European Journal of Endocrinology 10.1530/EJE-16-0455 Andrea M Isidori signs of the disease and the problems in obtaining a signs ofthediseaseand problemsinobtaininga challenge for the clinician, given the relatively few specific stalkpresentademanding primarily involvingthepituitary gland.Diseaseprocesses hypothalamus tothepituitary stalkconnectsthemedianeminenceof The pituitary Introduction degree ofaccuracy. gadolinium T1imageswiththeaimofdifferentiating betweenneoplasticandnon-neoplasticlesionswithahigh directing futuretherapy. We proposepossible texturalheterogeneitycriteriaofthepituitarystalkonpre-andpost- Conclusions: NewtechniquesofMRIimaginganalysismayidentifyclinicallysignificantneoplasticlesions,thus images (sensitivity:88.9%,specificity:91.7%). correlation betweenthetumourpathologyandpituitarystalkheterogeneityinpre-post-gadoliniumT1-weighted on sizecriteriaorprogressionwith30%sensitivity. However, texturalanalysisofMRIscansrevealedasignificant at presentation,withsecondaryhypogonadismthemostfrequentanteriorpituitarydefect.Neoplasiawassuggested follow-up (mean41.3 lesions. Intheremaining14patients,adiagnosisofnon-neoplasticdisorderwasassumedonbasislong-term Results: Diagnosiswasconsideredcertainfor22patients:46%neoplastic,32%inflammatoryand22%congenital biochemical, histopathologicalandlong-termfollow-updata. intensity, enhancementandtexture appearanceatMRI(evaluatedwiththeImageJprogramme),alongclinical, stalk thickeningevaluatedatauniversityhospitalinOxford,UK,2007–2015.We reviewedmorphology, signal Design andmethods:Retrospectiveobservationalstudyof36patients(meanage37 and theirassociationwithspecificMRIfeaturesinordertoprovidediagnosticprognosticguidance. Objective: Theaimwastoassesstheclinical,biochemicalandhistopathologicalcharacteristicsofpituitarystalklesions remains unclear. Context: Diseaseprocessesthataffect thepituitarystalkarebroad;diagnosisandmanagementoftheselesions Abstract 1 Emilia Sbardella assist indeterminingclinicalmanagement innovative MRIimaginganalysiswhichmay Pituitary stalkthickening:therole ofan University ofOxford,UK, Rome, Italy, and Oxford, UK Hospital, UniversityofOxford,UK, Department ofEndocrinology, OxfordCentreforDiabetes,EndocrinologyandMetabolism,Churchill DOI: 10.1530/EJE-16-0455 www.eje-online.orgwww.eje-online.org Clinical Study 4 Department ofNeurologicalSurgery, JohnRadcliffe Hospital,UniversityofOxford, 1,3 3 , Simon Cudlip , Robin NJoseph months, range:12–84).Diabetesinsipidusandheadachewerecommonfeaturesin4742% 3 Department ofExperimentalMedicine,SapienzaUniversityRome, © 2016EuropeanSociety ofEndocrinology © 2016EuropeanSociety ofEndocrinology E Sbardellaandothers 2 Department ofNeuroradiology, JohnRadcliffe Hospital, 4 andAshley BGrossman 2 , Bahram Jafar-Mohammadi Printed inGreatBritain 1 can beassociatedwithsignificant morbidity. Magnetic isrequired,giventhatsurgery when surgicalintervention highly problematic,anditremains unclearastohowand stalkis specifically withabnormalities ofthepituitary tissue sample.Themanagement ofdisordersassociated thickening Imaging inpituitarystalk Published byBioscientifica Ltd. 1 , years, range:4–83)withpituitary Downloaded fromBioscientifica.com at10/02/202104:11:53AM (2016) Endocrinology European Journal of ac.uk [email protected]. Email to ABGrossman should beaddressed Correspondence 175 175:4 : 4 175, 255–263
255–263 via freeaccess Clinical Study E Sbardella and others Imaging in pituitary stalk 175:4 256 thickening
resonance imaging (MRI) has proved to be an essential isolated/multiple anterior pituitary hormone deficiencies. tool in the evaluation of intracranial pathology and of the Baseline endocrine tests including serum GH, IGF1, LH, majority of lesions affecting the hypothalamo-pituitary FSH, testosterone or estradiol, prolactin, thyroid function, region (1, 2, 3, 4, 5, 6), but its role in determining when 09:00 h cortisol, plasma ACTH and dynamic function tests surgery is appropriate in this situation is controversial (7, 8). where available. Serum/CSF tumour and inflammatory The upper limit of normal of the width of the pituitary markers such as hCG, αFP and ACE were recorded when stalk is 3.25 mm near the median eminence and 1.9 mm performed at any point either at presentation or during at its insertion into the pituitary gland (9). Pituitary stalk the course of the disease process. lesions are often discovered on MRI either incidentally or during evaluation for symptoms related to various degrees MRI