NUTM1 重排肉瘤：PathologyOutlines 专题全文（10 月 12 日教科书更新）NUTM1 rearranged sarcoma (PathologyOutlines topic; Textbook Updates 12 October 2026)

Scope: full PathologyOutlines topic page “NUTM1 rearranged sarcoma” (all sections, on-site microscopic/IHC/molecular images with captions, differential diagnosis, practice questions). Listed in the 12 October 2026 Textbook Updates; the dura MALT lymphoma topic was published separately on this site on 2026-10-13.

Definition / general

• NUTM1 rearranged sarcoma is an emerging group of aggressive soft tissue sarcomas defined by chromosomal rearrangements involving the NUTM1 (NUT midline carcinoma family member 1) gene on chromosome 15q14, distinct from the more well known NUT carcinoma

Essential features

• Emerging group of aggressive soft tissue sarcomas
• Wide age range, no sex predilection, no predisposing factors
• Commonly involves somatic soft tissues and gastrointestinal tract
• Histology is variable, including fibrosarcomatous, round cell, epithelioid / rhabdoid and hyalinized / nested patterns, sometimes with amianthoid fiber-like collagen, immunoreactivity for NUT protein
• Defined by NUTM1 rearrangement, most commonly fused with MAD family genes (MXD4, MXD1, MXI1, MGA) rather than BRD3 / 4 (which are characteristic fusion partners in NUT carcinoma)

Terminology

• NUT rearranged sarcoma

ICD coding

• ICD-O: 8800/3 - sarcoma, NOS
• ICD-10: C49.9 - malignant neoplasm of connective and soft tissue, unspecified
• ICD-11: 2B5K - unspecified malignant soft tissue tumors or sarcomas of bone or articular cartilage of other or unspecified site

Epidemiology

• Extremely rare entity with few cases reported in literature (~70 cases)
• Wide age range: 1 - 78 years (Semin Diagn Pathol 2025;42:150941)
  • Typically affects middle aged adults (median age: 48 years)
  • 1 reported case in a 13 month old boy (Biomedicines 2024;12:1709)
• Slight female predilection (M:F = 1:1.7)
• No known geographic predilection; reported worldwide

Sites

• Most common in the somatic soft tissues, thoracic region, gastrointestinal tract and body cavity (Semin Diagn Pathol 2025;42:150941, Mod Pathol 2021;34:1547)
• Other locations include the mandible, kidney, bladder, penis, ovary, uterus, scalp, orbital area, brain and central nervous system (parietal lobe and dura) (Genes Chromosomes Cancer 2022;61:542, Semin Diagn Pathol 2025;42:150941)
• Pediatric cases primarily involve soft tissue and are located in the thoracic region; cases in the abdomen or pelvis have not been documented (Semin Diagn Pathol 2025;42:150941)

Pathophysiology

• NUTM1 gene, located on chromosome 15q, is normally expressed in the testis and promotes histone acetylation during spermatogenesis
• Most common fusion partners: genes from the MYC associated factor X (MAX) dimerization (MAD) transcription family (e.g., MXD1, MXD4, MXI1 [or MXD2] and MGA) rather than BRD3 or BRD4 (commonly seen in NUT carcinoma)
• MAD::NUTM1 fusion protein is hypothesized to dysregulate gene expression, potentially through blocking differentiation and promoting abnormal proliferation
• Unlike BRD4::NUT, it may not form megadomains or require BET proteins, potentially explaining resistance to BET inhibitors
• Rare partners include BCORL1, ZNF532, NSD3, ONECUT, BRD3 and BRD4 (Am J Surg Pathol 2018;42:636, Am J Surg Pathol 2024;48:930)
• No known precursor lesion

Etiology

• Unknown at this time

Diagrams / tables

Contributed by Bhagat Singh Lali, M.D.

Images hosted on other servers:

Clinical features

• Rapidly growing, usually deep seated, often painful or palpable mass
• Symptoms depend on the anatomic site (e.g., headache and hemiparesis for CNS tumors; obstruction, abdominal distension, weight loss, abdominal pain for GI tumors; shortness of breath for thorax tumors; ptosis in orbital primary) or with a mass discovered on imaging studies

Diagnosis

• Essential diagnostic criteria
  • Monomorphic spindled, epithelioid and rhabdoid cells in a partially hyalinized background
  • Evidence of NUTM1 rearrangement

Laboratory

• Unknown at this time

Radiology description

• No specific findings
• Imaging typically reveals an aggressive, heterogeneously enhancing soft tissue mass with necrosis and infiltrative margins (Mod Pathol 2021;34:1547)
• 18F-FDG PET / CT: demonstrates intense FDG avidity, identifies metastatic disease

Radiology images

Contributed by Divya Bansal, M.B.B.S., M.D., Himanshi Diwan, M.D., Sunil Pasricha, M.B.B.S., M.D. and Rakesh Oberoi, M.D.

