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CT and 99mTc bone scintigraphy imaging in Erdheim–Chester disease
European Journal of Radiology 84 (2015) 1586–1592
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European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
The role of 18FDG, 18FDOPA PET/CT and 99mTc bone scintigraphy imaging in Erdheim–Chester disease ˜ a , R. Martínez-Castillo a , J.L. Tirado-Hospital a , F.J. García-Gómez a,∗ , I. Acevedo-Bánez a J.I. Cuenca-Cuenca , V.M. Pachón-Garrudo a , R.M. Álvarez-Pérez a , R. García-Jiménez a , E. Rivas-Infante b , J.S. García-Morillo c , I. Borrego-Dorado a a
Department of Nuclear Medicine, Virgen del Rocío Universitary Hospital, Seville, Spain Department of Pathology, Virgen del Rocío Universitary Hospital, Seville, Spain c Department of Internal Medicine, Virgen del Rocío Universitary Hospital, Seville, Spain b
a r t i c l e
i n f o
Article history: Received 28 March 2015 Received in revised form 11 April 2015 Accepted 20 April 2015 Keywords: Erdheim–Chester disease PET/CT Bone scintigraphy 18FDG 18FDOPA
a b s t r a c t Erdheim–Chester disease (ECD) is a rare non-Langerhans cell histiocitosis, characterized by multisystemic xanthogranulomatous infiltration by foamy histiocytes that stain positively for CD68 marker but not express CD1a and S100 proteins. Etiology and pathogenesis are still unknown and only about 500 cases are related in the literature. Multisystemic involvement leads to a wide variety of clinical manifestations that results in a poor prognosis although recent advances in treatment. We present the clinical, nuclear medicine findings and therapeutic aspects of a serie of 6 patients with histopathological diagnosis of ECD, who have undergone both bone scintigraphy (BS) and 18F-fluorodeoxyglucose (18FDG)-PET/CT scans in our institution. A complementary 18F-fluorodopa (18FDOPA)-PET/CT was performed in one case. Three different presentations of the disease were observed in our casuistic: most indolent form was a cutaneous confined disease, presented in only one patient. Multifocal involvement with central nervous system (CNS) preservation was observed in two patients. Most aggressive form consisted in a systemic involvement with CNS infiltration, presented in three patients. In our experience neurological involvement, among one case with isolate pituitary infiltration, was associated with mortality in all cases. 18FDG-PET/CT and BS were particularly useful in despite systemic involvement; locate the site for biopsy and the treatment response evaluation. By our knowledge, 18FDOPA-PET/CT not seems useful in the initial staging of ECD. A baseline 18FDG-PET/CT and BS may help in monitoring the disease and could be considered when patients were incidentally diagnosed and periodically 18FDG-PET/CT must be performed in the follow up to evaluate treatment response. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The Erdheim–Chester disease (ECD) is an uncommon, non familiar, non-Langerhans cell histiocytosis, initially described by Jakob Erdheim and William Chester in 1930 as a lipid granulomatosis [1]. The eponym ECD was coined years later, after the publication of the work of the group of Jaffe et al. [2] Up-to-date, about 500 cases have been reported in the literature [3]. The etiology and pathogenesis of ECD remain unknown, but is characterized by multisystemic xanthomatous or xanthogranulomatous infiltration of involved tissues by foamy histiocytes that
∗ Corresponding author. Tel.: +34 680925869; fax: +34 955012079. E-mail address: [email protected] (F.J. García-Gómez). http://dx.doi.org/10.1016/j.ejrad.2015.04.022 0720-048X/© 2015 Elsevier Ireland Ltd. All rights reserved.
stain positively for CD68 marker but not express the CD1a, and the absence of Birbëck granules, as seen in Langerhans cell histiocytosis [4]. Recently, has been probed that S100 protein is positive up to 20% patients [5]. Individuals affected are typically adults between their 5–7th decades of life. Males and females are almost equally affected, through with a slight predilection for men. The multisystemic involvement leads to a wide variety of clinical manifestations. The most common presentation includes diffuse sclerotic lesions, present especially on the diaphysis of appendicular long bones. The osseous involvement is constant and characteristic, affecting up to 96% cases [6], but extra-osseous lesions have been described, including cardiovascular involvement, exophtalmos, central diabetes insipidus (CDI), xanthelasmas, interstitial lung disease, renal failure, retroperitoneal fibrosis, central nervous system involvement, bilateral enlargement or testis involvement [5]. The
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Table 1 Demographic, clinical, bone scintigraphy, 18FDG and 18FDOPA PET/CT scans findings and follow-up data of the 6 patients with confirmed diagnosis of ECD. Patient number
Sex
Age
Bone scintigraphy
Initial staging 18FDG-PET/CT
Control 18FDGPET/CT
Initial staging 18FDOPAPET/CT
Biopsy site
Clinical outcome
1
Male
43
Bilateral knee osteosclerosis
Progression of the disease
–
Cerebellum mass
Exitus 38 months after diagnosis
2
Female
48
Bilateral knee osteosclerosis
–
Negative findings
Tibiae
Exitus 6 months after diagnosis
3
Male
42
Left coxal hypermetabolic lesion
Cerebellum and spinal cord hypermetabolic focuses, with difuse bone increased uptake Parietal cortex irregularities. Hypermetabolic focuses in lung, adrenal, knees and soft tissues Supra/ infradiaphragmatic lymphatic and skeletal involvement
–
Coxal bone
Bone pain
4
Male
45
–
Male
66
–
Cheekbone skin Retroperitoneum
Exophthalmos
5
Negative findings Bilateral humeri and femurs increased uptake, with knee osteosclerosis
Partial response in first PET control. Progression of the disease in second PET control. –
6
Male
27
–
Retroperitoneum
Bilateral knee and ankle osteosclerosis
Negative findings Skeletal, mesentery, perirenal and perivascular involvement
Pituitary hypermetabolic lesion, with retroperitoneum and knees involvement
complications from these multisystemic affectation results in a poor prognosis with a 5 year survival rate of 41% [7] although recent advances in treatment. Because of the rarity of this disease, most papers are a consequence of multicentre compilation of cases [8]. We present the clinical, nuclear medicine findings and therapeutic aspects of a serie of 6 patients with histopathological diagnosis of ECD, who have undergone both two-phase bone scintigraphy, 18Ffluorodeoxyglucose (18FDG) PET/CT scans in our institution. A complementary 18F-fluorodopa (18FDOPA) PET/CT was performed in one case. 2. Materials and methods We retrospectively identified 6 patients with a diagnosis of ECD from clinical, imaging and pathologic reports from November 2010 up to date at our institution. Clinical records of all patients were reviewed, collecting the demographic, clinical, histological, imaging examinations and follow-up data. Part of these data could be found in Table 1. Our population (5 males and 1 female) present a median age at the time of clinical onset and pathological diagnosis of 45.33 ± 12.59 years (range: 27–66 years). Median follow-up was 15.66 months (range: 6–38 months). Histopathological examination confirmed the ECD diagnosis in all patients. It was based on histopathological demonstration of foamy histiocytes and/or immunohistochemical staining positively for CD68 and negatively for CD1a and S100, according to Veyssier–Belot criteria [8].
