Case Report Imaging Study of Pseudotumoral Chronic with Cystic-Like Pattern in a Sjögren Syndrome Patient

Stefan-Cristian Dinescu 1 ID , Anca Emanuela Musetescu 1,*, Paulina Lucia Ciurea 1, Diana Monica Girnita 2, Sineta Cristina Firulescu 1 and Ana-Maria Bumbea 3

1 Department of Rheumatology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Craiova 200349, Romania; [email protected] (S.-C.D.); [email protected] (P.L.C.); sineta.fi[email protected] (S.C.F.) 2 Faculty for Internal Medicine, Trihealth Good Samaritan Hospital, Cincinnati, OH 45220, USA; [email protected] 3 Department of Medical Rehabilitation, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Craiova 200349, Romania; [email protected] * Correspondence: [email protected]; Tel.: +40-723-055-385

Received: 12 February 2018; Accepted: 6 March 2018; Published: 7 March 2018

Abstract: Ultrasonography has become a valuable tool for the assessment of involvement in Sjögren syndrome. Diagnostic pitfalls can be encountered in late stages of the disease, in which morphologic changes may overlap with other pathologies of the salivary glands. We present the case of a female Sjögren syndrome patient with lack of significant sicca symptoms and unilateral occurrence of parotidomegaly, which prompted the suspicion of a tumor. Due to the atypical clinical profile, diagnosis of Sjögren syndrome was delayed, at which point, severe sialadenitis produced a cystic transformation of the parotid gland parenchyma.

Keywords: ultrasonography; Sjögren’s syndrome; parotid gland; sialadenitis

1. Introduction The ultrasound (US) assessment of parotid glands (PG) has become a common practice in the diagnostic work-up of Sjögren syndrome (SS) patients. The hallmark US feature in SS is parenchymal inhomogeneity (PIH), a structural change that occurs as a result of local lymphocytic infiltrate [1]. Ongoing research has helped to establish different grading systems based on the PIH, and has also hinted at the potential inclusion of the US exam in the currently accepted diagnostic criteria [2]. Appropriate evaluation by a rheumatologist may be greatly delayed in patients who tolerate a casual or lack sicca symptoms altogether. Diagnostic difficulties may be encountered if advanced structural changes have developed, and if imaging features mimic other PG pathologies, such as neoplastic or granulomatous disease [3]. We present the case of a female SS patient with scarce clinical symptoms, initially diagnosed with salivary gland tumor, in which the severe sialadenitis displayed atypical US features, with a predominantly cystic-like pattern.

2. Case Report We report the case of a 58-year-old female patient, with no significant disease history, except for a slow growing mass on her left , which became stiffer over time. The patient did not report any symptoms associated with impaired function of the salivary or lacrimal glands. She was referred to a department and, after raising the suspicion of a PG tumor, a computed tomography (CT) scan was performed. On CT scans, both PGs displayed pronounced structural abnormalities with

Reports 2018, 1, 3; doi:10.3390/reports1010003 www.mdpi.com/journal/reports Reports 2018, 1, 3 2 of 5

Reports 2018, 1, x FOR PEER REVIEW 2 of 5 predominantReports 2018, 1,cystic x FOR transformationPEER REVIEW and multiple calcifications (Figure1a), while on the CT sialography2 of 5 markedsialography , marked of sialectasis, over 7 mm of bilaterally, over 7 mm and nobilaterally, evidence and of otherno evidence potential of obstruction other potential in the ductalobstructionsialography system in weremarkedthe ductal depicted sialectasis, system (Figure were of1 b). depictedover 7 mm (Figure bilaterally, 1b). and no evidence of other potential obstruction in the ductal system were depicted (Figure 1b).

