Tumors of uncertain differentiation
2024-10-17 David Papke, MD , Paola Dal Cin, PhD Affiliation1.Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Keywords
mesenchymal neoplasm,sarcomaClassification
Definition
Many soft tissue tumors, mainly sarcomas, lack obvious differentiation toward a defined mesenchymal tissue type or have a phenotype that does not correspond to any defined normal tissue. Synovial sarcoma, for example, does not truly show synoviocytic differentiation, and it has no known normal tissue counterpart. Many emerging tumor types – including superficial ALK-rearranged myxoid spindle cell neoplasm, NUT-rearranged sarcoma, and pseudoendocrine sarcoma – fall into this group of tumors of uncertain nosology.1-4 The advance in molecular pathology techniques has led not only to a better understanding of the molecular pathogenesis of soft tissue neoplasms of uncertain differentiation, but also to the development of helpful diagnostic tools e.g. diagnostically useful FISH probes, surrogate immunohistochemical markers for known fusions, and the use of sequencing in diagnostic practice.
| Tumours of uncertain differentiation | Genetic event(s) |
|---|---|
| Intramuscular myxoma | GNAS mutations in exons 8 and 9, with “hotspots” at p.R201C and p.R201H, have been reported in 80-90% of sporadic cases.5 One study demonstrated that approximately 23% of myxomas carried GNAS variants in other locations other than the “hotspots".6 |
| Intramuscular myxomas have limited acquired chromosomes aberrations, mostly numerical ones with trisomy 7 and/or 8, and they have no recurrent structural alterations.6 | |
| Patients with the rare Mazabraud syndrome develop multiple fibrous dysplasias and intramuscular myxomas.7 | |
| Juxta-articular myxoma | GNAS mutations have not been detected in juxta-articular myxoma.8 A cytogenetic analysis of juxta-articular myxoma revealed two distinct cell populations with different karyotypes.9 |
| Deep (aggressive) angiomyxoma | Aggressive angiomyxoma is a soft-tissue neoplasm with a predilection for the pelvic and perineal regions and a tendency to recur locally. They harbor recurrent 12q13-15 rearrangements, as do many other mesenchymal tumor types; most breakpoints in these rearrangements are located outside of the HMGA2 gene locus, but they lead to increased expression of HMGA2 due to impaired negative regulation via its 5' regulation domain or the untranslated 3' region.10 The most frequent recurrent event is t(11;12)(q22-23;q14-15) associated HMGA2::YAP1 fusion.11 A single case was reported with del(12)(q14q23), associated with HMGA2::C12orf4.12 While a few tumors have shown 12q14-15 rearrangements, HMGA2 involvement was demonstrated either by FISH analysis or by immunohistochemistry.13,14 HMGA2 immunohistochemistry is sensitive but not specific because other vulvovaginal mesenchymal lesions also harbor HMGA2 rearrangement.15 |
| Atypical fibroxanthoma (AFX) | Atypical fibroxanthomas show recurrent mutations in FAT1, NOTCH1/2, CDKN2A, TP53, and the TERT promoter, and they show a range of DNA copy number alterations including losses of 9p and 13q.16,17 |
| Pleomorphic dermal sarcoma (PDS) | Pleomorphic dermal sarcoma (PDS) is another tumor type arising in sun-damaged skin of elderly patients, and it is on a genetic spectrum with AFX.16,18 However, PDS shows invasion into subcutis, and in contrast to AFX it has metastatic potential. |
| Angiomatoid fibrous histiocytoma (AFH) | Uncommon neoplasms of intermediate malignancy charactrerized by t(2;22)(q33;q12)/EWSR1::CREB1 fusion in most cases. Less commonly, it harbors t(12;22)(q12;q12)/EWSR1::ATF1, and, rarely, t(12;16) (q12;p11)/FUS::ATF1 fusions.19 |
| ALK expression by immunohistochemistry (IHC) has been reported in most AFH, but it is not secondary to ALK rearrangement or copy number gain.20 Durable response to crizotinib was reported in metastatic AFH with EWSR1::CREB1 fusion and ALK overexpression.21 | |
| Intracranial myxoid mesenchymal tumors and AFH-like neoplasms carry fusions involving FET family genes, usually EWSR1 but also rarely FUS, to a CREB family transcription factor (ATF1, CREB1, or CREM).22 | |