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Prognostic factors

• Overall survival: 13.4 months
• Adult cases demonstrate aggressive behavior (Semin Diagn Pathol 2025;42:150941)
  • Metastasis is seen in 50% of cases at presentation: lymph node, distant metastasis (lung, bones, liver) or peritoneal spread
  • Without metastasis at presentation: eventually 66% of patients developed local recurrence or distant metastasis
  • Excluding cases with a follow up period of < 1 year, 60% of deaths occurred within 2 years
  • Tumors with MGA rearrangements: 75% died of disease, 80% with local recurrence or metastasis
  • Tumors with MXD1 / MXD4 / MXI1 rearrangements: 56% died of disease, 75% with local recurrence or metastasis
• Pediatric cases follow a less aggressive clinical course
  • At presentation, 78% had no metastasis, out of which 42% eventually developed local recurrence or metastasis
  • Of 6 reported cases with at least 1 year of follow up, only 1 death (17%) was reported (Biomedicines 2024;12:1709)
    • In fact, this patient survived 25 years before succumbing to the disease (Biomedicines 2024;12:1709)
  • Pediatric NUT rearranged sarcomas may represent a distinct subset

Case reports

• 13 month old boy with NSD3::NUTM1 fusion sarcoma and prolonged survival (Biomedicines 2024;12:1709)
• 10 year old boy and 10 year old girl with MGA::NUTM1 fusion high grade spindle cell sarcoma (Cold Spring Harb Mol Case Stud 2018;4:a003194)
• 29 - 73 year old women with NUTM1 / NUTM2B rearranged intraabdominal sarcomas with ESR1 overexpression as a therapeutic target (Mod Pathol 2025;38:100816)
• 34 year old woman with a large pelvic mass (Genes Chromosomes Cancer 2018;57:557)
• 55 year old woman with a right kidney mass (J Immunother Precis Oncol 2025;8:113)

Treatment

• Wide local excision with negative margins for localized disease
• Clinical experience with systemic therapies is limited
• Trabectedin based or ifosfamide based regimens, especially in combination with doxorubicin (the backbone of soft tissue sarcoma), may offer a reasonable approach as frontline therapy (Semin Diagn Pathol 2025;42:150941)
• BET inhibitors may not be effective in NUT rearranged sarcomas
• Other strategies under investigation include EP300 histone acetyltransferase inhibitors and histone deacetylase inhibitors (vorinostat)

Clinical images

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Gross description

• Circumscribed with a solid, fleshy, white-tan to gray cut surface (Semin Diagn Pathol 2025;42:150941)
• May show hemorrhagic, whorled, cystic and friable areas
• Tumor sizes range from 1 to 22.5 cm
• Deeply located tumors are generally larger

Gross images

Images hosted on other servers:

Frozen section description

• Unknown at this time

Microscopic (histologic) description

• Tumor cells display uniform cytomorphology with minimal nuclear pleomorphism, in keeping with a fusion driven process (Semin Diagn Pathol 2025;42:150941)
• Single tumor may display 1 or multiple growth patterns, including
  • Fibrosarcomatous pattern: uniform spindled cells arranged in intersecting fascicles or a herringbone pattern
  • Round cell pattern: sheet-like proliferation of primitive round cells
  • Epithelioid / rhabdoid pattern: sheet-like proliferation of epithelioid to rhabdoid cells
  • Hyalinized / nested pattern: cords and nests of cells embedded in an abundant hyalinized stroma or tight clusters / alveolar pattern with scant stroma
• Tumor cells can be arranged in sheets, variably sized nests, cords, trabeculae or single filing pattern
• Rhabdoid cells often display a discohesive growth
• Microcystic spaces can be seen (Mod Pathol 2025;38:100729)
• Stroma: hyalinized to myxoid or minimal
• Osteoid-like matrix has also been described (Mod Pathol 2021;34:1547)
• Amianthoid fibers / collagen rosettes (24% of cases)
• Rare features: osteoclast-like giant cells and rosette formation
• Tumor necrosis: variable
• Mitotic activity: low to brisk
• Gastrointestinal tumors: diffuse infiltration of submucosa, muscularis propria and subserosa; mucosal involvement can also be seen (Mod Pathol 2021;34:1547)
• Tumor vasculature, hemangiopericytomatous or thick walled hyalinized vessels or arcades of smaller vessels cuffed by tumor cells
• Monstrous cells with microvacuolar cytoplasm, severe atypia and features reminiscent of Hodgkin cells are present in some tumor areas (Mod Pathol 2025;38:100816)
• MGA rearranged tumors: often have collagen plaques / amianthoid collagen, microcystic spaces and spindle morphology
• MXD4 rearranged tumors: often have epithelioid or rhabdoid features

Microscopic (histologic) images

Contributed by Divya Bansal, M.D., Sunil Pasricha, M.D., Bhagat Singh Lali, M.D. and Shobhna Sharma, M.D.

