Quantitative Single-Photon Emission Computed Tomography/Computed Tomography for Evaluation of Salivary Gland Dysfunction in Sjögren’s Syndrome Patients

PurposeThe purpose of the study was to investigate the usefulness of quantitative salivary single-photon emission computed tomography/computed tomography (SPECT/CT) using Tc-99m pertechnetate in Sjögren’s syndrome (SS).MethodsWe retrospectively reviewed quantitative salivary SPECT/CT data from 95 xerostomic patients who were classified as either SS (n = 47, male:female = 0:47, age = 54.60 ± 13.16 y [mean ± SD]) or non-SS (n = 48, male:female = 5:43, age = 54.94 ± 14.04 y) by combination of anti-SSA/Ro antibody, labial salivary gland biopsy, unstimulated whole saliva flow rate, and Schirmer’s test. Thyroid cancer patients (n = 43, male:female = 19:24, age = 46.37 ± 12.13 y) before radioactive iodine therapy served as negative controls. Quantitative SPECT/CT was performed pre-stimulatory 20 min and post-stimulatory 40 min after injection of Tc-99m pertechnetate (15 mCi). The %injected dose at 20 min and the %excretion between 20 and 40 min were calculated for parotid and submandibular glands, generating four quantitative parameters: %parotid uptake (%PU), %submandibular uptake (%SU), %parotid excretion (%PE), and %submandibular excretion (%SE). The most useful parameter for SS diagnosis was investigated.ResultsThe uptake parameters (%PU and %SU) were significantly different among the SS, non-SS, and negative controls (p = 0.005 for %PU and p < 0.001 for %SU, respectively), but the excretion parameters (%PE and %SE) were not (p > 0.05 for both). The %PU and %SU were significantly lower in SS than in the negative controls and non-SS (p < 0.05 for all pair-wise comparisons). Additionally, the %SU was significantly lower in non-SS than in the negative controls (p < 0.05). Receiver-operating characteristic analysis revealed that the %SU had the greatest area-under-the curve of 0.720 (95% confidence interval = 0.618–0.807). Using the optimal cut-off value of %SU ≤ 0.07%, SS was identified with a sensitivity of 70.21% and a specificity of 70.83%.ConclusionReduced submandibular uptake of Tc-99m pertechnetate at 20 min (%SU) was proved useful for the diagnosis of SS. Quantitative salivary gland SPECT/CT holds promise as an objective imaging modality for assessment of salivary dysfunction and may facilitate accurate classification of SS.

Related papers:

title: Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group
abstract: Classification criteria for Sjögren's syndrome (SS) were developed and validated between 1989 and 1996 by the European Study Group on Classification Criteria for SS, and broadly accepted. These have been re-examined by consensus group members, who have introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria.

title: 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjögren's Syndrome: A Consensus and Data‐Driven Methodology Involving Three International Patient Cohorts
abstract: To develop and validate an international set of classification criteria for primary Sjögren's syndrome (SS) using guidelines from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). These criteria were developed for use in individuals with signs and/or symptoms suggestive of SS.

title: Preliminary criteria for the classification of Sjögren's syndrome. Results of a prospective concerted action supported by the European Community.
abstract: Different sets of diagnostic criteria have been proposed for Sjögren's syndrome (SS), but none have been validated with a large series of patients or in a multicenter study. We conducted the present study involving 26 centers from 12 countries (11 in Europe, plus Israel), with the goals of reaching a consensus on the diagnostic procedures for SS and defining classification criteria to be used in epidemiologic surveys and adopted by the scientific community.



The study protocol was subdivided into two parts. For part I, questionnaires regarding both ocular and oral involvement were developed; they included 13 questions and 7 questions, respectively. For part II a limited set of diagnostic tests was selected, and the exact procedure to be followed in performing these tests was defined. Part I of the study included 240 patients with primary SS and 240 age- and sex-matched controls. Two hundred forty-six patients with primary SS, 201 with secondary SS, 113 with connective tissue diseases but without associated SS, and 133 control patients were studied in part II.



The study resulted in (a) the validation of a simple 6-item questionnaire for determination of dry eyes and dry mouth, which showed good discriminant power between patients and controls, to be used in the initial screening for sicca syndrome; and (b) the definition of a new set of criteria for the classification of SS. The sensitivity and specificity of the criteria in correctly identifying patients with either the primary or the secondary variant of SS were also determined.



Using the findings of this prospective multicenter European study, general agreement can be reached on the diagnostic procedures to be used for patients with SS. Final validation of the preliminary classification criteria for SS is underway.

title: Revised Japanese criteria for Sjögren’s syndrome (1999): availability and validity
abstract: The Japanese criteria for diagnosing Sjögren's syndrome (SS) were revised in 1999, and consist of four major areas: histopathology, oral examination, ocular examination, and serological examination. A diagnosis of SS can be made when the patient meets at least two of these four criteria. This report describes how the revised Japanese criteria were established. After the publication of the revised Japanese criteria (1999), a research study which focused on evaluating its availability and validity was carried out in 2001 using funds from Grant-in-Aids for Scientific Research supported by the Japan Society for the Promotion of Science. The availability of the revised criteria was investigated by a questionnaire study through the Japanese Medical Society for Sjögren's Syndrome, and the use of the revised criteria for diagnosing SS in these medical facilities was found to be 76%. To evaluate the validity of the revised criteria, the records of 900 patients, including SS patients and non-SS controls, from 54 clinical centers were registered and analyzed to calculate the accuracy of the criteria. The revised Japanese criteria were found to have 96.0% sensitivity, 90.5% specificity, and 94.5% accuracy for diagnosing SS.