| Both EWSR1::ATF1 and FUS::ATF1 fusions are promiscuous alterations that drive multiple mesenchymal tumor types.23,24 | |
| Ossifying fibromyxoid tumor (OFMT) | PHF1 rearrangement drives 80% of benign, atypical, and malignant lesions. Several partners genes have been identified. EP400 is the most common, followed by MEAF6 and EPC1. PHF1::TFE3 fusion occurs in a small subset, with PHF1 being the 5′ partner gene instead of the 3' partner, in both typical and malignant OFMT.25 |
| Other fusions are less frequently identified in OFMT, including ZC3H7B::BCOR, CREBBP::SKOR1, and KDM2A::WWTR1.26 Some of these fusions are also described in endometrial stromal sarcoma.27 These gene fusions not involving PHF1 correlate with aggressive behavior, as do those with TFE3.26 | |
| Both typical and malignant OFMTs show upregulation of EATT4 and MUC4, whereas they exhibit downregulation of MYEF2 and PMP22.28 | |
| Benign and malignant myoepithelial neoplasms of the soft tissue | Myoepithelial tumors (METs) are tumors that recapitulate the myoepithelial cells of salivary glands and represent a clinicopathologically heterogeneous group of tumors, ranging from benign (myoepithelioma and mixed tumor) to aggressive (myoepithelial carcinoma).29 |
| Genetically, myoepithelial tumor of the soft tissue represent a heterogenous group. Most METs, including both benign and malignant neoplasms, carry EWSR1 rearrangements with a large number of fusion partners so far desrcibed, e.g. POU5F1, PBX1, ZNF44, ATF1, PBX3, KLF15, VGLL1, and KLF17.29 In a minority, there are instead FUS fusions with a few gene partners identified so far, e.g. KLF17 and POU5F1. There are distinctive morphologic features associated with some of the specific fusions.30 A subset of myoepithelial carcinomas harbor SMARCB1 homozygous deletions.31 Some mixed tumors of soft tissue (and also of the skin) harbor PLAG1 gene rearrangement.32 | |
| Pleomorphic hyalinixing angiectatic tumor (PHAT) | der(10)t(1;10)(p22;q24) was initally observed in a single case with well-documented features of both classical PHAT and hemosiderotic fibrolipomatous tumor HFLT.33 Then rearrangements of the genes TGFBR3 at 1p22 and/or OGA at 10q24 were detected by FISH in 60% of PHAT, strictly defined as lesions showing features of both HFLT and classical PHAT, and in variable percentages of HFLT, myxoinflammatory fibroblastic sarcoma (MIFS), and hybrid MIFS/HFLT.34 |
| Targeted RNAsequencing identified FBXW4 (mapping 11 kb centromeric of OGA instead of MGEA5 as fusion partner of TGFBR3 in a single case of PHAT.35 | |
| The same balanced/unbalanced t(1;10)(p22;q24) has been detected in a subset of PHAT/HFLT hybrid cases, HFLT, myxoinflammatory fibroblastic sarcoma (MIFS), and HFLT/MIFS hybrid cases with differnt prevalence among different studies.36 | |
| Hemosiderotic fibrolipomatous tumor(HFLT) | A reciprocal t(1;10)(p22;q24) associated with TGFBR3::OGA fusion, as well as common amplifications on 3p11.1-12.1 region, usually in the form of marker or ring chromosome, are a charracteristic finding in HFLT.37 Tumors showing hybrid HFLT/MIFS morphology commonly also show TGFBR3 and/or OGA rearrangements as result of t(1;10)(p22;q24), while classic MIFS lacking areas resembling HFLT showed a very low frequency of such rearrangements.38,39 |
| HFLT harbors frequent amplification of VGLL3 but not BRAF rearrangement.40 | |
| Phosphaturic mesenchymal tumor (PMT) | Phosphaturic mesenchymal tumors are neoplasms associated with tumor-induced osteomalacia through overproduction of FGF23, a phosphaturic hormone. Most show FN1::FGFR1 fusion leading to overexpression of the 3′ FGFR1, and rarely they instead show FN1::FGF1.41 Recent RNA-sequencing revealed that 1) the FN1::FGFR1 breakpoints fusions were diverse; 2) there was also the reciprocal FN1::FGFR1 fusion in some cases; 3) new FGFR1 partner genes e.g. USP33 and TLN1; and 4) other novel fusions were identified.42 |
| pan-FGFR inhibitor drugs are a new treatment option for tumor-induced osteomalacia.43 | |
| The non-phosphaturic variant of PMT can harbor both FGF23 mRNA expression and its characteristic FN1::FGFR1 fusion.44 | |