Cytology description

• Singly scattered or clusters of tumor cells (Diagn Cytopathol 2022;50:E244)
• Small round tumor cells
• Rhabdoid cells
• High N:C ratio, small inconspicuous nucleoli and coarse chromatin
• Occasional nuclear molding can be seen
• Rare larger binucleated tumor cells can be seen
• Limitations
  • Small round cell morphology with or without rhabdoid cells can be seen in many tumors; a panel of immunohistochemical markers is usually required to at least narrow the differential diagnosis
  • Cell blocks are essential, not only for immunohistochemistry studies but also for the purpose of molecular diagnostics

Positive stains

• NUT
  • Near 100% sensitivity for the monoclonal NUT C52B1 antibody
  • Patchy to diffuse (varies between and within tumors), weak to strong, speckled nuclear pattern of immunoexpression
  • Recent papers reported negative NUT IHC in a tumor with NSD3::NUTM1 fusion and 2 other tumors harboring MXD1::NUTM1 and BCORL1::NUTM1 fusions (Mod Pathol 2019;32:764, Am J Surg Pathol 2018;42:636)
• CD99: may be focal to diffuse, usually weak
• Variably expressed, typically rare to focal cells (Semin Diagn Pathol 2025;42:150941)
  • Keratins (can be dot-like)
  • EMA
  • Claudin4
  • p63
  • Synaptophysin
  • GFAP
  • Smooth muscle actin
  • Desmin
  • Calponin
  • CD34
  • BCOR
  • MUC4
  • WT1
  • Neurofilament
  • S100 protein
  • SOX10
  • NKX2.2
  • Cyclin D1
  • TLE1
  • CD56
  • ERG1
  • ER, PR
• Rare cases, strong or diffuse
  • Keratins
  • S100 protein
  • Desmin
  • BCOR
  • MUC4
  • ER, PR
• If expressed, keratins may be positive in a subset of MXD1 / MXD4 / MXI1 rearranged tumors
  • Not typically expressed in tumors with MGA::NUTM1

Negative stains

• Myogenin, MyoD1
• Calretinin
• HMB45, MelanA
• ALK, pan-TRK, BRAF V600E
• MDM2
• STAT6
• CD117, DOG1
• PAX8
• SATB2
• SS18::SSX
• SMARCB1 (INI1) and SMARCA4 (BRG1) expression: intact
• H3K27me3 expression is retained or displays a mosaic pattern / patchy loss (Biomedicines 2024;12:1709, Histopathology 2023;83:712)
• Reference: Semin Diagn Pathol 2025;42:150941

Electron microscopy description

• Unknown at this time

Molecular / cytogenetics description

• FISH for NUTM1 gene rearrangement: probe for NUTM1 gene breakpoint at the 15q14 locus
  • Limitation: negative FISH, positive NUT IHC must be further investigated by FISH using a probe spanning the full length of the NUTM1 gene or by a sequencing method, preferably RNA sequencing
• RNA sequencing: identifies specific fusion partners and is recommended for definitive subclassification
  • Limitation: fusion panel coverage offered by some of the NGS platforms
• DNA based methylation profiling: distinct methylation cluster differing from those of NUT carcinoma and undifferentiated small round cell and spindle cell sarcomas
• Fusions involving genes from the MYC / MAX / MXD transcription family (e.g., MXD1, MXD4, MXI1 [or MXD2] and MGA)
• NUTM1 breakpoints: exon 2, 3 and 5
• Most common fusion partners: MXD4 and MGA, followed by MXI1 and MXD1
  • Gastrointestinal tract: MXD4 fusions are more common
  • Soft tissue: MGA fusions are more common
• MGA::NUTM1 has been found in all pediatric cases except 2 tumors (NSD3::NUTM1 and ONECUT::NUTM1)
• Interestingly, BRD3, a partner gene found in NUT carcinoma, has been reported in a tumor in the thigh (Am J Surg Pathol 2018;42:636)