title: Sjögren's syndrome. Proposed criteria for classification.
abstract: The term "Sjögren's syndrome" (SS) is frequently used to describe the occurrence of keratoconjunctivis sicca and xerostomia in association with an autoimmune disorder. However, well-defined criteria for the classification of SS have not been established, and this diagnosis is being applied to a wide spectrum of conditions, ranging from clear "autoimmune" disease in some patients, to sicca complaints without evidence of a systemic immune process in elderly patients. Here, we review the clinical and laboratory features of patients referred for evaluation of sicca symptoms. In particular, we emphasize the need for care in choosing the site for minor salivary gland biopsy, and we describe the histologic features that aid in the evaluation of these biopsy specimens. In an attempt to identify a population of patients whose conditions might have a common etiopathogenesis and, thus, a common treatment program, we propose the following criteria for a diagnosis of SS: 1) objective evidence of keratoconjunctivis sicca, as documented by rose bengal or fluorescein dye staining; 2) objective evidence of diminished salivary gland flow; 3) minor salivary gland biopsy, obtained through normal mucosa, with the specimen containing at least 4 evaluable salivary gland lobules, and having an average of at least 2 foci/4 mm2; 4) evidence of a systemic autoimmune process, as manifested by the presence of autoantibodies, such as rheumatoid factor and/or antinuclear antibody. The diagnosis of "definite SS" would be made when all 4 criteria are met; the diagnosis of "possible SS" would be made when 3 criteria are present. Specific exclusions for this diagnosis are preexisting lymphoma, graft-versus-host disease, sarcoidosis, and acquired immunodeficiency disease.(ABSTRACT TRUNCATED AT 250 WORDS)

title: American College of Rheumatology classification criteria for Sjögren's syndrome: A data‐driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance Cohort
abstract: We propose new classification criteria for Sjögren's syndrome (SS), which are needed considering the emergence of biologic agents as potential treatments and their associated comorbidity. These criteria target individuals with signs/symptoms suggestive of SS.

title: Role of nuclear scintigraphy in the characterization and management of the salivary component of Sjögren's syndrome.
abstract: The American-European Consensus Group, in its classification criteria of Sjögren's syndrome (SS), consigns dynamic salivary scintigraphy to providing objective evidence of xerostomia, a secondary role. In the current SS therapeutic environment, scintigraphy's ability to differentiate parenchymal damage from neuropathic or other derangements of the salivary apparatus may prove more valuable than its role as a diagnostic modality. The procedure itself is highly process-dependent and its discriminatory power task-dependent. A multiplicity of data collection protocols and interpretative approaches tends to corrode the validity of its diagnostic information. Salivary scintigraphy's clinical utility might be extended by standardization of its test protocol and uniformity in its interpretative algorithms.

title: Xerostomia in Sjögren's syndrome. Evaluation by sequential salivary scintigraphy.
abstract: Sequential salivary scintigraphy, or the visual recording with a gamma scintillation camera of the uptake, concentration, and excretion of 99m Tc pertechnetate by the major salivary glands after the administration of sodium pertechnetate Tc 99m, was performed on 20 female patients with Sjogren's syndrome. The results were compared with those of other procedures currently used to evaluate xerostomia. The scintigraphic findings closely paralleled the results of the salivary flow-rate determinations and contrast sialography and the patients' clinical symptoms, but did not correlate with the finding of lymphocytic infiltration in lip biopsy specimens or the detection of the anti-salivaryduct antibody. The scintigraphic examination proved to be extremely sensitive in depicting small asymmetric differences in parotid gland activity and in monitoring the improvement in salivary gland function with immunosuppressive therapy. Sequential salivary scintigraphy appears to be an easy, safe, and objective means of evaluating xerostomia in patients with Sjogen's syndrome.

title: Quantification of parotid gland uptake of pertechnetate using a gamma scintillation camera and a "region-of-interest" system.
abstract: The uptake of pertechnetate by the parotid glands was quantitated in 16 patients using a gamma camera with "region-of-interest" capabilities.The results correlated well with the subjective qualitative system previously used to categorize the studies. Patients with Sjogren’s syndrome had the lowest recorded uptakes in the series.The rate of pertechnetate accumulation, as opposed to the absolute level of concentration, was not a useful parameter of gland function.A 1 hour salivary gland uptake determination reliably separated normal patients from those with documented salivary gland diseases and appears to be a feasible diagnostic procedure.

title: Salivary and lacrimal gland dysfunction (sicca syndrome) after radioiodine therapy.
abstract: Salivary gland dysfunction has been described in patients undergoing radioiodine therapy but associated lacrimal gland dysfunction (sicca syndrome) has never been reported. We conducted a prospective cohort study with follow-up for up to 3 y in a tertiary care university center to determine the prevalence of sicca syndrome in patients after high-dose radioiodine treatment.



From January 1990 to December 1995, all patients undergoing radioiodine therapy (n = 79) with a standard dose of 925 MBq to 18.5 GBq (25-500 mCi) were interviewed using a standardized questionnaire to determine subjective ocular and oral dryness and were examined for objective lacrimal and salivary gland dysfunction.



After radioiodine treatment, 32.9% of the patients reported subjective xerostomia and 25.3% reported subjective xerophthalmia in the first year of follow-up. Xerostomia persisted to the second year of follow-up in 20.3% of cases and was still present >3 y after the last dose of radioiodine in 15.2% of cases. Xerophthalmia persisted to the second year of follow-up in 17.7% of cases and was still present in the third year of follow-up in 13.9% of cases. Severe xerostomia occurred in 4 patients. Reduced salivary and lacrimal gland function was documented in 40 (50.6%) and 14 (17.7%) of the 79 cases, respectively, in the first year of follow-up. Objective xerostomia persisted in 13.9% of cases to the second year of follow-up and was still present in all patients >3 y after the last radioiodine application. Keratoconjunctivitis sicca persisted in 11 patients (13.9%) to the second year of follow-up but was only present in 6 patients (7.6%) >3 y after the last radioiodine application. Additionally, 28/79 patients (35.4%) who had a normal salivary gland scintigraphy previously showed reduced salivary gland function in the third year of follow-up. No significant dependence on cumulative treatment was found for objective xerostomia or xerophthalmia, but doses >11.1 GBq (300 mCi) were related to stage 3 dysfunction on salivary gland scintigraphy.