| NTRK rerranged spindle cell neoplasms (SCN) | NTRK gene fusions involving either NTRK1, NTRK3, or, less frequently, NTRK2 are oncogenic drivers of various adult and pediatric tumour types of different lineages. The fusions typically occur in a mutually exclusive fashion, and the distribution and frequency in adult and pediatric tumors vary from low frequencies (commonly <1%) in a range of common tumor types and to at high frequencies (up to or greater than 90%) in rare cancer types. The presence of NTRK1 gene fusion is associated, in some types of neoplasia, with a favorable evolution, but the presence of NTRK2 may be associated with a poor prognosis.45 Somatic point mutations or amplification in the NTRK genes have been also identified, but so far they have not been shown to drive oncogenesis.46 |
| NTRK fusions have been associated with a wide clinicopathologic spectrum of soft tissue tumors types, ranging from benign to aggressive. Loss of CDKN2A also seems common in NTRK-rearranged spindle cell neoplasms, usually secondary to 9p deletions,47-49 although it is not clearly associated with malignancy based on published data so far. Other kinase fusions involving ALK, BRAF, RAF1, and RET drive tumors that are in the same clincopathologic spectrum as NTRK-SCN.47,50,51 Most reported NTRK-SCN show NTRK1 gene fusions, with various partners, and are characterized by spindle cell morphology. NTRK3 gene fusions have been described in sarcomas, some with fibrosarcoma-like morphollogy, presenting as high-grade sarcoma.52 NTRK-SCN were listed within the myofibroblastic/fibroblastic category in the 2022 WHO classification of pediatric tumors. | |
| Over 75% of NTRK fusion-positive cancers repond to first-generation TRK inhibitors, such as larotrectinib or entrectinib, regardless of tumour histology. Advanced-stage NTRK fusion-positive cancers eventually acquired resistance mediated by the acquisition of NTRK kinase domain mutations, as in other tyrosine kinase-altered tumors.46,53 | |
| Synovial sarcoma (SS) | Synovial sarcomas harbor a highly specific, usually balanced and reciprocal t(X;18)(p11.2;q11.2), which fuses SS18 either with SSX1 or with SSX2 in more than 95% of cases and in all morphologic subtypes. Molecular variants involving SSX4 and SS18L1 are very rare.54 Approximately two-thirds of synovial sarcomas harbor SS18::SSX1 (enriched for biphasic morphology), and one-third harbor SS18::SSX2 fusions (almost all lacking glandular differention).55 Data suggest that the specific fusion type does not have prognostic value.56 |
| Although highly specific, RT-PCR and SS18 break-apart FISH analyses are imperfect, and rare tumor with typical synovial sarcoma morphology but lacking SS18-SSX fusions could harbor unusual variant transcripts, which cannot be detected using routine molecular techniques.57. Highly sensitive immunohistochemistry (IHC) antibodies spesific for the SS18-SSX fusion sequence or forthe SSX C-terminus were recently introduced as a surrogate for FISH or other molecular testing.58 | |
| Losses and gains (e.g. chr. 8, 12q) of chromosomal segments have been reported in addition to the SS18::SSX2 fusion, as well as few non-recurrent mutations, affecting oncogenes and tumor suppressor genes such as TP53, HRAS and PTEN.59 | |
| Recently other variant SS fusions were reported: EWSR1::SSX1 fusion in 3 cases and a single case harboring MN1::SSX1 fusion.60 SS18::NEDD4 has been reported in primary renal synovial sarcoma.61 | |
| In addition new SS18 fusions were identified in a novel sarcoma type with CRTC1::SS18.62 MEF2C::SS18 was described in secretory adenocarcinoma salivary gland.63 SS18::NEDD4 was descdribed in a malignant cutaneous sarcoma that resembled epithelioid sarcoma;64 SS18::POU5F1 in undifferentiated round cell sarcoma;65 and GREB1::SS18 in uterine sarcoma.66 | |
