Head and Neck Pathology

https://doi.org/10.1007/s12105-020-01189-1

CASE REPORTS

FET(EWSR1)‑TFCP2 Rhabdomyosarcoma: An Additional Example of this

Aggressive Variant with Predilection for the Gnathic Bones
Ioannis G. Koutlas1   · Damon R. Olson2 · Jawhar Rawwas3

Received: 14 May 2020 / Accepted: 2 June 2020

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
An example of a mandibular rhabdomyosarcoma in a 15-year-old male is described featuring EWSR1-TFCP2 fusion with
homolateral lymph node metastasis and apparent metastasis to the thoracic vertebra T7. This type of rhabdomyosarcoma has
preference for the craniofacial skeleton. Histologically, the tumor was composed of spindle and epithelioid cells characterized
by nuclear pleomorphism, cytologic atypia and brisk mitotic activity. Immunohistochemically, it featured diffuse positive
nuclear staining MYOD1, only focal staining for myogenin and patchy cytoplasmic staining for desmin. Tumor cells were
positive for keratins and nuclear staining for SATB2 was also observed. Interestingly, tumor cells were diffusely positive for
calponin. Currently, the patient is under chemotherapy treatment.

Keywords  Rhabdomyosarcoma · Mandible · EWSR1-TFCP2

Introduction significant events in ERS, high frequency of FOXO1 fusions,

PAX3-FOXO1 and PAX7-FOXO1, highlight the majority of
Advances in molecular pathology have resulted in identifi- cases of ARS [2], while SSRS is mostly characterized by
cation of putative driver mutations in rhabdomyosarcoma VGLL2-related fusions [3] and MYOD1 mutations [4]. Very
(RS), the most frequent childhood soft tissue sarcoma with recently, SRF-FOXO1 and SRF-NCOA1 fusions have been
approximately 50% of the embryonal type occurring in the described in 3 cases of well-differentiated RS highlighting
area of the head and neck [1]. The identification of such the importance of molecular findings for prognosis [5].
mutations in the two major subtypes of RS, embryonal A rare RS type featuring spindle and epithelioid cells with
(ERS) and alveolar (ARS), as well as in the less frequent eosinophilic cytoplasm and characterized by EWSR1/FUS-
variants such as spindle cell/sclerosing (SSRS), epithelioid TFCP2 fusions has been recently recognized [6–9] with the
(EPIRS) and pleomorphic (PRS) RS, not only play a role in majority of cases reported in the craniofacial skeleton and
classification, but they may be important for stratification of especially the gnathic bones [9]. Since EWS and FUS pro-
patients when it comes to predicting tumor progression and teins are members of the FET (FUS, EWS, TAF15) RNA-
behavior, and for customized treatment given the availabil- binding protein family [10], this subtype of RS has also been
ity, in certain instances, of gene targeted therapies. Briefly, referred to as FET-TFCP2 RS [9]. Herein, we describe an
mutations of the genes involved in the FGFR4/RAS/AKT additional mandibular example of FET-TFCP2 RS carrying
pathway and high frequency PTEN hypermethylation are the EWSR1-TFCP2 fusion, further expanding the number
of cases reported thus far in the literature, with the purpose
to alert colleagues of its morphologic characteristics and
* Ioannis G. Koutlas
[email protected] aggressive clinical behavior.

1
Division of Oral and Maxillofacial Pathology, School
of Dentistry, University of Minnesota, 515 Delaware Street Case Report
SE #16‑116B, Minneapolis, MN 55455, USA
2
Department of Laboratory Medicine and Pathology, A 15-year-old male presented in October of 2019 with pain
Children’s Minnesota, Minneapolis, MN, USA
in the left posterior mandible which was treated with tooth
3
Pediatric Hematology and Oncology, Children’s Minnesota, extraction. However, the pain and swelling continued and
Minneapolis, MN, USA

