Calcifying nested stromal-epithelial tumor (CNSET) of the liver

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1 Cse report (CNSET) of the liver Victor Inole 1, Loredn Betrice Ungurenu *,1, Eugeni Moroșn 1, Cristin Dumitru Lupșcu 1,2 1 Grigore T. Pop University of Medicine nd Phrmcy, Isi, Romni; 2 Deprtment of Surgery, Sf. Spiridon University Emergency Hospitl, Isi, Romni Astrct (CNSET) of the liver is n extremely rre primry tumor of nonheptic nd non-iliry origins which generlly ffects children nd young dults, minly women. We report cse of 28-yer-old womn with history of orl contrceptive consumption for 9 yers, who underwent surgery for lrge right heptic mss tht proved to e CNSET, ccording to the pthology report. Postopertively the ptient hd slow recovery nd fter dischrge the ptient ws sent to the oncology deprtment where she underwent severl tretment cycles with Imtini. The cse report documented ll the clinicl nd histopthologicl fetures necessry for dignosis of CNSET. CNSET of liver should lwys e considered nd included in the differentil dignosis of heptic tumors especilly if the ptient is young womn with long history of orl contrceptive consumption nd n dominl plple mss. Keywords: clcifying nested stroml-epithelil tumor; heptic tumor; heptolstom; liver; mixed tumor Introduction (CNSET) of the liver is n extremely rre primry tumor of non-heptic nd non-iliry origins [1] consisting of nests of spindled nd epithelioid cells tht cn ssocite clcifiction or one formtion [2]. As fr s we know only 37 cses were previously descried in the literture under different nmes like: desmoplstic nested spindle cell tumor of the liver, ossifying mlignnt mixed epithelil nd stroml tumor of the liver [3], nested stroml epithelil tumor of the liver nd ossifying stroml-epithelil tumor [4]. It ws first Received: Ferury 2018; Accepted fter review: Mrch 2018; Pulished: Mrch *Corresponding uthor: Loredn Ungurenu, MD, PhD, Pthology Deprtment, Grigore T. Pop University of Medicine nd Phrmcy Isi, 16 Universittii Street, , Isi, Romni Emil: descried y Ishk et l. in 2001 [5] nd the term CNSET ws proposed y Mkhlouf et l. in 2009 [4]. It generlly ffects children nd young dults, minly women nd it is frequently locted in the right heptic loe [5]. Cse report Preopertive ssessment nd surgicl therpy A 28-yer-old Cucsin womn ws dmitted to Surgery Deprtment of our hospitl with upper dominl pin, stheni nd ftigue. The ptient hd history of orl contrceptive consumption for 9 yers, ut no history of heptitis, lcohol use, nd consumption of heptotoxic mediction or fmily history of heptic mlignncy. Physicl exmintion reveled pllor, pin in the upper dominl re nd lrge plple mss in the right hypochondric nd lumr region. No Cushingoid or other clinicl symptoms were present. DOI: / Arch Clin Cses 2018; 5(1):10-14

2 Lortory tests reveled low level of hemogloin (9.4 g/dl) nd hemtocrit (29.9 %). Serum levels of gmm-glutmyl trnsferse, sprtte trnsminse, lnine trnsminse, lph-fetoprotein, crohydrte ntigen 19-9 nd crcinoemryonic ntigen were norml. Serology results for heptitis B nd C were negtive. Adominl ultrsound nd computer tomogrphy (CT) reveled lrge nonhomogeneous mss with irregulr orders, Doppler signl nd smll nodulr clcifictions tht involved the right heptic loe entirely (Figure 1). The CT imges showed mss confined to the liver tht cused mss effect nd compression to the djcent structures. No iopsy ws tken. Bsed on the preopertive ssessment the ptient ws scheduled for liver resection, with presumptive dignosis of heptocellulr crcinom. Explortory lprotomy ws done followed y right heptectomy. Fig. 1. Ultrsound shows lrge nonhomogeneous mss with irregulr orders () nd Doppler signl present (). Pthology gross ppernce The tumor hd non-encpsulted, still well-defined, loulted feture. It ppered s lrge mss of out 34/19/12 cm tht occupied the entire right heptic loe. On cut surfce, the tumor ws solid, heterogeneous, with white res nd lrge cystic spces (Figure 2). Fig. 2. Gross imge showed reltive well defined non-encpsulted mss () with loulted, white, solid nd cystic ppernce on cut surfce () Pthology microscopicl nd immunohistochemicl nlysis Histology reveled multinodulr, loulted, non-encpsulted tumor composed from nests of spindle nd epithelioid cells with smll, centrl clcifictions, surrounded y moderte firous hypercellulr strom including lood vessels. Tumor cells hd irregulr shpe, scnt cytoplsm, ovl, hyperchromtic or vesiculr nuclei nd low nucler typi (Figure 3). The mitotic count ws low (1-2 mitosis/10 HPF). DOI: / Arch Clin Cses 2018; 5(1):10-14

