Soft Tissue Myoepithelioma in Children: A Rare Case Report of the Mediastinum and a Review of the Literature＊

DU Hong Mei and CAI Wei Song

Myoepithelioma (ME) is a rare tumor composed of myoepithelial cells that usually surround glandular tissue.MEs differ from mixed tumors as they present minimal or no ductal differentiation[1].MEs can originate from soft tissue and bones,but histogenesis remains uncertain.

MEs seldom occur in the mediastinum;most cases described have reported that the tumor originated from ectopic salivary gland tissue along the bronchial mucous glands or tracheobronchial tree,and the mediastinum was secondarily involved.Only four well-documented cases have been reported in the English literature on MEs originally occurring in the mediastinum (Supplementary Table S1available in www.besjournal.com).MEs are primarily found in the adult population but have also been described in children.

Here,we report a case of soft tissue ME in the mediastinum of a 9-year-old boy.A large heterogeneously enhanced soft tissue mass with multiple amorphous calcifications adjacent to the spine was detected in the right posterior mediastinum.The mass measured 7.3 × 5.9 × 7.4 cm3and had infiltrated the tenth posterior rib (Figure 1).Immunohistochemical staining of the initial ultrasound-guided needle biopsy revealed positive expression for S-100,ERG,CD99 (locally),and Ki67(3%) (Figure 2).Due to the invasiveness of the tumor,mesenchymal chondrosarcoma was the favored diagnosis,and one cycle of ifosfamide and doxorubicin was administered while the diagnosis was confirmed.

Next-generation sequencing (NGS) was performed considering the discrepancy between the proliferation index (Ki67,3%) and the invasive growth.NGS revealed aEWSR1-ZNF444gene fusion[t (19;22) (q13;q12)],where exon 7 ofEWSR1(rearrangement position: 29686175 on chromosome 22) was fused in-frame to exon 5 ofZNF444(rearrangement position: 56671149 on chromosome 19) (Figure 3,Supplementary Figure S1available in www.besjournal.com).In 2008,Brandal et al.[2]first reported that the translocation of t (1;22) (q23;q12)resulted in the fusion ofEWSR1-PBX1in soft tissue ME.To date,EWSR1gene rearrangements have been detected in nearly half of soft tissue myoepithelial tumor cases,with several reported fusion partners,includingPBX1(1q23),ZNF444(19q23),POU5F1(6p21),ATF1(12q13),andPBX3(9q339).Therefore,theEWSR1-ZNF444gene fusion suggested a diagnosis of ME.In addition toEWSR1gene rearrangements,uncommon fusions ofPLAG1,FUS,SRF,andOGTwith fusion partners,such asFOXO3,have been reported in soft tissue ME.SMARCB1/INI1deficiency is found in a significant subset of ME cases,particularly in malignant lesions[3].Different types of gene fusions/mutations dominate in different MEs (Supplementary Table S2available in www.besjournal.com).In addition,the present case carried aBUBIBgermline mutation(Supplementary Figure S1).BUBIBencodes a key protein in the mitotic spindle checkpoint;however,its association with ME is unknown.

Figure 1.Computed tomography (CT) images at the initial diagnosis.The three-dimensional CT scan showing a mixed density tumor expanding to the intervertebral foramina (A and B).Contrast-enhanced CT showing a large heterogeneously enhanced soft tissue mass with multiple amorphous calcifications in the right posterior mediastinum infiltrating the tenth posterior rib (C and D).

Figure 2.Histological and immunohistochemical results of the ultrasound-guided needle biopsies.Microscopic examination shows the tumor cells arranged in cords and sheets without ductal structures(A).The background was locally myxoid stroma with local calcification (B) and chondrometaplasia (C).Immunohistochemical staining reveals the positive expression of S-100 (D),CD99 (locally) (E),and Ki67(3%) (F).

Figure 3.Next-generation sequencing results of the ultrasound-guided needle biopsies.Sarcoma PanScan analysis revealed an EWSR1-ZNF444 gene fusion,where exon 7 of EWSR1 (rearrangement position:29686175 on chromosome 22) was fused in-frame to exon 5 of ZNF444 (rearrangement position:56671149 on chromosome 19) (A and B).