Salivary and lacrimal gland dysfunction (sicca syndrome) is relatively frequent after radioiodine therapy. In most cases this is a transient side effect, but in some patients it may persist for a long period or appear late.

title: Scintigraphic Evaluation of Salivary Gland Dysfunction in Patients with Thyroid Cancer After Radioiodine Treatment
abstract: Sialadenitis is a well-recognized adverse effect of high-dose radioactive iodine treatment. This study was undertaken to determine whether Tc-99m pertechnetate salivary gland scintigraphy may be used for objective assessment of salivary gland function in patients with thyroid cancer treated with I-131.  The study group consisted of 71 patients (16 men, 55 women) with a mean age of 44 years (range, 16 to 73 years). Twenty-six (37%) patients were not given any radioiodine, and 18, 16, and 11 patients received doses of 100, 150, or 200 mCi (or higher), respectively. Parotid and submandibular glands were evaluated based on a four-grade scoring system. Correlation between the type of surgery, administered dose, time since therapy, subjective symptoms, and findings of salivary gland scintigraphy were evaluated.  Subjective symptoms were questioned in 39 of the 45 patients who received radioactive iodine treatment. Fifty-four percent (21 of 39) of the patients reported xerostomia, of whom 86% (18 of 21) showed salivary gland dysfunction. Objective salivary gland dysfunction was observed in 69% (31 of 45) of patients. In 81% of the patients, the parotid glands were affected; in 13% of the patients, the submandibular glands were affected; and in 6%, both were affected (P < 0.000001). The frequency of salivary gland dysfunction showed a dose dependence to cumulative activity (P = 0.007). A greater complication rate was observed in patients with total thyroidectomy compared with subtotal surgery, although the correlation was not significant (P = 0.625).  Parenchymal damage to the salivary glands induced by radioactive iodine treatment can be evaluated by salivary gland scintigraphy. The impairment is worse in the parotid glands and increases with the total dose.

title: Scintigraphic evaluation of the salivary glands in patients with Sjögren's syndrome.
abstract: The clinical value of salivary gland scintigraphy (RI-sialography) was studied in 11 cases with definite Sjögren's syndrome. Time-activity curves which were obtained from computer-assisted analysis of RI-sialography were classified into 4 types (N:normal type, M:median type, F:flat type, S:sloped type), and the efficacy of scintigraphy in evaluating salivary gland function and the relationship between time-activity curves and other diagnostic methods are discussed. Flattened time-activity curves such as F- or S-type were more often seen in submandibular glands than in parotid glands. Flattened curves were not seen in the early stage of the inflammatory process; conversely, when we found a flattened curve, it suggested a wide destruction of the salivary gland tissues. Correlation between time-activity curve and sialography showed 90.9%, and correlation between time-activity curve and histopathological change in the minor salivary gland of the lower lip also showed 90.9%.

title: Salivary gland scintigraphy in subjects with and without symptoms of dry mouth and/or eyes, and in patients with primary Sjögren's syndrome.
abstract: The major salivary glands were examined with 99m-Tc-pertechnetate scintigraphy in randomly selected subjects with (n = 30) and without (n = 12) symptoms of dry mouth and/or eyes, and in patients with primary Sjögren's syndrome (1 degree SS, n = 17). The scans were quantitatively evaluated and compared to other objective tests used to diagnose 1 degree SS. As compared with those for asymptomatic subjects, most values for the scintigraphic variables were non-significantly lower for symptomatic subjects and the time-activity curves were slightly flatter for all major salivary glands. In patients with 1 degree SS most values for the scintigraphic variables were significantly lowered and the submandibular glands were the glands most affected, as reflected in a flat time-activity curve, while the parotid glands were mainly affected during stimulated secretion. The scintigraphic variables correlated with the self-rated dryness of mouth in symptomatic subjects and with the abnormality of sialometry results in patients with 1 degree SS. We conclude that salivary gland scintigraphy is a sensitive and valid method to measure salivary gland function and abnormalities.

title: Quantitative evaluation of salivary gland scintigraphy in Sjörgen's syndrome.
abstract: This study compared the quantitative characteristics of salivary gland scintigraphy in patients with Sjogren's syndrome with the histopathologic grading of labial biopsy.



Thirty-nine patients with Sjögren's syndrome were studied by salivary gland scintigraphy and labial biopsy. Twelve normal volunteers were also studied as a control group for scintigraphic parameters. After injection of 370 MBq 99mTc sodium pertechnetate, dynamic salivary scintigraphy with lemon juice stimulation was performed for 50 min. Functional parameters for the parotid and submandibular glands were calculated, and scintigraphic and histopathologic results were compared.



With the progression of histopathologic grades 1-4, the velocity of tracer secretion decreased in the parotid gland (P < 0.05), and the quantity of tracer accumulation decreased in the submandibular gland (P < 0.05). The histopathologic grade in patients with Sjögren's syndrome was correlated with these scintigraphic parameters (P < 0.05): Histopathologic grade = 2.304 - 0.014 x (submandibular gland maximum accumulation) + 0.196 x (parotid gland time interval of tracer secretion).



Decreased secretion velocity in the parotid gland and decreased accumulation in the submandibular gland were sensitive indicators of salivary gland disease in Sjögren's syndrome. The histopathologic grade was correlated with these scintigraphic parameters.

title: Sjögren's syndrome: comparison of assessments with quantitative salivary gland scintigraphy and contrast sialography.
abstract: This study compared the quantitative parameters of salivary gland scintigraphy and the sialographic stages in patients with Sjögren's syndrome.