Partial response in first PET control. Progression of the disease in second PET control. Progression of the disease in first PET control.
Retroperitoneal fibrosis
Central diabetes insipidus and retroperitoneal fibrosis
All patients have undergone at least one two-phase bone scintigraphy and an unenhanced 18FDG-PET/CT in order to establish an accurate extension of the disease or monitoring the therapeutic effects. The two-phase bone scintigraphy was performed after the intravenous injection of a dose of 740 MBq of 99mTc hydroxymethylene diphosphonate (99mTc-HDP) to obtain an accurate skeletal mapping or therapeutic response, and it consisted of planar images in the area more painful reported by the patient 5 min after the injection of radiotracer and a wholebody scan 120 min after the administration of 99mTc-HDP. The equipment used was a Siemens Symbia® S (Siemens, Erlangen, Germany) two head gammacamera with low energy and high resolution parallel hole collimators. In the other hand, the 18FDG-PET/CT was performed 60 min after the administration of a dose on weight-based of 18FDG (typically 370 MBq) under 6 h fasting, well hydration and the administration of a diuretic (10–20 mg i.v. furosemide) conditions. Metabolic response was defined as a significant reduction of Standardized Uptake Value (SUVmax) in the lesions, understanding as significant, SUVmax decreases greater than 25% of intensity. SUVmax decreases lower than 25% or increases of them were considered as stable disease or metabolic progression, respectively. In one case, a complementary 18FDOPA-PET/CT to determine their potential usefulness in the extension diagnosis and monitoring response to treatment of this rare disease was performed under identical conditions of fasting and hydration. Carbidopa was not administrated before of the radiotracer injection to inhibit the
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Fig. 1. 27 Year old male with history of retroperitoneal fibrosis, central diabetes insipidus, hypogonadotropic hypogonadism, secondary hypothyroidism. An initial staging 18FDG-PET/CT revealed a hypermetabolic focus contained in the sella turcica of the sphenoid bone, as shown the coronal, sagital and axial views of the scan. The hypermetabolic pituitary lesion reached a SUV maximum of 9 while a SUV maximum of 5 was measured in the adjacent cortex. In addition of the pituitary lesion, an irregular increase of the uptake in the retroperitoneum and knees were observed, reaching a SUV maximum of 5 in the retroperitoneum. The biopsy of retroperitoneal fibrosis leads to final diagnosis of ECD. A control 18FDG-PET/CT was performed 6 months after initiation of treatment with corticosteroids and interferon alpha and demonstrated progression of the disease, reaching a SUV maximum of 13.8 in the pituitary. Endocrinological decline and malaise was observed in spite of treatment.
peripheral aromatic amino acid decarboxylase, unlike as is done in patients with neuroendocrine tumours or parkinsonism. Two different PET/CT cameras (Siemens BiographTM 16 and Siemens BiographTM mCT-64. Siemens, Erlangen, Germany) were used for this purpose. All scans had been read of at least one of the cited authors, aware of the results of the previous tests and clinical data. The data was analysed by SPSS ver16.0 (Chicago, IL, USA). Continuous variables are expressed as mean, median and range, and the categorical variables are presented in percentage within the median ratio. 3. Results Three different presentations of the disease were observed in our casuistic: the most indolent form was a cutaneous confined disease, mainly facial, presented in only one patient, who demonstrated bone scintigraphy and 18FDG-PET/CT negative findings. Second form of presentation, presented in two patients, consisted in a multifocal involvement with central nervous system (CNS) preservation. According to the literature, the CNS preservation
might predict a better prognosis with stable disease after combined treatment. Third and most aggressive form consisted in a systemic involvement with CNS infiltration, presented in three patients. Two of them showed hypermetabolic masses at cerebellum and parietal cortex, leading to a neurological decline with exitus in 38 and 6 months, respectively. Third patient with neurological involvement was a 27 years old male, with history of retroperitoneal fibrosis and CDI, revealed a pituitary involvement in the initial staging 18FDGPET/CT (Fig. 1) as well as bone disease in the lower limbs. A control 18FDG-PET/CT after 6 months from starting treatment revealed progression of the disease, increasing the metabolic activity in the pituitary. Two phases bone scintigraphy demonstrated areas of increased osteoblastic activity in 5/6 (83.33% of cases), while the characteristic bilateral and symmetrical knee osteosclerosis in 4/6 patients (66.67%) as shown in Fig. 2. This bilateral and symmetrical “hot knee” scintigraphic pattern has been considerate as a quasi pathognomonic sign for ECD [11]. Only the patient with cutaneous confined disease has not significant findings in bone scan (Patient 4 in Fig. 2).
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Fig. 2. Bone scintigraphy compared to the six patients with histopathology confirmed disease. The bone involvement was observed in 5 of 6 patients, so that only the patient number 4 demonstrated negative findings in the bone scintigraphy. The characteristic bilateral and symmetrical knee osteosclerosis was observed in 4 patients (patients numbers 1, 2, 5 and 6). The patient number 3 showed an increased osteoblastic activity in the left coxal bone, which was chosen as the optimum location for biopsy which confirmed disease.
