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Rhabdomyosarcoma with TFCP2 rearrangement


Cale Michael Max Fletcher, B.Med., M.P.H.
Ruta Gupta, M.D.

Last author update: 30 December 2024
Last staff update: 30 December 2024

Copyright: 2021-2025, PathologyOutlines.com, Inc

PubMed Search: Rhabdomyosarcoma with TFCP2 rearrangement

Cale Michael Max Fletcher, B.Med., M.P.H.
Ruta Gupta, M.D.
Page views in 2024: 340
Page views in 2025 to date: 86
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Molecular / cytogenetics description | Molecular / cytogenetics images | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: Fletcher CMM, Gupta R. Rhabdomyosarcoma with TFCP2 rearrangement. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/mandiblemaxillarhabdomyosarcomaTFCP2.html. Accessed January 18th, 2025.
Definition / general
  • Highly aggressive malignancy with rhabdomyoblastic differentiation
  • Most commonly arises in the craniofacial bones of young adults
  • Characterized by the presence of TFCP2 rearrangement, with either TFCP2::FUS or TFCP2::EWSR1
Essential features
  • High grade malignancy, usually showing a combination of spindle cell and epithelioid morphologies; however, may also show round cell morphology
  • Evidence of rhabdomyoblastic differentiation, most reliably demonstrated by immunostaining for desmin, MyoD1 or myogenin
  • May show concomitant expression of cytokeratins (notably AE1 / AE3) and ALK by IHC
  • Confirmation of TFCP2 rearrangement by molecular modalities (e.g., FISH [dual color break apart probe] or RNA next generation sequencing [NGS])
Terminology
ICD coding
  • ICD-O: 8912/3 - intraosseous spindle cell rhabdomyosarcoma with TFCP2 / NCOA2 rearrangements
  • ICD-11: 2B66.Y & XH0GA1 - other specified malignant neoplasms of other and unspecified parts of mouth & rhabdomyosarcoma, NOS
Epidemiology
Sites
  • Majority (66.6%) of cases present in craniofacial bones (Histopathology 2024;84:776)
    • Mandible (34.1%), maxilla (31.8%), other craniofacial (34.1%)
  • Other skeletal locations (Histopathology 2024;84:776)
    • Pelvic bones, vertebrae, femur
  • Nonskeletal locations (Histopathology 2024;84:776)
    • Peritoneum and abdominal wall, chest wall and shoulder, bladder
  • Unknown primary site (3% of overall cases)
Pathophysiology
  • Transcription factor cellular promoter 2 (TFCP2) is involved in DNA synthesis and cell survival
    • Rearrangement of TFCP2 with a breakpoint at the 5' end of exon 2 preserves the DNA binding domain of the protein
    • TFCP2 encodes the late SV40 factor (LSF) oncoprotein, which is a transcription factor that functions as a coactivator for YAP, a key transcription factor downstream of the Hippo and Wnt signaling pathways (Histopathology 2021;79:347)
    • LSF overexpression has been implicated in a variety of cancers, including breast cancer (where it upregulates expression of epidermal growth factor receptor [EGFR]); it is overexpressed in most cases of hepatocellular carcinoma, pancreatic ductal adenocarcinoma and some cases of oral squamous cell carcinoma (Histopathology 2021;79:347)
  • TFCP2 is fused with either FUS or EWSR1
    • FUS and EWS are members of the FET RNA binding protein family (FUS, EWS, TAF15); these tumors have occasionally been referred to as FET::TFCP2 rhabdomyosarcomas (Head Neck Pathol 2021;15:374, EMBO Rep 2019;20:e45766)
    • FUS and EWSR1 have similar structures and are involved in a variety of cellular processes such as transcriptional regulation, RNA splicing and DNA damage repair; they are often identified as the 5' part of chimeric fusions driving various leukemias and sarcomas (Nat Commun 2024;15:51)
  • Despite being a fusion driven sarcoma, TFCP2 rearranged rhabdomyosarcomas show complex genomic profiles; genomic instability may be due to homologous recombination deficiency (Nat Commun 2024;15:51)
  • RNA sequencing shows extremely high ALK production in these tumors; this is a result of intragenic deletions and aberrant splicing, with preservation of the kinase domain, which causes the formation of short transcripts
    • Upstream, alternate promoters have been hypothesized to result in ALK activation and may be a direct result of the chimeric genes FUS::TFCP2 and EWSR1::TFCP2 (Nat Commun 2024;15:51, Mod Pathol 2020;33:404)
    • As ALK expression is by mechanisms other than rearrangement, these tumors are likely not susceptible to ALK inhibitors such as crizotinib (Nat Commun 2024;15:51)
  • Concomitant homozygous deletion of CDKN2A is present in virtually all cases, with codeletion of adjacent MTAP gene in most of these cases (Nat Commun 2024;15:51, Mod Pathol 2020;33:404)
  • Genomic evolution has been seen in a small subset of FUS::TFCP2 tumors, in which the local recurrence showed gain of intragenic ALK deletions and homozygous CDKN2A deletions compared to the original tumor; the genomes in these cases became increasingly complex, with evidence of homologous recombination deficiency (Nat Commun 2024;15:51)
  • Compared to other RMS subtypes, differentially expressed genes in rhabdomyosarcoma with TFCP2 rearrangement include ALK, TERT, IGFBP5 and PAPPA2
    • These genes are associated with biological processes relating to muscle (downregulation of troponins, myosin heavy chains) and keratinization (upregulation of multiple keratins) (Nat Commun 2024;15:51)
Etiology
  • Unknown
Clinical features
Diagnosis
  • Due to the rapid growth and aggressive nature of these tumors, which often leads to disfigurement in the head and neck region and site specific symptoms from mass effect, they can be suspected on clinical examination
  • Diagnosis can be suspected on imaging (such as computed tomography or magnetic resonance imaging) if a destructive mass is seen arising from the bone; however, histological and molecular diagnosis is essential
  • WHO blue book histological criteria for diagnosis
    • Essential: a high grade epithelioid, spindle cell or mixed tumor; MyoD1 or myogenin expression
    • Desirable: location in bone; TFCP2 rearrangement or typical immunophenotype with coexpression of AE1 / AE3 and ALK
  • Diagnosis relies on biopsy and subsequent immunohistochemistry / molecular testing
Radiology description
  • Computed tomography (CT): hypodense, lytic intraosseous lesion; often locally destructive at time of presentation, with extension into soft tissues in majority of cases (Transl Pediatr 2024;13:178)
  • Magnetic resonance imaging (MRI)
    • T1 weighted: hypointense and isointense signal in relation to soft tissues
    • T2 weighted: solid tumor component with hyperintense signal (Head Neck Pathol 2023;17:546)
Radiology images

