ABSTRACT
DUSP22 rearrangements are genetic alterations observed in a subset of systemic anaplastic large cell lymphoma (S-ALCL), primary cutaneous anaplastic large cell lymphoma (C-ALCL), and lymphomatoid papulosis (LyP). Previous investigations have shown that the LEF1+/TIA1- immunoprofile and MSC E116K mutations are highly associated with DUSP22 rearrangement in ALCL. However, the existing literature primarily focuses on S-ALCL. Our understanding of the LEF1/TIA1 immunoprofile and MSC mutation status in C-ALCL/LyP is still limited. In this study, we aimed to assess LEF1/TIA1 expression and MSC mutations in a cohort of 23 C-ALCL/LyP cases, along with a control group of histological mimickers. DUSP22 rearrangements were detected by fluorescence in situ hybridization in eight cases (6/10 C-ALCL, 2/13 LyP). We found LEF1 expression in five out of eight (63%) DUSP22-rearranged cases (3/6 C-ALCL, 2/2 LyP), and none of the 15 cases lacking DUSP22 rearrangements. Furthermore, we also found frequent LEF1 expression in adult T-cell leukemia/lymphoma (ATLL; 10 of 11, 91%) within the control group. TIA1 expression was consistently negative in all DUSP22-rearranged C-ALCL/LyP and ATLL cases tested. MCS E116K mutation was identified in one of five DUSP22-rearranged C-ALCL cases. RNA sequencing of a DUSP22-rearranged C-ALCL revealed a novel DUSP22::SNHG fusion coexisting with a CD58::WNT2B fusion. In conclusion, our findings demonstrated a lower rate of LEF1 expression in DUSP22-rearranged C-ALCL/LyP compared to previous reports that predominantly focused on S-ALCL. Moreover, we observed that the majority of ATLL cases also expressed LEF1, suggesting that the LEF1+/TIA1- immunoprofile does not differentiate DUSP22-rearranged C-ALCL/LyP from ATLL.
Subject(s)
Dual-Specificity Phosphatases , Gene Rearrangement , Immunophenotyping , Lymphoid Enhancer-Binding Factor 1 , Mitogen-Activated Protein Kinase Phosphatases , Skin Neoplasms , Humans , Dual-Specificity Phosphatases/genetics , Mitogen-Activated Protein Kinase Phosphatases/genetics , Male , Female , Middle Aged , Lymphoid Enhancer-Binding Factor 1/genetics , Lymphoid Enhancer-Binding Factor 1/analysis , Adult , Aged , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Ki-1 Antigen/genetics , Ki-1 Antigen/analysis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/analysis , Aged, 80 and over , In Situ Hybridization, Fluorescence , Mutation , Lymphomatoid Papulosis/genetics , Lymphomatoid Papulosis/pathology , Young Adult , Phenotype , Lymphoma, Primary Cutaneous Anaplastic Large Cell/genetics , Lymphoma, Primary Cutaneous Anaplastic Large Cell/pathology , Immunohistochemistry , Lymphoma, Large-Cell, Anaplastic/genetics , Lymphoma, Large-Cell, Anaplastic/pathology , Lymphoma, Large-Cell, Anaplastic/immunologyABSTRACT
Infant-type hemispheric glioma (IHG) is a rare pediatric brain tumor with variable response to chemotherapy and radiotherapy. Molecular insights into IHG can be useful in identifying potentially active targeted therapy. A male fetus was found to have congenital hydrocephalus at the gestational age of 37 weeks. Fetal MRI showed a 2.6 × 2.0-cm tumor located at the frontal horn of the left lateral ventricle, involving the left basal nuclei and thalamus. Tumor biopsy at the age of 2 days revealed an IHG consisting of spindle tumor cells with strong expression of GFAP and ALK. Targeted RNA sequencing detected a novel fusion gene of SOX5::ALK. After initial chemotherapy with cyclophosphamide, carboplatin, and etoposide for 2 cycles, the tumor size progressed markedly and the patient underwent a subtotal resection of brain tumor followed by treatment with lorlatinib, an ALK tyrosine kinase inhibitor with central nervous system (CNS) activity. After 3 months of treatment, reduction of tumor size was observed. After 14 months of treatment, partial response was achieved, and the infant had normal growth and development. In conclusion, we identified a case of congenital IHG with a novel SOX5::ALK fusion that had progressed after chemotherapy and showed partial response and clinical benefit after treatment with the CNS-active ALK inhibitor lorlatinib.