Combined with the NGS results,a pathological consultation at an external institution favored ME;thus,thoracotomy was performed,and the tumor was excised in the hospital.The tumor originated from the 9-11 intervertebral foramina,and the local ribs were deformed and damaged.As myoepithelial cells were situated along the outer aspect of the acini,the intercalated ducts,and the interlobar and interlobular striated ducts,we assumed that the ME originated from stem cells in the intervertebral foramina capable of differentiation following the soft tissue ME classification.Soft tissue MEs are usually described in the subcutis and deep soft tissue(intramuscular,within the fascia,and subfascial).Our case is the first arising from the intervertebral foramina to be reported in the English language literature.

A microscopic examination of the postoperative mass revealed tumor cells arranged in cords and sheets with a rare adenoid arrangement and no ductal structure (data not shown).The tumor cells demonstrated mild atypia without evident nucleoli or mitoses.No tumors were found in the involved lung tissue.The diagnosis of benign ME was confirmed based on these morphological features.This was different from the malignant diagnosis provided by the initial ultrasound-guided needle biopsy.The tumor,in our case,had invaded the tenth posterior rib,which has never been reported.The criteria for malignant ME are different,but an invasive growth pattern is a useful criterion for establishing malignancy in a patient with salivary ME.However,Hornick and Fletcher[4]reported that this criterion does not apply to soft tissue myoepithelial tumors,as benign tumors with microscopically infiltrative margins do not recur or metastasize.Thus,they proposed that the appearance of moderate or severe cellular atypia was associated with malignancy in soft tissue myoepithelial tumors;border infiltration did not correlate with aggressive behavior,nor did the mitotic rate,as no specific mitotic rate cutoff exists[4].Another study showed that a high Ki-67 labeling index (Ki67 LI,14%-60%) may support a malignant diagnosis,as high Ki-67 LI is seen in severe nuclear atypia,and cases with mild to moderate nuclear atypia also exhibit a Ki-67 LI ＞ 10%[5].In the present case,the tumor cells were mildly atypic without an evident nucleolus or mitoses and a Ki67 concentration of 8% in postoperative tissue.Therefore,benign ME was finally diagnosed.

Adjuvant therapy was not administered in this case.Surgery has been the predominant treatment modality for soft tissue ME.As incomplete excision of benign MEs has been reported to lead to recurrence or metastasis,complete resection is recommended.A conservative excision with a minimum 5 mm margin of uninvolved tissue is supported for cases of benign ME with possible capsular/adjacent tissue infiltration[6].Given its scarcity,the effects of adjuvant therapy on localized and metastatic diseases have not been clarified.Specialists support perioperative radiotherapy for malignant ME,where wide excision or amputation is suggested;chemotherapy has no distinct benefit.The prognosis for soft tissue ME is based on the histological appearance following the diagnostic criteria for malignant myoepithelial tumors.Hornick and Fletcher[4]studied 101 cases of myoepithelial tumors with moderate to severe cytological atypia and reported a local recurrence rate of 42% and a metastatic rate of 32%,whereas cytologically bland tumors recurred locally in 18% of cases and none metastasized.Another study showed that local relapse is seen in all tumor grades,with 5-year relapse rates of 29%vs.64% for low-gradevs.highgrade tumors,respectively[7].Our case recurred locally 6 months after surgery,which was attributed to the difficulty in completely removing the tumor from the intervertebral foramina.

Soft tissue ME occurs over a wide age range,with approximately 20% of the cases reported in children[8].The biological behavior of pediatric ME is similar to that seen in adults,although soft tissue ME in children has a high rate of malignancy[8].About 27 cases of soft tissue ME have been reported in patients ＜ 18 years old (Supplementary Table S3available in www.besjournal.com).Ectomesenchymal chondromyxoid tumor of the tongue,which has been classified into the pathological spectrum of soft tissue ME by the WHO,was not included.The 29 cases of soft tissue myoepithelial carcinoma in children reported by Gleason et al.[9]and the 7 cases reported by Bisogno et al.[10]were not included in our table because we could not distinguish which cases were mixed tumors.In total,17 of 27 (63%) pediatric cases (including the present case) located in different anatomic regions were malignant;3 of 9 cases of benign MEs demonstrated invasive growth,and 2 recurred.