evaluation of hypothalamic and/or pituitary dysfunction, especially in patients with isolated diabetes insipidus (DI). The All retrieved MRI scans were fully re-analysed by a differential diagnosis of masses affecting the pituitary stalk is neuroradiologist and, independently, by an endocrinologist wide, and can be grouped into three categories: congenital, expert in neuroendocrine imaging: both were blind to the inflammatory/infectious and neoplastic (8, 10, 11, 12). attributed diagnosis. Both investigators were asked to However, to obtain a definitive histological diagnosis would confirm stalk thickening, annotate the dimensions require biopsy of the stalk, which is a difficult procedure and length of the stalk, evaluate the homogeneity associated with considerable morbidity (13). Guidelines of the thickening, the presence or absence of the regarding the clinical management of such lesions are posterior hypophyseal bright spot (PHBS), and the MRI sparse, other than a recent review from the Mayo Clinic (6), characteristics and enhancement pattern (homogeneous/ and there are few centres with the large patient numbers and non-homogeneous) of the adenohypophysis and expertise to collate sufficient data on their management. neurohypophysis. Disagreement was discussed and We have, therefore, conducted a retrospective analysis consensus agreed. of patients with pituitary stalk thickening evaluated at a Although the patients were submitted to different large referral centre over the last decade. In particular, we protocols, all patients were included in the study on the have tested whether novel analysis of MRI imaging can condition that sagittal and coronal non-enhanced and/ offer a diagnostic advantage and guide management of or enhanced T1-weighted images of the hypothalamo- this rare condition. hypophyseal tract were present; this ultimately led to a collection of 33 T1-weighted pre-contrast and 32 European Journal European of Endocrinology T1-weighted post-contrast images. Patients and methods Analysis of hypothalamo-hypophyseal region was reviewed at subsequent MRI scans to assess changes We identified patients with pituitary stalk thickening by occurring throughout the follow-up period. The shape, an electronic and manual search of the weekly pituitary length and diameter of the pituitary stalk (PS) were surgical multidisciplinary group records, the neurosurgical measured proximally and distally from sagittal and operation lists of the neurosurgeon (SC) performing this coronal T1-weighted sequences (14). The stalk was procedure and our pituitary patient database; the text considered enlarged when the diameter was greater than words ‘pituitary stalk’ and ‘infundibulum’ were used in a 3.25 mm in its proximal portion and/or 1.9 mm in its computerised search. distal portion, as reported previously (9). The height and Inclusion criteria were age between 4 and 80 years, and depth of the anterior pituitary on the sagittal T1-weighted a cranial/pituitary MRI performed between January 2007 image, and width on the coronal T1-weighted image, and December 2015. Exclusion criteria were patients with were also recorded for each patient. inadequate imaging or a normal pituitary stalk at image Texture analysis (TA) of pituitary and brain MRI was revision, and patients with pituitary or brain radiation/ analysed using ImageJ 1.49v (NIH). The distribution surgery before the diagnostic MRI. of grey levels between pixels in a given region of interest (ROI) was described by means of the standard deviation (s.d.) of the ROI. Curves were obtained by Endocrine assessment manually placing the ROI to entirely cover the pituitary The following data were collected from medical records: stalk (examples are shown in Figs 1 and 2). White anthropometric parameters, signs and symptoms of DI or (the corpus callosum) and grey brain matter (frontal