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were attributed to postsurgical infection. Panoramic radio- followed by chemotherapy with Irinotecan, Vincristine and
graph (Fig. 1) and CT scan revealed destructive left pos- Erlotinib as the tumor had high EGFR expression. The
terior mandibular radiolucency exhibiting moth eaten-like patient did well afterwards with no evidence of recurrence of
irregular and ill-defined borders and loss of both buccal and his hepatoblastoma. Also, the patient presented with macro-
lingual plates thus suggesting an aggressive neoplasm. Posi- cephaly and delayed language and fine motor development.
tron emission tomography showed uptake in the mass and Li-Fraumeni syndrome was excluded by the Invitae sarcoma
also in the ipsilateral cervical lymph nodes. panel which detects alterations in 28 genes involved in sar-
The patient’s medical history was significant for fetal coma, including TP53, using sequencing and detection of
hepatoblastoma, mixed epithelial/mesenchymal type, at age deletions/dublications.
2 years with lung metastasis, which was treated initially with As there was considerable pain associated with the tumor,
Cisplatin, Doxorubicin, 5-Fluorouracil and Vincristine. The the clinical team opted to perform upfront debulking of the
patient developed pulmonary recurrence 2 years later, which majority of the left mandibular mass. At gross, received were
was treated with surgical resection of pulmonary metastases three white blood-tinged solid soft tissue fragments with
attached surface epithelium that measured 7.0 × 1.8 × 1.0 cm
in aggregate. Histopathologic preparations revealed fascicu-
lar and in areas storiform proliferation (Fig. 2a, b) of large
mostly of spindle (Fig. 2c), occasionally epithelioid and less
often round cells (Fig. 2d) with eosinophilic or amphophilic
cytoplasm and generally well-defined plasmalemmal mem-
branes. Individual cells exhibited spindle, ovoid or round
vesicular or hyperchromatic nuclei, prominent and occasion-
ally multiple nucleoli and atypical mitoses (Figs. 2e), with
areas featuring > 10/HPF. Foci of necrosis were also present
and rare calcifications (Fig. 2f), dystrophic or residual reac-
tive bone fragments, were noted.
Immunohistochemical evaluation for skeletal muscle
markers disclosed patchy but intense staining for desmin
Fig. 1  Panoramic radiograph reveals destructive lesion in the left pos- (Fig. 3a; DE-R-11, prediluted, Ventana, Tucson, AZ), dif-
terior side of the mandible (arrow) fuse nuclear staining for MyoD1 (Fig. 3b; 5.8A, prediluted,

Fig. 2  a Fascicular and in areas storiform proliferation of predomi- picture. e Nuclear pleomorphism with nuclei featuring, occasionally,
nantly spindle cells. b Intersecting fascicles of predominantly spindle multiple nucleoli and brisk mitotic activity. f Rare woven bone spic-
cells. c Fascicles composed of spindle cells featuring multiple atypi- ule infiltrated by neoplastic cells. The bone may be reactive residual
cal mitoses. d Mixed population of spindle, epithelioid and round bone or focus of dystrophic bone formation characterized by osteo-
cells. Epithelioid and round cells are present in the lower part of the clasia

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Fig. 3  a Patchy staining of

spindle and epithelioid cells
with desmin. b Most neoplastic
cell nuclei were stained with
MyoD1. c Only few nuclei
were positive for myogenin. d
Cytoplasmic and perinuclear
staining of neoplastic cells with
cytokeratin amntibody AE1/
AE3. e Diffuse cytoplasmic
staining of neoplastic cells for
calponin. f Nuclear staining
with SATB2 was observed in
many neoplastic cells. g Dif-
fuse nuclear staining with p53.
h Plasmalemmal staining for
β-catenin

Leica Novocastra, Newcastle upon Tyne, United Kingdom) actin (1A4, prediluted, Ventana) and smooth muscle myo-
but infrequent nuclear staining for myogenin (Fig. 3c; FD5, sin (SMMS-1, prediluted, Ventana) were negative. Selective
prediluted, Cell Marque, Rocklin, CA). Also observed were nuclear staining for SATB2 (Fig. 3f; EP281, prediluted, Cell
positive and of variable intensity cytoplasmic and peri- Marque) that varied in intensity was also observed. Also
or paranuclear staining for AE1/AE3 cytokeratin cocktail diffuse nuclear positive staining was obtained with p53
(Fig. 3d; AE1 + A3, prediluted, DAKO, Carpinteria, CA), (Fig. 3g; Bp53-11, prediluted, Ventana). Plasmalemmal
and diffuse and in areas intense cytoplasmic staining for staining for β-catenin (Fig. 3h; 14, prediluted, Ventana) was
calponin (Fig. 3e; CALP, 1:100, DAKO). Smooth muscle diffuse while ALK-1 (ALK-1, 1:50, DAKO) was negative.

