monal abnormalities (ACTH, serum cortisol, CLU val-ues were quite similar to the staging ones). Duringpostoperative follow-up patients 1 and 2 showed acomplete normalization of all the hormonal indices ofadrenocortical functionality. The clinical featuresimproved but did not completely disappear and CT-scan demonstrated a slight increase in the residual

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Figure 4.—TREND and UPT% ROC curves. Se: sensitivity; Sp: speci-ficity.

TABLE IV.—Summary of clinical, hormonal and radiological data of the 4 patients with bilateral adrenocortical adenoma studied.

Patient 1 Patient 2 Patient 3 Patient 4

Staging Presurgry Postsurgery Staging Presurgery Postsurgery Staging End Staging Endfollow-up follow-up

Age (y) 63 50 61 57Sex (M/F) F F M MACTH (ng/L) 5 5 12 10 5 15 10.2 10 10 11Serum cortisol (nmol/L) 480 552 220 300 700 200 424 412 700 680UFC (nmol/24 h) 230 320 200 125 350 180 155 160 250 252Dexamethasone test* + + - -

OB OB↑Clinical symptomatology OB H OB↑ H↑ OB NIDDM NIDDM NIDDM OB OB

H H↑ H↓Right CT mass diameter (cm) 1.7 1.7 3 3 3 3.5 3 3 3 3Left CT mass diameter (cm) 3.4 4 3.5 3.5 2 2.2 2 2Right TREND 0.008 0.010 0.002 0.010Left TREND 0.018 0.024 0.009 0.06Follow-up (mo) 10 13 5 19 35 43

*: 1 mg overnight, OB: obesity, H: hypertension, +: positive, -: negative, ↑ : increased, ↓ : decreased

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adrenal mass. No steroid replacement was necessaryin any case nor was any adrenal insufficiency noted.

Staging TREND values derived from the 8 adrena-ls examined, showed abnormal slope values (whichwere higher than the slope cut-off previously derived)only for the left adrenals of patients 1 and 2 (Table IV).

Discussion

Adrenocortical scintigraphy is a useful and noninvasive technique for the functional characterisationof adrenal masses. By complementing the excellentanatomical detail provided by CT and MRI, [131I]-NP-59 scan is accurate in detecting hypersecreting adreno-cortical adenoma and destructive or space occupy-ing lesions. To this end, Gross and Shapiro criteria 8-

10 are widely adopted in a variety of contexts. Theseinclude the following: 1) exclusive uptake by thetumor with no visualisation of the contralateral gland;2) prevalent uptake with visualisation of the con-tralateral gland; 3) symmetrical uptake with normalbilateral adrenal uptake, and 4) reduced or absentuptake by the tumor, also defined as “discordantuptake pattern” in contrast to the exclusive and theprevalent uptakes which are defined as “concordantuptake patterns”. A concordant uptake pattern is diag-nostic for adenoma or hyperplasia with 100% speci-ficity and 93% sensitivity whereas a discordant uptakepattern suggests malignancies with 100% specificityand sensitivity.10, 22, 23 However, the widespread use ofconventional planar acquisition in adrenal diseaselimits the sensitivity of the scintigraphic approach indetecting small masses. Lesions which measure lessthan 2 cm in diameter may not have sufficient hypersecreting tissues to produce a visible adrenal uptakeasymmetry and, thus, result in a concordant pattern(benign adenomas). Hence, the nature of those lesionsis usually misunderstood due to their relative sym-metrical uptake pattern.

To overcome planar scintigraphy spatial resolutionlimitation in detecting and characterising smaller adren-al lesions, the use of SPECT acquisition was suggest-ed (Figure 5).12, 24-26 However, in spite of the currentavailability of multidetector scintillation cameras withimproved resolution, tomography is not yet routine-ly used.

In this study we investigated the behavior of adren-al adenomas, according to their different functional sta-tus, by quantifying a physiological phenomenon such

as the adrenal cholesterol uptake, modified by thepresence of adenoma. Moreover, the adopted ROItechnique instead of visual analysis enabled us toreduce operator subjectivity in scan interpretation.

The adrenal avidity in [131I]-NP-59 uptake is repre-sented by the slope value. Indeed, greater incrementsof adrenal uptake in the 3 acquisition days, are respon-sible for greater slope increase. Hence, fundamentalparameters to be taken into account include not onlythe absolute uptake value, but also the incrementalrate. Moreover, it is interesting to observe both theslight, but significant, relationship between A/L72 val-ues and CT adrenal adenoma dimension, as well as thelack of correlation between TREND and adenomadiameter. These data constitute the limits of an exclu-sive morphological approach in investigating adreno-cortical dysfunction.

Our data showed a significant difference betweenGR1 and GR2 adenomatous adrenal TREND(p<0.0002) as well as A/L values (starting from the

1-RIGHT ADRENALR ROI2-LEFT ADRENALR ROI3-LIVER ROI

RIGHT A/L 24:0.90LEFT A/L 24:0.55

RIGHT A/L 48:1.11LEFT A/L 48:0.78

RIGHT A/L 72:1.50LEFT A/L 72:0.90

Rightadrenal

Figure 5.—Typical SPECT study in one patient with concordant pat-tern (CP) according to the Gross and Shapiro criteria. CT scan demon-strated a 2 cm right corticoadrenal adenoma. Ten transaxial slices,beginning with the first one in which the adrenal gland appeared, wereadded in the caudal direction to obtain the total activity in the adre-nal regions. A standard elliptical region of interest (ROI), at 24, 28 48and 72 hours after 131I-NP-59 injection, were manually drawn to esti-mate counts/pixel in liver, normal and pathological adrenals.Subsequently, adrenal-liver ratio (A/L) was estimated bilaterally.

