Tumors of uncertain differentiation
2026-05-04 Paola Dal Cin, PhD Affiliation1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)
Keywords
uncertain differentiation, benign neoplasms, intermediate neoplasms,malignant neoplasms,melanocytic differentiation, receptor tyrosine kinase fusionsClassification
Definition
Soft tissue tumors of uncertain differentiation have been classified as benign, intermediate and malignant neoplasms. 1 Those tumors with uncertain nosology or aberrant melanocytic differentiation may require extensive workup or be misdiagnosed as melanomas, and molecular studies are steps leading to accurate classification of melanocytic neoplasia. 2-5
Molecular genetic testing for receptor tyrosine kinase fusions e.g. NTRK1, NTRK2, NTRK3, RET, MET, EGFR, ROS1, ALK or downstream effector molecule fusions ABL1, BRAF or RAF1 or activating point mutations is required for a conclusive diagnosis and determination of therapy. 6
| Tumors of uncertain differentiation | Genetic events |
|---|---|
| Benign neoplasms of uncertain differentiation | |
| Cellular neurothekeoma | Rare benign cutaneous neoplasms most commonly in children and young adults, with a female predominance Single cases addressing genetic alterations in neurothekeomas have been reported so far: with 4 mutations PIK3CA , ALK , SMO and ERBB3; 7, a NF1 c.4333-2dup variant; 8 immunohistochemical expression of TFE3 lacking TFE3 alteration by FISH analysis 9 and a somatic mutation in FLCN in a patient with a cutaneous plexiform hybrid tumor of perineurioma and cNTK. 10 Recent data showed that fusions are not major driver events or associated with any virus; only two genes were recurrently mutated, MAPK1 and MKRN1 and CDKN2A and MTAP were the most common deleted genes , both on 9p21.3. 11 |
| Epithelioid fibrous histiocytoma | Epithelioid fibrous histiocytoma (EFH) is probably biologically distinct from dermatofibroma (conventional fibrous histiocytoma) and its subtypes.It harbors mainly ALK rearrangement or rarely PRKC ,RET and NTRK3 rearrangements as mutually exclusive events.12-14 SQSTM1 and VCL are the most common ALK fusion partners and many other single rarely fusions partners among other DCTN1, ETV6, PPFIBP1, SPECC1L, TPM3, PRKAR2A, MLPH, CLTC, and EML4. 14,15 |
| Non-neural granular cell tumour | They are, benign dermal neoplasm that occurs in children and young adults, characterized by ALK rearrangements. 16,17 |
| PEComa | Cutaneous PEComas seem to be clinically and genetically distinct from their visceral and soft tissue counterparts ,since they do not harbor TFE3 rearrangements.18 However, recently a small series of NONO::TFE3 fusion cutaneous epithelioid and spindle cell tumor were reported morphologically as PEComa but with an unusual immunophenotype of SOX10 and p63 positivity, 19 as well as cutaneous cases described as fibroma-like PEComa associated with tuberous sclerosis have been reported . 20,21 |
| Intermediate neoplasms of uncertain differentiation | |
| Angiomatoid fibrous histiocytoma | Tumors most frequently occur as dermal or subcutaneous lesions in the extremities, with t(2;22)(q33;q12) / EWSR1::CREB1 the most frequent chromosome aberration, followed by t(12;22)(q13;q12)/ EWSR1::ATF1 fusion and rarely also FUS::ATF1 fusion. The presence of EWSR1::CREB1 fusion should only be used to support the diagnosis of AFH in the appropriate morphologic contex, since it is a promuscous fusion. 22 |
| NTRK-rearranged spindle cell neoplasm | NTRK-rearranged spindle cell tumors may arise at any anatomical site, at any age. although the younger age group more commonly affected. 23 Identification of NTRK-rearranged tumors presents a new challenge for surgical pathologists given the variable and relatively non-specific features. A broad morphological spectrum roughly divided into three subgroups as low-grade, intermediate-grade and high-grade. 24 |
