ABSTRACT
Undifferentiated round cell sarcomas (URCS) represent a diverse group of tumors, including conventional Ewing sarcoma, round cell sarcoma with EWSR1/FUS-non-ETS fusions, CIC-rearranged sarcoma, and sarcoma with BCOR alterations. Since 2018, 3 cases of URCS with a novel CRTC1::SS18 gene fusion have been reported in the literature. Herein, we report 3 additional cases of CRTC1::SS18 sarcoma, thereby doubling the number of described cases and expanding the clinicopathologic features of this rare translocation sarcoma. Together with the previously reported cases, we show that the male-to-female ratio is 1:2 with a median age of 34 years (range, 12-42 years). Tumors occurred primarily in intramuscular locations involving the lower extremity. Histologically, all tumors contained uniform round-to-epithelioid cells with a moderate amount of eosinophilic cytoplasm growing in sheets and nests with prominent desmoplastic stroma reminiscent of desmoplastic small round cell tumor. Immunohistochemical results were nonspecific, demonstrating variable expression of CD99 (patchy), ALK, GATA3, and cyclin D1. RNA sequencing revealed CRTC1::SS18 gene fusions in all cases, involving exons 1 to 2 of CRTC1 (the 5' partner gene) on chromosome 19 and either exon 2 or exon 4 of SS18 (the 3' partner gene) on chromosome 18. The clinical course was variable. Although 1 previously reported case demonstrated aggressive behavior with a fatal outcome, 2 others had a relatively indolent course with gradual growth for 6 to 7 years prior to resection. Two cases developed metastatic disease, including 1 case with bilateral lung metastasis and 1 with locoregional spread to a lymph node. By analyzing the clinicopathologic features, we aimed to improve recognition of this rare translocation sarcoma to better understand its biologic potential, optimize patient management, and expand the current classification of URCS.
ABSTRACT
The calcified chondroid mesenchymal neoplasm (CCMN) represents a recently recognized tumor type with only 50 well-documented cases in the English-language literature. Herein we report an additional case of CCMN presenting as a large mass in the temporomandibular joint region of a 41-year-old female. A review of previously reported cases and the current case of CCMN shows the following features: 1) average age 52 years (range 14-87 years) and an approximately even sex distribution; 2) most frequently involved sites: distal extremities (including foot, hand, wrist, forearm) (n=41) and temporomandibular joint/temporal/parotid region (n=9); 3) multilobular soft tissue tumor with chondroid to cartilaginous matrix, often grungy or lace-like calcifications, and variable cytologic atypia; 4) frequently detected FN1 rearrangement (n=15), including FN1 fusion with FGFR2 (n=7) or other receptor tyrosine kinases; 5) 2 reported local recurrences (after incomplete excision); 6) no reports of malignant biologic behavior.
Subject(s)
Calcinosis , Neoplasms , Adult , Female , Humans , Calcinosis/pathology , Calcinosis/diagnostic imaging , Calcinosis/surgery , Diagnosis, Differential , Temporomandibular Joint Disorders/pathology , Temporomandibular Joint Disorders/diagnostic imaging , Temporomandibular Joint Disorders/surgery , Neoplasms/diagnosis , Neoplasms/pathology , Neoplasms/therapyABSTRACT
Recurrent gene rearrangements result in gene fusions that encode chimeric proteins, driving the pathogenesis of many hematologic neoplasms. The fifth edition World Health Organization classification and International Consensus Classification 2022 include an expanding list of entities defined by such gene rearrangements. Therefore, sensitive and rapid methods are needed to identify a broad range of gene fusions for precise diagnosis and prognostication. In this study, we validated the FusionPlex Pan-Heme panel analysis using anchored multiplex PCR/targeted RNA next-generation sequencing for routine clinical testing. Furthermore, we assessed its utility in detecting gene fusions in myeloid and lymphoid neoplasms. The validation cohort of 61 cases demonstrated good concordance between the FusionPlex Pan-Heme panel and other methods, including chromosome analysis, fluorescence in situ hybridization, RT-PCR, and Sanger sequencing, with an analytic sensitivity and specificity of 95% and 100%, respectively. In an independent cohort of 28 patients indicated for FusionPlex testing, gene fusions were detected in 21 patients. The FusionPlex Pan-Heme panel analysis reliably detected fusion partners and patient-specific fusion sequences, allowing accurate classification of hematologic neoplasms and the discovery of new fusion partners, contributing to a better understanding of the pathogenesis of the diseases.