Meanwhile, the 18FDG-PET/CT revealed hypermetabolic focuses in 5/6 (83.33% patients). The system mainly affected was the skeletal system, involved in 5/6 patients, followed by CNS involvement in 3/6 patients, lung, lymphatic or adrenal pathological uptake. The maximum standardized uptake value for the positive lesions ranged from 3.5 in skeletal to 26.4 in cerebellum. In this sense, 18FDG-PET/CT provided valuable information regarding extension assessment and biopsy guidance. A total of six 18FDG-PET/CT scans were undergone during the treatment with interferon pegylate in four patients, demonstrating a partial metabolic response in terms of metabolic activity, in the early stages of the treatment in two patients (interval from baseline PET/CT: 4 and 5 months, respectively), although control studies in later stages of treatment revealed metabolic progression of the disease in all cases from the sixth month of the baseline study. PET scans timeline from one of these patients is shown in Fig. 3. One patient underwent an 18FDOPA-PET/CT, after clinical interview, comprehensive explanation, verbal and written informed consent from the patient, with identical conditions of fasting and hydration than 18FDG scans. No inhibitor of peripheral aromatic amino acid decarboxylase was administrated before of the radiotracer injection. 18FDOPA is being a promising PET radiopharmaceutical that is still underused in clinical practice for oncologic purposes [9]. In this case, negative findings were observed in the 18FDOPA scan, while parietal cortex irregularities and hypermetabolic in lungs, adrenal, knees and soft tissues focuses were revealed in the 18FDG scan. A comparative review of both scans can be found in Fig. 4. A summary of findings observed in bone scintigraphy, 18FDG and 18FDOPA-PET/CT could be found in Table 1. The bone scintigraphy and 18FDG-PET/CT findings were also useful in identifying the appropriate site for biopsy in five patients: cerebellum, tibiae, pelvis and retroperitoneum. Only the patient with cutaneous confined disease showed no significant findings by nuclear imaging. In this patient, the ECD was confirmed after facial cutaneous biopsy.
4. Discussion The ECD is a rare, non familiar and non-Langerhans cell histiocytosis with multiorgan involvement, described in 1930 [1]. The etiology of ECD is unknown yet thought to be associated with an intense TH1 immune response. It may also be associated with the V600E BRAF mutation, as described in as many as half of the patients in recent studies [10]. Based on the recent studies, ECD can now be defined as a clonal disorder marked by frequent hyperactivation of mitogen-activated protein kinase signaling in which an inflammatory milieu is important in the pathogenesis and clinical manifestations of the disease [11]. To our knowledge, about 500 cases have been reported in the literature v. The diagnosis of ECD relies on established imaging and histological criteria, being the typical histological findings usually obtained after the imagenological location of optimum site for biopsy, sufficient to confirmation [5]. The clinical course of ECD is largely dependent on the extent and distribution of the disease. The bone involvement is almost universal in the ECD, which is usually combined with infiltration of at least one more organ system, reaching the 96% of cases in the literature. The most common manifestation is a mixed pattern with lytic and sclerotic lesions in the metaphyseal and diaphyseal regions of the long tubular bones, hindering the differential diagnosis with Langerhans cell histiocytosis [5,12]. In this regard, the bone scintigraphy allows a global evaluation of skeletal abnormalities, which helps to detect silent bone involvement [13]. Bone scintigraphy has pathognomonic features, characterized by a symmetric activity of the appendicular skeleton without reaching the epiphyseal regions. In our serie, the bone involvement was present in five of six patients, while the pathognomonic pattern was observed in four of them allowing locating an optimum location for bone biopsy. Approximately 50% of the patients have extra-skeletal manifestations, so that neurological symptoms as the first clinical manifestations of ECD have been reported in less than one third of
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Fig. 3. 18FDG-PET/CT timeline in a 66 year old male with confirmed ECD after knee biopsy guided by bone scintigraphy (patient number 5 in Fig. 2). The first 18FDG-PET/CT revealed an increased uptake of radiotracer in the axial and peripheral skeletal reaching a SUV maximum of 11.7 in the left femur, as well as in the mesentery, perirenal and perivascular locations. The patient began treatment with pegylated inferferon and a second 18FDG-PET/CT was performed in order to evaluate the response four months after starting treatment. The control scan demonstrated a partial response in the mesentery, perirenal and perivascular locations, whereas that a stable disease was observed in the skeletal reaching a SUV maximum of 12 in the right humerus. Despite continuing with steroids and interferon treatment, a progression of the disease was demonstrated in a third 18FDG-PET/CT, performed 10 months after starting treatment, which showed increased metabolic activity in regions already described.
cases [14]. Many patients have CNS involvement resulting in CDI. The CDI was documented in half of patients in a recent review of 110 patients with ECD [20]. CDI has been reported in approximately one quarter of the patients with ECD, caused by infiltration of the pituitary gland [6]. In our serie, only one of the three patients with CNS involvement debuted with CDI, demonstrating an hypermetabolic focus in the sille turcica by 18FDG-PET/CT (Fig. 1), according with the infiltration of the pituitary gland. Endocrinological decline was observed 6 months after initiation of treatment with corticosteroids and interferon. In this point, a follow-up 18FDG-PET/CT scan revealed progression of disease, with increased metabolic activity in the pituitary. In other patients, intra and extra-axial brainstem lesions, spinal, epidural and extradural lesions have also been reported [15]. Lesions of the brain, meninges, facial bones, and orbits are frequently observed and should be systematically sought on the brain MR, even if these patients are asymptomatic
[16]. In our serie, the CNS involvement occurs with other symptoms, among CDI, such as motor impairment or cerebellar ataxia [17]. Only one of the three patients with CNS involvement began with parkinsonism. The initial staging 18FDG-PET/CT showed up to four hypermetabolic cerebellar lesions and in the C1 and T10 levels of the spinal cord, reaching a SUV maximum of 26.4 expressing a high rate of cell proliferation. The biopsy of the cerebellar mass of best accessibility, largest and highest proliferation rate allowed establishing the final diagnosis of ECD. The CNS involvement confers a worse prognosis [8], so some groups suggest obtaining a baseline brain magnetic resonance imaging [18]. Agree with this statement, both patients with CNS involvement (excluding the patient with isolate pituitary infiltration) progressed to a poor outcome, neurological decline and exitus 6 and 38 months after diagnosis. In addition to the above, some patients might be largely asymptomatic or experience limited urinary complications, particularly
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Fig. 4. 48 Year old female with history of IIA left breast invasive ductal carcinoma who undergone a control bone scintigraphy. Bone scan (patient number 2 in Fig. 2), revealed a moderate bilateral and symmetrical bone osteosclerosis. Due to the pathognomonic finding in bone scan, a tibiae biopsy was performed and leads to the diagnosis of ECD. An initial staging 18FDG-PET/CT showed parietal cortex irregularities and hypermetabolic focuses in the lung (SUV maximum: 5.7), adrenal (SUV maximum 5.4), knees and soft tissues. According to the technical facilities and availability, an 18FDOPA-PET/CT was performed, after clinical interview, comprehensive explanation, verbal and written informed consent from the patient, intended to prove useful in the initial diagnosis of this condition. The 18FDOPA scan was not useful, not evidencing any of the hypermetabolic lesions described in the 18FDG scan. Post-hoc cranial MRI demonstrated the tegmentum, parietal cortex and internal capsule involvement. Neurological decline and exitus occurred 6 months after the diagnosis.