Contributed by Cale Michael Max Fletcher, B.Med., M.P.H. and Ruta Gupta, M.D.
PET / CT images

PET / CT images



Images hosted on other servers:
CT and MRI - mandibular lesion

CT and MRI: mandibular lesion

CT - hypodense lytic lesion

CT: hypodense lytic lesion

CT - destructive maxillary lesion

CT: destructive maxillary lesion

Prognostic factors
  • Overall prognosis is poor, compounded by the fact that most tumors present at a locally advanced stage, often with bone and soft tissue destruction
  • Distant metastases involving bone, lung or lymph nodes are present at diagnosis or follow up in 65% of cases (Mod Pathol 2020;33:404)
  • Unfavorable prognostic factors
    • Age
      • When stratified by age, patients ages 18 - 24 show the worst prognosis (1 year overall survival of 0%) (Histopathology 2024;84:776)
    • Use of standard chemotherapy (as opposed to escalated, intensive, multimodal regimens)
    • Presence of CDKN2A gene alteration
      • Most commonly, homozygous deletion of CDKN2A gene; however, amplification has also been reported (Histopathology 2024;84:776)
      • 0.5 year overall survival: 59% (positive for CDKN2A gene alteration) versus 77% (negative for CDKN2A gene alteration) (Histopathology 2024;84:776)
    • Presence of ALK gene alteration
  • Favorable
    • Age
      • Patients > 50 years of age have 1 year and 3 year overall survival rates of 82% and 45%, respectively (Histopathology 2024;84:776)
    • Location
      • Overall prognosis appears more favorable for tumors arising in the mandible compared to other craniofacial bones
      • Disease free survival appears higher for tumors arising in the mandible; however, the paucity of cases precludes the establishment of statistical significance (Virchows Arch 2020;477:725)
      • Risk of progressive disease appears lower for tumors arising in the mandible; Chrisinger et al. identified 16 cases with progressive disease, of which only 1 case had a primary tumor arising in the mandible (Virchows Arch 2020;477:725)
Case reports
Treatment
  • Primary treatment is heterogeneous, ranging from surgery alone to a combination of neo / adjuvant multimodal therapies, including chemotherapy, radiation therapy and targeted therapies; overall, different combinations of treatment modalities were of no statistical significance (Histopathology 2024;84:776)
  • Surgery
    • Mainstay of treatment; however, tumor deemed too advanced for surgery in a significant proportion of cases (Histopathology 2024;84:776)
  • Chemotherapy and radiation therapy
    • No established protocol
    • Case reports include use as neoadjuvant, adjuvant and monotherapy
    • Neoadjuvant chemotherapy may result in longer progression free survival in some cases (Nat Commun 2024;15:51)
  • Targeted therapies
    • ALK inhibitors
      • Anecdotal cases of disease stabilization have been reported following combined radiotherapy and ALK inhibitors (Histopathology 2023;82:478)
      • Overall, tumors with advanced stage and extensive pretreatment show limited sensitivity to ALK inhibitors (Nat Commun 2024;15:51)
      • In cases of metastatic disease, some cases may show partial response to ALK inhibitors (Nat Commun 2024;15:51)
    • Vascular endothelial growth factor (VEGF) inhibitors
      • Have been used either alone or in conjunction with ALK inhibitors
      • Most cases showed progressive disease despite therapy (Histopathology 2023;82:478)
Clinical images