Supplementary Table S1.Review of cases of primary myoepithelioma in mediastinum

Supplementary Table S2.Gene alteration in myoepithelioma of different sites

Supplementary Table S3.Review of soft tissue myoepithelioma in children below 18 years olda

Supplementary Figure S1.Circular genetic map of the result of next-generation sequencing.Circular genetic map revealed a Somatic MGA:c.6565 deletion,a Germline BUB1B:c.948-966 deletion and a Fusion EWSR1(E7): ZNF444(E5).

Malignant ME predominance has been reported in children[8],and malignant MEs have a worse prognosis,with a mortality rate of 43% (after 26 months) in childrenvs.13% (after 50 months) in adults[4,9].The location of the tumor and infiltration of the rib were discomforting features in our case.The recurrence after the surgery posed a difficult situation for treatment.Radiotherapy may harm the nerves passing through the intervertebral foramina,chemotherapy has no demonstrated distinct benefit in the literature,and repeated surgery can be traumatic for children.It is also unknown whether the lesion becomes malignant during recurrence.Therefore,more studies on the tumorigenesis mechanisms of ME are warranted.

Ethical ApprovalAll procedures performed in studies involving human participants followed the ethical standards of the institutional and/or national research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.The committees of Shengjing Hospital of China Medical University approved the case details for publishing (approval number 2021PS619K).

Consent for PublicationThe patient’s parents provided written informed consent for the case details to be published.

#Correspondence should be addressed to CAI Wei Song,E-mail: caiws@sj-hospital.org

Biographical note of the first author: DU Hong Mei,female,born in 1987,MD,Lecturer,majoring in pediatric oncology.

Received:December 21,2021;

Accepted:April 22,2022

References for Supplementary Tables

1.Hashmi AA,Khurshid A,Faridi N,et al.A large mediastinal benign myoepithelioma effacing the entire hemithorax: case report with literature review.Diagn Pathol,2015;10,100.

2.Habu T,Soh J,Toji T,et al.Myoepithelioma occurring in the posterior mediastinum harboring EWSR1 rearrangement: a case report.Jpn J Clin Oncol,2018;48,851-4.

3.Arab M,Danel C,D'attellis N,et al.A rare inferior middle mediastinal tumor resection under extra-corporeal circulation.Ann Thorac Surg,2005;79,1413-5.

4.?im?ek B and Esenda?li G.Parachordoma/myoepithelioma of soft tissue at posterior mediastinum.Virchows Archiv,2021;479(SUPPL 1),S306.

5.Antonescu CR,Zhang L,Chang NE,et al.EWSR1-POU5F1 fusion in soft tissue myoepithelial tumors.A molecular analysis of sixty-six cases,including soft tissue,bone,and visceral lesions,showing common involvement of the EWSR1 gene.Genes Chromosomes Cancer,2010;49,1114-24.

6.Lee JC,Chou HC,Wang CH,et al.Myoepithelioma-like Hyalinizing Epithelioid Tumors of the Hand With Novel OGT-FOXO3 Fusions.Am J Surg Pathol,2020;44,387-95.

7.Urbini M,Astolfi A,Indio V,et al.Identification of SRF-E2F1 fusion transcript in EWSR-negative myoepithelioma of the soft tissue.Oncotarget,2017;8,60036-45.

8.Segawa K,Sugita S,Aoyama T,et al.Myoepithelioma of soft tissue and bone,and myoepithelioma-like tumors of the vulvar region: Clinicopathological study of 15 cases by PLAG1 immunohistochemistry.Pathol Int,2020;70,965-74.

9.Yorozu T,Nagahama K,Morii T,et al.Myoepithelioma-like Hyalinizing Epithelioid Tumor of the Foot Harboring an OGT-FOXO1 Fusion.Am J Surg Pathol,2021;45,287-90.

10.Trevino M,Moorthy C,Kafchinski L,et al.Foot plantar soft tissue malignant myoepithelioma tumor: Case report and review of the literature.Clin Imaging,2020;61,90-4.