Subject(s)
Aminopyridines , Brain Neoplasms , Carcinoma, Non-Small-Cell Lung , Glioma , Lactams , Lung Neoplasms , Pyrazoles , Infant , Child , Male , Humans , Infant, Newborn , Lung Neoplasms/drug therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Anaplastic Lymphoma Kinase/genetics , Lactams, Macrocyclic/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Brain Neoplasms/therapy , Brain Neoplasms/drug therapy , Glioma/therapy , Glioma/drug therapy , SOXD Transcription FactorsABSTRACT
AIMS: Risk stratification of atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS), diagnosed using breast biopsy, has great clinical significance. Clinical trials are currently exploring the possibility of active surveillance for low-risk lesions, whereas axillary lymph node staging may be considered during surgical planning for high-risk lesions. We aimed to develop a machine-learning algorithm based on whole-slide images of breast biopsy specimens and clinical information to predict the risk of upstaging to invasive breast cancer after wide excision. METHODS AND RESULTS: Patients diagnosed with ADH/DCIS on breast biopsy were included in this study, comprising 592 (740 slides) and 141 (198 slides) patients in the development and independent testing cohorts, respectively. Histological grading of the lesions was independently evaluated by two pathologists. Clinical information, including biopsy method, lesion size, and Breast Imaging Reporting and Data System (BI-RADS) classification of ultrasound and mammograms, were collected. Deep DCIS consisted of three deep neural networks to evaluate nuclear grade, necrosis, and stromal reactivity. Deep DCIS output comprised five parameters: total patches, lesion extent, Deep Grade, Deep Necrosis, and Deep Stroma. Deep DCIS highly correlated with the pathologists' evaluations of both slide- and patient-level labels. All five parameters of Deep DCIS were significantly associated with upstaging to invasive carcinoma in subsequent wide excisional specimens. Using multivariate logistic regression, Deep DCIS predicted upstaging to invasive carcinoma with an area under the curve (AUC) of 0.81, outperforming pathologists' evaluation (AUC, 0.71 and 0.69). After including clinical and hormone receptor status information, performance further improved (AUC, 0.87). This combined model retained its predictive power in two subgroup analyses: the first subgroup included unequivocal DCIS (excluding cases of ADH and DCIS suspicious for microinvasion) (AUC, 0.83), while the second excluded cases of high-grade DCIS (AUC, 0.81). The model was validated in an independent testing cohort (AUC, 0.81). CONCLUSION: This study demonstrated that deep-learning models can refine histological evaluation of ADH and DCIS on breast biopsies, which may help guide future treatment planning.