One hundred sixteen patients suspected of having Sjögren's syndrome were examined with salivary gland scintigraphy and contrast sialography. When contrast sialography was used as the gold standard, Sjögren's syndrome was diagnosed in 50 of these 116 patients; Sjögren's syndrome was not seen in the other 66 patients. After injection of 370 MBq 99mTc-sodium pertechnetate, dynamic salivary gland scintigraphy with lemon juice stimulation was performed for 50 min. Functional parameters for the parotid and submandibular glands were calculated, and scintigraphic and sialographic results were compared.



With the progression of sialographic stages from 0 to 4, the quantity of tracer accumulation decreased in the submandibular gland (P < 0.0001), and the quantity of tracer secretion decreased in the parotid gland (P < 0.0001). The sialographic stage in patients with Sjögren's syndrome was correlated with these scintigraphic parameters (P < 0.0001): sialographic stage = 3.243 - 0.337 x (submandibular gland uptake ratio) - 0.026 x (parotid gland maximum secretion).



The decreased accumulation in the submandibular gland and the decreased secretion in the parotid gland were highly sensitive indicators of salivary gland disease in Sjögren's syndrome. The sialographic stage was correlated with these scintigraphic parameters.

title: A study to standardize quantitative evaluation of parotid gland scintigraphy in patients with Sjögren's syndrome.
abstract: To standardize quantitative parotid gland scintigraphy for diagnosing Sjögren's syndrome (SS).



Forty-five patients with SS and 23 controls were studied. Dynamic images were obtained up to 50 min after the injection of 185 MBq 99mTc-pertechnetate and salivary excretion was stimulated with lemon juice orally at 40 min after the injection. Peak count and uptake speed in the uptake phase, and excretion speed and excretion fraction in the excretion phase were calculated.



The levels of peak count, uptake speed, and excretion speed in the patients with SS were significantly lower than the levels in the controls, whereas there was no significant difference of excretion fraction level between the patients with SS and the controls. The calculations of peak count and excretion speed levels, which were closely related with the focus scores of minor salivary glands and the amount of stimulated whole saliva, showed higher reproducibility, sensitivity, and specificity than those of uptake speed and excretion fraction levels.



The calculations of peak count and excretion speed were eligible to standardize quantitative parotid gland scintigraphy for diagnosing SS.

title: Absolute quantification in SPECT
abstract: Single-photon emission computed tomography (SPECT) allows the three-dimensional visualization of radioactivity within the human body and is widely used for clinical purposes. In SPECT, image quality is compromised by several factors including photon attenuation, photon scatter, the partial volume effect, and motion artefacts. These variables also confound the capacity of SPECT to quantify the concentration of radioactivity within given volumes of interest in absolute units, e.g. as kilobecquerels per cubic centimetre. In the last decade, considerable technical progress has been achieved in SPECT image reconstruction, involving, in particular, the development of iterative image reconstruction techniques. Furthermore, hybrid cameras integrating a SPECT camera with an X-ray CT scanner have become commercially available. These systems allow the acquisition of SPECT and CT datasets registered to each other with a high anatomical accuracy. First studies have shown that iterative SPECT image reconstruction techniques incorporating information from SPECT/CT image datasets greatly increase the accuracy of SPECT in quantifying radioactivity concentrations in phantoms and also in humans. This new potential of SPECT may improve not only diagnostic accuracy, but also dosimetry for internal radiotherapy.

title: An Evidence-Based Review of Quantitative SPECT Imaging and Potential Clinical Applications
abstract: SPECT has traditionally been regarded as nonquantitative. Advances in multimodality γ-cameras (SPECT/CT), algorithms for image reconstruction, and sophisticated compensation techniques to correct for photon attenuation and scattering have, however, now made quantitative SPECT viable in a manner similar to quantitative PET (i.e., kBq⋅cm−3, standardized uptake value). This review examines the evidence for quantitative SPECT and demonstrates clinical studies in which the accuracy of the reconstructed SPECT data has been assessed in vivo. SPECT reconstructions using CT-based compensation corrections readily achieve accuracy for 99mTc to within ±10% of the known concentration of the radiotracer in vivo. Quantification with other radionuclides is also being introduced. SPECT continues to suffer from poorer photon detection efficiency (sensitivity) and spatial resolution than PET; however, it has the benefit in some situations of longer radionuclide half-lives, which may better suit the biologic process under examination, as well as the ability to perform multitracer studies using pulse height spectroscopy to separate different radiolabels.

title: Maximum Standardized Uptake Value of (99m)Tc Hydroxymethylene Diphosphonate SPECT/CT for the Evaluation of Temporomandibular Joint Disorder.
abstract: To evaluate the diagnostic accuracy of the quantitative parameter standardized uptake value (SUV) at single photon emission computed tomography (SPECT)/computed tomography (CT) for the evaluation of temporomandibular joint (TMJ) disorder (TMD).  This study was approved by the institutional review board, and the need for informed consent was waived. Forty-four TMJs in 22 patients with TMD (five men and 17 women; mean age ± standard deviation, 30.0 years ± 12.1) were evaluated. The patients underwent planar bone scintigraphy and SPECT/CT 3-4 hours after injection of technetium 99m hydroxymethylene diphosphonate. The planar scintigraphy parameter of relative ratio (RR) and SPECT/CT parameters mean SUV (SUVmean) and maximum SUV (SUVmax) were compared for the visual assessment of TMD on planar scintigraphy images and for the presence of TMJ arthralgia. Group comparisons, receiver operating characteristic analysis, and Pearson correlation analysis were conducted.  SUVmax gradually increased from normal (2.82 ± 0.73) to mild or moderately abnormal (3.56 ± 0.76, P < .05) and then to severely abnormal (4.86 ± 1.25, P < .05). However, RR and SUVmean did not vary significantly according to visual grade (P > .05). On the other hand, SUVmax was significantly greater in arthralgic TMJs (4.15 ± 1.11) than in nonarthralgic TMJs (2.97 ± 0.75, P < .001), as was SUVmean (1.63 ± 0.42 vs 1.30 ± 0.31, respectively; P = .005). However, there was no significant difference in RR (3.61 ± 0.57 vs 3.76 ± 0.68, P = .45). In receiver operating characteristic curve analyses for arthralgic TMJ, SUVmax had the greatest area under the curve (area of 0.815).  SUVmax derived from bone SPECT/CT may be useful for the evaluation of TMD.