| Although panTRK immunohistochemistry, which recognizes the highly conserved C-terminus of all three TRK proteins, is relatively sensitive for mesenchymal tumors with NTRK1 and NTRK2, but less for NTRK3 fusions. FISH or next generation sequencing (NGS) should be considered where available and appropriate for confirmation of the immunohistochemical findings. However, false negative or false positive results can occur with both techniques. 25 | |
| The molecular background of NTRK-tumors lead to the constitutive activation of the MAP kinase signaling pathway as the other kinases gene alteration. 26 LMNA::NTRK1, TPR::NTRK1, or TPM3::NTRK1 are the most frequent fusions , than those involve NTRK2 or NTRK3 rearrangements. 27,28 | |
| Atypical fibroxanthoma | Atypical fibroxanthoma (AFX) is a rare tumor mostly developing in UV sun-damaged skin of elderly white patients. AFXs have been also rarely reported in young patients with Li–Fraumeni syndrome 29 and xeroderma pigmentosum. 30.Clinicopathological features as well as mutational profile e.g. TP53 and, frequently also CDKN2A, TERT promoter, and NOTCH1 alterations , are like pleomorphic dermal sarcoma (PDS), but they differ in prognosis and for presence of ASXL1 mutation present only in AFX. 31 |
| Superficial CD34-positive fibroblastic tumor | Superficial CD34-positive fibroblastic tumor (CD34FT) is an indolent lesion but may rarely metastasize to lymph nodes without adverse outcomes. affecting predominantly the superficial soft tissues of the limbs of young adults.32 Immunohistochemistry for CADM3, in combination with the characteristic morphological features, is a valuable adjunct in the diagnosis. 33 PRDM10 rearrangements are often but not always present (~60). MED12 is the most common partner gene follow by CITED2 and rare cases with RAB30 and ARHGAP32. 34 |
| Malignant neoplasms of uncertain differentiation | |
| Pleomorphic dermal sarcoma | Pleomorphic dermal sarcoma (PDS) occurs also in chronically UV radiation–exposed skin . Both PDS and atypical fibroxanthoma (AFX) have been shown to harbor UV-signature mutations, particularly involving TP53 and TERT promotor mutations, and , among others, also alterations as FAT1, NOTCH1/NOTCH2, CDKN2A,COL1A1, and PDGFRA , suggesting that they are genetically related tumors. However, PDS has a more aggressive course than AFX, with higher risk for local recurrence and metastases ,as consequence of high number of copy number variations (CNVs) during tumor progression e.g. amplification of BRAF and PDGFRA,loss of KIT and PDGFRA and gain of KNSTRN and IDH1. 35,36 |
| Epithelioid sarcoma | Both types of epithelioid sarcoma (ES} the conventional or distal type and the proximal type (more aggressive behavior) are characterized by inactivation of the SMARCB1 aka hSNF5 / SMARCB1 gene on chromosome 22q11, resulting in loss of nuclear expression of INI1 by IHC in approximately 90% of cases. 37 |
| CRTC1::TRIM11 cutaneous tumour | Cutaneous melanocytic tumor with a dermal-based melanocytic tumor, is characterized by the presence of CRTC1::TRIM11 fusion, but the molecular function of this fusion remains still unknown. Typical driver mutations seen in more common melanocytic neoplasms, kinase fusions and EWS rearrangements were absent. 38,39 TRIM11 immunohistochemistry is not specific for diagnosis.40 While early reports of CRTC1::TRIM11 cutaneous tumors suggested a predominantly indolent clinical course, a few cases have been documented with lymph node and distant.41-43 |
| Dermal clear cell sarcoma | Primary cutaneous clear cell sarcoma (PCS) is a rare malignancy and difficult to differentiate from melanoma. Smaller tumor size and negative sentinel lymph node biopsy (SLNB) status were significantly associated with a better disease-free survival.44 So far single cases with EWSR1::CREM fusion were reported. 45,46 |