Images hosted on other servers:
Swelling, maxillary alveolar ridge

Swelling, maxillary alveolar ridge

Gross description
  • Outer surface of tumor may show a pale, bossellated appearance; hemorrhagic change is common
  • Cut surface of the tumor is nodular, firm, pale and glistening
Gross images

Contributed by Cale Michael Max Fletcher, B.Med., M.P.H. and Ruta Gupta, M.D.
Anterior maxillectomy specimen

Anterior maxillectomy specimen

Left maxillectomy specimen   Left maxillectomy specimen

Left maxillectomy specimen

Microscopic (histologic) description
  • Malignant tumor with varied morphology
  • Most commonly, the tumor is biphasic (spindle cell and epithelioid) but may comprise either spindle cell, epithelioid, round cells or any combination of the 3 (Histopathology 2024;84:776)
    • Combined spindle cell and epithelioid = 58%
    • Pure spindle cell = 18%
    • Pure epithelioid = 9%
    • Pure round cell = 1.5%
    • Combined spindle and round cell = 1.5%
    • Combined spindle cell, epithelioid and round cell = 1.5%
  • Tumor grows in sheets or fascicles with extensive infiltration at the advancing front
  • Tumor cells are typically large with prominent nucleoli; although some areas may appear monotonous (typical for fusion sarcomas), pleomorphism can be marked (due to aneuploidy)
  • Mitotic activity ranges from 3 - 66 mitotic figures/10 high power fields (Mod Pathol 2020;33:404)
  • Necrosis is often present (Nat Commun 2024;15:51, Histopathology 2024;84:776)
  • Rhabdomyoblasts are rare
    • Focally present in 11% of cases and always associated with dominant spindle cell and epithelioid subtypes (Histopathology 2024;84:776)
    • Rhabdomyoblastic lineage confirmed through use of immunohistochemistry for MyoD1 and myogenin
Microscopic (histologic) images

Contributed by Cale Michael Max Fletcher, B.Med., M.P.H. and Ruta Gupta, M.D.
Ulcerated lesion

Ulcerated lesion

Sheet-like growth

Sheet-like growth

Hard palate origin

Hard palate origin

Extensive bony destruction

Extensive bony destruction

Areas of marked pleomorphism

Areas of marked pleomorphism

Rhabdoid appearance

Rhabdoid appearance


Architecture

Architecture

Relatively uniform cells

Relatively uniform cells

Bone destruction

Bone destruction

Frequent mitoses

Frequent mitoses

Desmin

Desmin

MyoD1

MyoD1


Myogenin

Myogenin

AE1 / AE3

AE1 / AE3

ALK (D5F3)

ALK (D5F3)

S100

S100

SOX10

SOX10

Cytology description
  • Unknown
Positive stains
Negative stains
Molecular / cytogenetics description
  • Molecular testing is required to confirm the presence of TFCP2 rearrangement, through use of a variety of molecular modalities (Histopathology 2021;79:347)
    • Fluorescent in situ hybridization: dual color break apart probe can be used to confirm presence of TFCP2 rearrangement
    • RNA next generation sequencing
  • Characterized by TFCP2 rearrangement, which is fused at the 5' end to either FUS or EWSR1
  • Despite being a fusion associated sarcoma, these tumors have complex genetic profiles; these include cases of aneuploidy (with associated chromothripsis of 1p and 3p), CDKN2A/B inactivation, unbalanced translocations and gene amplification (including MDM2) (Mod Pathol 2020;33:404)
  • ALK
    • Majority of cases associated with ALK gene alteration, most commonly gene deletions - internal hemizygous, hemizygous or homozygous internal deletion (Mod Pathol 2020;33:404)
      • Overexpression by IHC likely due to a truncated isoform that lacks part of or the entire extracellular domain of the receptor tyrosine kinase; this results in overexpression by an undescribed alternative promoter (Pathology 2019;51:116, Nat Commun 2024;15:51)
  • CDKN2A
  • Differentially expressed genes compared to other RMS subtypes
Molecular / cytogenetics images