(a) (b) (a) (b) Figure 1. (a) CT (computed tomography) scan, scan, axial axial sectio sectionn of the head, both PGs (parotid glands) Figure 1. (a) CT (computed tomography) scan, axial section of the head, both PGs (parotid glands) are enlarged enlarged and and display display structural structural abnormalities, abnormalities, with with multiple multiple cystic cystic formations formations (arrowheads); (arrowheads); (b) are enlarged and display structural abnormalities, with multiple cystic formations (arrowheads); (b) (CTb) CTsialography scan scan displays displays bilateral bilateral marked marked sial sialectasisectasis with with quasi-total quasi-total involvement involvement of of glandular glandular CT sialography scan displays bilateral marked sialectasis with quasi-total involvement of glandular parenchyma (arrowheads). parenchyma (arrowheads). At this point, she was admitted to our department in order to further evaluate a possible At this point, she was admitted to our department in order to further evaluate a possible autoimmuneAt this etiology.point, she Serologic was admitted profile to revealed our departme positivent inanti-Ro-52 order to andfurther anti-SS-A evaluate antibodies, a possible autoimmune etiology. Serologic profile revealed positive anti-Ro-52 and anti-SS-A antibodies, negative negativeautoimmune anti-La/SSB etiology. antibodies Serologic and profile rheumatoid revealed factor. positive Schirmer anti-Ro-52 test was andnegative. anti-SS-A Histopathology antibodies, anti-La/SSB antibodies and rheumatoid factor. Schirmer test was negative. Histopathology exam examnegative confirmed anti-La/SSB the presence antibodies of lymphocytic and rheumatoid aggregates factor. Schirmer(Figure 2a), test with was predominantlynegative. Histopathology CD20+ B confirmed the presence of lymphocytic aggregates (Figure2a), with predominantly CD20+ cellexam subpopulation confirmed the on presence immunohistochemistry of lymphocytic aggregates exam, some (Figure with 2a), pseudonodular with predominantly distribution, CD20+ B subpopulation on immunohistochemistry exam, some with pseudonodular distribution, associated associatedcell subpopulation with marked on sialectasis immunohistochemistry (Figure 2b). exam, some with pseudonodular distribution, withassociated marked with sialectasis marked (Figure sialectasis2b). (Figure 2b).

(a) (b) (a) (b) Figure 2. (a) minor salivary gland histopathology features on Hematoxylin–Eosin stain show FigurelymphocyticFigure 2. (2.a ) (minorasialadenitis) minor salivary salivary as gland mononuclear histopathologygland histopathology cell featuresaggregates onfeatures Hematoxylin–Eosin adjacent on Hematoxylin–Eosinto glandular stain showacini; lymphocytic stain(b) CD20 show sialadenitisimmunostaining,lymphocytic as mononuclearsialadenitis 200×, distribution cellas mononuclear aggregates of B cell adjacent subpopulation cell aggregates to glandular and adjacent acini; marked (b )to CD20sialectasis glandular immunostaining, (asterisk). acini; ( b ) 200 CD20×, distributionimmunostaining, of B cell 200×, subpopulation distribution and of marked B cell subpopulation sialectasis (asterisk). and marked sialectasis (asterisk). On grey-scale US images, the structure of the glandular parenchyma was greatly altered. Both On grey-scale US images, the structure of the glandular parenchyma was greatly altered. Both PGs Ondisplayed grey-scale intense US images,hypo/anechoic the structure areas, ofsome the glandularexceeding parenchyma6 mm in diameter was greatly (Figure altered. 3a). These Both PGs displayed intense hypo/anechoic areas, some exceeding 6 mm in diameter (Figure 3a). These PGsstructural displayed changes intense were hypo/anechoic distributed to a areas, significant some extent exceeding throughout 6 mm in both diameter PGs, having (Figure a3 a).near These total structural changes were distributed to a significant extent throughout both PGs, having a near total structuralinvolvement. changes Homogenous were distributed areas of toresidual a significant glandu extentlar tissue throughout were scarcely both PGs,observed. having Based a near on total the involvement. Homogenous areas of residual glandular tissue were scarcely observed. Based on the involvement.Salaffi et al. scoring Homogenous system areas [4], ofa residualgrade 4 glandularPIH was tissueestablished. were scarcely In Doppler observed. mode, Based increased on the Salaffi et al. scoring system [4], a grade 4 PIH was established. In Doppler mode, increased Salaffivascularity et al. was scoring observed system in [4 the], a residual grade 4 PIHtissue was (Fig established.ure 3b), scoring In Doppler 2 on a mode,semi-quantitative increased vascularity scale [5]. vascularity was observed in the residual tissue (Figure 3b), scoring 2 on a semi-quantitative scale [5]. was observed in the residual tissue (Figure3b), scoring 2 on a semi-quantitative scale [5].