Subject(s)
Breast Neoplasms , Carcinoma, Ductal, Breast , Carcinoma, Intraductal, Noninfiltrating , Deep Learning , Humans , Female , Carcinoma, Intraductal, Noninfiltrating/pathology , Breast/pathology , Breast Neoplasms/pathology , Biopsy , Necrosis/pathology , Carcinoma, Ductal, Breast/pathology , Retrospective Studies , Hyperplasia/pathologyABSTRACT
The understanding of schwannoma tumorigenesis has been reshaped by the recent identification of SH3PXD2A::HTRA1 fusion in 10% of intracranial/spinal schwannomas. Nonetheless, pathologic features of schwannomas harboring this fusion, as well as its prevalence outside intracranial/spinal locations, have not been characterized. We screened 215 consecutive schwannomas for their clinicopathologic characteristics and fusion status using reverse-transcriptase polymerase chain reaction (RT-PCR). Among 29 (13.5%) fusion-positive schwannomas, the most prevalent location was peripheral somatic tissue (30.7%, 19/62), followed by spinal/paraspinal (18.4%, 7/38), body cavity/deep structures (10%, 2/20), intracranial (1.3%, 1/75), and viscera (0/13). All 8 cellular, 4 microcystic/reticular, and 3 epithelioid schwannomas were fusion-negative, as were 41/42 nonschwannomatous peripheral nerve sheath tumors. Remarkably, a distinct 'serpentine' palisading pattern, comprising ovoid/plump cells shorter than usual schwannian cells in a hyalinized stroma, was identified in most fusion-positive cases and the schwannomatous component of the only fusion-positive malignant peripheral nerve sheath tumor. To validate this finding, 60 additional cases were collected, including 36 with (≥10% arbitrarily) and 24 without appreciable serpentine histology, of which 29 (80.6%) and 2 (8.3%) harbored the fusion, respectively. With percentages of 'serpentine' areas scored, 10% was determined as the optimal practical cut-off to predict the fusion status (sensitivity, 0.950; specificity, 0.943). Fusion positivity was significantly associated with serpentine histology, smaller tumors, younger patients, and peripheral somatic tissue, while multivariate logistic linear regression analysis only identified serpentine histology and location as independent fusion-predicting factors. RNA in situ hybridization successfully detected the fusion junction, highly concordant with RT-PCR results. Gene expression profiling on 18 schwannomas demonstrated segregation largely consistent with fusion status. Fusion-positive cases expressed significantly higher HTRA1 mRNA abundance, perhaps exploitable as a biomarker. In summary, we systematically characterize a series of 60 SH3PXD2A::HTRA1 fusion-positive schwannomas, showing their distinctive morphology and location-specific prevalence for the first time.
Subject(s)
Nerve Sheath Neoplasms , Neurilemmoma , Humans , Neurilemmoma/pathology , Nerve Sheath Neoplasms/pathology , Cell Transformation, Neoplastic , Adaptor Proteins, Vesicular TransportABSTRACT
Phosphaturic mesenchymal tumors (PMT) are uncommon neoplasms that cause hypophosphatemia/osteomalacia mainly by secreting fibroblast growth factor 23. We previously identified FN1::FGFR1/FGF1 fusions in nearly half of the PMTs and frequent KL (Klotho or α-Klotho) overexpression in only those with no known fusion. Here, we studied a larger cohort of PMTs for KL expression and alterations. By FN1 break-apart fluorescence in situ hybridization (FISH) and reappraisal of previous RNA sequencing data, 6 tumors previously considered "fusion-negative" (defined by negative results of FISH for FN1::FGFR1 fusion and FGF1 break-apart and/or of RNA sequencing) were reclassified as fusion-positive PMTs, including 1 containing a novel FN1::ZACN fusion. The final cohort of fusion-negative PMTs included 33 tumors from 32 patients, which occurred in the bone (n = 18), soft tissue (n = 10), sinonasal tract (n = 4), and brain (n = 1). In combination with previous work, RNA sequencing, RNA in situ hybridization, and immunohistochemistry showed largely concordant results and demonstrated KL/α-Klotho overexpression in 17 of the 28 fusion-negative and none of the 10 fusion-positive PMTs studied. Prompted by a patient in this cohort harboring germline KL upstream translocation with systemic α-Klotho overexpression and multifocal PMTs, FISH was performed and revealed KL rearrangement in 16 of the 33 fusion-negative PMTs (one also with amplification), including 14 of the 17 cases with KL/α-Klotho overexpression and none of the 11 KL/α-Klotho-low fusion-negative and 11 fusion-positive cases studied. Whole genomic sequencing confirmed translocation and inversion in 2 FISH-positive cases involving the KL upstream region, warranting further investigation into the mechanism whereby these rearrangements may lead to KL upregulation. Methylated DNA immunoprecipitation and sequencing suggested no major role of promoter methylation in KL regulation in PMT. Interestingly, KL-high/-rearranged cases seemed to form a clinicopathologically homogeneous group, showing a predilection for skeletal/sinonasal locations and typically matrix-poor, cellular solitary fibrous tumor-like morphology. Importantly, FGFR1 signaling pathways were upregulated in fusion-negative PMTs regardless of the KL status compared with non-PMT mesenchymal tumors by gene set enrichment analysis, perhaps justifying FGFR1 inhibition in treating this subset of PMTs.
