Congenital Malignant Ectomesenchymoma Presenting as a Neck Mass in a Newborn

Abstract

Background: Malignant Ectomesenchymoma (MEM) is a rare, aggressive soft tissue neoplasm with both neuroectodermal and mesenchymal differentiation. Congenital cases are extremely uncommon, posing significant diagnostic and therapeutic challenges. Case Presentation: We report a case of a full-term male neonate presenting with a large congenital neck mass and respiratory distress at birth. Imaging revealed a lobulated, heterogeneously enhancing mass in the left submandibular region with a mass effect on the airway. Open biopsy and gross resection on day six of life confirmed MEM with rhabdomyoblastic and neuroectodermal differentiation. Post-surgical staging classified the tumor as Stage I, Clinical Group II. Despite initial chemotherapy with Vincristine, Actinomycin, and Cyclophosphamide (VAC), tumor recurrence was detected at week nine of chemotherapy, necessitating a transition to Vincristine, Irinotecan, and Temozolomide (VIT). Discussion: MEM is an extremely rare neoplasm in infants, particularly in congenital presentations. Diagnosis is challenging due to its mixed histopathological features and broad differential diagnosis, including rhabdomyosarcoma, fibrosarcoma, lymphangioma, and neuroblastoma. Management typically involves multimodal therapy, with surgical resection being the mainstay of treatment. Chemotherapy is often tailored to the tumor’s most aggressive component, though standardized treatment protocols remain undefined. Conclusions: This case highlights the importance of early recognition and a multidisciplinary approach in managing congenital MEM, as a differential diagnosis of soft tissue masses in infants, particularly in the head and neck region.

1. Introduction

Malignant Ectomesenchymoma (MEM) is an exceedingly rare soft tissue neoplasm. MEM is considered a skeletal muscle malignancy [1], presumed to originate from migratory neural crest cells, but the exact etiology is unclear [2,3,4]. MEM is biphasic, characterized by neuroectodermal (with components of varying degrees of maturation) and mesenchymal elements (often featuring predominantly rhabdomyoblastic differentiation) [3,4].

MEM tumors may develop at any site within the soft tissue or central nervous system. Most commonly, it presents in the soft tissues within the abdomen, pelvis, or external genitalia; and less commonly, within the head–neck regions or mediastinum [3]. Most cases are diagnosed in infants or children under 2 years of age; congenital presentations are exceedingly uncommon, with less than 100 cases reported in the literature [3,4]. MEM poses significant diagnostic and therapeutic challenges due to its mixed nature and rarity. This case report describes a newborn with congenital MEM of the neck admitted to the Neonatal Intensive Care Unit (NICU).

2. Case Presentation

A caucasian full-term, large for-gestational-age male neonate, born via cesarean section at 39 weeks gestation, was admitted to a level-four NICU in Kentucky for a large mass on the left lateral aspect of his neck, and respiratory distress. The pregnancy was complicated by gestational diabetes, maternal history of incompletely treated latent tuberculosis, and a vascular malformation on a lower extremity. Additionally, there is a non-contributory family history of head and neck cancer. Notably, routine prenatal ultrasound was unremarkable at 38.0 weeks.

At birth, the newborn physical examination revealed a large, non-tender firm submandibular mass, measuring approximately 5 cm × 2 cm on the left neck, below the ear. The mass was mobile and well demarcated, without overlying skin changes (Figure 1). Stridulous at rest, the infant was most comfortable laying on his left side but was otherwise well appearing. He was maintained on continuous positive airway pressure (CPAP) and supplemental oxygen.

Initial laboratory investigations demonstrated no significant anemia, leukocytosis, or thrombocytopenia and normal hepatic function tests. Homovanillic acid (HVA), vanillylmandelic acid (VMA) measurements, and coagulation panel were within normal limits. Evaluation by pediatric otolaryngology showed a patent airway with bulging of the left posterior pharyngeal wall, demonstrating a mass effect on the airway.