| Ewings sarcoma | Cutaneous Ewing sarcoma (EWS) is rare typically small tumor (less than 5cm), with less arising at any anatomical location, particularly particular at distal, truncal and head/neck locations, compared to classical EWS and may have better prognosis than those with Ewing sarcoma at other anatomical sites. 47-49 Cutaneous Ewing sarcomas is driven by transcription factors encoded by chimeric FET::ETS gene fusions, more commonly EWSR1::FLI1 than EWSR1::ERG. |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 28802505 | 2017 | Soft Tissue Tumors of Uncertain Histogenesis: A Review for Dermatopathologists. | Buehler D et al |
| 2 | 34991102 | 2022 | PRAME Expression in Challenging Dermal Melanocytic Neoplasms and Soft Tissue Tumors With Melanocytic Differentiation. | Kline N et al |
| 3 | 35338512 | 2022 | Nevus, melanoma, or something else? Mesenchymal neoplasms with melanocytic differentiation. | Evangelou Z et al |
| 4 | 37120349 | 2023 | The new and old in superficial mesenchymal tumors with uncertain origin and/or melanocytic differentiation. | Alkashash A et al |
| 5 | 37982498 | 2024 | Pitfalls of PRAME Immunohistochemistry in a Large Series of Melanocytic and Nonmelanocytic Lesions With Literature Review. | Turner N et al |
| 6 | 32506523 | 2020 | Soft tissue tumors characterized by a wide spectrum of kinase fusions share a lipofibromatosis-like neural tumor pattern. | Kao YC et al |
| 7 | 3607557 | 1987 | Improving turkey poult quality by correcting incubator humidity to match eggshell conductance. | Meir M et al |
| 8 | 39578817 | 2024 | Atypical cellular neurothekeoma: a case report with a novel NF1 mutation. | de la Guardia V et al |
| 9 | 36802993 | 2023 | Expression of TFE3 in Cellular and Myxoid Type of Neurothekeoma: Four Cases in Young Children and Adolescents. | Cheng Y et al |
| 10 | 40015928 | 2025 | A Case of Hybrid Cellular Neurothekeoma and Perineurioma With a Folliculin Gene Mutation. | Prechtel TJ et al |
| 11 | 41365817 | 2026 | Cellular neurothekeoma is driven by copy number deletions, providing potential diagnostic and therapeutic avenues. | Sousa-Squiavinato ACM et al |
| 12 | 30289773 | 2019 | Epithelioid Fibrous Histiocytoma: A Concise Review. | Felty CC et al |
| 13 | 32701707 | 2020 | Epithelioid Fibrous Histiocytoma: A Concise Review: Erratum. | |
| 14 | 39329254 | 2024 | Epithelioid Fibrous Histiocytoma Is on a Continuum With Superficial ALK -rearranged Myxoid Spindle Cell Neoplasm : A Clinicopathologic Series of 35 Cases Including Alternate RET and NTRK3 Fusions. | DeSimone MS et al |
| 15 | 35289445 | 2022 | Molecular investigation of ALK-rearranged epithelioid fibrous histiocytomas identifies CLTC as a novel fusion partner and evidence of fusion-independent transcription activation. | Georgantzoglou N et al |
| 16 | 29742298 | 2018 | A subset of so-called dermal non-neural granular cell tumours are underlined by ALK fusions, further supporting the idea that they represent a variant of epithelioid fibrous histiocytoma. | Perret RE et al |
| 17 | 30001233 | 2018 | Cutaneous Non-Neural Granular Cell Tumors Harbor Recurrent ALK Gene Fusions. | Cohen JN et al |
| 18 | 23711163 | 2013 | Cutaneous PEComa does not harbour TFE3 gene fusions: immunohistochemical and molecular study of 17 cases. | Llamas-Velasco M et al |
| 19 | 3760637 | 1986 | [Function and gene expression of RuBisCO]. | Takabe T et al |
| 20 | 34586486 | 2022 | Fibroma-like PEComa: a newly recognized soft tissue neoplasm in tuberous sclerosis patients-imaging features and review of literature. | Bajaj G et al |
| 21 | 41499353 | 2026 | Fibroma-Like PEComa as an Early Indicator of Tuberous Sclerosis Complex: Confirmed With Strong GPNMB Expression and TSC2 Germline Mutation. | Yin X et al |
| 22 | 37156707 | 2023 | Gene fusions in superficial mesenchymal neoplasms: Emerging entities and useful diagnostic adjuncts. | Fischer GM et al |
| 23 | 30585824 | 2019 | Expanding the Spectrum of Pediatric NTRK-rearranged Mesenchymal Tumors. | Davis JL et al |