Subject(s)
Mesenchymoma , Paranasal Sinuses , Soft Tissue Neoplasms , Humans , In Situ Hybridization, Fluorescence , Fibroblast Growth Factor 1/genetics , Soft Tissue Neoplasms/genetics , Mesenchymoma/genetics , Mesenchymoma/pathology , Translocation, Genetic , Paranasal Sinuses/pathologyABSTRACT
BACKGROUND: Laser hair removal is an increasingly prevalent trend of cosmetic procedures. The purpose of this study was to assess the effectiveness of hair reduction among several types of laser interventions. METHODS: The selected studies searched in PubMed and EMBASE were assessed for quality of evidence, and extracted data on absolute hair count and hair reduction rate. Qualitative data were synthesized using standardized mean difference (SMD) in frequentist network meta-analysis because various measurement units were used among selected studies. Inconsistency and small study effects were examined by design-by-treatment interaction model and comparison-adjusted funnel plot. RESULTS: A total of 13 randomized controlled trials (RCTs) (n = 652) were contributed to network meta-analysis. Pooled results revealed that diode laser showed significantly lower absolute hair count within three-month (SMD = -13.21, 95% confidence interval [CI]: -22.25 to -4.17) and around six months follow-up (SMD = -11.01, 95% CI: -18.24 to -3.77) as compared with those in control group, but no significant difference among laser interventions. All side effects observed were transient without leaving any permanent scars. CONCLUSION: Eliminating unwanted hair with lasers or intense pulsed light is safe and effective; however, which type of intervention is more beneficial in the long-term process should be studied with a longer follow-up time.
Subject(s)
Hair Removal , Laser Therapy , Humans , Hair Removal/methods , Network Meta-Analysis , Hair , Lasers, Semiconductor/therapeutic use , Cicatrix/etiology , Laser Therapy/adverse effects , Treatment OutcomeABSTRACT
Twelve Asian patients with sarcoma received interval-compressed (ic-) chemotherapy scheduled every 14 days with a regimen of vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1200-2200 mg/m2) (VDC) alternating with a regimen of ifosfamide (9000 mg/m2) and etoposide (500 mg/m2) (IE), with filgrastim (5-10 mcg/kg/day) between cycles. Carboplatin (800 mg/m2) was added for CIC-rearranged sarcoma. The patients were treated with 129 cycles of ic-VDC/IE with a median interval of 19 days (interquartile range [IQR], 15-24 days. Median nadirs (IQR) were neutrophil count, 134 (30-396) × 106/L at day 11 (10-12), recovery by day 15 (14-17) and platelet count, 35 (23-83) × 109/L at day 11 (10-13), recovery by day 17 (14-21). Fever and bacteremia were observed in 36% and 8% of cycles, respectively. The diagnoses were Ewing sarcoma (6), rhabdomyosarcoma (3), myoepithelial carcinoma (1), malignant peripheral nerve sheath tumor (1), and CIC-DUX4 Sarcoma (1). Seven of the nine patients with measurable tumors responded (one CR and six PR). Interval-compressed chemotherapy is feasible in the treatment of Asian children and young adults with sarcomas.