3 Fig. 3. Microscopicl fetures of CNSET:. loulr non-encpsulted tumor, composed of nests of spindle nd epithelioid cells, surrounded y firous hypercellulr strom with lood vessels (HE, x40);. centrl clcifictions of nests (HE, x40) Due to the unusul histologicl ppernce, the immunohistochemicl (IHC) tests were done in stepwise fshion, in order to confirm nd/or to exclude certin presumle entities. Therefore, the pnel of mrkers included CD117, DOG1 nd CD34 for gstrointestinl stroml tumor (GIST), CK AE1/AE3, CK5, CK7, CK20, TTF-1 nd p63 for crcinom of digestive, pulmonry or squmous origin, Synptophysin nd Chromogrnin A for neuroendocrine neoplsi, S100, Meln-A nd HMB45 for mlignnt melnom, HSA for heptocellulr crcinom or heptolstom, Vimentin nd SMA for srcom nd Ki-67 to evlute the mitotic ctivity. Tumor cells were positive for CK AE1/AE3, S100, foclly positive for CD117 nd Vimentin, while negtive for the rest of the mrkers. Ki-67 showed positivity in less thn 10% of tumor cells. A rre nd lesser known entity, CNSET, hd to e proven using CD56, WT1 nd EMA. Tumor cells were positive for CD56, foclly positive for WT1 nd negtive for EMA, pttern consistent with the dignosis of CNSET (Figure 4). Postopertive ssessment Postopertively the ptient hd slow recovery with smll fluid collection in right hypochondric region, right lumr region nd hypogstrium tht resolved in the following weeks. After dischrge the ptient ws sent to oncology deprtment to continue the tretment with severl chemotherpy cycles of Imtini. Discussion (CNSET) of the liver is n extremely rre tumor occurring minly in femles (76%) with nerly 70% of reported cses in children [5]. This rre entity typiclly displys nests of spindled nd epithelioid cells tht ssocite clcifictions or one formtion, surrounded y moderte firovsculr stom [1-7]. The smll numer of CNSETs reported in literture mkes it chllenging to properly evlute the clinicl ehvior nd outcome in ptients with this type of tumors [1, 8]. So fr, only three metsttic cses hve een reported (lung, liver nd lymph nodes) nd few cses hd recurrences, fetures which confirm tht CNSET could e considered low-grde mlignncy [3, 5, 9]. The pthogenesis of CNSET remins uncertin. A few cses hd Cushing syndrome tht resolved fter surgery [3, 8]. Three cses were reported in ptients with Beckwith-Weidemn syndrome [1]. Similr to our cse, few others hd history of orl contrceptive pills consumption ut no direct ssocition ws proven [5]. DOI: / Arch Clin Cses 2018; 5(1):10-14

4 Other theories suggest the impliction of WT1, due to its role in the trnsformtion of mesenchyml cells into epithelil cells [5] nd of Bet-ctenin nd other mesenchymlepithelil trnsition fctors like: SNAIL, SLUG, TWIST, c-met, vimentin nd E-cdherin. Aprt from E-cdherin, ll others hve n incresed expression in the CNSET tumor cells. This hypothesis needs further reserch nd vlidtion due to the smll numer of cses included in the study [10]. c d e Fig. 4. IHC profile of CNSET:. strong CK AE1/AE3 positivity, cytoplsmic stining of tumor cells (nti-ae1/ae3 A, x40);. strong CD 56 positivity, memrne stining of tumor cells (nti-cd 56 A, x40); c. wek WT1 positivity, nucler stining of tumor cells (nti-wt1 A, x40); d. negtive EMA, memrne stining of tumor cells (nti-ema A, x40); e. strong Vimentin positivity, cytoplsmic stining of spindle cells (nti-vimentin A, x40). DOI: / Arch Clin Cses 2018; 5(1):10-14