| Epithelioid sarcoma (ES) | Initially deletion and rearrangement events involving the 22q11.2 locus were reported in ES by cytogenetic analysis. Then loss of INI1 protein expression was observed in several cases of ES using immunohistochemistry.67 Both classic and proximal type ES lose INI1 function due to the homozygous deletion of tumor supressor gene SMARCB1, bi- or single-allelic deletions, point mutations, or epigenetic mechanisms.68,69 Because of the close proximity of SMARCB1 and EWSR1 on 22q11.2, larger SMARCB1 deletions may encompass the EWSR1 locus and may therefore be misinterpreted as EWSR1 rearrangement.70 |
| Because ES is a member of the SMARCB1/INI1‐deficient tumor family,71,72 tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma.73 | |
| Alveolar of soft part sarcoma (ASPS) | The unbalanced translocation der(17)t(X;17)(p11:q25) is associated with ASPSCR1::TFE3.74,75 Other reported TFE3 gene partners are HNRNPH3, DVL2 and PRCC.76 |
| Both TFE3 immunostaining and FISH analysis are diagnostically useful but non-specific, because other TFE3-rearranged neoplasms can be in the differential diagnosis, especially PEComa.77 | |
| The association between sex and prognosis remains controversial.78 Atezolizumab is an anti-programmed death-ligand 1 (PD-L1) monoclonal antibody and is the first systemic therapy approved for unresectable ASPS.79 | |
| Clear cell sarcoma of the soft tissue (CCS) | Most clear cell sarcomas, previously designated as “melanoma of the soft parts”, harbor t(12;22)(q13;q12) associated with EWSR1::ATF1 fusion. A small porportion instead show t(2;22)(q34;q12) associated with EWSR1::CREB1 fusion.80 FISH analysis for EWSR1 is crucial to distinguish CCS from melanoma.81 |
| EWSR1::ATF1 and EWSR1::CREB1 fusions are associated with several other tumor types, with variable behavior and prognosis, including angiomatoid fibrous histiocytoma, myoepithelial neoplasms, hyalinizing clear cell carcinoma, clear cell odontogenic carcinoma, mesothelioma, and intracranial myxoid mesenchymal tumors.23,82 | |
| Malignant gastrointestinal neuroectodermal tumor (GNET), also known as clear cell sarcoma-like tumor of gastrointestinal tract, similarly harbors EWSR1::CREB1 and, rarely, EWSR1::ATF1 fusions. However, in contrast to clear cell sarcoma, it lacks expression of secondary melanocytic proteins HMB45 and melan-A, and it shows much more aggressive clinical behavior.83 | |
| Extraskeletal myxoid chondrosarcoma (EMC) | EMC is chracaterized by several chromosomal translocations involving the NR4A3 gene at 9q22. The most frequent translocation is t(9;22) (q22;q12) associated with EWSR1::NR4A3. Less commonly, it shows t(9;17)(q22; q11),t(9;15)(q22;q21) or t(3;9)(q12;q22) translocations fusing NR4A3 with TAF15, TCF12, and TFG, respectively. The non-EWSR1::NR4A3 EMCs are associated with higher-grade histology and larger tumor size.84 Other rare fusion partners have been reported,85 including FUS.86 |
| Occasionally, in the absence of NR4A3 fusion transcripts, truncating mutations, homozygous deletion or microdeletions in SMARCB1 have been reported.87 | |
| KIT mutation has been reported to co-occur with NR4A3 rearrangement. Imatinib tratement provided a strong and sustained treatment response in such a case.88 | |
| Desmoplastic small round cell tumour (DSRCT) | DSRCT is an aggressive round cell tumor that mostly occurs in children and young adults. It often presents with widespread abdominal disease, and it shows a male predominance. DSRCT as a genomically quiet cancer defined by a balanced t(11;22)(p13:q12) associated with EWSR1::WT1 fusion, with a paucity of secondary mutations; recurrent alterations include mutations to FGFR4, ARID1A, TP53, TERT, MSH3, and KMT2C, and recurrent loss of heterozygosity (LOH) at 11p, 11q, and 16q.89 |
| A few non-DSRCT tumors carrying a EWSR1::WT1 fusion have been reported, mainly arising in and outside of the the female genital tract.90 | |
| Extrarenal rhabdoid tumor (ERT) | ERT mainly affects infants and children, and it is morphologically and genetically identical to those occuring in the kidney and brain; regardless of primary tumor location, ERT has a dismal prognosis.91 The majority of ERTs are sporadic and arise de novo as a consequence of homozygous loss of SMARCB1 caused by deletions, unbalanced 22q11.2 translocations, or monosomy 22 with a somatic mutation on the other allele.92 Rare mutations/deletion of SMARCA4 at 19p13 can ocurr.93 |