Subject(s)
Hematologic Neoplasms , Neoplasms , Humans , In Situ Hybridization, Fluorescence , Hematologic Neoplasms/diagnosis , Hematologic Neoplasms/genetics , Base Sequence , Gene Fusion , Sequence Analysis, RNA/methods , High-Throughput Nucleotide Sequencing/methods , Heme , Oncogene Proteins, Fusion/genetics , Neoplasms/geneticsABSTRACT
Ewing sarcoma is a small round blue cell tumor typically characterized by an EWSR1 rearrangement and expression of CD99 and NKX2.2, without expression of hematopoietic markers such as CD45. CD43 is an alternative hematopoietic immunohistochemical marker often utilized in the workup of these tumors and its expression typically argues against Ewing sarcoma. We report a 10-year-old with history of B-cell acute lymphoblastic leukemia presenting with an unusual malignant shoulder mass with variable CD43 positivity, but with an EWSR1::FLI1 fusion detected by RNA sequencing. Her challenging workup highlights the utility of next-generation DNA-based and RNA-based sequencing methods in cases with unclear or conflicting immunohistochemical results.
Subject(s)
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Sarcoma, Ewing , Sarcoma , Soft Tissue Neoplasms , Female , Humans , Child , Sarcoma, Ewing/pathology , Immunohistochemistry , RNA-Binding Protein EWS/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Biomarkers, Tumor/geneticsABSTRACT
Treatments for adults with newly-diagnosed acute lymphoblastic leukemia (ALL) may be prohibitively toxic and/or resource-intense. To address this, we performed a phase II study of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH). Imatinib or dasatinib was added for Ph + disease; rituximab was added when CD20+. Fifty-three patients were evaluable: 28 with Ph + disease, and 25 with Ph-. All patients had ≥1 high-risk clinical feature. Measurable residual disease-negativity by multiparameter flow cytometry within 4 cycles was achieved in 71% in patients with Ph + ALL and 64% in Ph - ALL. Median overall survival (OS) was 49 months, with a 2-year OS of 71%. Median relapse-free survival (RFS) in the 47 patients that attained morphologic remission was 24 months, with a 2-year RFS of 57%. Early mortality was 2%. In summary, DA-EPOCH yields deep and durable remissions in adults with ALL comparable to some resource-intense strategies but with a low rate of treatment-related death.
Subject(s)
Doxorubicin , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Adult , Humans , Vincristine/adverse effects , Prednisone/adverse effects , Etoposide/adverse effects , Cyclophosphamide/adverse effects , Doxorubicin/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Rituximab/adverse effectsABSTRACT
Although well known as a fusion partner in hematological malignancies, fusion genes involving the ABL proto-oncogene 1 (ABL1), mapping to chromosomal region 9q34.12, have only been anecdotally reported in five soft tissue tumors. These neoplasms have been variously reported as perineurioma, angiofibroma, and solitary fibrous tumor, and all have harbored a GAB1::ABL1 gene fusion; however, the nosology and clinicopathological characteristics of soft tissue tumors carrying this rare fusion have not been delineated. We herein describe eight tumors containing the GAB1::ABL1 fusion and review previously reported cases in a series to define their morphological spectrum, address immunohistochemical evidence for a line of differentiation, with special reference to the presence or absence of a perineurial immunophenotype, and gather insight into their behavior. The patients included four females and four males, aged 13-37 years (median, 24 years). Two cases each originated in the shoulder area, trunk, hands, and lower extremities, with a size range of 1.5-8 cm (median, 3.4 cm). Four tumors were deep and four superficial. All tumors were morphologically similar, being composed of bland fibroblast-like spindle to ovoid cells diffusely arranged in a paucivascular fibrous to fibromyxoid stroma with variable resemblance to soft tissue perineurioma. Mitotic activity was generally low (0-8 mitoses in 10 high-power fields [HPFs]; median, 1). All lesions had at least focally infiltrative margins, but they otherwise lacked pleomorphism and necrosis. Immunohistochemistry showed focal reactivity for CD34 (5/7), epithelial membrane antigen (EMA) (3/8), claudin1 (2/3), GLUT1 (4/6), and S100 (2/7); other markers, including MUC4 (0/7), desmin (0/9), and smooth muscle actin (SMA) (0/4), were negative. RNA sequencing revealed a GAB1::ABL1 fusion in all cases with exon 6 of GAB1 fused to exon 2 of ABL1. Treatments included various forms of surgical intervention in seven cases; one tumor was biopsied only. Limited follow-up was available for five patients. One tumor regrew rapidly within 1 month to 1.5 cm after an initial marginal excision and was re-excised with close margins. Four patients were disease-free at 1, 3, 14, and 25 months of follow-up. Metastases have not, to date, been observed. This series characterizes "GAB1::ABL1 fusion-positive spindle cell neoplasm" as a distinct entity, with overlapping features with soft tissue perineurioma and predilection for children and young adults.