title: Quantitative single-photon emission computed tomography/computed tomography for technetium pertechnetate thyroid uptake measurement
abstract: Technetium pertechnetate (99mTcO4) is a radioactive tracer used to assess thyroid function by thyroid uptake system (TUS). However, the TUS often fails to deliver accurate measurements of the percent of thyroid uptake (%thyroid uptake) of 99mTcO4. Here, we investigated the usefulness of quantitative single-photon emission computed tomography/computed tomography (SPECT/CT) after injection of 99mTcO4 in detecting thyroid function abnormalities. We retrospectively reviewed data from 50 patients (male:female = 15:35; age, 46.2 ± 16.3 years; 17 Graves disease, 13 thyroiditis, and 20 euthyroid). All patients underwent 99mTcO4 quantitative SPECT/CT (185 MBq = 5 mCi), which yielded %thyroid uptake and standardized uptake value (SUV). Twenty-one (10 Graves disease and 11 thyroiditis) of the 50 patients also underwent conventional %thyroid uptake measurements using a TUS. Quantitative SPECT/CT parameters (%thyroid uptake, SUVmean, and SUVmax) were the highest in Graves disease, second highest in euthyroid, and lowest in thyroiditis (P < 0.0001, Kruskal–Wallis test). TUS significantly overestimated the %thyroid uptake compared with SPECT/CT (P < 0.0001, paired t test) because other 99mTcO4 sources in addition to thyroid, such as salivary glands and saliva, contributed to the %thyroid uptake result by TUS, whereas %thyroid uptake, SUVmean and SUVmax from the SPECT/CT were associated with the functional status of thyroid. Quantitative SPECT/CT is more accurate than conventional TUS for measuring 99mTcO4 %thyroid uptake. Quantitative measurements using SPECT/CT may facilitate more accurate assessment of thyroid tracer uptake.

title: Maximum standardised uptake value of quantitative bone SPECT/CT in patients with medial compartment osteoarthritis of the knee.
abstract: To evaluate the correlation between the maximum standardised uptake value (SUVmax) from bone single-photon-emission computed tomography/computed tomography (SPECT/CT) and other imaging parameters for medial compartment osteoarthritis (OA) of the knee.



Patients (n=26; male:female=2:24; age, 55.3±5.8 years) underwent quantitative knee SPECT/CT using technetium-99m (Tc-99m) hydroxymethylene diphosphonate (HDP) before surgical operation for medial OA of the knee. SUVmax was calculated using dedicated quantitative software. Visual grades of tracer uptake on bone SPECT/CT and Kellgren-Lawrence (KL) OA scores on plain radiographs were assessed using a five-point scale. Magnetic resonance imaging (MRI) scores (n=22) and patient symptom scores were also assessed.



The operated knees (n=34) had a greater SUVmax than the non-operated knees (n=18) in the medial compartment (14.1±6.1 versus 5.3±4.4, p<0.0001). In the medial compartment, the SUVmax was significantly correlated with SPECT/CT visual grades (rho=0.794, p<0.0001), KL scores (rho=0.703, p<0.0001), and MRI scores (rho=0.714-0.808, p≤0.0002); however, SUVmax and other imaging parameters were not correlated with patient symptom scores (p>0.05).



The SUVmax of quantitative bone SPECT/CT was highly correlated with traditional imaging parameters for medial compartment OA severity of the knee. Quantitative bone SPECT/CT is a promising imaging technique for the objective assessment of knee OA.

title: Quantitative Single-Photon Emission Computed Tomography/Computed Tomography for Glomerular Filtration Rate Measurement
abstract: PurposeWe propose a quantitative Tc-99m diethylenetriaminepentaacetic acid (DTPA) single-photon emission computed tomography/computed tomography (SPECT/CT) for glomerular filtration rate (GFR) measurement.MethodsQuantitative SPECT/CT data obtained at 2–3 min post-Tc-99m DTPA injection (370 MBq) were used to determine % injected doses (%IDs) for individual kidneys. The reproducibility of %ID measurement was tested and compared with planar scintigraphy. Cr-51 ethylenediaminetetraacetic acid (EDTA) GFR was used as reference standard. Nine young volunteers, representing normal GFR, and ten older volunteers, reflecting impaired GFR, were enrolled. The established GFR equation derived from these volunteers was applied to 19 renal tumor patients post-partial nephrectomy.ResultsAt 2−3 min, %ID was most reproducible with the highest intraclass correlation (ICC) (0.9379) and lowest % coefficient of variation (CV) (6.5259%), which were more reliable than the ICC (0.9368) and %CV (6.7689%) of planar scintigraphy. Cr-51 EDTA GFR (93.16 ± 24.81 ml/min) correlated significantly with %ID (7.66 ± 2.15%, r = 0.7906, p = 0.0001), yielding an equation: Cr-51 EDTA GFR (ml/min) = (%ID × 9.1462) + 23.0653. This equation revealed significant decreases in total and nephrectomized kidney GFR (p = 0.0012 and p < 0.0001, respectively) from preoperative to 3-month postoperative measurements.ConclusionsQuantitative Tc-99m DTPA SPECT/CT produces reliable and clinically applicable %ID estimates that translate to the GFR of individual kidneys.