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(a) (b) (a) (b) Figure 3. US (ultrasound) image of PGs, longitudinal section. (a) left PG displays severe structural FigureFigure 3. 3.US US (ultrasound) (ultrasound) image image of of PGs, PGs, longitudinal longitudinal section. section. (a(a)) left left PG PG displays displays severe severe structural structural changes, multiple large and well-defined, almost anechoic areas, with a maximum diameter of 16 changes,changes, multiple multiple large large and and well-defined, well-defined, almost almost anechoic anechoic areas, areas, with with a maximum a maximum diameter diameter of 16 mm;of 16 mm; (b) power Doppler of left PG shows a moderate vascularization index, with spots inside the (bmm;) power (b) power Doppler Doppler of left PG of showsleft PG a moderateshows a moderate vascularization vascularization index, with index, spots insidewith spots the hypoechoic inside the hypoechoic areas and along the residual glandular tissue surrounding the . areashypoechoic and along areas the and residual along glandular the residual tissue glandular surrounding tissue thesurrounding cysts. the cysts. Through the relative adjacent distribution of hypoechoic areas, well-defined margins and ThroughThrough thethe relativerelative adjacentadjacent distributiondistribution ofof hypoechoichypoechoic areas,areas, well-definedwell-defined marginsmargins andand surrounding tissue resembling septa, the PGs acquired a more cystic-like pattern, with limited surroundingsurrounding tissuetissue resemblingresembling septa,septa, thethe PGsPGs acquiredacquired aa moremore cystic-likecystic-like pattern,pattern, withwith limitedlimited functional tissue (Figure 4a). Multiple hyperechoic formations, with posterior acoustic echo, pointed functionalfunctional tissue tissue (Figure (Figure4 a).4a). Multiple Multiple hyperechoic hyperechoic formations, formations, with with posterior posterior acoustic acoustic echo, echo, pointed pointed to the development of (Figure 4b). We also examined the degree of tissue stiffness using toto the the development development of of sialolithiasis sialolithiasis (Figure (Figure4 b).4b). We We also also examined examined the the degree degree of of tissue tissue stiffness stiffness using using the Acoustic Radiation Force Impulse (ARFI) technique (Figure 4c). We performed 5 measurements thethe Acoustic Acoustic Radiation Radiation Force Force Impulse Impulse (ARFI) (ARFI) technique technique (Figure (Figure4 c).4c). We We performed performed 5 5 measurements measurements on each PG and obtained a mean overall shear wave velocity of 2.06 m/s. This measurement could onon each each PG PG and and obtained obtained a a mean mean overall overall shear shear wave wave velocity velocity of of 2.06 2.06 m/s. m/s. This This measurement measurement could could not be interpreted as pathologic, due to the limited data published so far concerning reference values notnot be be interpreted interpreted as as pathologic, pathologic, due due to to the the limited limited data data published published so so far far concerningconcerning reference reference values values in healthy subjects [6], and due to a lack of established cut-off values. A written informed consent inin healthy healthy subjects subjects [ 6[6],], and and due due to to a a lack lack of of established established cut-off cut-off values. values. A A written written informed informed consent consent was obtained from the patient regarding the inclusion in a research project and eventual publishing waswas obtained obtained from from the the patient patient regarding regarding the the inclusion inclusio inn in a researcha research project project and and eventual eventual publishing publishing of of medical data. medicalof medical data. data.