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Downloaded from Bioscientifica.com at 10/02/2021 04:11:53AM via free access European Journal of Endocrinology of thisarticle). 2 and Tables 1 operator (ES)wereused(Supplementary reliability fortheentireset,dataobtainedbyone agreement wascalculatedand,giventhesubstantial ROIs andrecordedtexturalparameters.Inter-observer physicians (AMIandES)independentlyplacedthe in T1-weightedimagespre-andpost-gadolinium.Two sagittal andcoronalslices.Allparametersweremeasured gland in bothwe measured thetexture in thepituitary normalise thedatameasuredatPSlevels.Additionally, biochemically stable. then yearly if the lesion was morphologically and 6 and subsequentlyevery MRI3 and pituitary evaluation, endocrinetests,serumtumourmarkers and imagingresults,butusuallyconsistedofclinical according toclinicalhistory, symptoms,biochemical Each patientreceivedapersonalisedfollow-upprotocol Follow-up cortex circonvolution) intensity and deviation ( post-gadolinium T1imagewithmeangreyvalue,standard ImageJ analysisofapituitarystalkgerminomaincoronal Figure 1 this figureisavailableathttp://dx.doi.org/10.1530/EJE-16-0455. circumscribed regionofinterest(ROI).Afullcolourversion supplementary datagivenattheend, seesectiononsupplementary Clinical Study s . d . ), minimum and maximum grey value of the ), minimumandmaximumgreyvalueofthe months after diagnosis/surgery months afterdiagnosis/surgery months forthefirstyear, and E Sbardellaandothers s . d . wereusedto
parameters wasperformedwith analysisoftheinter-class agreement: reliabilityanalysis forquantitativetextural the Cohen-kcoefficient was usedforinter-observer two ratersforthetextural heterogeneity analysisdata, data. Thedatapresentedaremean We usedSPSS(version17)forstatisticalanalysis ofthe Data analysis Table 5Supplementary ). Data and neoplastic lesions(reportedinSupplementary group ofpatientswithhistologicallyconfirmednon- analysis comparingneoplasticlesionsandjustthesub- size onfollow-up(>12 stalkchanges,orremainedstablereducedin pituitary initiation/suspension ofdrugsknowntoaffectpituitary/ were eitherhistologicallyprovenorresponded to clinical follow-up. Specifically, non-neoplastic lesions pathology findings,whenavailable,oronthebasisof The reference diagnosis was defined onthebasisof Reference diagnosis grey value,standarddeviation( follow-up) inacoronalpost-gadoliniumT1imagewithmean ImageJ analysisofanon-neoplasticlesion(stableat36 Figure 2 org/10.1530/EJE-16-0455. colour versionofthisfigureisavailableathttp://dx.doi. grey valueofthecircumscribedregioninterest(ROI).Afull thickening Imaging inpituitarystalk We performedaseparatetextureMRI image months). Downloaded fromBioscientifica.com at10/02/202104:11:53AM s . d . ), minimumandmaximum 175:4 ± s . www.eje-online.org d . Astherewere months 257 via freeaccess Clinical Study E Sbardella and others Imaging in pituitary stalk 175:4 258 thickening
correlation coefficients. We performed receiver-operating pituitary tissue, while three had stable imaging and no characteristic (ROC) curves to evaluate the combination of new endocrine defect at 2–5 years follow-up. sensitivity and specificity for each possible test positivity In the sub-group of middle-age patients (19–59 years), cutoff, and we used the area under the ROC curve to 1/20 patients had a germinoma, one a pituicytoma, one express the overall diagnostic accuracy of the index a Langerhans cell histiocytosis and 3/20 (15%) a Rathke test. P < 0.05 was considered indicative of a statistically cleft cyst. Interestingly, all seven inflammatory lesions fell significant difference. STARD guidelines were followed for in this age category. The remaining 7/20 patients (35%) reporting diagnostic accuracy of this study (15). did not undergo biopsy and showed stable lesions at This project was registered as an audit (Datix ID follow-up. number 4062), and registered as such with Oxford In the older age group (>60 years), one had a metastatic University Hospitals Trust. adenocarcinoma of breast origin as the first evidence of metastasis after 8 years from the primary diagnosis, while one was diagnosed with a Rathke cleft cyst; four of the six Results did not undergo surgery and presented stable lesions at Characteristics of the study population 3–5 years of follow-up. Overall, germinomas were diagnosed at an average age of A total of 42 cases fulfilled the search criteria; of these, 12.5 ± 4.9 years (range 9–21); 4/6 patients with germinomas 6 were excluded based on the absence of a pre-defined had blood tumour markers performed (αFP, hCG, CEA and mandatory image slice. Thus, 36 patients (61% males) ACE) and all were negative, as were the CSF tumour markers with pituitary stalk thickening were included, with a in the only patient in whom these were assessed. In 5/6 mean age at diagnosis of 37 years (range 4–83, s.d. 22.9). patients, CSF analysis for cells alone was performed, but in The nature of pituitary stalk lesion was histologically only one case was this diagnostic of germinoma. proven in 18 patients (50%) and attributed with a high grade With regard to the three patients with ipilimumab- of certainty in 4 more patients for a total of 22 patients. induced hypophysitis, biopsy was not performed, but Overall, we identified neoplastic lesions in 10 patients the diagnosis was considered certain because symptoms, (46%), inflammatory lesions in 7 (32%) and congenital clinical findings and images all improved significantly anomalies in 5 patients (22%). Of the 10 neoplastic after drug withdrawal. lesions, 2 were considered to be relatively benign: a craniopharyngioma and a pituicytoma. Malignant tumours