title: Evaluation of Salivary Gland Dysfunction Using Salivary Gland Scintigraphy in Sjögren’s Syndrome Patients and in Thyroid Cancer Patients after Radioactive Iodine Therapy
abstract: PurposeSalivary gland scintigraphy (SGS) provides an objective means of diagnosing salivary gland dysfunction in Sjögren’s syndrome (SS) patients and in thyroid cancer patients after radioactive iodine (RAI) therapy. In the present study, SGS was performed in SS patients and in thyroid cancer patients post-RAI, and scintigraphic parameters were compared.MethodsTwenty-eight SS patients (males:females = 1:27, age 53.3 ± 11.9 years), 28 controls (males:females = 3:25, age 54.1 ± 10.1 years), and 92 thyroid cancer patients (males:females = 28:64, age 46.2 ± 12.9) who had undergone a session of high-dose RAI therapy (mean dose, 5.2 ± 1.5 GBq) were included. SGS was performed using Tc-99m pertechnetate (925 MBq). Scintigraphic parameters (parotid uptake ratio PU, submandibular uptake ratio SU, percentage parotid excretion %PE, and percentage submandibular excretion %SE) were measured and compared for SS, thyroid cancer post-RAI, and control patients.ResultsPU, SU, %SE, and %PE were all significantly lower in SS than in post-RAI thyroid cancer or control patients (p < 0.05), whereas only %PE was significantly lower in post-RAI thyroid cancer patients than in controls (p < 0.05). SU and %SE were found to be correlated with the unstimulated whole salivary flow rate.ConclusionScintigraphic parameters derived from SGS can play a crucial role in the detection of salivary gland dysfunction in SS patients and in post-RAI thyroid cancer patients.

title: 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer.
abstract: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent.  guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer.



The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations for therapeutic interventions. We developed a similarly formatted system to appraise the quality of such studies and resultant recommendations. The guideline panel had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members.



The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, use of molecular markers, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to screening for thyroid cancer, staging and risk assessment, surgical management, radioiodine remnant ablation and therapy, and thyrotropin suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using imaging and serum thyroglobulin, thyroid hormone therapy, management of recurrent and metastatic disease, consideration for clinical trials and targeted therapy, as well as directions for future research.



We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

title: Salivary hypofunction and xerostomia: diagnosis and treatment.
abstract: Salivary gland hypofunction and complaints of xerostomia are common in elderly patients, irrespective of their living situation. Medication use is frequently related to dry mouth symptoms and reductions in salivary flow rates. Patients with reduced salivary flow are at increased risk for caries, oral fungal infections, swallowing problems, and diminished or altered taste. Oral health care providers should institute aggressive preventive measures and recommend palliative care for patients with significant reduction in salivary gland function. The systemic agents pilocarpine and cevimeline may help selected patients. Selective use of fluoride-releasing restorative materials and conservative treatment plans are recommended for this patient group.

title: The European Community Study Group on diagnostic criteria for Sjögren's syndrome. Sensitivity and specificity of tests for ocular and oral involvement in Sjögren's syndrome.
abstract: To establish a definitive set of diagnostic criteria in a multicentre European study a selected number of oral and ocular tests were performed on a large number of patients with Sjögrens Syndrome (SS) and controls. The diagnostic accuracy of each test for patients with primary and secondary SS and for controls at different ages, was studied. Each centre received a clinical chart describing the series of tests to be conducted. The tests included: questionnaires for dry eye and dry mouth symptoms, Schirmer's-I-test (ScT), tear fluid lactoferrin level (TFLL), break-up time (BUT) and rose Bengal score (RBS) for the eye evaluation; unstimulated and stimulated whole saliva collection (UWSC and SWSC), salivary gland scintigraphy (SGS), parotid sialography (PS) and minor salivary gland biopsy (MSGB) for oral involvement. Data from 22 centres and 11 countries was collected on a total of 447 patients with SS (246 with primary SS and 201 with secondary SS) and 246 controls (of whom 113 had a connective tissue disease without SS). Among the ocular symptoms, the feeling of dry eye and 'sand in the eye' were the ones most commonly recorded in patients with SS. Similarly, the feeling of dry mouth, appearing either spontaneously or when the patient was eating or breathing, was the most frequent subjective oral symptom. Among the ocular tests, ScT showed the best balance between sensitivity and specificity (76.9% and 72.4% respectively), while RBS was the most specific test (81.7%). ScT and RBS gave also sufficiently concordant results. TFLL and BUT gave considerably less reliable results, which were not concordant with each other or with the other ocular tests. The quantitative lacrimal tests ScT and TFLL produced significantly different results in elderly controls, while RBS did not. Abnormal results for all of the ocular tests were less marked and less frequent in patients with secondary SS than in those with primary SS. The oral tests (except SWSC) were generally more reliable than the ocular tests in diagnosing SS. In particular, PS was the most specific diagnostic tools (100%), while MSGB (where the presence of at least one inflammatory focus was considered as indicative for the diagnosis) showed a good balance between sensitivity and specificity (82.4% and 86.2%, respectively). The tests showed a good degree of agreement, and, with the exception of UWSC, were not influenced by age. In the oral, as in the ocular tests, abnormal results were less frequent and less marked in patients with secondary SS. The results clearly show that ScT and RBS (for the eye evaluation), and SGS, PS, MSGB and UWSC (for salivary gland involvement) are the most reliable tests for the diagnosis of SS. The clinician should be aware, however, that the test results may vary depending on the age of the patient and the type of SS (primary or secondary).

title: Salivary Spect and Factor Analysis in Sjögren's Syndrome
abstract: Salivary SPECT and factor analysis in Sjögren's syndrome were performed in 17 patients and 6 volunteers as controls. The ability of SPECT to detect small differences in the level of uptake can be used to separate glands from background even when uptake is reduced as in the patients with Sjögren's syndrome. In control and probable Sjögren's syndrome groups the uptake ratio of the submandibular gland to parotid gland on salivary SPECT (S/P ratio) was less than 1.0. However, in the definite Sjögren's syndrome group, the ratio was more than 1.0. Moreover, the ratio in all patients with sialectasia, which is characteristic of Sjögren's syndrome, was more than 1.0. Salivary factor analysis of normal parotid glands showed slowly increasing patterns of uptake and normal submandibular glands had rapidly increasing patterns of uptake. However, in the definite Sjögren's syndrome group, the factor analysis patterns were altered, with slowly increasing patterns dominating both in the parotid and submandibular glands. These results suggest that the S/P ratio in salivary SPECT and salivary factor analysis provide additional radiologic criteria in diagnosing Sjögren's syndrome.