(a) (b) (c) (a) (b) (c) Figure 4. (a) PG parenchyma displaying pseudotumoral features, with cystic-like pattern; (b) Figure 4. (a) PG parenchyma displaying pseudotumoral features, with cystic-like pattern; (b) Figuresialolithiasis 4. (a) PG parenchymashown as multiple displaying hyperechoic pseudotumoral formations features, with(arrowheads) cystic-like pattern;with posterior (b) sialolithiasis acoustic sialolithiasis shown as multiple hyperechoic formations (arrowheads) with posterior acoustic shownattenuation as multiple (arrows); hyperechoic (c) ARFI formations US of PG, (arrowheads) with region of with interest posterior set at acoustic 1cm under attenuation the skin, (arrows); quantifies attenuation (arrows); (c) ARFI US of PG, with region of interest set at 1cm under the skin, quantifies (c)the ARFI grade US ofof PG,glandular with region stiffness of interestat 2.04 m/s. set at 1cm under the skin, quantifies the grade of glandular stiffnessthe grade at 2.04of glandular m/s. stiffness at 2.04 m/s. 3. Discussion 3.3. DiscussionDiscussion The main pathologic feature that develops in SS is autoimmune destructive sialadenitis, with The main pathologic feature that develops in SS is autoimmune destructive sialadenitis, with focalThe mononuclear main pathologic cell feature aggregates, that develops predominantly in SS is autoimmune in the periductal destructive areas sialadenitis, [7] and withsubsequent focal focal mononuclear cell aggregates, predominantly in the periductal areas [7] and subsequent mononucleardevelopment cell of aggregates, sicca symptoms. predominantly Particularities in the periductal encountered areas in [ 7our] and patient subsequent reside development in the lack of development of sicca symptoms. Particularities encountered in our patient reside in the lack of ofsignificant sicca symptoms. sicca symptoms Particularities and encounteredalso the unilateral in our occurrence patient reside of inparotidomegaly, the lack of significant prompting sicca the significant sicca symptoms and also the unilateral occurrence of parotidomegaly, prompting the symptomssuspicion and of alsoa PG the tumor. unilateral Curiously, occurrence the functional of parotidomegaly, reserve of prompting PGs was theprovided suspicion by the of a scarce PG suspicion of a PG tumor. Curiously, the functional reserve of PGs was provided by the scarce tumor.residual Curiously, tissue, which the functional maintained reserve sufficient of PGs secretory was provided function. by the scarce residual tissue, which residual tissue, which maintained sufficient secretory function. maintainedThe sufficientmain US secretoryfeatures observed function. in SS include decreased parenchymal echogenity, multiple The main US features observed in SS include decreased parenchymal echogenity, multiple small,The mainoval hypoechoic US features observedareas, unclear in SS includeborders decreasedand hyperechogenic parenchymal reflections. echogenity, All multiple these changes small, small, oval hypoechoic areas, unclear borders and hyperechogenic reflections. All these changes ovalaccount hypoechoic for an areas,overall unclear PIH of borders the salivary and hyperechogenic glands [1]. Further reflections. grading All of these the changesPIH is established account account for an overall PIH of the salivary glands [1]. Further grading of the PIH is established through semi-quantitative scoring systems [4,8,9]. Although studies on US features of salivary through semi-quantitative scoring systems [4,8,9]. Although studies on US features of salivary glands in SS have helped outline some common features, they remain mostly unspecific, especially glands in SS have helped outline some common features, they remain mostly unspecific, especially

Reports 2018, 1, 3 4 of 5 for an overall PIH of the salivary glands [1]. Further grading of the PIH is established through semi-quantitative scoring systems [4,8,9]. Although studies on US features of salivary glands in SS have helped outline some common features, they remain mostly unspecific, especially when the clinical profile does not support a clear diagnosis. In the presence of multiple hypoechoic areas scattered in the salivary gland parenchyma, one must also take in consideration other types of chronic sialadenitis, such as Küttner tumor and granulomatous disease (e.g., ), HIV parotiditis or hematogenous metastases [3]. Structural damage to the salivary glands with similar clinical and imaging features to SS can also develop in an underlying (HCV) , in which sialotropism of HCV can lead to chronic sialdenitis [10]. In advanced stages of SS, severe ductal inflammation causes marked intraglandular sialectasis, which in turn may result in the formation of numerous cystic spaces. At this point, US exam reveals large anechoic areas with well-defined margins [11]. In a study by Takashima S. et al., PG pseudotumors were divided into solid types, formed by local massive lymphocytic infiltration, and cystic types produced by severely dilated intralobular ducts [12]. Benign tumors of the PG, such as and Warthin tumor, can display cystic features, but are usually solitary and unilateral. Conditions associated with bilateral cystic structures include acquired immunodeficiency syndrome, polycystic disease of the PG, pseudocystic appearance of or metastatic lymph nodes with central fluid collection [3].

4. Conclusions Atypical clinical presentation of SS may considerably delay a correct diagnosis. Although US has become a valuable tool for the assessment of salivary gland involvement in SS, diagnostic pitfalls can be encountered in late stages of the disease, in which morphologic features may overlap with other pathologies of the salivary glands.

Author Contributions: Stefan-Cristian Dinescu and Anca Emanuela Musetescu collected the patient data and performed the imaging study; Sineta Cristina Firulescu and Ana-Maria Bumbea contributed with the literature review and wrote the paper; Paulina Lucia Ciurea and Diana Monica Girnita contributed to the proof reading and final editing. Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations

US Ultrasound PG Parotid Glands SS Sjögren Syndrome PIH Parenchymal Inhomogeneity CT Computed Tomography ARFI Acoustic Radiation Force Impulse HCV Hepatitis C Virus

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