Neck Ultrasound demonstrated a well-circumscribed 7.1 × 4.1 × 4.7 cm hyperechoic lesion in the submandibular region with mild internal color Doppler flow. A contrast-enhanced magnetic resonance imaging (MRI) revealed a large, lobulated, multi-spatial, heterogeneously enhancing, 2.2 × 5.2 × 5.1 cm mass centered in the left neck and extending medially. Significant mass effect with enhancement was seen on adjacent structures including the oropharynx and larynx with soft tissue stranding, and edema was present (Figure 2). Head MRI showed an incidental right-sided prominence of the extra-axial space.

Open biopsy and gross resection of the mass were performed on day six of life Grossly, the tumor was lobulated, composed of pink-tan tissue, and non-adherent to surrounding tissues (Figure 3). Histological examination showed spindled, stellate, and ovoid cells, with tumor cell cross striations, occasional strap cells, and varied tumor cellularity (Figure 4a–e). There were focal features of neuroectodermal differentiation including Schwannian stroma and maturing ganglion cells. Immunohistochemical staining was positive for S100, synaptophysin, and SOX-10 in areas of neuroectodermal differentiation, while the majority of the spindled cell tumor mass was immunoreactive for desmin, myogenin, and SMA indicative of rhabdomyoblastic differentiation; overall findings were consistent with a diagnosis of malignant ectomesenchymoma (MEM). The Ki-67 proliferative index approached 60–70% in cellular foci. Genetic testing revealed no clinically significant variants of pediatric inherited cancer risk genes. A Comprehensive Cancer Next Generation Sequencing (NGS) Panel (

Table A1. (a) Comprehensive Cancer Next Generation Sequencing (NGS) Panel DNA gene list (543 genes). Only CNV analysis or ^—Internal Tandem Duplication (ITD) interrogated; $—Exon 1 region not entirely sequenced [11,12]. (b) Comprehensive Cancer Next Generation Sequencing (NGS) Panel RNA gene list (183 genes) * CTNNB1 exon—level (large) deletions, ^—EGFRvIII, and $—MET exon 14 skipping variant interrogated in addition to gene fusion [12].