title: The utility of SPECT in determining the relationship between radiation dose and salivary gland dysfunction after radiotherapy
abstract: Salivary gland scintigraphy (SGS) is used to depict salivary gland dysfunction after radiotherapy (RT). The aim of this study was to investigate the utility of SGS combined with single photon emission computed tomography (SPECT). Twenty-one patients with a carcinoma of head and neck underwent SGS before and 1 month after RT. After injection of 370 MBq 99Tcm-pertechnetate, a biplanar dynamic acquisition (12×1 min) was started, followed by a SPECT acquisition during 4 min. Carbachol was then injected and a second dynamic study (16×1 min) was performed, again followed by a SPECT acquisition. The salivary excretion fraction (SEF) was calculated both from the geometric mean planar image for each parotid and from the SPECT data for each transverse plane through the parotids. The RT-induced changes in the SEF (dSEF) were correlated with the mean radiation dose calculated using tomography-based dosimetry. The mean radiation dose to the parotids was 44 Gy (range 4.4-68.1 Gy). The mean range of the variation in radiation dose to the transverse slices within the parotids of a patient was 24 Gy (range 6.2-51.9 Gy). Considering all transverse planes through the parotids in all patients, a linear correlation was found between the dSEF calculated using SGS-SPECT and the radiation dose (r = 0.45, P = 0.0001). Thirteen patients had a variation in radiation dose within the parotids of more than 20 Gy. In nine of these a significant intra-individual correlation between radiation dose and the dSEF of the transverse parotid slices was found (r range 0.55-0.97; P value range 0.037-0.0001). In conclusion, SGS-SPECT can be used for monitoring radiation-induced parotid gland dysfunction. It offers the unique possibility for the assessment of intra-individual dose-dysfunction curves in patients with large variations in the radiation dose within the parotids.

title: A Point-Scoring System for the Clinical Diagnosis of Sjögren's Syndrome Based on Quantified SPECT Imaging of Salivary Gland
abstract: To establish a point-scoring diagnostic system for Sjögren's syndrome (SS) based on quantified SPECT imaging of salivary gland, and evaluate its feasibility and performance compared with 2002 AECG criteria and 2012 ACR criteria.  213 patients with suspected SS enrolled in this study. The related clinical data of all patients were collected. All patients were evaluated and grouped on a clinical basis and posttreatment follow-up by rheumatology specialists as the unified standard (SS group with 149 cases and nSS group with 64 cases). From SPECT imaging of salivary gland, Tmax, UImax, Ts and EFs were derived for bilateral parotid and submandibular glands, and compared between the groups. A point-scoring diagnostic system for SS was established based on the quantified SPECT imaging of salivary gland. We estimated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for the new diagnostic system, compared with 2002 AECG criteria and 2012 ACR criteria.  When 7.0 was used as the cut-off point, the sensitivity, specificity, PPV, NPV and accuracy for the new point-scoring system in diagnosing SS were 89.93% (134/149), 93.75% (60/64), 97.10% (134/138), 80.00% (60/75) and 91.08% (194/213), respectively. The new point-scoring diagnostic system based on quantified SPECT imaging of salivary gland keeps the specificity comparatively to 2002 AECG criteria and 2012 ACR criteria, but improves the sensitivity significantly (P<0.01).  The new point-scoring diagnostic system for SS based on quantified SPECT imaging of salivary gland may be superior to 2002 AECG criteria and 2012 ACR criteria, with higher sensitivity and similar specificity in the diagnosis of SS. Additionally, it also has good feasibility in the clinical settings.

title: Variability of quantitative scintigraphic salivary indices in normal subjects.
abstract: Several quantitative measures of salivary uptake and discharge have been proposed recently in the scintigraphic evaluation of xerostomia. We investigated the scatter of four time-activity curve C(TAC)-derived indices in a group of volunteer subjects who met extensive inclusionary and exclusionary criteria of salivary normalcy.



Thirty-one adult volunteers underwent dynamic salivary scintigraphy with gustatory stimulation. Any candidates with subjective xerostomia, conditions or medications associated with dry mouth, salivary gland enlargement or pregnancy were excluded from study. All subjects had normal oral exams, xerostomia scores and unstimulated whole-mouth salivary flow rates. After the intravenous administration of 99mTcO-4, scintigraphy was performed with generation of TACs derived from regions of interest centered about the four major salivary glands and the oral cavity. At 45 min postinjection, hard lemon candy was given for 15 min as a gustatory stimulus. The following functional indices were calculated for each gland: partitioned percentage (PP) of total prestimulated activity, maximum net uptake ratio (NUR) and its time of occurrence (TNUR) and percentage stimulated discharge fraction (DF).



The following ranges were observed: parotid PP, 22%-49%; submandibular PP, 4%-31%; parotid NUR, 2.2-16.0; submandibular NUR,  TNUR, 8-45 min; submandibular TNUR, 2-45 min; parotid DF, 20%-99%; and submandibular DF, 27%-98%. Every subject except one 91-yr-old man showed frequent periodic unstimulated oral transfer of salivary activity with a rising oral TAC and responded to gustatory stimulation.