11.Bisogno G,Tagarelli A,Schiavetti A,et al.Myoepithelial carcinoma treatment in children: A report from the TREP project.Pediatric Blood and Cancer,2014;61,643-6.

12.Dickson BC,Antonescu CR,Argyris PP,et al.Ectomesenchymal Chondromyxoid Tumor: A Neoplasm Characterized by Recurrent RREB1-MKL2 Fusions.Am J Surg Pathol,2018;42,1297-305.

13.Puls F,Arbajian E,Magnusson L,et al.Myoepithelioma of bone with a novel FUS-POU5F1 fusion gene.Histopathology,2014;65,917-22.

14.Baneckova M,Uro-Coste E,Ptakova N,et al.What is hiding behind S100 protein and SOX10 positive oncocytomas? Oncocytic pleomorphic adenoma and myoepithelioma with novel gene fusions in a subset of cases.Hum Pathol,2020;103,52-62.

15.Suurmeijer AJH,Dickson BC,Swanson D,et al.A morphologic and molecular reappraisal of myoepithelial tumors of soft tissue,bone,and viscera with EWSR1 and FUS gene rearrangements.Genes Chromosomes Cancer,2020;59,348-56.

16.Flucke U,Palmedo G,Blankenhorn N,et al.EWSR1 gene rearrangement occurs in a subset of cutaneous myoepithelial tumors: a study of 18 cases.Mod Pathol,2011;24,1444-50.

17.Antonescu CR,Zhang L,Shao SY,et al.Frequent PLAG1 gene rearrangements in skin and soft tissue myoepithelioma with ductal differentiation.Genes Chromosomes Cancer,2013;52,675-82.

18.Kilpatrick SE,Hitchcock MG,Kraus MD,et al.Mixed tumors and myoepitheliomas of soft tissue: a clinicopathologic study of 19 cases with a unifying concept.Am J Surg Pathol,1997;21,13-22.

19.Waldrop C,Kathuria SS,Toretsky JA,et al.Myoepithelioma metastatic to the orbit.Am J Ophthalmol,2001;132,594-6.

20.Van Den Berg E,Zorgdrager H,Hoekstra HJ,et al.Cytogenetics of a soft tissue malignant myoepithelioma.Cancer Genet Cytogenet,2004;151,87-9.

21.Harada O,Ota H and Nakayama J.Malignant myoepithelioma (myoepithelial carcinoma) of soft tissue.Pathol Int,2005;55,510-3.

22.Hallor KH,Teixeira MR,Fletcher CD,et al.Heterogeneous genetic profiles in soft tissue myoepitheliomas.Mod Pathol,2008;21,1311-9.

23.Herlihy EP,Rubin BP and Jian-Amadi A.Primary myoepithelioma of the orbit in an infant.J AAPOS,2009;13,303-5.

24.Guedes A,Barreto BG,Barreto LG,et al.Metastatic parachordoma.J Cutan Pathol,2009;36,270-3.

25.Rekhi B,Sable M and Jambhekar NA.Histopathological,immunohistochemical and molecular spectrum of myoepithelial tumours of soft tissues.Virchows Arch,2012;461,687-97.

26.Park SJ,Kim AR,Gu MJ,et al.Imprint cytology of soft tissue myoepithelioma: a case study.Korean J Pathol,2013;47,299-303.

27.Gupta K,Klimo P,Jr.and Wright KD.A 2-Year-Old Girl with Dysmetria and Ataxia.Brain Pathol,2016;26,126-7.

28.Baldovini C,Sorrentino S,Alves CA,et al.Congenital Myoepithelial Carcinoma of Soft Tissue Associated With Cystic Myoepithelioma.Int J Surg Pathol,2018;26,78-83.

29.Bhanvadia VM,Agarwal NM,Chavda AD,et al.Myoepithelioma of soft tissue in the gluteal region:Diagnostic pitfall in cytology.Cytojournal,2017;14,14.

30.De Cates C,Borsetto D,Scoffings D,et al.Skull Base Parachordoma/Myoepithelioma.J Int Adv Otol,2020;16,278-81.