5 The differentil dignosis of this rre entity includes desmoplstic smll round cell tumor (DSRCT), synovil srcom, heptolstom nd endocrine tumors [4, 6]. Opposite to CNSET, DSRCT cn e found minly in dolescent mles nd is highly ggressive, lcks the firovsculr strom nd the myofirolstic collrs [4, 6, 7]. On IHC, DSRCT is positive for desmin nd the moleculr iology shows ESW1 to WT1 fusion chrcteristic for this tumor [4]. The presence of hemngiopericytic vsculr pttern nd the positivity for CD99 re in fvor of synovil srcom, lthough cses with osteoid formtion nd clcifiction hve een descried [4, 6, 11]. Heptolstom, prticulrly mixed, epithelil nd mesenchyml sutypes re rrely seen in dults nd re chrcterized y fetl nd/or emryonl heptocyte differentition components. It lcks the typicl CNSET strom pttern nd it is positive for HepPr-1 nd AFP [4, 7]. CNSET cn e differentited from endocrine tumors y the strom pttern, positivity for CD56 nd the negtivity for neuroendocrine mrkers [6]. Surgery seems to e the gold stndrd for therpy. In regrds to chemotherpy, there re no well-defined protocols tht cn e pplied, which suggests n individulized pproch to the course of tretment [7]. Conclusion CNSET of liver is rre primry tumor of non-heptic nd non-iliry origins tht is considered low-grde mlignncy. The dignosis of CNSET should e estlished on morphology nd IHC, especilly when the ptient is young womn with n dominl plple mss, history of orl contrceptive consumption nd Cushingoid symptoms or history of Beckwith-Weidemn syndrome. Conflict of interest The uthors hve no conflict of interest to declre. Ptient consent Written informed consent ws otined from the ptient for puliction of this cse. References 1. Khoshnm N, Roinson H, Cly MR, et l. (CNSET) of the liver in Beckwith-Wiedemnn syndrome. Eur J Med Genet 2017; 60(2): Hmilton SR, Altonen LA (Eds): World Helth Orgniztion Clssifiction of Tumours. Pthology nd Genetics of Tumours of the Digestive System. IARC Press: Lyon Weed VB, de Reuver PR, Brs H et l. Cushing syndrome s presenting symptom of clcifying nested stroml-epithelil tumor of the liver in n dolescent oy: cse report. J Med Cse Rep 2016; 10: Mkhlouf HR, Adul-Al HM, Wng G, Goodmn ZD. Clcifying nested stromlepithelil tumors of the liver: clinicopthologic, immunohistochemicl, nd moleculr genetic study of 9 cses with longterm follow-up. Am J Surg Pthol 2009; 33(7): Schffer LR, Sheht BM, Yin J, et l. (CNSET) of the liver: newly recognized entity to e considered in the rdiologist's differentil dignosis. Clin Imging 2016; 40(1): Fryer E, Chetty R. Unusul nd rre tumours of the liver. Dign Histopthol 2012; 18(10): Procopio F, Di Tommso L, Armeni S, et l. Nested stroml-epithelil tumour of the liver: An unusul liver entity. World J Heptol 2014; 6(3): Grzi GL, Vetrone G, d'errico A, et l. Nested stroml-epithelil tumor(nset) of the liver: cse report of n extremely rre tumor. Pthol Res Prct 2010;206(4): Meletni T, Cntini L, Lnese A, et l. Are liver nested stroml epithelil tumors lwys low ggressive? World J Gstroenterol 2017; 23(46): Assmnn G, Kppler R, Zeindl-Eerhrt E, et l. β-ctenin muttions in 2 nested stroml epithelil tumors of the liver-- neoplsi with defective mesenchyml-epithelil trnsition. Hum Pthol 2012; 43(11): Oviedo Rmírez MI, Bs Bernl A, Ortiz Ruiz E, et l. Desmoplstic nested spindle cell tumor of the liver in n dult. Ann Dign Pthol 2010; 14(1):44-49 DOI: / Arch Clin Cses 2018; 5(1):10-14

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