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48th hour examination). In addiction, while an A/Lsignificant difference existed between pathologicaland the contralateral adrenal in both GR1 and GR2patient groups, pathological adrenal mean TRENDwas different from the contralateral one only in GR2.In other words, adrenals with no-functioning adeno-mas (GR1/AD+) are set on a higher uptake level thannormal contralateral glands (GR1/AD-) but they are allthe same in terms of uptake incremental rate (Figure2B, Table III).

The ANOVA applied to the A/L values which wererelated to the contralateral morphologically normaladrenals, did not show significant differences betweenGR1 and GR2; this suggests the presence of adrenalparenchyma which are still normal in both cases. Thisapproach can be utilised even to follow-up the atro-phy grade of normal glands after a prolonged and, inmost cases, subtle cortisol hyper production (Table II).

Recently, we evaluated a cohort of patients withunilateral incidentaloma by using a SPECT semi-quantitative index of [131I]-NP-59 adrenocortical uptake(UPT%).13 The results of this investigation wereencouraging (global accuracy 90%) but should beproven after a long term clinical follow-up.

To discriminate between patients with a “sub-clin-ical” or a “pre-clinical” CS, a specific TREND valuewas determined. To classify those patients with uni-lateral adrenal incidentaloma at risk who would devel-op an overt CS, TREND showed a good global diag-nostic accuracy (74%). Results suggest that TREND isperhaps less reliable than UPT%, but PairROC analy-sis does not show significant differences between the2 parameters. The higher UPT% sensitivity, is proba-bly related to the capability of this index to take intoaccount both the, adenomatous and normal con-tralateral adrenal. Indeed, UPT% is related to boththe adenoma functional status and the suppressiondegree of the contralateral adrenal. Hence, in thispopulation with high pre-test disease probability(67%), the higher UPT% accuracy is probably due toits sensitivity.

On the other hand, TREND analysis offers anautonomous biological functional standardization ofthe single adrenal, hence it is utilized even in cases ofbilateral adenomas or hyperplasia. As each method isbased on relative measurements of paired organs,UPT% suffers when the adrenals are bilaterallyinvolved. In addition to the estimation of renal func-tion based on DMSA, relative uptake is not accuratein assessing damage to each kidney in the case of

bilateral disease, thus, the major UPT% limit arises inbilateral adenomas/macronodular hyperplasia.

To this end, the [131I]-NP-59 uptake TREND analy-sis plays an important role. The idea of the currentstudy to consider TREND as a parameter which reflectsthe biological behavior of adrenal adenomas on thebasis of their functionality, derives from the need toovercome the non-availability of UPT% in the caseof bilateral adrenal involvement.

Our preliminary results, obtained from the analysisof patients with bilateral adenomas, seem to confirmthe clinical usefulness of the new parameter proposedbut they need to be proven on a large patient popu-lation. Hence, TREND may be used to identify theadrenal at risk of functional autonomy in patientswith bilateral adrenocortical neo-formations. Further-more, once its clinical reliability has been confirmed,this non-invasive diagnostic approach may be con-sidered as a possible alternative to adrenal vein cor-tisol sampling in the planning of a sparing adrena-lectomy. Moreover, since [131I]-NP-59-SPECT scan cancharacterise adrenals in 3 days, it reduces dietary andpharmacological patient discomfort.

Conclusions

Based on our results, TREND seems to be a para-meter which closely reflects single adrenal physio-logical behavior, and that overcomes the dimension-al criteria (higher mass diameter is equal to higherfunction) in evaluating adrenocortical adenoma func-tional status, even in the case of bilateral adrenalinvolvement. Thus, the possibility of quantifying evencontralateral adrenal uptake as a standardized index,provides additional useful information about normaladrenal parenchyma status and, hence, indirectly,adenoma functional autonomy.

In conclusion, even if PET technology is becomingthe preferred functional image mode especially inoncological patients, nowadays [131I]-NP-59 scintigra-phy remains a simple, cost effective and accuratetechnique for the investigation of patients with inci-dentally discovered adrenal masses, with laboratoryproven hormonal imbalance. Moreover, the tomo-graphic approach as opposed to the planar one, offersthe possibility to obtain (semi)quantitative indiceswhich are useful in the estimation of adrenal functionaldegree, especially when hormonal results are notcompletely clarifying and, in addition, during patient

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follow-up with the aim to identify those lesions thatcan lead to overt clinical syndromes as a result ofhormonal hyperproduction.

Finally, SPECT technique with (semi)quantitativeapproach permits an old and underused imagingmodality such as [131I]-NP-59 scintigraphy to acquiregreater clinical relevance in the management of inci-dentalomas, playing a role not only in the confirma-tion of radiological and/or hormonal features, butalso in providing functional information related toadrenal status.

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