(a)
ABL1	ABL2	ABRAXAS1 *	ACVR1	ACVR1B *	ADGRA2 *	AIP	AKT1	AKT2	AKT3
ALK	AMER1	APC	AR	ARAF	ARFRP1 *	ARID1A	ARID1B $	ARID2	ASXL1
ATM	ATR	ATRX	AURKA	AURKB	AXIN1	AXIN2	AXL	B2M	BAP1
BARD1	BCL10 *	BCL11B *	BCL2	BCL2L1 *	BCL2L2 *	BCL6	BCL7A	BCOR ^	BCORL1
BIRC3	BLM	BMPR1A	BRAF	BRCA1	BRCA2	BRCC3 *	BRD3 *	BRD4	BRINP3 *
BRIP1	BTG1	BTK	BUB1B *	C19MC	CALR	CARD11	CASP8 *	CBFB	CBL
CBLB	CBLC	CCN6	CCND1	CCND2	CCND3	CCNE1	CD19 *	CD274	CD28 *
CD40 *	CD58	CD79A	CD79B	CDC73	CDH1	CDK12	CDK4	CDK6	CDK8
CDKN1A	CDKN1B	CDKN1C	CDKN2A	CDKN2B	CDKN2C	CEBPA	CHD2	CHD4	CHEK1
CHEK2	CIC	CIITA *	COL1A1	CREBBP	CRKL	CRLF2	CSF1R	CSF3R	CSNK1A1 *
CTCF	CTLA4 *	CTNNA1 *	CTNNB1	CUL3	CUX1	CXCR4	CYLD	DAXX	DDR2
DDX3X	DDX41	DGCR8	DICER1	DIS3L2	DKC1	DNM2	DNMT3A	DOT1L	DROSHA
EBF1	EED	EFNB2 *	EGFR	EGR2 *	EIF1AX	ELOC	EMSY *	EP300	EPCAM
EPHA3	EPHA5	EPHA7 *	EPHB1	EPHB4 *	ERBB2	ERBB3	ERBB4	ERCC1 *	ERCC2
ERCC3 *	ERCC4 *	ERCC5 *	ERG *	ERRFI1 *	ESR1	ETNK1	ETS1 *	ETV1 *	ETV4 *
ETV5 *	ETV6	EWSR1 *	EXT1	EXT2	EZH2	FANCA	FANCB	FANCC	FANCD2 *
FANCE *	FANCF *	FANCG *	FANCI	FANCL *	FANCM *	FAS	FAT1	FAT3 *	FBXO11
FBXW7	FGF10 *	FGF14 *	FGF19	FGF23 *	FGF3	FGF4	FGF6 *	FGFR1	FGFR2
FGFR3	FGFR4	FH	FLCN	FLT1	FLT3 ^	FLT4	FOXA1	FOXL2	FOXO1 *
FOXP1	FOXR2 *	FRK	FRS2 *	FUBP1	FUS *	GABRA6 *	GATA1	GATA2	GATA3
GATA4 *	GATA6 *	GEN1 *	GID4 *	GLI1	GLI2	GNA11	GNA13	GNA14	GNAQ
GNAS	GNB1	GPC3 *	GREM1 *	GRIN2A	GRM3 *	GSK3B	H1-4	H3-3A	H3-3B
H3C2	H3C3	HDAC4	HDAC9	HGF	HIF1A	HMGA2 *	HNF1A	HOXB13 *	HRAS
HSD3B1	HSP90AA1 *	ID3	IDH1	IDH2	IGF1R	IGF2 *	IKBKE	IKZF1	IKZF2
IKZF3	IL2RG *	IL6ST	IL7R	INHBA *	INPP4B	IRF2	IRF4	IRF8 *	IRS2 *
ITK *	ITPKB *	JAK1	JAK2	JAK3	JAZF1 *	JUN *	KAT6A *	KBTBD4	KCNJ5
KDM4C	KDM5A	KDM5C	KDM6A	KDR	KEAP1	KEL *	KIF1B *	KIF5B *	KIT
KLF2	KLF4	KLHL6 *	KMT2A	KMT2B	KMT2C	KMT2D	KRAS	LEF1	LIFR *
LMO1	LRP1B *	LYN *	LYST *	LZTR1	MAGI2 *	MAML2 *	MAP2K1	MAP2K2	MAP2K4
MAP3K1	MAP3K14	MAP3K3 *	MAP3K7 *	MAPK1	MAPK3	MAX	MCL1	MDM2	MDM4
MECOM	MED12	MEF2B	MEN1	MET	MITF	MLH1	MLH3	MLLT1	MN1
MPL	MRE11	MSH2	MSH3	MSH6	MTOR	MUTYH	MYB	MYBL1	MYC
MYCL *	MYCN	MYD88	MYH9 *	MYOD1	NBN	NCOA2 *	NCOR1	NCOR2	NF1
NF2	NFE2	NFE2L2	NFKBIA	NFKBIE	NKX2-1	NOTCH1	NOTCH2	NOTCH3	NPM1
NRAS	NSD1	NSD2	NT5C2	NTHL1	NTRK1	NTRK2	NTRK3	NUP214 *	NUP93 *
NUTM1 *	OTX2	PAK3	PALB2	PAX3 *	PAX5	PAX7 *	PAX8 *	PBRM1	PDCD1