ABSTRACT
Extraskeletal myxoid chondrosarcoma (EMC) is an ultrarare sarcoma typically exhibiting myxoid/reticular histology and NR4A3 translocation. However, morphologic variants and the relevance of non-EWSR1::NR4A3 fusions remain underexplored. Three challenging pan-Trk-expressing cases, featuring cellular to solid histology, were subjected to RNA exome sequencing (RES), unveiling different NR4A3-associated fusions. Alongside RES-analyzed cases, fluorescence in situ hybridization was performed to confirm 58 EMCs, with 48 available for pan-Trk immunostaining and KIT sequencing. Except for 1 (2%) NR4A3-rearranged EMC without identifiable partners, 46 (79%), 9 (16%), and 2 (3%) cases harbored EWSR1::NR4A3, TAF15::NR4A3, and TCF12::NR4A3 fusions, respectively. Five EWSR1::NR4A3-positive EMCs occurred in the subcutis (3) and bone (2). Besides 43 classical cases, there were 8 cellular, 4 rhabdoid/anaplastic, 2 solid, and 1 mixed tumor-like variants. Tumor cells were oval/spindle to pleomorphic and formed loose myxoid/reticular to compact sheet-like or fascicular patterns, imparting broad diagnostic considerations. RES showed upregulation of NTRK2/3, KIT, and INSM1. Moderate-to-strong immunoreactivities of pan-Trk, CD117, and INSM1 were present in 35.4%, 52.6%, and 54.6% of EMCs, respectively. KIT p. E554K mutation was detected in 2/48 cases. TAF15::NR4A3 was significantly associated with size >10 cm (78%, P = .025). Size >10 cm, moderate-to-severe nuclear pleomorphism, metastasis at presentation, TAF15::NR4A3 fusion, and the administration of chemotherapy portended shorter univariate disease-specific survival, whereas only size >10 cm (P = .004) and metastasis at presentation (P = .032) remained prognostically independent. Conclusively, EMC may manifest superficial or osseous lesions harboring EWSR1::NR4A3, underrecognized solid or anaplastic histology, and pan-Trk expression, posing tremendous challenges. Most TAF15::NR4A3-positive cases were >10 cm in size, ie, a crucial independent prognosticator, whereas pathogenic KIT mutation rarely occurred.
Subject(s)
Chondrosarcoma , Receptors, Steroid , Sarcoma , TATA-Binding Protein Associated Factors , Humans , In Situ Hybridization, Fluorescence , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Chondrosarcoma/genetics , Chondrosarcoma/diagnosis , Sarcoma/genetics , TATA-Binding Protein Associated Factors/genetics , Repressor Proteins/genetics , DNA-Binding Proteins/genetics , Receptors, Steroid/genetics , Receptors, Thyroid Hormone/geneticsABSTRACT
Bizarre parosteal osteochondromatous proliferation (BPOP) (Nora lesion) is a benign bone surface lesion, which most commonly occurs in the digits of young patients and has a high rate of recurrence. Histologically, it is composed of a mixture of disorganized bone, cartilage, and spindle cells in variable proportions and characterized by amorphous "blue bone" mineralization. Recurrent chromosomal abnormalities, including t(1;17)(q32-42;q21-23) and inv(7)(q21.1-22q31.3-32), have been reported in BPOP. However, the exact genes involved in the rearrangements remain unknown. In this study, we analyzed 8 BPOP cases affecting the fingers, toe, ulna, radius, and fibula of 5 female and 3 male patients, aged 5 to 68 years. RNA sequencing of 5 cases identified genetic fusions between COL1A2 and LINC-PINT in 3 cases and COL1A1::MIR29B2CHG fusion in 1, both validated using fluorescence in situ hybridization and reverse transcription (RT)-PCR. The remaining fusion-negative case harbored 3 COL1A1 mutations as revealed by whole-exome sequencing and confirmed using Sanger sequencing. All these genetic alterations were predicted to cause frameshift and/or truncation of COL1A1/2. The chromosomal locations of COL1A2 (7q21.3), LINC-PINT (7q32.3), COL1A1 (17q21.33), and MIR29B2CHG (1q32.2) were consistent with the breakpoints identified in the previous cytogenetic studies. Subsequent screening of 3 BPOPs using fluorescence in situ hybridization identified 1 additional case each with COL1A1 or COL1A2 rearrangement. Our findings are consistent with reported chromosomal abnormalities and implicate the disruption of type I collagen, and perhaps of either noncoding RNA gene as a tumor suppressor, in the tumorigenesis of BPOP. The prevalence and tumorigenic mechanisms of these COL1A1/2 alterations in BPOP require further investigation.