So-called quantitative indices may perform poorly in the scintigraphic evaluation of xerostomic patients because the effects of normal simultaneous glandular trapping, uptake, oral discharge and possible vascular washout combine to widen reference limits. Coordinated analysis of oral cavity and glandular activities, glandular index averaging and better temporal resolution may help improve diagnostic performance.

title: Radiation apoptosis of serous acinar cells of salivary and lacrimal glands
abstract: Xerostomia and xerophthalmia are common and potentially serious local side effects of radiotherapy for head and neck cancer. Clinical observations supported by experimental findings show that radiation, even in low doses, causes acute diminutions of saliva and tears by rapidly killing the serous cells of the salivary and lacrimal glands, respectively. Serous acini of salivary and lacrimal glands have similar developmental, morphologic, and functional characteristics. Serous acinar cells are functionally mature, secretory epithelial cells that normally do not divide and are long lived. Irradiation of the salivary and lacrimal glands of rhesus monkeys resulted in selective death of serous acinar cells within 24 hours. The paradigm for acute radiation seroadenosis is intermitotic or interphase cell death caused by apoptosis.

title: Quantitative evaluation of salivary gland dysfunction after radioiodine therapy using salivary gland scintigraphy
abstract: AimThe most frequent non-thyroidal complication of high-dose 131I therapy for thyroid carcinoma is salivary gland dysfunction, which may be transient or permanent. In this study, we assessed radioiodine-induced permanent salivary gland dysfunction using quantitative salivary gland scintigraphy. MethodsSalivary scintigraphy was performed with 99mTc-pertechnetate on 50 thyroid carcinoma patients who had been given radioiodine for thyroid ablation; 20 normal subjects were imaged as the control population. Dynamic scintigraphy was performed and time–activity curves for four major salivary glands were generated. The glandular functional parameters maximum secretion, time at maximum count and uptake ratio of the parotid and submandibular glands were calculated. Correlation of the administered dose and subjective symptoms with findings of salivary gland scintigraphy was evaluated. ResultsThe maximum secretion and uptake ratio were decreased in 46% and 42% of patients who received radioiodine therapy, respectively. Salivary gland dysfunction correlated well with the administered dose. The parotid glands were more affected than the submandibular glands. Fifty-two per cent of patients were symptomatic, 69.23% of whom showed salivary gland dysfunction. ConclusionParenchymal damage to the salivary glands induced by radioactive iodine treatment can be evaluated by salivary gland scintigraphy. The impairment was worse in parotid glands and increased with the total dose. The maximum secretion and uptake ratio were found to be sufficiently sensitive to distinguish the severity of the damage.

title: Scintigraphic features of chronic sialadenitis and Sjögren's syndrome: a comparison.
abstract: An abnormal salivary scintigram is an accepted objective criterion in the diagnosis of primary and secondary Sjogren's syndrome, an immune-mediated disorder characterized by xerostomia and kerato-conjunctivitis sicca. However, chronic sialadenitis constitutes a major differential diagnostic consideration in the xerostomic population. We investigated 39 cases of biopsy-confirmed chronic sialadenitis and 152 individuals with first- or second-degree Sjogren's syndrome, according to international classification criteria. We analysed scintigraphic defects in terms of glands per patient, distribution patterns, kinetics and severity. Relative to Sjogren's syndrome, chronic sialadenitis showed significantly fewer defective glands per patient, less frequent dual parotid-submandibular defects, fewer combined deficits of uptake and discharge, and milder uptake failure. No statistically significant differences were found in the frequency of single gland abnormality, predilection for submandibular involvement, and respective proportions of uptake-only and discharge-only defects. Unevaluable discharge due to low uptake, although comprising only 34% of test-positive cases, appeared to be a highly specific but insensitive scintigraphic marker for Sjogren's syndrome. In non-irradiated xerostomic populations, scintigraphy provides specific, albeit limited, diagnostic information. The procedure's ability to distinguish uptake failure from secretory failure may be a useful asset in guiding clinical management strategies and estimating outcomes.

title: Does lemon candy decrease salivary gland damage after radioiodine therapy for thyroid cancer?
abstract: Salivary gland dysfunction is one of the common side effects of high-dose radioiodine therapy for thyroid cancer. The purpose of this study was to determine whether an early start of sucking lemon candy decreases salivary gland injury after radioiodine therapy.



The incidence of the side effects of radioiodine therapy on the salivary glands was prospectively and longitudinally investigated in 2 groups of patients with postsurgical differentiated thyroid cancer with varying regimens for sucking lemon candy. From August 1999 to October 2000, 116 consecutive patients were asked to suck 1 or 2 lemon candies every 2-3 h in the daytime of the first 5 d after radioiodine therapy (group A). Lemon candy sucking was started within 1 h after radioiodine ingestion. From November 2000 to June 2002, 139 consecutive patients (group B) were asked to suck lemon candies in a manner similar to that of group A. In the group B, lemon candies were withheld until 24 h after the ingestion of radioiodine. Patients with salivary gland disorders, diabetes, collagen tissue diseases, or a previous history of radioiodine therapy or external irradiation to the neck were excluded. Thus, 105 patients in group A and 125 patients in group B were available for analysis. There were no statistical differences in the mean age (55.2 y vs. 58.5 y), average levels of serum free thyroxine (l-3,5,3',5'-tetraiodothyronine) (0.40 ng/dL vs. 0.47 ng/dL), and the mean dose of (131)I administered (3.96 GBq vs. 3.87 GBq) between the 2 groups. The onset of salivary side effects was monitored during hospital admission and regular follow-up on the basis of interviews with patients, a visual analog scale, and salivary gland scintigraphy using (99m)Tc-pertechnetate. When a patient showed a persistent (>4 mo) dry mouth associated with a nonfunctioning pattern on salivary gland scintigraphy, a diagnosis of xerostomia was established.



The incidences of sialoadenitis, hypogeusia or taste loss, and dry mouth with or without repeated sialadenitis in group A versus group B were 63.8% versus 36.8% (P < 0.001), 39.0% versus 25.6% (P < 0.01), and 23.8% versus 11.2% (P < 0.005), respectively. Permanent xerostomia occurred in 15 patients in group A (14.3%) and 7 patients in group B (5.6%) (P < 0.05). In both groups, bilateral involvement of the parotid gland was the most frequently seen and was followed by bilateral involvement of the submandibular gland.



An early start of sucking lemon candy may induce a significant increase in salivary gland damage. Lemon candy should not be given until 24 h after radioiodine therapy.