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Neoplastic cells revealed the presence of lysosomes deco- In preparation for local control with proton beam therapy,
rated by CD68 (PGM-1, prediluted, DAKO). S100 (poly- imaging was repeated and showed an area of new uptake in
clonal, prediluted, Ventana), CD34 (Qbend/10, prediluted, the anterior aspect of thoracic vertebra T7 transverse pro-
Ventana), and ERG (EPR3864, prediluted, Ventana) were cess. MRI showed a small soft tissue mass strongly sugges-
negative. tive of metastasis. The patient received proton beam therapy
P a r a f f i n t i s s u e b l o ck wa s fo r wa r d e d t o to the left mandible tumor site, left involved cervical lymph
FoundationOne®CDx for genomic evaluation which dis- node chain and the metastatic lesion at T7. Because the
closed EWSR-TFCP2 fusion with TP53-Y236H (706T > C) patient’s disease progressed on chemotherapy, it was decided
mutation and harboring a tumor mutational burden of 2 to switch his chemotherapy to Irinotecan and Temozolamide.
mutations/megabase. The molecular signature of the tumor The patient remains on ongoing therapy.
revealed other variants of, however presently, unknown
significance including, per report, ABL1 (K867R), ARID2
(S1618Y), FGF4 (S54L), FGFR2 (R165W), FGFR4 Discussion
(V288I), FLT1 (T770S), IRF8 (R284W), LRP1B (K452N
and M131I), MKI67 (P1935S), PTCH1 (L1397I), ROS1 Primary intraosseous RS are exceedingly rare. However,
(G1027D) and SDHD (T112I). Based on the Foundation the head and neck skeleton is the most frequently involved
One®CDx report there was no available targeted therapy. site which may be expected given the preponderance of
The patient underwent surgical resection of the tumor, RS for the head and neck including the oral mucosa [9].
maintaining the mandibular joint and underwent left hemi- Recently, examples of intraosseous RS with a distinctive
mandibulectomy reconstruction with fibular free flap. spindle, epithelioid and less often round cytomorphology
Homolateral lymph node dissection was also done which and FET-TFCP2 gene fusions have been described [7–9].
revealed 2/8 Level 1 and 2/13 Level 4 positive lymph nodes These tumors are aggressive and frequently the patients
(Fig. 4). The patient was treated with combination chemo- experience metastatic disease with more than 60% of them
therapy by alternating courses of Vincristine, Actinomycin dying of the disease [9].
D and Cyclophosphamide with courses of Etoposide and Table 1 summarizes the clinicopathologic and molecu-
Ifosfamide. Alternating Etoposide/Ifosfamide with Vincris- lar findings of craniofacial FET-TFCP2 RS reported in
tine, Actinomycin D and Cyclophosphamide offered the pos- the literature [6–9, 11, 12]. Briefly, 16 patients have been
sibility of decreasing cumulative toxicity of any one chemo- reported in the literature, nine females and 7 males, with
therapeutic agent. Doxorubicin was not used in the treatment age distribution 11–72 years and average age of 30.63 years
regimen because of previous therapy with Doxorubicin (total (SD: ± 20.21). The most common location is the mandible.
dose 240 mg/m2) and the finding of decreased cardiac func- One case has been designated as hard palate and gingiva.
tion on follow-up echocardiogram. Histologically, eleven cases featured both spindle and epi-
thelioid cells, three epithelioid or ovoid phenotype while two
were purely spindle.
Skeletal muscle immunohistochemistry for FET-TFCP2
RS has revealed diffuse staining with Myo-D1, variable
nuclear staining with myogenin that in our example was
focal, and cytoplasmic staining with desmin which was also
patchy in our preparation. We concur with other reports that
Myo-D1 is the most sensitive among skeletal muscle mark-
ers and should be included in the immunohistochemical
panel [8, 9]. Positive pancytokeratin AE1/AE3, frequently
strong and diffuse, is observed in FET-TFCP2 RS [7–9] as it
is also generally the case in RS. Positive staining for keratin
cocktail, however, may have diagnostic and clinical implica-
tions in the absence of a skeletal muscle panel which will
support the diagnosis of anaplastic spindle cell carcinoma
over RS.
Staining for calponin was also observed in our case with
all other performed smooth muscle markers being negative.
Notwithstanding the possibility of non-specific staining by
Fig. 4  Low power microphotograph of lymph node metastasis.
(insert). High power reveals infiltrated lymph node by RS character- the CALP antibody, the positive staining observed may be
ized by spindle, epithelioid and few round cells the result of affinity of calponin with alpha-actinin-actin and