European Journal European of Endocrinology included six primary germinomas, one Langerhans cell Clinical findings and endocrine evaluation histiocytosis and one secondary lesion from a breast At the time of diagnosis, DI was present in 17 patients carcinoma. Of inflammatory lesions, three patients had a (47%), headache in 15 patients (42%), visual problems lymphocytic hypophysitis, one a secondary hypophysitis in 9 (25%), lethargy in 5 (14%), weight loss in 5 (14%), associated with a ruptured Rathke cleft cyst, and three dizziness in 4 (11%), poor appetite in 3 (8%) and ipilimumab-induced hypophysitis. With regard to the three diminished libido in 3 males (8%). In three cases (8%), patients with ipilimumab-induced hypophysitis, biopsy PST was an incidental finding (Table 1). was not performed, but the diagnosis were considered Of the 28 patients who had hormonal tests performed certain because symptoms, clinical findings and images all at the time of diagnosis, 16/28 (57%) had at least one improved significantly after drug withdrawal. anterior pituitary hormonal deficit, while 5/28 (18%) Of the congenital lesions, four were Rathke cleft cysts patients had more than one anterior pituitary axis affected and one PST was considered to be due to ectopic posterior (3 had panhypopituitarism). Secondary hypogonadism pituitary tissue, as judged by the results of multiple was the most common endocrine deficiency (36%), subsequent MRI although, biopsy in this case was not followed by GH deficiency (21%), adrenal insufficiency performed. (21%) and thyroid hormone deficiency (18%) (Table 2). Two additional patients could not be fully evaluated, presenting to our centre already receiving hydrocortisone Diagnosis according to age sub-groups replacement therapy. Considering inflammatory lesions In the young patients (<18 years), germinoma alone (7 patients): three showed ACTH deficiency, one was diagnosed in 5/10 patients (50%): one had a did not have ACTH deficiency, while in the remaining craniopharyngioma, one a congenital ectopic posterior three patients, the pituitary–adrenal axis was not assessed.
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Downloaded from Bioscientifica.com at 10/02/2021 04:11:53AM via free access European Journal of Endocrinology TSH deficit ACTH deficit GH deficit Diminished libido Poor appetite Secondary hypogonadism Dizziness Panhypopituitarism Lethargy More than1anteriorpituitaryhormonaldeficits Weight loss At least1anteriorpituitaryhormonaldeficit Visual problems Diabetes insipidus(DI) *Significant difference betweenneoplasticandnon-neoplastic lesions. Hormonal deficit Table 2 while onedevelopedGHdeficiency2 hypogonadism at1and3 germinoma. Two patientsdevelopedhypogonadotrophic result ofanenlarginglesion,subsequentlyconfirmedasa hypogonadism developed1 of DI.Specifically, inonepatient,hypogonadotrophic deficitoccurredaftertheonset and thenewpituitary deficitthatwasabsentatpresentation developed apituitary 10 ACTHdeficiency, 3hypothyroidism,2GHdeficiency. hypogonadism, was found:2permanentDI,3secondary neoplastic PST(75%vs20%;P =0.003, hypogonadismwasadistintintivefeatureof secondary 4%; 43%; deficit(100%vs presence ofatleastoneanteriorpituitary the hypogonadism(57%vs29%;P =0.03), secondary was agreaterprevalenceofDI(80%vs35%;P =0.014), the non-neoplasticpatients,informergroup,there hormonaldeficiencies. DI, 11alsohadanteriorpituitary patients hadACTHdeficiency. Ofthe17patientswith stalklesions pituitary Thus, 3/4(75%)ofinflammatory *Significant difference betweenneoplasticandnon-neoplasticlesions. Headache symptoms Presenting non-neoplastic lesions. patients, patientswithneoplasticlesionsand Table 1 Clinical Study During follow-upofnon-operatedpatients,four As a result of surgery, new onset of the following disorders Comparing thegroupofpatientswithneoplasmsto P P = = 0.004). Inparticular, thecombinationofDIplus 