when the infiltrate causes ureteral obstruction and chronic renal insufficiency. Approximately 30% patients with diagnosis of ECD noted a retroperitoneal or urologic involvement, but some groups have reported incidences of up to 85% because the increased frequency of cross-sectorial imaging [19]. Meanwhile, the hairy
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kidney appearance in the majority of patients with ECD do indeed have some form of retroperitoneal involvement [6]. Urinary retention and polyuria predominated, noting that many of these patients were also diagnosed with CDI [20]. Half of our patients showed hypermetabolic irregularities in the initial staging 18FDG-PET/CT located in retroperitoneum and perirenal area, while the last patient of our serie, a 27 year old male, combined a CDI with retroperitoneal fibrosis. Cardiac involvement has been also reported in literature in the form of infiltration of the right heart, the right atrium and less commonly pericardial effusion and periarterial infiltration [21]. No evidences of cardiac involvement have been observed in our population. Regarding treatment, there have been few prospective therapeutic studies and no randomized controlled trials in ECD because its difficulty in view of the extreme rarity of the condition. A recent multicentre retrospective analysis has demonstrated that interferon alpha and pegylated interferon alpha may be useful in consolidative therapy for patients with CNS preservation [7]. Treatment with Vemurafenib, a newly approved BRAF inhibitor, should be considered for patients with severe and refractory BRAFV600E histiocytosis [22]. Corticosteroids may reduce edema acutely, for example in severe exophthalmos, but are not considered effective monotherapy [12]. When CNS involvement occurs, high-dose methotrexate may be an effective salvage agent [23]. It is well known that the most inflammatory cells have increased uptake of glucose which is enhanced in the presence of local cytokines. In this entity, histiocytes have been found to express a pattern of proinflammatory cytokines and chemokines responsible for local activation and recruitment of histiocytes. Therefore, imaging glucose metabolism by the means of 18FDG-PET holds significant promise in imaging focal inflammation [24]. Thereby, the 18FDG-PET/CT plays an important role in the management of this disease. It has been reported that 18FDG imaging allows accurate evaluation of the extent of the disease at baseline by detecting the visceral and vascular infiltration [25], discarding systemic involvement, locate the site for biopsy, as well as assessment of response to any specific therapy [26]. Up to now, radiography, 99m-Tc bone scintigraphy, MRI, and CT have been the main imaging methods used in the diagnosis and follow up of patients with ECD. While, CT and HRCT are useful for better detection and characterization of lung, pleural, aortic and skeletal abnormalities, MR imaging has proven its usefulness in characterization of cardiac and pericardial involvement. Furthermore, CT is also the most widely technique used for image-guided biopsy. However, none of these imaging modalities is able to provide a global assessment of the extent and activity of the disease [27]. In this vein, the sensitivity varied greatly among the different sites of involvement we studied, but 18FDG-PET scanning showed excellent specificity when compared with most other imaging modalities. This suggests that 18FDG scanning may be interesting in the initial assessment of selected patients, with an optional bone scintigraphy, but may best serve during follow up of the disease [28]. In this way, 18FDGPET/CT should be performed every 3–6 months for all patients following the initiation of treatment, and the interval between scans can be increased once disease has stabilized [29]. However, definitive evidence of any change in patient management or outcome due to 18FDG-PET/CT in the follow-up period is lacking. On the other hand, the 18FDOPA-PET has been historically used for the evaluation of parkinsonian syndromes in research settings, as well as can be a useful tool for the detection of different neuroendocrine tumours, in the detection staging/restaging of carcinoid tumours, for confirmation of diagnosis of pheochromocytoma/paraganglioma and for detection of persistent and residual medullary thyroid cancer [30].
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One 18FDOPA-PET/CT was performed to determine their potential usefulness in the extension diagnosis or monitoring response to treatment of this rare disease, after clinical interview with the patient, comprehensive explanation, verbal and written informed consent from the patient. 18FDOPA scan was performed under identical conditions of fasting and hydration than 18FDG scans. No inhibitor of peripheral aromatic amino acid decarboxylase was administrated before of the radiotracer injection. To our best knowledge, no evidence of previous 18FDOPA-PET/CT has been reported in a patient with ECD. In our case, negative findings were observed in the 18FDOPA scan, while systemic involvement was revealed in the 18FDG scan. A comparative review of both scans can be found in Fig. 4. According to these findings in this only case report, we found that 18FDOPA-PET/CT not seems useful in the initial staging of ECD. 5. Conclusion The multifocal nature of involvement in ECD can produce a wide variety of clinical signs. In our experience, neurological involvement, among the isolate pituitary infiltration, was associated with mortality in all cases. Characteristic long bone osteosclerosis was detected in 4/6 patients, while bone infiltration was observed in 5/6 patients. To the best of our knowledge, the 18FDOPA-PET/CT not seem useful in the initial staging of ECD based on a single case report, unlike the bone scintigraphy and the 18FDG-PET/CT that were particularly useful in despite systemic involvement, locate the optimum site for biopsy and treatment response evaluation. In this context, a baseline 18FDG-PET/CT with an optional bone scintigraphy may help in monitoring the disease and could be considered when patients were incidentally diagnosed and periodically followup 18FDG-PET/CT must be performed in the follow up to evaluate the treatment response. Conflict of interest statement None declared. References [1] Chester W. Uber lipoidgranulomatose. Virchows Arch A: Pathol Anat Histol 1930;279:561–602. [2] Jaffe HL. Lipid cholesterol granulomatosis. In: Lea F, editor. Metabolic, degenerative and inflammatory disease of bone and joints. Philadelphia, PA: Lea and Febiger; 1972. p. 535–41. [3] Haroche J, Arnaud L, Cohen-Aubart F, Hervier B, Charlotte F, Emile JF, et al. Erdheim–Chester disease. Rheum Dis Clin North Am 2013;39:299–311. [4] Egan AJ, Boardman LA, Tazelaar HD, Swensen SJ, Jett JR, Yousem SA, et al. Erdheim–Chester disease: clinical, radiologic, and histopathologic findings in five patients with interstitial lung disease. Am J Surg Pathol 1999;23:17–26. [5] Haroche J, Arnaud L, Amoura Z. Erdheim–Chester disease. Curr Opin Rheumatol 2012;24:53–9. [6] Mazor RD, Manevich-Mazor M, Shoenfeld Y. Erdheim–Chester disease: a comprehensive review of the literature. Orphanet J Rare Dis 2013;8:137.