PDCD1LG2 *	PDGFB *	PDGFRA	PDGFRB	PDK1 *	PHF6	PHOX2B	PIGA	PIK3C2B *	PIK3CA
PIK3CB	PIK3CD	PIK3CG	PIK3R1	PIK3R2	PIM1	PLAG1 *	PLCG1	PLCG2	PML *
PMS1	PMS2	POLD1 *	POLE	POLR2A	POT1	PPARG *	PPM1D	PPP2R1A	PRDM1
PREX2	PRKAR1A	PRKCA	PRKCI *	PRKDC	PRKN	PRPF40B	PRPF8	PRSS8 *	PTCH1
PTEN	PTPN11	PTPRD	PTPRT	QKI *	RAB35 *	RAC1	RAD21	RAD50	RAD51
RAD51B	RAD51C	RAD51D	RAF1	RANBP2 *	RARA *	RASA1	RB1	RBM10	RECQL *
RECQL4 *	REL *	RELA *	RET	RHOA	RICTOR	RINT1 *	RIT1	RNF43	ROS1 *
RPS15	RPS19	RPS20 *	RPS6KA3	RPTOR	RRAGC	RSPO2 *	RSPO3 *	RUNX1	RUNX1T1 *
SAMD9	SAMD9L	SBDS *	SDHA	SDHAF2	SDHB	SDHC	SDHD	SETBP1	SETD2
SF1	SF3A1	SF3B1	SGK1	SH2B3	SIX1	SIX2	SLIT2 *	SLX4	SMAD2
SMAD3	SMAD4	SMARCA4	SMARCB1	SMARCE1	SMC1A	SMC3	SMO	SNCAIP *	SOCS1
SOS1	SOX10 *	SOX2	SOX9 *	SPEN	SPOP	SPTA1	SRC	SRP72	SRSF2
SS18 *	STAG2	STAT3	STAT4 *	STAT5B	STAT6	STK11	SUFU	SUZ12	SYK *
TAF1	TBL1XR1	TBX3	TBXT *	TCF12	TCF3	TCF7L2	TEK	TENT5C *	TERC
TERT	TET1 *	TET2	TFE3 *	TFEB *	TGFBR2	TMEM127	TMPRSS2 *	TNFAIP3	TNFRSF14
TOP1	TOP2A *	TP53	TP63	TPMT *	TRAF3	TRAF7	TRRAP	TSC1	TSC2
TSHR	TYK2	U2AF1	U2AF2	USP6 *	USP7	VAV1	VEGFA	VHL	WRN
WT1	XPC *	XPO1	XRCC2 *	YAP1 *	YWHAE *	ZBTB2 *	ZFTA *	ZMYM3	ZNF217 *
ZNF703 *	ZNF750	ZRSR2
(b)
ABL1	ABL2	AKT3	ALK	ARHGAP26	AXL	BCL10	BCL11B	BCL2	BCL6
BCOR	BCORL1	BCR	BIRC3	BRAF	BRD3	BRD4	BTG1	C11ORF95	CAMTA1
CARD11	CBFB	CBL	CCND1	CCND3	CDK6	CHIC2	CIC	CIITA	COL1A1
CREBBP	CRLF2	CSF1R	CTNNB1 *	DEK	DNAJB1	DUSP22	EBF1	EGFR ^	EP300
EPC1	EPOR	ERBB2	ERG	ETV1	ETV4	ETV5	ETV6	EWSR1	FER
FGFR1	FGFR2	FGFR3	FGR	FLT3	FOS	FOSB	FOXO1	FOXP1	FOXR2
FUS	GLI1	GLI2	GLIS2	HLF	HMGA2	HTRA1	IKZF1	IKZF2	IKZF3
IRF4	ITK	JAK1	JAK2	JAK3	JAZF1	KAT6A	KIF5B	KLF2	KMT2A
LMO1	LYN	MALT1	MAML2	MAST1	MAST2	MEAF6	MECOM	MEF2D	MET $
MKL1	MKL2	MLLT10	MLLT4	MN1	MSMB	MYB	MYBL1	MYC	MYH11
MYH9	NCOA1	NCOA2	NCOA3	NF1	NF2	NFKB2	NOTCH1	NOTCH2	NPM1
NR4A3	NRG1	NSD1	NTRK1	NTRK2	NTRK3	NUMBL	NUP214	NUP98	NUTM1
PAG1	PAX3	PAX5	PAX7	PAX8	PDCD1LG2	PDGFB	PDGFRA	PDGFRB	PHF1
PIK3CA	PKN1	PLAG1	PML	PPARG	PRDM1	PRDM16	PRKACA	PRKCA	PRKCB
PTCH1	PTK2B	PVT1	QKI	RAF1	RARA	RELA	RET	ROS1	RSPO2
RSPO3	RUNX1	RUNX1T1	SETD2	SS18	SSX1	SSX2	SSX4	STAT6	SUZ12
SYK	TAF15	TAL1	TBL1XR1	TCF12	TCF3	TERT	TET1	TFE3	TFEB
TFG	THADA	TMPRSS2	TOP1	TP63	TYK2	USP6	VGLL2	WHSC1	YAP1
YWHAE	ZCCHC7	ZNF384