0.007) andcomplaintofseverelethargy(40%vs Distribution ofhormonaldeficitsinallpatients,patientswith neoplasticlesionsandpatientswithnon-neoplasticlesions. Description ofsymptomsonpresentationinall 15/36 (41.7%) 4/36 (11.1%) 5/36 (13.9%) 5/36 (13.9%) 9/36 (25%) 3/36 (8.3%) 3/36 (8.3%) (n =36) All years respectivelyafterdiagnosis, year afterdiagnosisasthe 1/10 (10%) 1/10 (10%) 1/10 (10%) 4/10 (40%) 2/10 (20%) 3/10 (30%) 4/10 (40%) Neoplastic E Sbardellaandothers lesions (n =10) years aftertheonset Tables 1 and2). Non-neoplastic 11/26 (42.3%) 2/26 (7.7%) 2/26 (7.7%) 3/26 (11.5%) 1/26 (3.8%)* 3/26 (11.5%) 6/26 (23.1%) lesions (n =26) 10/28 (35.7%) 16/28 (57.1%) 17/36 (47.2%) 5/28 (17.9%) 6/28 (21.4%) 6/28 (21.4%) 3/28 (10.7%) 5/28 (17.8%) All (n =36)
one craniopharingiomaandpituicytoma. MRI. All turned out to be neoplastic: two germinomas, diagnosis, becauseofanenlargementthelesionsat during follow-up, between 3 and 12 stalkbiopsy follow-up, fourpatientsrequiredapituitary imaging wasstableandnobiopsyperformed. of DI;however, ofthelastthreepatientsdescribed,MRI ( ±2.3; 11.62.7; 9.7 vs vs (16 ±2.8 (11.3 ±0.8 depth in termsofheight(8.3 lesions significantly greaterthannon-inflammatory size criteriaorprogressionwith30%sensitivity. neoplasms onhistology. Neoplasiawassuggestedon Moreover, alllesionsenlargingduringfollow-upshowed confirmed asneoplastic,achieving100%sensitivity. post-contrast imagesinthelowerpartofstalkwere upper partofthestalkandabove5.6mmforcoronal mm in diameter for coronal post-contrast images in the 3.2 ±0.9; 4.4 ±1.7; vs coronal post-contrastimagingforbothupper(6.4 contrast upperregion(6.6 4.3 ±1.6; vs (6.3 ±3.2 part upper neoplastic PSTwasmeasuredatthecoronalpre-contrast difference inthediameterofneoplasticandnon- 3.InMRIimaging,astatisticallysignificant Table gland are shown in anterior pituitary 3);height,depthandthewidthof slices (Table portion ofthePSinsagittalandcoronalT1-weighted sections, anddiametersattheproximaldistal terms oflengthinsagittalandcoronalT1-weighted Measurements ofthestalkonMRIwereexpressedin MRI characteristics thickening Imaging inpituitarystalk Supplementary Table 3Supplementary ). Concerning thedimensionsoflesionsduring Regarding size, inflammatory lesionswerealso Regarding size,inflammatory Neoplastic lesions(n =10) P
= 8/10 (80%) 0.04). Specifically, alllesionsabove9.1 2/7 (28.6%) 3/7 (42.9%) 2/7 (28.6%) 4/7 (57.1%) 1/7 (14.3%) 2/7 (28.6%) 7/7 (100%) P
= 0.04) andlowerregions(4.6 P Downloaded fromBioscientifica.com at10/02/202104:11:53AM
= 0.002) of the pituitary gland 0.002) ofthepituitary ± 2.5 vs4.9 ± 2.4 vs6 Non-neoplastic lesions(n =26) P P .2, aitl post- sagittal =0.02), .0) n width and =0.008) 175:4 months since first ± 3/21 (14.3%) 3/21 (14.3%) 4/21 (19%) 6/21 (28.6%)* 2/21 (9.5%) 3/21 (14.3%) 9/21 (42.8%)* 9/26 (34.6%)* www.eje-online.org 2.2; P ± Supplementary 2.2; P 0.04) and =0.04) ± =0.03), 2.3 vs 259 ± 3.2 via freeaccess Clinical Study E Sbardella and others Imaging in pituitary stalk 175:4 260 thickening
Table 3 Pituitary stalk diameter characteristics on T1-weighted MRI images comparing all patients, patients with neoplastic
lesions and patients with non-neoplastic lesions. Data are presented as mean ± s.d. (min–max)
All Neoplastic lesions Non-neoplastic lesions Pituitary stalk diameter characteristics, mm (n = 36) (n = 10) (n = 26) Length sagittal 7.7 ± 2.7 (3–16) 8.3 ± 2.6 (5–4) 7.4 ± 2.8 (3–16) Length coronal 7.3 ± 2.7 (3–14) 7.9 ± 2.8 (4–3) 7.0 ± 2.7 (3–4) Stalk diameter sagittal upper part pre gadolinium 5.3 ± 2.4 (2.3–1.7) 6.4 ± 2.7 (4–0.6) 5 ± 2.2 (2.3–1.7) Stalk diameter sagittal lower part pre gadolinium 4.6 ± 2.4 (2.3–5.4) 5.3 ± 4.5 (2.9–5.4) 4.4 ± 1.6 (2.3–0.9) Stalk diameter coronal upper part pre gadolinium 4.9 ± 2.1 (2–2) 6.3 ± 3.2 (3.6–2) 4.3 ± 1.6* (2–0.6) Stalk diameter coronal lower part pre gadolinium 3.6 ± 1.8 (1.5–0.6) 4.6 ± 2.3 (2.2–0.6) 3.4 ± 1.4 (1.5–0.9) Stalk diameter sagittal upper part post gadolinium 5.3 ± 2.4 (1.6–2.1) 6.6 ± 2.5 (4–1.8) 4.9 ± 2.2* (1.6–2.1) Stalk diameter sagittal lower part post gadolinium 3.9 ± 1.3 (2–0.6) 3.9 ± 1.3 (2–0.7) 3.8 ± 1.3 (2.1–0.6) Stalk diameter coronal upper part post gadolinium 4.9 ± 2.3 (1.6–2.7) 6.4 ± 3.2 (3.5–2.7) 4.4 ± 1.7* (2.5–0.1) Stalk diameter coronal lower part post gadolinium 3.6 ± 1.6 (2.2–0.2) 4.6 ± 2.3 (2.2–0.2) 3.2 ± 0.9* (2.2–0.6) Absence of posterior pituitary bright spot (PPBS) 24/33 (72.8%) 8/8 (100%) 16/25 (64%)
*Significant difference between neoplastic and non-neoplastic lesions.