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The role of 18FDG, 18FDOPA PET/CT and 99mTc bone scintigraphy imaging in Erdheim–Chester disease ˜ a , R. Martínez-Castillo a , J.L. Tirado-Hospital a , F.J. García-Gómez a,∗ , I. Acevedo-Bánez a J.I. Cuenca-Cuenca , V.M. Pachón-Garrudo a , R.M. Álvarez-Pérez a , R. García-Jiménez a , E. Rivas-Infante b , J.S. García-Morillo c , I. Borrego-Dorado a a
Department of Nuclear Medicine, Virgen del Rocío Universitary Hospital, Seville, Spain Department of Pathology, Virgen del Rocío Universitary Hospital, Seville, Spain c Department of Internal Medicine, Virgen del Rocío Universitary Hospital, Seville, Spain b
a r t i c l e
i n f o
Article history: Received 28 March 2015 Received in revised form 11 April 2015 Accepted 20 April 2015 Keywords: Erdheim–Chester disease PET/CT Bone scintigraphy 18FDG 18FDOPA
a b s t r a c t Erdheim–Chester disease (ECD) is a rare non-Langerhans cell histiocitosis, characterized by multisystemic xanthogranulomatous infiltration by foamy histiocytes that stain positively for CD68 marker but not express CD1a and S100 proteins. Etiology and pathogenesis are still unknown and only about 500 cases are related in the literature. Multisystemic involvement leads to a wide variety of clinical manifestations that results in a poor prognosis although recent advances in treatment. We present the clinical, nuclear medicine findings and therapeutic aspects of a serie of 6 patients with histopathological diagnosis of ECD, who have undergone both bone scintigraphy (BS) and 18F-fluorodeoxyglucose (18FDG)-PET/CT scans in our institution. A complementary 18F-fluorodopa (18FDOPA)-PET/CT was performed in one case. Three different presentations of the disease were observed in our casuistic: most indolent form was a cutaneous confined disease, presented in only one patient. Multifocal involvement with central nervous system (CNS) preservation was observed in two patients. Most aggressive form consisted in a systemic involvement with CNS infiltration, presented in three patients. In our experience neurological involvement, among one case with isolate pituitary infiltration, was associated with mortality in all cases. 18FDG-PET/CT and BS were particularly useful in despite systemic involvement; locate the site for biopsy and the treatment response evaluation. By our knowledge, 18FDOPA-PET/CT not seems useful in the initial staging of ECD. A baseline 18FDG-PET/CT and BS may help in monitoring the disease and could be considered when patients were incidentally diagnosed and periodically 18FDG-PET/CT must be performed in the follow up to evaluate treatment response. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The Erdheim–Chester disease (ECD) is an uncommon, non familiar, non-Langerhans cell histiocytosis, initially described by Jakob Erdheim and William Chester in 1930 as a lipid granulomatosis [1]. The eponym ECD was coined years later, after the publication of the work of the group of Jaffe et al. [2] Up-to-date, about 500 cases have been reported in the literature [3]. The etiology and pathogenesis of ECD remain unknown, but is characterized by multisystemic xanthomatous or xanthogranulomatous infiltration of involved tissues by foamy histiocytes that
∗ Corresponding author. Tel.: +34 680925869; fax: +34 955012079. E-mail address: [email protected] (F.J. García-Gómez). http://dx.doi.org/10.1016/j.ejrad.2015.04.022 0720-048X/© 2015 Elsevier Ireland Ltd. All rights reserved.
stain positively for CD68 marker but not express the CD1a, and the absence of Birbëck granules, as seen in Langerhans cell histiocytosis [4]. Recently, has been probed that S100 protein is positive up to 20% patients [5]. Individuals affected are typically adults between their 5–7th decades of life. Males and females are almost equally affected, through with a slight predilection for men. The multisystemic involvement leads to a wide variety of clinical manifestations. The most common presentation includes diffuse sclerotic lesions, present especially on the diaphysis of appendicular long bones. The osseous involvement is constant and characteristic, affecting up to 96% cases [6], but extra-osseous lesions have been described, including cardiovascular involvement, exophtalmos, central diabetes insipidus (CDI), xanthelasmas, interstitial lung disease, renal failure, retroperitoneal fibrosis, central nervous system involvement, bilateral enlargement or testis involvement [5]. The
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Table 1 Demographic, clinical, bone scintigraphy, 18FDG and 18FDOPA PET/CT scans findings and follow-up data of the 6 patients with confirmed diagnosis of ECD. Patient number
Sex
Age
Bone scintigraphy
Initial staging 18FDG-PET/CT
Control 18FDGPET/CT
Initial staging 18FDOPAPET/CT
Biopsy site
Clinical outcome
1
Male
43
Bilateral knee osteosclerosis
Progression of the disease
–
Cerebellum mass
Exitus 38 months after diagnosis
2
Female
48
Bilateral knee osteosclerosis
–
Negative findings
Tibiae
Exitus 6 months after diagnosis
3
Male
42
Left coxal hypermetabolic lesion
Cerebellum and spinal cord hypermetabolic focuses, with difuse bone increased uptake Parietal cortex irregularities. Hypermetabolic focuses in lung, adrenal, knees and soft tissues Supra/ infradiaphragmatic lymphatic and skeletal involvement
–
Coxal bone
Bone pain
4
Male
45
–
Male
66
–
Cheekbone skin Retroperitoneum
Exophthalmos
5
Negative findings Bilateral humeri and femurs increased uptake, with knee osteosclerosis
Partial response in first PET control. Progression of the disease in second PET control. –
6
Male
27
–
Retroperitoneum
Bilateral knee and ankle osteosclerosis
Negative findings Skeletal, mesentery, perirenal and perivascular involvement
Pituitary hypermetabolic lesion, with retroperitoneum and knees involvement
complications from these multisystemic affectation results in a poor prognosis with a 5 year survival rate of 41% [7] although recent advances in treatment. Because of the rarity of this disease, most papers are a consequence of multicentre compilation of cases [8]. We present the clinical, nuclear medicine findings and therapeutic aspects of a serie of 6 patients with histopathological diagnosis of ECD, who have undergone both two-phase bone scintigraphy, 18Ffluorodeoxyglucose (18FDG) PET/CT scans in our institution. A complementary 18F-fluorodopa (18FDOPA) PET/CT was performed in one case. 2. Materials and methods We retrospectively identified 6 patients with a diagnosis of ECD from clinical, imaging and pathologic reports from November 2010 up to date at our institution. Clinical records of all patients were reviewed, collecting the demographic, clinical, histological, imaging examinations and follow-up data. Part of these data could be found in Table 1. Our population (5 males and 1 female) present a median age at the time of clinical onset and pathological diagnosis of 45.33 ± 12.59 years (range: 27–66 years). Median follow-up was 15.66 months (range: 6–38 months). Histopathological examination confirmed the ECD diagnosis in all patients. It was based on histopathological demonstration of foamy histiocytes and/or immunohistochemical staining positively for CD68 and negatively for CD1a and S100, according to Veyssier–Belot criteria [8].