| Loss of SMARCB1 expression by IHC is highly sensitive for diagnosis, but it is not specific, because there are other tumor types driven by SMARCB1 inactivation.71,72 | |
| Among patients newly diagnosed with ERT, 25–30% have a SMARCB1 germline alteration that predisposed them to rhabdoid tumor and schwannomatosis: rhabdoid tumor predisposition syndrome (RTPS1) OMIM:609322 and rarely RTPS2 (omin:613325}. The spectrum of germline mutations is similar to somatic mutations, and missense mutations are almost never identified. In most cases with germline mutations, the germline sequences of the parents are normal.94,95 | |
| PEComa | There is a large category of rare neoplasms throughout the body that are now classified under the umbrella term “PEComa,” including angiomyolipoma and lymphangioleiomyomatosis.96 Most soft tissue PEComas are sporadic. The loss of heterozygosity (LOH) of TSC1 or TSC2 is detected in PEComas arising in patients with tuberous sclerosis complex (TSC), an autosomal dominant genetic disorder caused by germline mutations in either TSC1 OMIM:191100 or TSC2 OMIM:191092.96 The activation of the mTOR pathway by these TSC1-2 alterations has been targeted therapeutically with mTOR inhibitors.97 TSC2 alterations are mainly seen in sporadic PEComas, with concurrent TP53 mutations in malignant tumors.98 |
| A subset of PEComa carries TFE3 fusions with SFPQ, DVL2, NONO, and ASPSCR1,99,100 and these PEComas lack TSC2 alterations.98 So far, a single aggressive PEComa demonstrated a heterozygous germline TSC1 deletion with concomitant TFE3 activation via a large 36 Mbp region gain encompassing TFE3, and coexistent TP53 mutation.101 | |
| Both TFE3 immunostaining and FISH analysis are useful in diagnosis, but not specific because of other TFE3-rearranged neoplasms, especially alveolar soft part sarcoma, show morphologic overlap with TFE3-rearranged PEComa.77 | |
| Intimal sarcoma | Intimal sarcoma is an exceedingly rare, highly aggressive undifferentiated sarcoma that arises in the pulmonary artery and less frequently in the aorta or its branches. It harbors complex structural rearrangements with a high frequency of MDM2 amplification, with CDK4 co-amplification and frequent PDGFRA amplification. Additional aberrations include: EGFR and NOTCH2 gains; CDKN2A/CDKN2B loss; ATM, PTCH1, and PDGFRB mutations; and PDE4DIP::NOTCH2 and MRPS30::ARID2 fusions.102-104 |
| Koyama and colleagues reported on the safety and activity of milademetan, another MDM2–p53 antagonist, in patients with intimal sarcoma.105 | |
| Undifferentiated pleomorphic sarcoma (UPS) of soft tissue | UPS is a diagnosis of exclusion. UPS shows genomic complexity such as whole genome doubling (WGD) and chromothripsis resulting in aneuploidy, loss of heterozygosity (LOH), and numerous genomic rearrangements.106 One of the key morphological features of UPS is the presence of large cells with cytologically atypical nuclei, suggesting aneuploidy, i.e. the presence of abnormal numbers of chromosomes and consequently DNA content, strongly associated with TP53 mutations as an early event. UPS frequently harbors disruptive rearrangements (chromothrypsis) in the tumour suppressor genes TP53, ATRX, and RB1. |
| Besides WGD and chromothripsis, a distinctive genomic phenotype seen in UPS is the presence of genome-wide LOH that suggests a near-haploid precursor to the tumour. Two tumor supressor genes RB1 and CDKN2A are mutated, mainly through deep deletions in a mutually exclusive manner, in UPS, with RB1 being more commonly altered. Other aberrations include: loss-of-function mutations or deletions of PTEN; recurrent amplifications of chromosome 3p and11q, in which regions VGLL3 and YAP1 are found, respectively; recurrent complex structural rearrangements of 5p15.33 band, proximal to TERT, e.g. TRIO::TERT, and rarely TERT mutations. |
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Citation
David Papke, MD ; Paola Dal Cin, PhD
Tumors of uncertain differentiation
Atlas Genet Cytogenet Oncol Haematol. 2024-10-17
Online version: http://atlasgeneticsoncology.org/solid-tumor/209276/tumors-of-uncertain-differentiation