) molecular profiling revealed loss of PTCH-1 in the tumor. The patient subsequently tested negative for germline variants of PTCH-1, alterations of which have been reported in cases of nevoid basal cell carcinoma syndrome (NBCCS), fetal rhabdomyoma, as well as rhabdomyosarcoma.

Staging work-up included a post-resection positron emission tomography (PET) scan, computed tomography (CT) chest, and bone marrow biopsy, all of which showed no evidence of metastatic disease. Post-surgical MRI documented the removal of most of the mass; however, there was still some mass effect on the aerodigestive tract, including residual mass effect upon the airway (Figure 5). The final staging classified the tumor as stage I, clinical group II. Multidisciplinary care coordination involved neonatology, pediatric otolaryngology, pediatric oncology, and pediatric surgery.

Following tumor resection, chemotherapy with Vincristine, Actinomycin, and Cyclophosphamide (VAC) was initiated. After nine weeks of chemotherapy, restaging imaging demonstrated a new enhancing 0.8 × 1.5 × 2.1 cm mass in the left retropharyngeal space, causing mass effect on the surrounding structures, and nodal involvement, concerning residual or recurrent disease (Figure 6). Biopsy findings were consistent with residual disease or recurrence of MEM, and the patient was transitioned to a regimen of vincristine, irinotecan, and temozolomide (VIT).

3. Discussion

Malignant Ectomesenchymoma (MEM) is an extremely rare heterogeneous soft tissue neoplasm, comprising both neuroectodermal and mesenchymal elements. MEM is considered a skeletal muscle malignancy [1]. The exact etiology is unclear, but it is presumed to arise from migratory neural crest cells [2,3,4]. The mesenchymal component features predominantly rhabdomyoblastic differentiation, such as spindle cells and primitive round cell patterns. The accompanying neuroectodermal component may have varying degrees of maturation, presenting as neuroblastoma, ganglioneuroblastoma, ganglioneuroma, or ganglion cells [3,4].

MEM tumors may develop at any site within the soft tissue or central nervous system. Most commonly, it presents in the soft tissues within the abdomen, pelvis, or external genitalia; and less commonly, within the head–neck regions or mediastinum [3]. Most cases are diagnosed in infants or children under 2 years of age [4]; congenital presentations are exceedingly uncommon, with less than 100 cases globally reported in the literature [3,5]. MEM poses significant diagnostic and therapeutic challenges due to its mixed nature and rarity. This case report describes a newborn with congenital MEM of the neck admitted to a Neonatal Intensive Care Unit (NICU). To our knowledge, this is the first case of MEM that was clinically present at birth and located within the neck. Congenital presentation of MEM is particularly uncommon, with only a few cases reported in the literature. The rarity of MEM, particularly in the congenital form, poses challenges to diagnosis, treatment, and understanding of its pathophysiology.

Most MEM in infants arise from pelvic, retroperitoneal, and urogenital sites, followed by head and neck regions, as seen in our patient, then intracranial and extremity sites, manifesting as painless, rapidly enlarging masses [3]. Some studies suggest MEM shows a male predominance [3,5] and is most often observed in the first two years of life. The pathogenesis of MEM is unclear, though it is believed to arise from undifferentiated neural crest cells, which differentiate into both ectodermal (epithelial) and mesodermal (mesenchymal) tissues [6,7]. Some literature suggests mutations in P53, and cell cycle control pathway regulators could be the drivers of tumorigenesis. Clinical presentation in infants is often nonspecific which can make diagnosis challenging. Most cases present rapidly enlarging masses in the pelvis, abdomen, external genitalia, and head and neck region [4,5,6]. Symptoms can vary depending on the location and size of the tumor, visible swelling, signs of local invasion, or systemic symptoms. Masses in the head and neck region may manifest with symptoms of difficulty breathing or feeding due to obstruction of the aerodigestive tract. The differential diagnosis for congenital neck masses in neonates includes vascular or lymphatic malformations, thyroglossal duct cysts, branchial cleft cysts, or other soft tissue tumors such as congenital fibrosarcoma, hemangiomas, lymphangiomas, and neuroblastomas [5].