Subject(s)
Bone Neoplasms , Neoplasms, Connective Tissue , Soft Tissue Neoplasms , Female , Humans , Male , Cell Proliferation , Chromosome Aberrations , In Situ Hybridization, Fluorescence , Mutation , Child, Preschool , Child , Adolescent , Young Adult , Adult , Middle Aged , AgedABSTRACT
Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease with the colorectum as its major target organ. Involvement of the upper gastrointestinal tract in UC is rare and presents with nonspecific endoscopic and microscopic characteristics. Recent studies have demonstrated proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA) to be a serological marker for differentiating UC from Crohn's disease in children and for detecting disease activity and nonresponse to steroid therapy and antitumor necrotizing factor-α agents. Herein, we report a 13-year-old female patient mainly presenting with recurrent bilious vomiting who was initially diagnosed with acute gastroenteritis. Intestinal pseudo-obstruction was confirmed through observation of a patent but segmentally dilated jejunum in the barium follow-through examination and other imaging; such obstruction can be attributed to backwash ileitis, superior mesenteric artery syndrome, ileus due to hypokalemia, or PR3-associated enteritis. Laboratory data revealed leukocytosis with neutrophil predominance and serum antinuclear antibody and PR3-ANCA positivity. Overlapping syndrome with autoimmune diseases was suspected. Pathology revealed a crypt abscess with aggregates of neutrophils consistent with UC but did not indicate vasculitis. The in situ immunohistochemical staining revealed PR3 density mainly in the colon and focally in the duodenum. To our knowledge, this is the first case report with in situ pathological evidence of PR3 in inflamed intestinal tissues in a patient with UC and with rare initial presentation of intestinal pseudo-obstruction-induced recurrent bilious vomiting. Whether the clinical features of the present case constitute overlap syndrome with other autoimmune disease or a disease variation of UC warrants further investigation. Notably, the patient's serum PR3-ANCA titers remained high in coincidence with increased disease activity and nonresponse to steroid therapy, but became lower after infliximab treatment. PR3-ANCA as a potential serum biomarker to aid in making differential diagnoses of UC in children, correlating disease activity, and predicting therapeutic responses was also reviewed.
ABSTRACT
NTRK-rearranged mesenchymal neoplasms mostly affect the soft tissues of pediatric patients. Given the responsiveness to selective NTRK inhibitors, it remains critical to identify those ultra-rare cases occurring in the viscera of adults. In five females and two males aged 18-53 years, we characterized visceral mesenchymal tumors harboring TPM3-NTRK1 [uterine cervix (N = 2), pleura, prostate], LMNA-NTRK1 (lung), SQSTM1-NTRK3 (heart), and NTRK3 rearrangement with unknown fusion partner (colon/mesocolon) with RNA sequencing, FISH, RT-PCR, and immunohistochemistry. The tumors exhibited spindled to ovoid/epithelioid or pleomorphic cells, often arranged in fascicles, and were low-to-intermediate-grade and high-grade in three and four cases, respectively. Keloid-like stromal collagen and perivascular hyalinization was noted in five. Adenosarcoma-like appearances were observed in two, manifesting frond-like protrusions in one cervical tumor and phyllodes-like architecture in the prostatic tumor. Abrupt high-grade transformation into pleomorphic liposarcoma was found in another cervical tumor, while the pleural tumor contained intermixed rhabdomyoblasts. Pan-TRK immunostaining was positive in all cases. All cases expressed CD34, while five were S100-positive. CDKN2A homozygous deletion with concomitant p16 loss occurred in 4/7. Whole-exome sequencing identified TP53 mutation (c.672+2T>C, involving a splice site, with concomitant protein loss) in a cervical sarcoma, limited to its heterologous liposarcomatous component. At least moderate pan-TRK immunoreactivity was present in varying proportions of potential pathologic mimics, with BCOR-positive sarcoma (56%, 5/9), undifferentiated uterine sarcoma (50%, 3/6), and spindle cell/sclerosing rhabdomyosarcoma (33%, 2/6) being among the most frequent. This underscored the unsatisfactory specificity of pan-TRK immunohistochemistry and warranted molecular confirmation in the diagnosis of adult NTRK-rearranged visceral mesenchymal neoplasms. The current report highlights the ever-expanding clinicopathologic and genetic spectrum of this entity by describing the unprecedented cardiac and pleural locations and heterologous differentiation, as well as the second NTRK-rearranged "prostatic stromal sarcoma," while substantiating CDKN2A deletion as a frequent occurrence.