Subject(s)
Nerve Sheath Neoplasms , Soft Tissue Neoplasms , Female , Humans , Male , Young Adult , Adaptor Proteins, Signal Transducing , Biomarkers, Tumor , Cell Differentiation , Fibroblasts/pathology , Nerve Sheath Neoplasms/genetics , Soft Tissue Neoplasms/pathology , Adolescent , AdultABSTRACT
BACKGROUND: Inflammatory myofibroblastic tumor (IMT) is an ultra-rare soft tissue neoplasm associated with fusion proteins encompassing the anaplastic lymphoma kinase (ALK) protein fused to a variety of partner proteins. Data regarding response to ALK-targeting agents based on fusion partner is limited. CASE: A 30-year-old female sought emergency care after onset of abdominal and lower back pain in 2019. Computed tomography (CT) demonstrated a cystic, mesenteric mass within the pelvis measuring up to 8.9 cm. Complete laparoscopic excision of the mass from the mesentery of the right colon and terminal ileum was performed. Pathologic assessment revealed IMT with a fusion between sequestosome 1 and ALK (SQSTM1::ALK), described in only two other cases of IMT. Four months after surgery, CT revealed multi-focal, unresectable disease recurrence. She was referred to the University of Washington/Fred Hutchinson Cancer Center and placed on therapy with alectinib, after which she experienced a partial response. Three years after IMT recurrence, disease remains under control. CONCLUSION: This is the third reported case of IMT associated with the novel SQSTM1::ALK fusion protein, and the second treated with alectinib. Treatment with the ALK inhibitor alectinib appears to be active in this setting.
Subject(s)
Neoplasm Recurrence, Local , Piperidines , Female , Humans , Adult , Anaplastic Lymphoma Kinase/genetics , Anaplastic Lymphoma Kinase/metabolism , Sequestosome-1 Protein/metabolismABSTRACT
HEY1-NCOA2 fusion is most described in mesenchymal chondrosarcoma. This is the first case report of a primary renal spindle cell neoplasm of uncertain malignant potential with a HEY1::NCOA2 fusion identified by Fusionplex RNA-sequencing that is histologically distinct from mesenchymal chondrosarcoma. The neoplasm was identified in a 33-year-old woman without significant past medical history who underwent partial nephrectomy for an incidentally discovered renal mass. The histologic features of the mass included spindle cells with variable cellularity and monotonous bland cytology forming vague fascicles and storiform architecture within a myxoedematous and collagenous stroma with areas of calcification. The morphologic and immunophenotypic features were not specific for any entity but were most similar to low-grade fibromyxoid sarcoma. To date, the patient has not had recurrence, and the malignant potential of the neoplasm is uncertain.