Partial response in first PET control. Progression of the disease in second PET control. Progression of the disease in first PET control.
Retroperitoneal fibrosis
Central diabetes insipidus and retroperitoneal fibrosis
All patients have undergone at least one two-phase bone scintigraphy and an unenhanced 18FDG-PET/CT in order to establish an accurate extension of the disease or monitoring the therapeutic effects. The two-phase bone scintigraphy was performed after the intravenous injection of a dose of 740 MBq of 99mTc hydroxymethylene diphosphonate (99mTc-HDP) to obtain an accurate skeletal mapping or therapeutic response, and it consisted of planar images in the area more painful reported by the patient 5 min after the injection of radiotracer and a wholebody scan 120 min after the administration of 99mTc-HDP. The equipment used was a Siemens Symbia® S (Siemens, Erlangen, Germany) two head gammacamera with low energy and high resolution parallel hole collimators. In the other hand, the 18FDG-PET/CT was performed 60 min after the administration of a dose on weight-based of 18FDG (typically 370 MBq) under 6 h fasting, well hydration and the administration of a diuretic (10–20 mg i.v. furosemide) conditions. Metabolic response was defined as a significant reduction of Standardized Uptake Value (SUVmax) in the lesions, understanding as significant, SUVmax decreases greater than 25% of intensity. SUVmax decreases lower than 25% or increases of them were considered as stable disease or metabolic progression, respectively. In one case, a complementary 18FDOPA-PET/CT to determine their potential usefulness in the extension diagnosis and monitoring response to treatment of this rare disease was performed under identical conditions of fasting and hydration. Carbidopa was not administrated before of the radiotracer injection to inhibit the
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Fig. 1. 27 Year old male with history of retroperitoneal fibrosis, central diabetes insipidus, hypogonadotropic hypogonadism, secondary hypothyroidism. An initial staging 18FDG-PET/CT revealed a hypermetabolic focus contained in the sella turcica of the sphenoid bone, as shown the coronal, sagital and axial views of the scan. The hypermetabolic pituitary lesion reached a SUV maximum of 9 while a SUV maximum of 5 was measured in the adjacent cortex. In addition of the pituitary lesion, an irregular increase of the uptake in the retroperitoneum and knees were observed, reaching a SUV maximum of 5 in the retroperitoneum. The biopsy of retroperitoneal fibrosis leads to final diagnosis of ECD. A control 18FDG-PET/CT was performed 6 months after initiation of treatment with corticosteroids and interferon alpha and demonstrated progression of the disease, reaching a SUV maximum of 13.8 in the pituitary. Endocrinological decline and malaise was observed in spite of treatment.
peripheral aromatic amino acid decarboxylase, unlike as is done in patients with neuroendocrine tumours or parkinsonism. Two different PET/CT cameras (Siemens BiographTM 16 and Siemens BiographTM mCT-64. Siemens, Erlangen, Germany) were used for this purpose. All scans had been read of at least one of the cited authors, aware of the results of the previous tests and clinical data. The data was analysed by SPSS ver16.0 (Chicago, IL, USA). Continuous variables are expressed as mean, median and range, and the categorical variables are presented in percentage within the median ratio. 3. Results Three different presentations of the disease were observed in our casuistic: the most indolent form was a cutaneous confined disease, mainly facial, presented in only one patient, who demonstrated bone scintigraphy and 18FDG-PET/CT negative findings. Second form of presentation, presented in two patients, consisted in a multifocal involvement with central nervous system (CNS) preservation. According to the literature, the CNS preservation
might predict a better prognosis with stable disease after combined treatment. Third and most aggressive form consisted in a systemic involvement with CNS infiltration, presented in three patients. Two of them showed hypermetabolic masses at cerebellum and parietal cortex, leading to a neurological decline with exitus in 38 and 6 months, respectively. Third patient with neurological involvement was a 27 years old male, with history of retroperitoneal fibrosis and CDI, revealed a pituitary involvement in the initial staging 18FDGPET/CT (Fig. 1) as well as bone disease in the lower limbs. A control 18FDG-PET/CT after 6 months from starting treatment revealed progression of the disease, increasing the metabolic activity in the pituitary. Two phases bone scintigraphy demonstrated areas of increased osteoblastic activity in 5/6 (83.33% of cases), while the characteristic bilateral and symmetrical knee osteosclerosis in 4/6 patients (66.67%) as shown in Fig. 2. This bilateral and symmetrical “hot knee” scintigraphic pattern has been considerate as a quasi pathognomonic sign for ECD [11]. Only the patient with cutaneous confined disease has not significant findings in bone scan (Patient 4 in Fig. 2).
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Fig. 2. Bone scintigraphy compared to the six patients with histopathology confirmed disease. The bone involvement was observed in 5 of 6 patients, so that only the patient number 4 demonstrated negative findings in the bone scintigraphy. The characteristic bilateral and symmetrical knee osteosclerosis was observed in 4 patients (patients numbers 1, 2, 5 and 6). The patient number 3 showed an increased osteoblastic activity in the left coxal bone, which was chosen as the optimum location for biopsy which confirmed disease.