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Table 1  Reported individuals with craniofacial rhabdomyosarcomas exhibiting FET-TFCP2 

Gender/age Location Cytology Fusion Follow-up information

Le Loarer et al. [9] 16Fa Sphenoid bone Spindle and epithelioid FUS-TFCP2 DOD (15 mo)
Le Loarer et al. [9] 32M Hard palate and gingiva Spindle and epithelioid EWSR1-TFCP2 DOD (8 mo)
Le Loarer et al. [9] 20M Orbito-temporo-sphenoid area Spindle and epithelioid FUS-TFCP2 DOD (6 mo)
Le Loarer et al. [9] 17Fb Cervico-occipital area Rounded FUS-TFCP2 AWD (15 mo)
Le Loarer et al. [9] 31M Occipital bone Spindle and epithelioid FUS-TFCP2 DOD (6mo)
Le Loarer et al. [9] 32M Mandible Spindled FUS-TFCP2 AWD (14 mo)
Le Loarer et al. [9] 58F Mandible Spindle and epithelioid FUS-TFCP2 ANED (21 mo)
Le Loarer et al. [9] 12F Mandible Spindle and epithelioid FUS-TFCP2 ANED (21 mo)
Le Loarer et al. [9] 11F Maxilla Epithelioid EWSR1-TFCP2 DOD (Unknown)
Le Loarer et al. [9] 25M Mandible Epithelioid EWSR1-TFCP2 ANED (20 mo)
Zhu et al. [11] 74F Maxilla Oval to spindle FUS-TFCP2 Unknown
Dashti et al. [7] 72M Mandible Spindle FUS-TFCP2 ANED (2 mo)
Agaram et al. [4] 33F Maxilla Ovoid to short spindle EWSR1-TFCP2 NED (108 mo)
Agaram et al. [4] 27F Skull Spindle and epithelioid EWSR1-TFCP2 Unknown
Flaitz et al. [12] 15F Mandible Spindle and epithelioid FUS-TFCP2 Unknown
Present case 15M Mandible Spindle and epithelioid EWSR1-TFCP2 AWD (7 mo)

DOD dead of disease, AWD alive with disease, ANED alive no evidence of disease
a
 Initially reported by Watson et al. [6]
b
 Subsequently reported by Brunac et al. as an example successfully responding to radiation and ALK inhibitor treatment