Subject(s)
Bone Neoplasms , Chondrosarcoma, Mesenchymal , Female , Humans , Adult , Bone Neoplasms/genetics , Bone Neoplasms/pathology , Chondrosarcoma, Mesenchymal/genetics , Chondrosarcoma, Mesenchymal/surgery , Chondrosarcoma, Mesenchymal/pathology , Nephrectomy , Nuclear Receptor Coactivator 2/genetics , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Basic Helix-Loop-Helix Transcription Factors/geneticsABSTRACT
We describe a case of a myoepithelial carcinoma of the superficial parotid gland in a 46-year-old male harboring a novel CTCF::NCOA2 gene fusion. To our knowledge, this novel gene fusion has not been described previously in myoepithelial carcinoma. A 46-year-old male patient presented with a mass involving the superficial left parotid gland with extension into the external auditory canal (EAC) and erosion of the conchal cartilage. Histologically, the neoplasm was composed of uniform spindled, epithelioid/ovoid cells arranged in cords and nests within hyalinized to myxoid stroma. On immunohistochemistry (IHC), the tumor cells demonstrated patchy and variable staining for low molecular weight cytokeratin (CAM5.2), pan-cytokeratin (OSCAR), and S-100. Overall, the morphological and immunohistochemical attributes supported a locally aggressive tumor of myoepithelial differentiation consistent with myoepithelial carcinoma. Molecular analysis using a custom 115-gene gene panel by targeted RNA sequencing, showed an in-frame CTCF::NCOA2 fusion. In addition to reporting this novel fusion in myoepithelial carcinoma, we also discuss relevant differential diagnosis, and provide a brief review of NCOA2 gene function in both normal and neoplastic contexts.
Subject(s)
Carcinoma , Myoepithelioma , Parotid Neoplasms , Male , Humans , Middle Aged , Parotid Gland/pathology , Parotid Neoplasms/genetics , Parotid Neoplasms/chemistry , Parotid Neoplasms/diagnosis , Carcinoma/genetics , Myoepithelioma/genetics , Myoepithelioma/pathology , Keratins/genetics , Nuclear Receptor Coactivator 2/geneticsABSTRACT
Desmoid fibromatosis (DF) is a locally aggressive soft tissue neoplasm with frequent recurrences. DF is characterized by alterations in the Wnt/ß-catenin pathway, with the majority showing sporadic mutations in CTNNB1 , whereas others have germline mutations in APC . Immunohistochemical staining for ß-catenin is often difficult to interpret and can be negative in up to 30% of cases. Prior studies have shown that some DFs lacking nuclear expression of ß-catenin may carry activating CTNNB1 mutations. Droplet digital polymerase chain reaction (ddPCR) has been used effectively in detecting mutations in formalin-fixed, paraffin-embedded (FFPE) samples of various cancer types. In this study, we assess the diagnostic utility of ddPCR to detect CTNNB1 mutations in DF with ß-catenin expression on immunohistochemistry (IHC), as well as in diagnostically challenging cases. Of the 28 DFs with nuclear ß-catenin expression by IHC, 24 cases showed a CTNNB1 mutation by ddPCR using primers against the most common point mutations in CTNNB1 . The most frequent mutation was T41A (n=14; 50%), followed by S45F (n=8; 33%) and S45P (n=3;12%). We identified 8 additional (myo)fibroblastic lesions of uncertain classification, which were negative for nuclear ß-catenin expression by IHC. We detected CTNNB1 mutations in 3 unknown lesions, including S45F (n=2) and S45P (n=1). ddPCR is a sensitive, rapid and cost-efficient methodology to detect common CTNNB1 mutations in DF, especially in diagnostically challenging cases.
Subject(s)
Fibromatosis, Aggressive , beta Catenin , Humans , beta Catenin/genetics , beta Catenin/metabolism , Fibromatosis, Aggressive/diagnosis , Fibromatosis, Aggressive/genetics , Fibromatosis, Aggressive/pathology , Mutation , Polymerase Chain Reaction , TechnologyABSTRACT
Malignant peripheral nerve sheath tumors ( MPNSTs) are aggressive tumors with poor prognosis that do not typically respond well to standard chemotherapy. Recently, point mutations involving BRAF V600E have been demonstrated in a subset of MPNST, offering the possibility of targeted treatment. However, the reported prevalence of these alterations is variable. Mutations involving NRAS, which is also involved in the MAPK/ERK pathway and amenable to targeted inhibitors, have not been well characterized in MPNST. In this study, we validated droplet digital polymerase chain reaction for the detection of BRAF V600E and NRAS Q61 mutations and evaluate the prevalence of BRAF V600E and NRAS Q61 mutations in 79 cases of MPNST, including 45 sporadic, 27 NF-1 associated, and 7 radiation-associated tumors. We detected actionable BRAF or NRAS mutations in 3 of 44 sporadic MPNSTs (6.8%), including 2 BRAF V600 and 1 NRAS Q61 mutations, as well as 1 NRAS Q61 mutation in a tumor that was ultimately considered to represent melanoma. These 3 cases with positive mutations were exclusively in sporadic, high-grade MPNST (FNCLCC grade 3 of 3), with a prevalence of 11.5% in this group (3.8% NRAS Q61 mutations and 7.7% BRAF V600 mutations). None of the tumors associated with NF-1 or prior radiation had detectable mutations in the genes tested. Overall, the prevalence of these alterations offers the possibility of targeted therapy in this aggressive type of sarcoma and suggests the potential benefit of routine clinical testing.