Molecular / cytogenetics images

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Sample pathology report

• Cecum, resection:
  • High grade sarcoma with MXD4::NUTM1 fusion (see comment)
  • Comment: The tumor is composed of primitive small round to epithelioid cells arranged in solid sheets with interspersed rhabdoid cells. Mitotic activity is high (up to 15/10 high power fields [HPF]) with focal necrosis. By immunohistochemistry, the tumor cells show diffuse and strong nuclear expression of NUT. Pancytokeratin (AE1 / AE3) is focally positive. SMARCA4 and SMARCA2 expression are retained. FISH for NUTM1 rearrangement is positive (breakapart probe). RNA sequencing confirms an MXD4::NUTM1 gene fusion. These findings are diagnostic of NUTM1 rearranged sarcoma, an aggressive mesenchymal neoplasm distinct from NUT carcinoma. The prognosis for patients with NUT rearranged gastrointestinal sarcomas is poor.

Differential diagnosis

• Spindle cell morphology
  • Monomorphic synovial sarcoma:
    • Novel SS18::SSX and SSX C terminus immunostains: highly sensitive and specific for synovial sarcoma
    • SS18::SSX1, SSX2 or SSX4 are diagnostic of synovial sarcoma
  • Solitary fibrous tumor (SFT):
    • Diffuse STAT6 expression in SFT (consistently negative in NUT rearranged sarcoma)
    • Defining molecular feature is NAB2::STAT6 fusion
  • Malignant peripheral nerve sheath tumor (MPNST):
    • Distinguishing can be challenging
    • History of radiation therapy, neurofibromatosis type 1 or a tumor arising in a neurofibroma or peripheral nerve
    • Complete loss of H3K27me3 strongly supports malignant peripheral nerve sheath tumor
    • Intact or heterogeneous H3K27me3 expression may necessitate molecular testing
    • NUT IHC negative
  • Kinase rearranged spindle cell neoplasm:
    • Coexpression of CD34 and S100 protein without SOX10, along with a surrogate marker (e.g., pan-TRK, ALK, BRAF)
  • Gastrointestinal stromal tumor (GIST):
    • CD117 and DOG1 positive in GIST (consistently negative in NUT rearranged sarcoma)
  • Sarcomatoid carcinoma:
    • Keratin expression cannot resolve the differentials
    • Precursor epithelial lesion, low grade carcinoma or a conventional component supports sarcomatoid carcinoma
  • Sarcomatoid mesothelioma:
    • WT1 (can be rarely seen in NUT rearranged sarcoma)
    • Sarcomatoid mesothelioma may lose expression of keratin and mesothelial markers
    • Multiple serosal nodules and thickened pleura or peritoneum suggest mesothelioma
    • Loss of surrogate markers BAP1 or MTAP immunostains (indicating loss of BAP1 and CDKN2A genes, respectively) supports mesothelioma
• Round cell morphology
  • Ewing sarcoma:
    • More common
    • NKX2.2 and strong membranous diffuse CD99 combination (NKX2.2 can be focally positive, weak and patchy CD99 expression in NUT rearranged sarcomas)
    • EWSR1::ETS fusion
    • NUT IHC negative
  • Round cell sarcoma with EWSR1::non-ETS fusions:
    • Variable hyalinized, myxohyaline or myxoid stroma; may focally express keratin
    • EWSR1 / FUS::NFATC2 - EWSR1 rearrangement and amplification by FISH
    • EWSR1::PATZ1 coexpression of myogenic and neural markers
    • NUT IHC negative
  • CIC rearranged sarcoma:
    • WT1 and ETV4 expression supports CIC rearranged sarcoma
    • CIC gene rearrangement
  • BCOR altered sarcoma:
    • Express BCOR, cyclin D1 and SATB2 (NUT rearranged sarcoma are SATB2 negative, although data is limited)
    • Rearrangement or internal tandem duplication of BCOR
  • Desmoplastic small round cell tumor (DSRCT):
    • Consistently express keratin and desmin (dot-like pattern) (NUT rearranged sarcoma may be desmin positive but this is typically focal)
  • Poorly differentiated synovial sarcoma:
    • SS18::SSX IHC
    • Downregulation of INI1
  • Lymphoma:
    • T or B lymphoblastic lymphoma (T / B LBL):
      • Primitive round cell morphology
      • CD45+, TdT+, CD1a / CD34+ alongside CD3 (T cell) or PAX5 (B cell) markers
    • Diffuse large B cell lymphoma:
      • Dyscohesive sheets of large cells
      • CD45+, CD20+, PAX5+
    • Burkitt lymphoma:
      • High grade starry sky round cell morphology
      • CD20+, MYC+, Ki67 ~100%
    • Anaplastic large cell lymphoma (ALCL):
      • Pleomorphic / epithelioid cells
      • CD30+, ALK1 variable, T cell markers
    • Plasmablastic lymphoma:
      • CD45- / CD20- undifferentiated morphology
      • CD138+, MUM1+, light chain restricted
  • Small cell carcinoma:
    • Distinguishing can be challenging; NUT IHC is negative
• Epithelioid / rhabdoid and nested / hyalinized morphology
  • Sclerosing epithelioid fibrosarcoma (SEF):
    • Overlapping features, including epithelioid cells and hyalinized / sclerotic stroma (NUT rearranged sarcoma may be positive for MUC4, with even diffuse expression confounding diagnosis)
    • EWSR1::FUS rearrangement
    • NUT IHC: negative
  • SWI / SNF deficient neoplasms (including epithelioid sarcoma and malignant rhabdoid tumor):
    • Loss of INI1 or BRG1 expression
    • Keratin staining does not help distinguish between these entities
  • Malignant gastrointestinal neuroectodermal tumor (GNET) and clear cell sarcoma:
    • Diffusely positive S100 and SOX10 expression with or without melanocytic marker expression
  • Extraskeletal osteosarcoma:
    • Unequivocal lace-like osteoid formation around individual cells, at least focally
  • Myoepithelial tumors:
    • Frequently express keratin, S100 protein, SOX10, SMA, p63, calponin and GFAP
    • Subset also has EWSR1 rearrangement
  • Poorly differentiated carcinoma:
    • NUT IHC negative
  • Melanoma:
    • HMB45, MelanA, SOX10 positive
  • Epithelioid mesothelioma:
    • WT1 diffuse strong positive
    • NUT IHC negative
• NUT carcinoma:
  • Characterized by primitive epithelioid cells with squamous differentiation, typically as abrupt keratinization
  • In ~66% of NUT carcinomas, the NUTM1 fusion partner is BRD4, with the remaining tumors harboring BRD3, NSD3, ZNF532, ZNF592 or ZNF618
  • Clinical and radiologic correlation remains the most useful tool, though some tumors may be difficult to classify
• NUTM2 rearranged sarcomas:
  • Shared morphologic features with NUTM1 rearranged sarcomas
  • NUTM2 fusions may show weak / absent staining for the NUT immunostain
• CIC::NUTM1 sarcomas:
  • Have immunophenotypic, transcriptomic and methylation profiles similar to other CIC rearranged sarcomas
  • May show only weak or focal NUT staining with ETV4 coexpression, requiring FISH or RNA sequencing for confirmation
  • Better classified as a molecular variant of CIC rearranged sarcomas