Images hosted on other servers:
FISH - split signal, TFCP2   FISH - split signal, TFCP2

FISH: split signal, TFCP2

Videos

Rhabdomyosarcoma, practical approach, current classification and novel molecular findings

Sample pathology report
  • Maxilla, anterior maxillectomy:
    • Rhabdomyosarcoma with TFCP2 rearrangement (see comment)
    • Comment: There is a high grade spindle cell neoplasm with its epicenter in the maxillary bone. The tumor is composed of fascicles and whorls of spindle shaped cells with elongated nuclei and small to moderate amount of eosinophilic cytoplasm. The nuclei are hyperchromatic and show moderate nuclear pleomorphism. Mitotic rate is focally elevated. The tumor demonstrates variable cellularity with the intraosseous component demonstrating areas of high cellularity and marked nuclear pleomorphism. Occasional rhabdomyoblasts are present in the center of the tumor. There is extensive bone destruction and the tumor infiltrates into the adjacent soft tissues and the submucosal tissues in the left gingivolabial region. The tumor is focally seen in the submucosa of the respiratory epithelium lining the left nasal floor. In these areas, the tumor demonstrates an infiltrative growth pattern and mild nuclear pleomorphism. The tumor extends to margins at the left maxillary tuberosity and the gingival submucosal tissues around tooth 25. Immunohistochemistry (with working external controls) shows strong diffuse staining in malignant cells for desmin, MyoD1 and ALK1 (D5F3). There is patchy positive staining for AE1 / AE3. Malignant cells are negative for p40, high molecular weight cytokeratin and SOX10. Fluorescent in situ hybridization (dual color break apart probe) shows a split signal for TFCP2.
Differential diagnosis
Board review style question #1
Which immunohistochemical stain profile would be most consistent with a rhabdomyosarcoma with TFCP2 rearrangement?

  1. Positive: AE1 / AE3, INI1 (lost); negative: MyoD1, desmin, S100, SOX10
  2. Positive: desmin, MyoD1, AE1 / AE3, ALK; negative: S100, SOX10, INI1 (retained)
  3. Positive: desmin, MyoD1; negative: AE1 / AE3, ALK, S100, SOX10, INI1 (retained)
  4. Positive: S100 / SOX10 (patchy), MyoD1 (patchy), desmin (patchy); negative: AE1 / AE3, INI1 (retained)
Board review style answer #1
B. Positive: desmin, MyoD1, AE1 / AE3, ALK; negative: S100, SOX10, INI1 (retained). Positive immunostaining for desmin, MyoD1, AE1 / AE3 and ALK are the most common positive immunostains for rhabdomyosarcoma (RMS) with TFCP2 rearrangement. Answer A is incorrect because this immunoprofile is most consistent with epithelioid sarcoma. Loss of INI1 and negativity for desmin / MyoD1 are incompatible with RMS with TFCP2 rearrangement. Answer C is incorrect because this immunoprofile is most consistent with an alternative variant of rhabdomyosarcoma (e.g., spindle cell rhabdomyosarcoma). RMS with TFCP2 rearrangement shows frequent positivity for AE1 / AE3 and ALK. Answer D is incorrect because patchy immunostaining for desmin and MyoD1 can be found in rhabdomyoblastic foci within malignant peripheral nerve sheath tumor. SOX10 is negative in RMS with TFCP2 rearrangement.

Comment Here

Reference: Rhabdomyosarcoma with TFCP2 rearrangement
Board review style question #2


A high grade malignancy with the appearance shown above is identified within the mandible of a 30 year old man. Which molecular finding is diagnostic of rhabdomyosarcoma with TFCP2 rearrangement?

  1. Fusion with ERG
  2. Fusion with FLI1
  3. Fusion with FOXO1
  4. Fusion with FUS or EWSR1
Board review style answer #2
D. Fusion with FUS or EWSR1 (FUS::TFCP2, EWSR1::TFCP2) is characteristically found in rhabdomyosarcoma with TFCP2 rearrangement. Answer A is incorrect because ERG fusion (EWSR1::ERG) is characteristically found in Ewing sarcoma. Answer B is incorrect because FLI1 fusion (EWSR1::FLI1) is characteristically found in Ewing sarcoma. Answer C is incorrect because FOXO1 fusion (PAX3::FOXO1) is characteristically found in alveolar rhabdomyosarcoma.

Comment Here

Reference: Rhabdomyosarcoma with TFCP2 rearrangement

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