Subject(s)
Neurofibrosarcoma , Humans , Prevalence , Proto-Oncogene Proteins B-raf/genetics , Polymerase Chain Reaction , Mutation , Membrane Proteins/genetics , GTP Phosphohydrolases/geneticsABSTRACT
In this study, we present two extra-renal pediatric spindle cell neoplasms with epidermal growth factor receptor (EGFR) internal tandem duplications (ITD). Histologically, these tumors demonstrated the same histologic features seen in other tyrosine kinase-altered spindle cell neoplasms, with one case showing abundant adipose tissue with cellular fibrous septae resembling lipofibromatosis and the other case showing fascicles of spindled cells resembling infantile fibrosarcoma. There was variable expression of CD34, S100, and SMA, and all cases were negative for panTRK. This case series adds to our molecular understanding of the spectrum of tyrosine kinase-altered spindle cell neoplasms and represents the first reported examples of EGFR ITDs in extra-renal tumors. The presence of EGFR alterations in the absence of gene fusions represents a potential therapeutic target and necessitates a broader testing panel for this group of tumors.
Subject(s)
Fibrosarcoma , Soft Tissue Neoplasms , Child , ErbB Receptors/genetics , Fibrosarcoma/pathology , Gene Fusion , Humans , Protein-Tyrosine Kinases/genetics , Soft Tissue Neoplasms/geneticsABSTRACT
Solitary fibrous tumors are mesenchymal fibroblastic tumors that were originally described as intrathoracic lesions but have since been found to occur in many other locations. They may rarely occur as paratesticular masses. Here we present a peculiar case of a solitary fibrous tumor arising in the paratesticular region and exhibiting leiomyoma-like morphology. Confirmation of the tumor as a solitary fibrous tumor was achieved by RNA sequencing showing NAB2::STAT6 fusion. Possible explanations for the unusual tumor morphology include entrapment of normal smooth muscle elements and tumor differentiation into smooth muscle type cells.
Subject(s)
Genital Neoplasms, Male , Leiomyoma , Solitary Fibrous Tumors , Male , Humans , Biomarkers, Tumor/genetics , Solitary Fibrous Tumors/pathology , STAT6 Transcription Factor/genetics , Sequence Analysis, RNA , Leiomyoma/diagnosisABSTRACT
AIMS: Recurrent alterations in receptor tyrosine kinase (RTK) and downstream effectors are described in infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN) and a subset of spindle cell sarcomas, provisionally designated 'NTRK-rearranged' spindle cell neoplasms. These two groups of tumours demonstrate overlapping morphologies and harbour alterations in NTRK1/2/3, RET, MET, ABL1, ROS1, RAF1 and BRAF, although their relationship is not fully elucidated. We describe herein a cohort of paediatric tumours with clinicopathological features not typical for inflammatory myofibroblastic tumour, but rather with similarities to cCMN/IFS harbouring ALK fusions. METHODS AND RESULTS: Clinicopathological features were assessed and partner agnostic targeted RNA sequencing on clinically validated platforms were performed. Tumours occurred in patients aged from 2 to 10 years (median age 2 years) with a 2:2 male to female ratio and an average size of 8.4 cm. Two tumours arose in soft tissues and two in the kidney. Morphological features included spindle to ovoid cells arranged in long fascicles or haphazardly within a myxoid to collagenised stroma; a subset of cases had either dilated, ectatic vessels or focal perivascular hyalinosis. By immunohistochemistry, all cases tested showed cytoplasmic expression of anaplastic lymphoma kinase (ALK) and one case demonstrated co-expression of CD34 and S100. CONCLUSIONS: This series of ALK-rearranged IFS-like tumours expands the spectrum of targetable kinases altered in these tumours and reinforces the potential overlap between IFS/cCMN-like tumours and the provisional entity of 'NTRK-rearranged' spindle cell neoplasms.