There was no direct relationship between the pattern data, has been employed in several neurodegenerative of enhancement and the extent of the lesions. In addition, disorders and is highly reproducible (16, 17). One way to we were not able to identify any correlation between evaluate texture is to measure the standard deviation (s.d.) hypopituitarism and the pattern of enhancement or size of the mean grey value of a given region of interest (ROI). of the lesion. Comparing neoplastic and non-neoplastic PST, None of patients with neoplastic PST showed the texture analysis revealed a significantly higher degree normal PHBS (sensitivity of 100%), as compared with 64% of heterogeneity expressed as standard deviation of of patients with non-neoplastic lesions (P = 0.02) (specificity the PST in patients with neoplastic lesions compared of 36%). Furthermore, in our population, the simultaneous with non-neoplastic lesions (sagittal pre-gadolinium, absence of the PHBS and presence of DI was significantly P = 0.02; coronal pre-gadolinium, P = 0.03; sagittal post- higher in patients with neoplastic lesions compared gadolinium, P < 0.001; coronal post-gadolinium, P < 0.001, with the non-neoplastic group (7/8 (88%) vs 5/25 (20%); Table 4). These findings were confirmed when corrected P = 0.001) with 88% sensitivity and 80% specificity. for the s.d. of white and grey neural tissues. European Journal European of Endocrinology The MRI patterns of thickening of the stalk in We performed ROC curve analysis to identify a the upper, median and lower part are shown in possible criterion of textural heterogeneity to differentiate Supplementary Table 4. The strongest association with neoplastic from non-neoplastic stalk lesions. We found a specific pattern of thickening on cranial MRI was that criteria for differentiating these two lesion categories for congenital lesions; with one exception, 4/5 such for sagittal pre-gadolinium images of 7.55 s.d. with a lesions showed a thickening of the median part of the sensitivity of 71.4% and a specificity of 84.6% (AUC: stalk. The most frequent diagnosis in this category was 0.786, CI: 95% 0.499-1), coronal pre-gadolinium images a Rathke cleft cyst. Of the inflammatory lesions, 5/7 of 8.2 s.d. with a sensitivity of 71.4% and a specificity showed a thickening of the upper part of the stalk, while of 87.5% (AUC: 0.774, CI: 95% 0.499-1), sagittal post- for neoplastic lesions, 5/10 showed a thickening of the gadolinium images of 11.84 s.d. with a sensitivity of upper part and 5/10 a thickening of the median part of 87.5% and a specificity of 95.8% (AUC: 0.943, CI: 95% the stalk. In 25 patients (69%), the abnormal imaging was 0.832-1; Fig. 1) and coronal post-gadolinium images of limited to the pituitary stalk and showed a suprasellar 11.61 s.d. with a sensitivity of 88.9% and a specificity of extension in 6 patients (17%). 91.7% (AUC: 0.968, CI: 95% 0.915-1).