Practice question #1

A 56 year old woman presented with a 5.5 cm colonic mass. Biopsy shows a high grade neoplasm composed of spindled, primitive small round to few rhabdoid cells. The tumor cells show diffuse, strong nuclear staining for NUT by immunohistochemistry, are pancytokeratin negative and retain SMARCA4 (BRG1) and SMARCB1 (INI1) expression. FISH for NUTM1 rearrangement is positive. Which of the following is the most appropriate diagnosis?

1. Ewing sarcoma
2. Malignant rhabdoid tumor
3. NUT carcinoma
4. NUTM1 rearranged sarcoma
5. SMARCA4 deficient undifferentiated tumor

Practice answer #1

D.NUTM1 rearranged sarcoma. The clinical presentation (colonic mass, middle aged adult), histology (spindled, primitive small round to rhabdoid), diffuse strong NUT nuclear staining and presence of NUTM1 rearrangement without squamous differentiation are diagnostic of NUTM1 rearranged sarcoma. Answer A is incorrect because Ewing sarcoma typically shows membranous CD99, nuclear NKX2.2 positivity, EWSR1::ETS fusion and NUT negativity. Answer B is incorrect because malignant rhabdoid tumors typically occur in young children, show loss of SMARCB1 (INI1) expression and are not defined by NUTM1 rearrangement. Answer C is incorrect because NUT carcinoma typically shows squamous differentiation, commonly occurs in midline structures (mediastinum, head / neck) and often involves BRD3 / 4 fusions, though it can also express NUT. Answer E is incorrect because SMARCA4 deficient undifferentiated tumors show loss of SMARCA4 (BRG1) nuclear expression, whereas this tumor showed retained expression.

Reference: NUTM1 rearranged sarcoma