Subject(s)
Anaplastic Lymphoma Kinase/genetics , Fibrosarcoma/genetics , Gene Rearrangement , Kidney Neoplasms/genetics , Sarcoma/genetics , Soft Tissue Neoplasms/genetics , Child , Child, Preschool , Female , Humans , MaleABSTRACT
OBJECTIVES/HYPOTHESIS: The diffuse sclerosing variant of papillary thyroid carcinoma (DSV) may be more aggressive than conventional well-differentiated non-DSV related papillary thyroid carcinomas (N-PTC). STUDY DESIGN: Retrospective chart review. METHODS: Retrospective review of clinical outcomes for patients 21 years of age or younger who underwent initial surgery for PTC at a single institution from January 1, 2005 to April 1, 2020. Genomic analysis was performed using targeted next-generation sequencing. Data were analyzed using Fischer's exact test and Kaplan-Meier curve log-rank test. RESULTS: Our cohort consisted of 72 patients, nine with DSV and 63 with N-PTC. Age at diagnosis was comparable (15.4 vs. 16.2 years, respectively, P = .46). DSV were more likely to be in the high-risk American Thyroid Academy pediatric risk group (100% vs. 41.3%, P = .004), to present with regional cervical lymph node metastases (100% vs. 60.3%, P = .036), and to present with distant metastases (67% vs. 22%, P = .005). No mortality seen in either group over 27.5 (interquartile range 14.8, 46.00) months average follow-up. Throughout the follow-up period, DSV were more likely to experience progression than N-PTC (hazard ratio = 5.7 [95% confidence interval 1.7-20.0; P = .0056]). In a subset of 19 patients with aggressive disease who had molecular testing as part of clinical care we detected RET fusions in nearly all DSV compared to a minority of N-PTC (83% vs. 15.4%, P = .0095). CONCLUSIONS: Pediatric patients with DSV have more advanced disease at diagnosis and are more likely to experience progression of disease compared to patients with N-PTC. The prevalence of RET fusions in our cohort recapitulates the frequency of this alteration described in prior studies. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:1132-1138, 2022.
Subject(s)
Adenocarcinoma , Carcinoma, Papillary , Thyroid Neoplasms , Child , Humans , Retrospective Studies , Thyroid Cancer, Papillary/pathology , Thyroid Cancer, Papillary/surgery , Thyroid Neoplasms/pathologyABSTRACT
Infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN) commonly harbors the classic ETV6-NTRK3 translocation. However, there are recent reports of mesenchymal tumors with IFS-like morphology harboring fusions of other receptor tyrosine kinases or downstream effectors, including NTRK1/2/3, MET, RET, and RAF1 fusions as well as one prior series with BRAF fusions. Discovery of these additional molecular drivers contributes to a more integrated diagnostic approach and presents important targets for therapy. Here we report the clinicopathologic and molecular features of 14 BRAF-altered tumors, of which 5 had BRAF point mutations and 10 harbored one or more BRAF fusions. Of the BRAF fusion-positive tumors, one harbored two BRAF fusions (FOXN3-BRAF, TRIP11-BRAF) and another harbored three unique alternative splice variants of EPB41L2-BRAF. Tumors occurred in ten males and four females, aged from birth to 32 years (median 6 months). Twelve were soft tissue based; two were visceral including one located in the kidney (cCMN). All neoplasms demonstrated ovoid to short spindle cells most frequently arranged haphazardly or in intersecting fascicles, often with collagenized stroma and a chronic inflammatory infiltrate. No specific immunophenotype was observed; expression of CD34, S100, and SMA was variable. To date, this is the largest cohort of BRAF-altered spindle cell neoplasms with IFS-like morphology, including not only seven novel BRAF fusion partners but also the first description of oncogenic BRAF point mutations in these tumors.