Pituitary stalk texture analysis Discussion
Texture analysis (TA) is a software-based image processing In this retrospective analysis, we describe the presenting that allows to evaluate the distribution of grey levels in features, aetiological spectrum, associations between a given region of interest (ROI). It provides quantitative clinical and biochemical data with imaging characteristics,
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Downloaded from Bioscientifica.com at 10/02/2021 04:11:53AM via free access European Journal of Endocrinology However, neitherthepatternofMRI enhancementnor probably duetocompression oftheposteriorlobe(19). patients withlargeintrasellar massesandemptysellae, present inmosthealthyindividuals andisabsentinmany confirmed previous finding reporting thatthe PHBSis showed 88%sensitivityand80%specificity. Theseresults simultaneous absence of the PHBS and presence of DI between neoplasticandnon-neoplasticlesions,whilethe sensitivity butonly36%specificityindistinguishing present inpatientswithneoplasticlesions. because these two conditions were significantly more hypogonadism presenting withDIplussecondary we recommendmorecarefulevaluationofpatients dimension duringthefollow-upperiod.Inparticular, group, withneoplasticstalklesionsincreasingin neoplastic diseasecompared with thenon-neoplastic deficitinpatientswith at leastoneanteriorpituitary hypogonadism, severelethargyandthepresenceof a significantlyincreasedprevalenceofDI,secondary affected and 11% had panhypopituitarism. We found axes 18% patientshadmorethanoneanteriorpituitary hormonal deficit,had atleastone anterior pituitary cortisol and thyroid dysfunction,andinparticular 57% previously (6 deficiency,most commonanteriorpituitary asreported hypogonadismwasthe endocrine evaluation.Secondary underestimated, as someofour patients did not have full ( function wasfrequentlypresent,asreportedpreviously dys cases followedbyheadache,whileanteriorpituitary gland and stalk. and texture characteristics of the pituitary studies formorphology, signalintensity, enhancement decade. We havealsofocusedonreviewingMRIimaging lesions seeninouruniversityhospitaloverthelast stalk histopathology andclinicaloutcomesofpituitary Textural heterogeneity neoplastic lesionsandpatientswithnon-neoplasticlesions.Dataarepresentedinmillimetresasmean Table 4 Pituitary stalk(sagittalT1 Pituitary stalk(coronalT1 Pituitary stalk(coronalT1 Pituitary stalk(sagittalT1 6, 18).However, dysfunctionwas itislikelythatpituitary pre-gadolinium) pre-gadolinium) post-gadolinium) post-gadolinium) Clinical Study The absence of the normal PHBS showed 100% DI wasthe initial presentationin nearly halfofthe PituitarystalktexturalheterogeneitycharacteristicsonT1-weightedMRIimagescomparingallpatients,patientswith ), followedbydeficiencyofGH,ACTH/ .3 (4.568–4.206) 10.465 ±4.233 (3.305–7.496) 10.909 ±5.870 .8 (2.877–13.478) 6.572 ±2.484 .2 (3.844–3.624) 6.876 ±3.923 E Sbardellaandothers All (n =36) are largercomparedwith non-neoplastic lesions.All neoplastic change,demonstrating thatneoplasticstalks diameter dimensionsand the presenceorabsenceof lesions appearedroundonMRI. stalk from theMayoClinicthatmostcongenitalpituitary of Rathkecleft cysts. However, weconfirm thefindings our populationof22%wheretherewasapredominance 9% prevalence(6),lowercomparedwiththatreportedin With regardtocongenitallesions,Turcu reporteda et al. although theyshouldnotprovidedifficultyindiagnosis. use, itislikelythatsuchpatientswillbeseenmoreoften, metastatic cancerssuchasmelanomaandtheirincreasing recent introduction of these drugs for the treatment of immune checkpointinhibitors(22,23,24,25).With the to numbers ofpatientswithhypophysitissecondary may beslightlyinflatedbytheinclusion ofincreasing patients (6),nottoodissimilartothe32%wefound.This lesionscomprised30%(21)and20%of inflammatory stalk biopsy.undergoing a pituitary In previous studies, related to the higher percentage, and 50% of patients 46% ofallpatientswithcertainpathology, possibly the mosthighlyrepresentedcategory, accountingfor (37/152: 24%)(6).Inourseries,neoplasticlesionswere proportion undergoinghistopathologicalconfirmation high prevalenceoftumourlesions(32%)withalower stalklesionstodate,showedasimilar studies onpituitary , inoneofthelargest al. (21). Morerecently, Turcu et neoplastic lesions(37%),especiallyintheadultgroup proven byhistopathology, showingapredominanceof Only asmallsubsetofpatients(40%)hadtheirdiagnoses including 65subjects,44adultsand21paediatricpatients. lesions first largecaseseriesonpituitary/infundibular (21)published the stalklesions. Hamilton et al. pituitary in keepingwithpreviousdata(20). the sizeoflesionpredictedhypophysealdysfunction, thickening Imaging inpituitarystalk .6 (3.844–3.642) 10.871 ±6.462 .1 (10.046–4.206) 15.660 ±4.015 (9.072–7.496) 18.449 ±6.683 .1 (4.482–3.478) 8.948 ±3.315 Neoplastic lesions(n =10) This studyhasshownacorrelation betweenstalk There areafewpublishedcaseseriesonpatientswith Downloaded fromBioscientifica.com at10/02/202104:11:53AM Non-neoplastic lesions(n =26) .0* (2.877–0.178) 5.932 ±1.804* .0* (3.889–0.889) 5.711 ±1.704* .9* (4.568–3.440) 8.517 ±2.193* (3.305–2.332) 8.380 ±2.478* ± s . d . (min–max) 175:4 www.eje-online.org 261 via freeaccess Clinical Study E Sbardella and others Imaging in pituitary stalk 175:4 262 thickening