Meanwhile, the 18FDG-PET/CT revealed hypermetabolic focuses in 5/6 (83.33% patients). The system mainly affected was the skeletal system, involved in 5/6 patients, followed by CNS involvement in 3/6 patients, lung, lymphatic or adrenal pathological uptake. The maximum standardized uptake value for the positive lesions ranged from 3.5 in skeletal to 26.4 in cerebellum. In this sense, 18FDG-PET/CT provided valuable information regarding extension assessment and biopsy guidance. A total of six 18FDG-PET/CT scans were undergone during the treatment with interferon pegylate in four patients, demonstrating a partial metabolic response in terms of metabolic activity, in the early stages of the treatment in two patients (interval from baseline PET/CT: 4 and 5 months, respectively), although control studies in later stages of treatment revealed metabolic progression of the disease in all cases from the sixth month of the baseline study. PET scans timeline from one of these patients is shown in Fig. 3. One patient underwent an 18FDOPA-PET/CT, after clinical interview, comprehensive explanation, verbal and written informed consent from the patient, with identical conditions of fasting and hydration than 18FDG scans. No inhibitor of peripheral aromatic amino acid decarboxylase was administrated before of the radiotracer injection. 18FDOPA is being a promising PET radiopharmaceutical that is still underused in clinical practice for oncologic purposes [9]. In this case, negative findings were observed in the 18FDOPA scan, while parietal cortex irregularities and hypermetabolic in lungs, adrenal, knees and soft tissues focuses were revealed in the 18FDG scan. A comparative review of both scans can be found in Fig. 4. A summary of findings observed in bone scintigraphy, 18FDG and 18FDOPA-PET/CT could be found in Table 1. The bone scintigraphy and 18FDG-PET/CT findings were also useful in identifying the appropriate site for biopsy in five patients: cerebellum, tibiae, pelvis and retroperitoneum. Only the patient with cutaneous confined disease showed no significant findings by nuclear imaging. In this patient, the ECD was confirmed after facial cutaneous biopsy.
4. Discussion The ECD is a rare, non familiar and non-Langerhans cell histiocytosis with multiorgan involvement, described in 1930 [1]. The etiology of ECD is unknown yet thought to be associated with an intense TH1 immune response. It may also be associated with the V600E BRAF mutation, as described in as many as half of the patients in recent studies [10]. Based on the recent studies, ECD can now be defined as a clonal disorder marked by frequent hyperactivation of mitogen-activated protein kinase signaling in which an inflammatory milieu is important in the pathogenesis and clinical manifestations of the disease [11]. To our knowledge, about 500 cases have been reported in the literature v. The diagnosis of ECD relies on established imaging and histological criteria, being the typical histological findings usually obtained after the imagenological location of optimum site for biopsy, sufficient to confirmation [5]. The clinical course of ECD is largely dependent on the extent and distribution of the disease. The bone involvement is almost universal in the ECD, which is usually combined with infiltration of at least one more organ system, reaching the 96% of cases in the literature. The most common manifestation is a mixed pattern with lytic and sclerotic lesions in the metaphyseal and diaphyseal regions of the long tubular bones, hindering the differential diagnosis with Langerhans cell histiocytosis [5,12]. In this regard, the bone scintigraphy allows a global evaluation of skeletal abnormalities, which helps to detect silent bone involvement [13]. Bone scintigraphy has pathognomonic features, characterized by a symmetric activity of the appendicular skeleton without reaching the epiphyseal regions. In our serie, the bone involvement was present in five of six patients, while the pathognomonic pattern was observed in four of them allowing locating an optimum location for bone biopsy. Approximately 50% of the patients have extra-skeletal manifestations, so that neurological symptoms as the first clinical manifestations of ECD have been reported in less than one third of
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Fig. 3. 18FDG-PET/CT timeline in a 66 year old male with confirmed ECD after knee biopsy guided by bone scintigraphy (patient number 5 in Fig. 2). The first 18FDG-PET/CT revealed an increased uptake of radiotracer in the axial and peripheral skeletal reaching a SUV maximum of 11.7 in the left femur, as well as in the mesentery, perirenal and perivascular locations. The patient began treatment with pegylated inferferon and a second 18FDG-PET/CT was performed in order to evaluate the response four months after starting treatment. The control scan demonstrated a partial response in the mesentery, perirenal and perivascular locations, whereas that a stable disease was observed in the skeletal reaching a SUV maximum of 12 in the right humerus. Despite continuing with steroids and interferon treatment, a progression of the disease was demonstrated in a third 18FDG-PET/CT, performed 10 months after starting treatment, which showed increased metabolic activity in regions already described.
cases [14]. Many patients have CNS involvement resulting in CDI. The CDI was documented in half of patients in a recent review of 110 patients with ECD [20]. CDI has been reported in approximately one quarter of the patients with ECD, caused by infiltration of the pituitary gland [6]. In our serie, only one of the three patients with CNS involvement debuted with CDI, demonstrating an hypermetabolic focus in the sille turcica by 18FDG-PET/CT (Fig. 1), according with the infiltration of the pituitary gland. Endocrinological decline was observed 6 months after initiation of treatment with corticosteroids and interferon. In this point, a follow-up 18FDG-PET/CT scan revealed progression of disease, with increased metabolic activity in the pituitary. In other patients, intra and extra-axial brainstem lesions, spinal, epidural and extradural lesions have also been reported [15]. Lesions of the brain, meninges, facial bones, and orbits are frequently observed and should be systematically sought on the brain MR, even if these patients are asymptomatic
[16]. In our serie, the CNS involvement occurs with other symptoms, among CDI, such as motor impairment or cerebellar ataxia [17]. Only one of the three patients with CNS involvement began with parkinsonism. The initial staging 18FDG-PET/CT showed up to four hypermetabolic cerebellar lesions and in the C1 and T10 levels of the spinal cord, reaching a SUV maximum of 26.4 expressing a high rate of cell proliferation. The biopsy of the cerebellar mass of best accessibility, largest and highest proliferation rate allowed establishing the final diagnosis of ECD. The CNS involvement confers a worse prognosis [8], so some groups suggest obtaining a baseline brain magnetic resonance imaging [18]. Agree with this statement, both patients with CNS involvement (excluding the patient with isolate pituitary infiltration) progressed to a poor outcome, neurological decline and exitus 6 and 38 months after diagnosis. In addition to the above, some patients might be largely asymptomatic or experience limited urinary complications, particularly
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Fig. 4. 48 Year old female with history of IIA left breast invasive ductal carcinoma who undergone a control bone scintigraphy. Bone scan (patient number 2 in Fig. 2), revealed a moderate bilateral and symmetrical bone osteosclerosis. Due to the pathognomonic finding in bone scan, a tibiae biopsy was performed and leads to the diagnosis of ECD. An initial staging 18FDG-PET/CT showed parietal cortex irregularities and hypermetabolic focuses in the lung (SUV maximum: 5.7), adrenal (SUV maximum 5.4), knees and soft tissues. According to the technical facilities and availability, an 18FDOPA-PET/CT was performed, after clinical interview, comprehensive explanation, verbal and written informed consent from the patient, intended to prove useful in the initial diagnosis of this condition. The 18FDOPA scan was not useful, not evidencing any of the hypermetabolic lesions described in the 18FDG scan. Post-hoc cranial MRI demonstrated the tegmentum, parietal cortex and internal capsule involvement. Neurological decline and exitus occurred 6 months after the diagnosis.