Subject(s)
Proto-Oncogene Proteins B-raf/genetics , Sarcoma/genetics , Sarcoma/pathology , Adolescent , Adult , Female , Fetus , Humans , Infant , Infant, Newborn , Male , Oncogene Fusion , Point MutationABSTRACT
Translocations involving FN1 have been described in a variety of neoplasms that share the presence of a cartilage matrix and may also contain a variable extent of calcification. Fusions of FN1 to FGFR1 or FGFR2 have been reported in nine soft tissue chondromas, mostly demonstrated indirectly by FISH analysis. Delineation of FN1 fusions with various partner genes will facilitate our understanding of the pathogenesis and diagnostic classification of these neoplasms. In this study, we present molecular, clinical, and pathologic features of 12 cartilaginous soft tissue neoplasms showing a predilection for the TMJ region and the distal extremities. We analyzed for gene fusions with precise breakpoints using targeted RNA-seq with a 115-gene panel. We detected gene fusions in ten cases, including three novel fusions, FN1-MERTK, FN1-NTRK1, and FN1-TEK, each in one case, recurrent FN1-FGFR2 fusion in five cases, FN1-FGFR1 in one case, and FGFR1-PLAG1 in one case. The breakpoints in the 5' partner gene FN1 ranged from exons 11-48, retaining the domains of a signal peptide, FN1, FN2, and/or FN3, while the 3' partner genes retained the transmembrane domain, tyrosine kinase (TK) domains, and/or Ig domain. The tumors are generally characterized by nodular/lobular growth of polygonal to stellate cells within a chondroid matrix, often accompanied by various patterns of calcification, resembling those described for the chondroblastoma-like variant of soft tissue chondroma. Additional histologic findings include extensive calcium pyrophosphate dihydrate deposition in two cases and features resembling tenosynovial giant cell tumor (TGCT). Overall, while the tumors from our series show significant morphologic overlap with chondroblastoma-like soft tissue chondroma, we describe findings that expand the morphologic spectrum of these neoplasms and therefore refer to them as "calcified chondroid mesenchymal neoplasms." These neoplasms represent a spectrum of chondroid/cartilage matrix-forming tumors harboring FN1-receptor TK fusions that include those classified as soft tissue chondroma as well as chondroid TGCT.
Subject(s)
Fibronectins/genetics , Neoplasms, Connective Tissue/genetics , Neoplasms, Connective Tissue/pathology , Soft Tissue Neoplasms/genetics , Soft Tissue Neoplasms/pathology , Adult , Aged , Calcinosis/genetics , Calcinosis/pathology , Female , Fibroblast Growth Factor 2/genetics , Humans , Male , Middle Aged , Oncogene Fusion/genetics , Receptor, Fibroblast Growth Factor, Type 1/genetics , Receptor, TIE-2/genetics , Receptor, trkA/genetics , c-Mer Tyrosine Kinase/geneticsABSTRACT
The knowledge of clinical features and, particularly, histopathological spectrum of EWSR1-PATZ1-rearranged spindle and round cell sarcomas (EPS) remains limited. For this reason, we report the largest clinicopathological study of EPS to date. Nine cases were collected, consisting of four males and five females ranging in age from 10 to 81 years (average: 49 years). Five tumors occurred in abdominal wall soft tissues, three in the thorax, and one in the back of the neck. Tumor sizes ranged from 2.5 to 18 cm (average 6.6 cm). Five patients had follow-up with an average of 38 months (range: 18-60 months). Two patients had no recurrence or metastasis 19 months after diagnosis. Four patients developed multifocal pleural or pulmonary metastasis and were treated variably by surgery, radiotherapy, and chemotherapy. The latter seemed to have little to no clinical benefit. One of the four patients was free of disease 60 months after diagnosis, two patients were alive with disease at 18 and 60 months, respectively. Morphologically, low, intermediate, and high-grade sarcomas composed of a variable mixture of spindled, ovoid, epithelioid, and round cells were seen. The architectural and stromal features also varied, resulting in a broad morphologic spectrum. Immunohistochemically, the following markers were most consistently expressed: S100-protein (7/9 cases), GFAP (7/8), MyoD1 (8/9), Pax-7 (4/5), desmin (7/9), and AE1/3 (4/9). By next-generation sequencing, all cases revealed EWSR1-PATZ1 gene fusion. In addition, 3/6 cases tested harbored CDKN2A deletion, while CDKN2B deletion and TP53 mutation were detected in one case each. Our findings confirm that EPS is a clinicopathologic entity, albeit with a broad morphologic spectrum. The uneventful outcome in some of our cases indicates that a subset of EPS might follow a more indolent clinical course than previously appreciated. Additional studies are needed to validate whether any morphological and/or molecular attributes have a prognostic impact.