lesions above 9.1 mm in diameter for coronal post- to require urgent intervention as compared with contrast images in the upper part of the stalk and above more indolent lesions best served by a conservative 5.6 mm for coronal post-contrast images in the lower observational approach. It is possible that more part of the stalk were neoplastic, and all lesions enlarging sophisticated image analysis as suggested here may during follow-up showed neoplasms on histology. expedite attainment of a definitive diagnosis, leading While previous studies were unable to establish to more rapid and effective therapy. any imaging parameter which would help identify the nature of PST (6), we have evaluated for the first time Supplementary data the textural heterogeneity in terms of intensity of the This is linked to the online version of the paper at http://dx.doi.org/10.1530/ pituitary stalk with the programme ImageJ. There was a EJE-16-0455. significant correlation between the presence of neoplasia in the pituitary stalk and the standard deviation (s.d.) of the texture of the stalk in sagittal pre- and post- Declaration of interest The authors declare that there is no conflict of interest that could be gadolinium and in coronal pre- and post-gadolinium perceived as prejudicing the impartiality of the research reported. T1-weighted images. We have also proposed possible textural heterogeneity criteria for the pituitary stalk for sagittal pre- and post-gadolinium and coronal pre- and Funding This research did not receive any specific grant from any funding agency in post-gadolinium T1 images. These textural heterogeneity the public, commercial or not-for-profit sector. criteria were more accurate for post-gadolinium images. ImageJ is a free open-source application to process images, simple to use, and we suggest that this analysis Acknowledgements might offer a powerful, cheap and available tool that We thank Dr Giulia Puliani for her advice on ImageJ programme. every experienced neuroendocrinologist could use in clinical practice. References 1 Maghnie M, Cosi G, Genovese E, Manca-Bitti ML, Cohen A, Limitations Zecca S, Tinelli C, Gallucci M, Bernasconi S, Boscherini B et al. Central diabetes insipidus in children and young adults. Our study has several limitations: first of all, the small New England Journal of Medicine 2000 343 998–1007. (doi:10.1056/ NEJM200010053431403) sample, even though collected from a major centre over
European Journal European of Endocrinology 2 Aizer AA, Sethi RV, Hedley-Whyte ET, Ebb D, Tarbell NJ, Yock TI & a prolonged period, with the lack of tissue-confirmed Macdonald SM. Bifocal intracranial tumors of nongerminomatous diagnoses in half the cases. Indeed, while in our germ cell etiology: diagnostic and therapeutic implications. Neuro-oncology 2013 15 955–960. (doi:10.1093/neuonc/not050) population the rate of histological confirmation is higher 3 Ricciuti A, De Remigis A, Landek-Salgado MA, De Vincentiis L, compared with previous studies (6, 21), it is probably still Guaraldi F, Lupi I, Iwama S, Wand GS, Salvatori R & Caturegli P. insufficient for definitive conclusions. However, one of Detection of pituitary antibodies by immunofluorescence: approach and results in patients with pituitary diseases. Journal of Clinical the main limitations is the retrospective nature of data Endocrinology and Metabolism 2014 99 1758–1766. (doi:10.1210/ collection and our own institutional referral bias that may jc.2014-1049) overestimate severe conditions and may underestimate 4 Di Iorgi N, Allegri AE, Napoli F, Calcagno A, Calandra E, Fratangeli N, Vannati M, Rossi A, Bagnasco F, Haupt R et al. Central diabetes many asymptomatic lesions or lesions with lower clinical insipidus in children and young adults: etiological diagnosis and impact. Nevertheless, given that performing biopsy of long-term outcome of idiopathic cases. Journal of Clinical Endocrinology pituitary stalk is a technically demanding technique and Metabolism 2014 99 1264–1272. (doi:10.1210/jc.2013-3724) 5 Di Iorgi N, Morana G & Maghnie M. Pituitary stalk thickening on that has significant risk of morbidity, the diagnosis MRI: when is the best time to re-scan and how long should we was frequently based on clinical findings, biochemical continue re-scanning for? Clinical Endocrinology 2015 83 449–455. evaluation and serial MRI. (doi:10.1111/cen.2015.83.issue-4) 6 Turcu AF, Erickson BJ, Lin E, Guadalix S, Schwartz K, Scheithauer BW, In conclusion, the spectrum of pathology involving Atkinson JL & Young WF Jr. Pituitary stalk lesions: the Mayo Clinic experience. Journal of Clinical Endocrinology and Metabolism 2013 98 the pituitary stalk is broad, ranging from indolent to 1812–1818. (doi:10.1210/jc.2012-4171) more malignant lesions that can have a dramatically 7 Guzzo MF, Bueno CB, Amancio TT, Rosemberg S, Bueno C, Arioli EL, altered prognosis. We suggest that stalk lesions above Glezer A & Bronstein MD. An intrasellar germinoma with normal tumor marker concentrations mimicking primary lymphocytic a certain size, or which enlarge on follow-up, or which hypophysitis. Arquivos Brasileiros de Endocrinologia e Metabologia 2016 show defined textural characteristic, are more likely 57 566–570.
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