when the infiltrate causes ureteral obstruction and chronic renal insufficiency. Approximately 30% patients with diagnosis of ECD noted a retroperitoneal or urologic involvement, but some groups have reported incidences of up to 85% because the increased frequency of cross-sectorial imaging [19]. Meanwhile, the hairy
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kidney appearance in the majority of patients with ECD do indeed have some form of retroperitoneal involvement [6]. Urinary retention and polyuria predominated, noting that many of these patients were also diagnosed with CDI [20]. Half of our patients showed hypermetabolic irregularities in the initial staging 18FDG-PET/CT located in retroperitoneum and perirenal area, while the last patient of our serie, a 27 year old male, combined a CDI with retroperitoneal fibrosis. Cardiac involvement has been also reported in literature in the form of infiltration of the right heart, the right atrium and less commonly pericardial effusion and periarterial infiltration [21]. No evidences of cardiac involvement have been observed in our population. Regarding treatment, there have been few prospective therapeutic studies and no randomized controlled trials in ECD because its difficulty in view of the extreme rarity of the condition. A recent multicentre retrospective analysis has demonstrated that interferon alpha and pegylated interferon alpha may be useful in consolidative therapy for patients with CNS preservation [7]. Treatment with Vemurafenib, a newly approved BRAF inhibitor, should be considered for patients with severe and refractory BRAFV600E histiocytosis [22]. Corticosteroids may reduce edema acutely, for example in severe exophthalmos, but are not considered effective monotherapy [12]. When CNS involvement occurs, high-dose methotrexate may be an effective salvage agent [23]. It is well known that the most inflammatory cells have increased uptake of glucose which is enhanced in the presence of local cytokines. In this entity, histiocytes have been found to express a pattern of proinflammatory cytokines and chemokines responsible for local activation and recruitment of histiocytes. Therefore, imaging glucose metabolism by the means of 18FDG-PET holds significant promise in imaging focal inflammation [24]. Thereby, the 18FDG-PET/CT plays an important role in the management of this disease. It has been reported that 18FDG imaging allows accurate evaluation of the extent of the disease at baseline by detecting the visceral and vascular infiltration [25], discarding systemic involvement, locate the site for biopsy, as well as assessment of response to any specific therapy [26]. Up to now, radiography, 99m-Tc bone scintigraphy, MRI, and CT have been the main imaging methods used in the diagnosis and follow up of patients with ECD. While, CT and HRCT are useful for better detection and characterization of lung, pleural, aortic and skeletal abnormalities, MR imaging has proven its usefulness in characterization of cardiac and pericardial involvement. Furthermore, CT is also the most widely technique used for image-guided biopsy. However, none of these imaging modalities is able to provide a global assessment of the extent and activity of the disease [27]. In this vein, the sensitivity varied greatly among the different sites of involvement we studied, but 18FDG-PET scanning showed excellent specificity when compared with most other imaging modalities. This suggests that 18FDG scanning may be interesting in the initial assessment of selected patients, with an optional bone scintigraphy, but may best serve during follow up of the disease [28]. In this way, 18FDGPET/CT should be performed every 3–6 months for all patients following the initiation of treatment, and the interval between scans can be increased once disease has stabilized [29]. However, definitive evidence of any change in patient management or outcome due to 18FDG-PET/CT in the follow-up period is lacking. On the other hand, the 18FDOPA-PET has been historically used for the evaluation of parkinsonian syndromes in research settings, as well as can be a useful tool for the detection of different neuroendocrine tumours, in the detection staging/restaging of carcinoid tumours, for confirmation of diagnosis of pheochromocytoma/paraganglioma and for detection of persistent and residual medullary thyroid cancer [30].
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One 18FDOPA-PET/CT was performed to determine their potential usefulness in the extension diagnosis or monitoring response to treatment of this rare disease, after clinical interview with the patient, comprehensive explanation, verbal and written informed consent from the patient. 18FDOPA scan was performed under identical conditions of fasting and hydration than 18FDG scans. No inhibitor of peripheral aromatic amino acid decarboxylase was administrated before of the radiotracer injection. To our best knowledge, no evidence of previous 18FDOPA-PET/CT has been reported in a patient with ECD. In our case, negative findings were observed in the 18FDOPA scan, while systemic involvement was revealed in the 18FDG scan. A comparative review of both scans can be found in Fig. 4. According to these findings in this only case report, we found that 18FDOPA-PET/CT not seems useful in the initial staging of ECD. 5. Conclusion The multifocal nature of involvement in ECD can produce a wide variety of clinical signs. In our experience, neurological involvement, among the isolate pituitary infiltration, was associated with mortality in all cases. Characteristic long bone osteosclerosis was detected in 4/6 patients, while bone infiltration was observed in 5/6 patients. To the best of our knowledge, the 18FDOPA-PET/CT not seem useful in the initial staging of ECD based on a single case report, unlike the bone scintigraphy and the 18FDG-PET/CT that were particularly useful in despite systemic involvement, locate the optimum site for biopsy and treatment response evaluation. In this context, a baseline 18FDG-PET/CT with an optional bone scintigraphy may help in monitoring the disease and could be considered when patients were incidentally diagnosed and periodically followup 18FDG-PET/CT must be performed in the follow up to evaluate the treatment response. Conflict of interest statement None declared. References [1] Chester W. Uber lipoidgranulomatose. Virchows Arch A: Pathol Anat Histol 1930;279:561–602. [2] Jaffe HL. Lipid cholesterol granulomatosis. In: Lea F, editor. Metabolic, degenerative and inflammatory disease of bone and joints. Philadelphia, PA: Lea and Febiger; 1972. p. 535–41. [3] Haroche J, Arnaud L, Cohen-Aubart F, Hervier B, Charlotte F, Emile JF, et al. Erdheim–Chester disease. Rheum Dis Clin North Am 2013;39:299–311. [4] Egan AJ, Boardman LA, Tazelaar HD, Swensen SJ, Jett JR, Yousem SA, et al. Erdheim–Chester disease: clinical, radiologic, and histopathologic findings in five patients with interstitial lung disease. Am J Surg Pathol 1999;23:17–26. [5] Haroche J, Arnaud L, Amoura Z. Erdheim–Chester disease. Curr Opin Rheumatol 2012;24:53–9. [6] Mazor RD, Manevich-Mazor M, Shoenfeld Y. Erdheim–Chester disease: a comprehensive review of the literature. Orphanet J Rare Dis 2013;8:137.
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