| 24 | 38332737 | 2024 | Comprehensive clinicopathological, molecular, and methylation analysis of mesenchymal tumors with NTRK and other kinase gene aberrations. | Klubíčková N et al |
| 25 | 32278476 | 2020 | NTRK-rearranged mesenchymal tumours: diagnostic challenges, morphological patterns and proposed testing algorithm. | Wong DD et al |
| 26 | 34958503 | 2022 | Mesenchymal neoplasms with NTRK and other kinase gene alterations. | Davis JL et al |
| 27 | 27259011 | 2016 | Recurrent NTRK1 Gene Fusions Define a Novel Subset of Locally Aggressive Lipofibromatosis-like Neural Tumors. | Agaram NP et al |
| 28 | 30276917 | 2018 | A novel group of spindle cell tumors defined by S100 and CD34 co-expression shows recurrent fusions involving RAF1, BRAF, and NTRK1/2 genes. | Suurmeijer AJH et al |
| 29 | 24299451 | 2014 | Atypical fibroxanthoma arising in a young patient with Li-Fraumeni syndrome. | Lee SM et al |
| 30 | 27046537 | 2016 | Atypical Fibroxanthoma in a 13-Year-Old Guatemalan Girl with Xeroderma Pigmentosum. | Chappell AG et al |
| 31 | 34202213 | 2021 | Clinicopathological and Genomic Profiles of Atypical Fibroxanthoma and Pleomorphic Dermal Sarcoma Identify Overlapping Signatures with a High Mutational Burden. | Ak M et al |
| 32 | 35713642 | 2022 | Superficial CD34-Positive Fibroblastic Tumor: A Clinicopathologic, Immunohistochemical, and Molecular Study of 59 Cases. | Anderson WJ et al |
| 33 | 34969957 | 2022 | Overlapping morphological, immunohistochemical and genetic features of superficial CD34-positive fibroblastic tumor and PRDM10-rearranged soft tissue tumor. | Puls F et al |
| 34 | 38278599 | 2024 | Superficial CD34-Positive Fibroblastic Tumor. | Perret R et al |
| 35 | 29312620 | 2017 | Copy number variations in atypical fibroxanthomas and pleomorphic dermal sarcomas. | Helbig D et al |
| 36 | 38278604 | 2024 | Pleomorphic Dermal Sarcoma. | Saleh JS et al |
| 37 | 26645461 | 2016 | Epithelioid Sarcoma: Diagnostic Features and Genetics. | Thway K et al |
| 38 | 35993578 | 2022 | Cutaneous Melanocytic Tumor With CRTC1::TRIM11 Translocation : An Emerging Entity Analyzed in a Series of 41 Cases. | Hanna J et al |
| 39 | 40857736 | 2025 | CRTC1::TRIM11 Cutaneous Tumor Mimicking Primary Dermal Melanoma: Case Report With Literature Review. | Hirai I et al |
| 40 | 40772495 | 2025 | Is TRIM11 Immunohistochemical Positivity Specific for the Diagnosis of CRTC1::TRIM11 Cutaneous Tumors? | Chen S et al |
| 41 | 36177516 | 2023 | Cutaneous melanocytic tumour with CRTC1::TRIM11 fusion in a case with recurrent local lymph node and distant pulmonary metastases at early stage: aggressive rather than indolent? | Yang L et al |
| 42 | 37944913 | 2024 | CRTC1::TRIM11 cutaneous tumor: An update with local recurrence and lung metastasis in a pediatric patient. | Vest BE et al |
| 43 | 40452552 | 2025 | Malignant CRTC1::TRIM11 Cutaneous Tumor With Lethal Outcome: Histopathologic and Molecular Findings. | Beatson ME et al |
| 44 | 32157275 | 2020 | Primary Cutaneous Clear Cell Sarcoma, Clinical Outcome With Sentinel Lymph Nodes Status. | Alhatem A et al |
| 45 | 31305268 | 2019 | Expanding the Phenotypic Spectrum of Mesenchymal Tumors Harboring the EWSR1-CREM Fusion. | Yoshida A et al |
| 46 | 39420989 | 2024 | Dermal cutaneous clear cell sarcoma defined by novel EWSR1-CREM fusion. | Hornback CJ et al |
| 47 | 37093679 | 2023 | Clinical characteristics of primary cutaneous and subcutaneous Ewing sarcoma. | Aiba H et al |
| 48 | 38866368 | 2024 | Superficial Neurocristic EWSR1::FLI1 Fusion Tumor: A Distinctive, Clinically Indolent, S100 Protein/SOX10-Positive Neoplasm. | Folpe AL et al |
| 49 | 40074591 | 2025 | Primary cutaneous/subcutaneous Ewings sarcoma. | Valentin T et al |
Citation
Paola Dal Cin, PhD
Tumors of uncertain differentiation
Atlas Genet Cytogenet Oncol Haematol. 2026-05-04
Online version: http://atlasgeneticsoncology.org/solid-tumor/209370