filamin, two proteins observed in skeletal muscle with tan- of cases, 11 out 14 (78.5%), both at the transcription and
dem calponin homology domains [13]. It is also possible that protein levels due to ALK genomic deletion as a result of
these neoplastic cells express calponin in a manner similar apparent alternative transcription initiation. ALK positivity
to inflammatory leiomyosarcoma (low-grade inflammatory has been observed in all other individual cases reported in
myogenic tumor), a very rare and somewhat indolent soft tis- the gnathic bones [7–9]. However, positive immunostaining
sue tumor expressing skeletal muscle markers [14]. Among for ALK does not always suggest ALK rearrangement [9].
reported cases of FET-TFCP2 RS there is one example of Patients with FET-TFCP2 RS and ALK upregulation may be
FUS-TFCP2 RS of the maxillary gingiva displaying a myo- benefited with use of ALK inhibitors, e.g. alectinib [9, 19].
genic profile that included smooth muscle actin and calde- Since chemotherapy for intraosseous rhabdomyosarcoma
smon [11]. That tumor was negative for keratin. Of interest is not well established, it was decided to treat the patient
is also a case of an apparent epithelioid rhabdomyosarcoma presented herein with chemotherapy effective for rhabdo-
of the mandible which was positive for h-caldesmon and myosarcoma and Ewing sarcoma. The TP53 mutation identi-
smooth muscle actin [15]. However, molecular analysis was fied in our patient probably does not represent a targetable
not performed. alteration in this tumor and most likely confers an aggressive
Nuclear reaction for SATB2 has not been reported in the phenotype and resistance to chemotherapy [20].
literature in the few cases of RS where such stains were The genes of the FET RNA-binding protein family are
performed, specifically SSRS and pleomorphic RS [16, 17]. found to be involved in deleterious genomic rearrange-
SATB2 is not observed in normal skeletal muscle nuclei ments with other transcription factor genes in a variety of
nor in smooth or heart muscle. Although the importance carcinomas, sarcomas and in acute leukemia [10]. Fusions
of this reaction in our patient is unknown, one should note of FET proteins with various transcription factors are well
that SATB2 is a nuclear partner of Zfp423, a transcriptional described in the literature, e.g. EWS-FLI1 in Ewing sar-
factor which, besides participating in adipocytic and, when coma. Both EWS and FUS are expressed in skeletal and
suppressed, osteoblastic lineage commitment, is essential smooth muscle nuclei [21]. It is also hypothesized that
in muscle regeneration [18]. Tight regulation of Zfp423 is Ewing sarcoma may be a tumor of mammalian muscle
essential for normal progression of muscle progenitors from progenitor cell origin [22] because of expression of PAX7,
proliferation to differentiation [18]. a rhabdomyosarcoma marker. EWSR1-DUX4 fusion has
ALK upregulation [7, 8] have been reported in both ERS been described in one example of RS [23]. These findings
and ARS. In the largest study of FET-TFCP2 RS to this date suggest the EWSR1 aberrations, although rare, could be
[9] ALK overexpression has been observed in the majority expected in RS. Most FET-TFCP2 RS are hybrid spindle/

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epithelioid tumors and FUS-TFCP2 is most frequently cytokeratin and ALK negative. The number reported in the
encountered in craniofacial RS. literature is small, two, and the location in both cases was
TFCP2 (transcription factor cellular promoter 2), also the iliac bone [8].
known as CP2, TFCP2C, LSF(late simian virus 40 [SV40] In summary, we presented an additional example of FET-
factor), LBP-1c (leader binding protein1c) and LBP-1d TFCP2 RS of the craniofacial skeleton to raise awareness of
[24], is a member of the Grainyhead-like (GRHL) tran- this aggressive neoplasm with generally poor prognosis. It is
scription factors and is important for (a) organ devel- apparent that diagnosis of sarcomas, including those devel-
opment, e.g. as a coordinator in the development of oping in bone should be investigated, when possible, for spe-
epithelial, intercalated and principal cells in the kidney cific gene abnormalities to aid diagnosis, provide prognostic
collecting ducts, ductal cell maturation and branching information, and/or identify gene-specific targeted therapies.
in salivary glands, (b) mammalian sex determination by
affecting SRY transcription, folliculogenesis and sper- Acknowledgement  We are indebted to Mr. Brian Dunnette for his help
with the illustrations.
matogenesis/ spermatogonia, (c) maintenance of the
pluripotency of embryonic stem cells in mice [25], (d)
epithelial-mesenchymal transition [26, 27], and (e) tumor
metastasis [27]. In breast cancer, TFCP2 regulates the
expression of epidermal growth factor receptor (EGFR)
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