Due to the aggressive nature of MEM, a rapid increase in size is often noted during the first few months of life. Diagnosis relies on the combination of imaging studies, histopathological evaluation, and immunohistochemical markers. Imaging ultrasound, CT, and MRI aid in assessing the extent of tumor involvement. Our patient underwent a contrast-enhanced MRI of the head and neck, which revealed a large, enhancing mass exhibiting a mass effect on surrounding tissue, suggestive of a neoplastic lesion. The differential diagnosis for a congenital mass in the neonate is broad and includes conditions such as sarcomas (such as rhabdomyosarcoma (RMS), neuroblastoma, teratoma, benign/malignant triton tumor, and ganglioneuroma), which may be present similarly. MEM has several analogous characteristics with RMS, including anatomic distribution, demographic, and histologic features [3]. The biphasic pattern of MEM makes the tumor histologically distinctive, as it demonstrates both glandular epithelial differentiation and mesenchymal features. Most cases demonstrate rhabdomyoblastic differentiation [7,8], such as spindle cells (which may resemble cartilage or fibrous tissue), chondroid differentiation, and neuroblastic features [6]. The neuroectodermal components present in MEM can encompass a range of neuroblastic phenotypes, including scattered ganglion cells, ganglioneuroma, ganglioneuroblastoma, and neuroblastoma [5,9]. Associated immunohistochemical markers include neural markers such as S100 protein, synaptophysin, and mesenchymal markers such as desmin, and myogenin [5,6,7]. In our case, the tumor exhibited a predominantly rhabdomyoblastic spindle cell proliferation as well as focal clustered ganglion cells enmeshed in mature Schwannian stroma, findings consistent with the diagnosis of MEM.

Management of MEM is challenging due to its aggressive nature and the heterogeneity of the tumor, which complicates both diagnosis and treatment. Adequate biopsy specimen is essential for accurate diagnosis and regimen selection, based on the highly variable biphasic nature of MEM, an inadequate sample may be histologically indistinguishable from RMS or the neuroectodermal components [9]. Consensus supports a multimodal approach to treatment, including surgical resection, chemotherapy, and radiation therapy [3,5,8]. Complete surgical excision is the primary treatment modality when feasible for MEM, offering an excellent prognosis if complete resection is achieved [5,10]. This is especially true for tumors that are benign or low-grade malignant. If the tumor is unable to be resected due to size, invasion of surrounding tissue, or metastasis to distant sites, the prognosis is poorer. Adjuvant chemotherapy and radiation therapy are indicated when the tumor invades critical structures such as the brainstem, spinal cord, or large vessels, or it has metastasized to other sites. No standard chemotherapy protocol for infants exists. Instead, chemotherapy regimens are tailored for individual cases and typically based on the “most aggressive component” of the mesenchymal elements, which is usually the rhabdomyosarcoma [5,8,9]. Adjuvant radiotherapy can be considered but there is limited data on the role of radiotherapy in MEM, with potentially significant long-term side effects on growth and development [5].

Close follow-up is necessary to monitor for recurrence, although recurrence rates are typically low when clear surgical margins are obtained. Gross total resection was achieved in our case with a negative post-resection PET scan, with recurrence within three months. The prognosis for neonates with MEM depends on several factors, including tumor size, location, extent of local invasion, and completeness of resection [3,5,8]. Pellegrino et al. found that “MEMs have the same prognosis as other pediatric chemotherapy sensitive soft tissue sarcomas, with 82% (14/17) of children affected by MEM surviving with no evidence of disease (NED) following multimodality treatment approach” [3]. Further characterization of tumorigenesis and molecular analysis may aid in establishing novel therapies and treatment protocols [4].

This case report has several limitations. As a single-case study, the findings are not directly generalizable. The rarity of MEM limits the availability of comparative cases in the literature, making it challenging to draw definitive conclusions about disease patterns, treatment efficacy, or prognosis. Furthermore, the lack of long-term follow-up data available for the case prevents us from assessing the patient’s long-term response to treatment or the possibility of recurrence. Another limitation is the absence of further comprehensive molecular and genetic analyses, which could have provided further insights into the tumor’s pathogenesis and potential therapeutic targets. Lastly, due to the limited literature on MEM, our discussion is based on the limited number of previously reported cases.

4. Conclusions

Congenital ectomesenchymoma is an extraordinarily rare aggressive tumor that presents significant diagnostic and management challenges in neonates. This case highlights the importance of early recognition, comprehensive imaging, and histochemical analysis of MEM, as a differential diagnosis of soft tissue masses in infants, particularly in the head and neck region.