Subject(s)
Endometrial Neoplasms , Neoplasms, Connective and Soft Tissue , Sarcoma , Soft Tissue Neoplasms , Uterine Cervical Neoplasms , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Child , Endometrial Neoplasms/genetics , Female , Gene Rearrangement , Homozygote , Humans , Male , Neoplasms, Connective and Soft Tissue/genetics , Oncogene Proteins, Fusion/genetics , Receptor, trkA/analysis , Receptor, trkA/genetics , Sarcoma/genetics , Sequence Deletion , Soft Tissue Neoplasms/genetics , Uterine Cervical Neoplasms/genetics , Viscera/chemistry , Viscera/pathologyABSTRACT
Inflammatory leiomyosarcoma is a rare myogenic tumor with striking inflammatory infiltrates and a specific genomic pattern of near-haploidization despite exception(s). Recent studies demonstrated that inflammatory leiomyosarcoma shares substantially overlapping features with histiocyte-rich rhabdomyoblastic tumor, including expression of rhabdomyoblastic markers such as myogenin, MyoD1, and PAX7 and a high prevalence of genomic near-haploidization, suggesting that they represent a unifying entity, for which the term inflammatory rhabdomyoblastic tumor was coined. In this study, we identified 4 pulmonary tumors histologically typical of inflammatory leiomyosarcomas, all in men (aged 26 to 49), presented as slow-growing well-defined nodules ranging from 1.4 to 3.5 cm, and following uneventful postoperative courses. All tumors were positive for desmin immunostaining, while only 1 and 2 were focally positive for smooth muscle actin and smooth muscle myosin heavy chain, respectively. They showed no expression of myogenin, MyoD1, or PAX7 by immunohistochemistry or RNA sequencing. Copy number analyses by whole-exome sequencing (N=1), OncoScan single-nucleotide polymorphism array (2), and fluorescence in situ hybridization (1) revealed/suggested diploid genomes. Together with a previously reported case, all these pulmonary "inflammatory leiomyosarcomas" seemed clinically, pathologically, and genomically alike. Despite a superficial resemblance to conventional inflammatory leiomyosarcoma in somatic soft tissues (now preferably termed inflammatory rhabdomyoblastic tumor), they differ in the lack of convincing rhabdomyoblastic differentiation and genomic near-haploidization. Therefore, we propose that these pulmonary tumors probably represent a distinct entity, for which the exact line of differentiation, and perhaps the most suitable terminology to better reflect its nature, remains to be determined. The term inflammatory rhabdomyoblastic tumor seems inappropriate for this group of tumors.
Subject(s)
Biomarkers, Tumor/genetics , Cell Differentiation , Diploidy , Leiomyosarcoma/genetics , Leiomyosarcoma/pathology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Adult , Gene Dosage , Genetic Predisposition to Disease , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Leiomyosarcoma/classification , Leiomyosarcoma/surgery , Lung Neoplasms/classification , Lung Neoplasms/surgery , Male , Middle Aged , Phenotype , Pneumonectomy , Predictive Value of Tests , Terminology as Topic , Treatment Outcome , Tumor Burden , Exome SequencingABSTRACT
The clinicopathologic relevance of various gene rearrangements underlying dermatofibrosarcoma protuberans (DFSP) remains insufficiently characterized. In 188 DFSPs, we determined PDGFB, COL1A1, PDGFD, COL6A3, and EMILIN2 rearrangements by fluorescence in situ hybridization (FISH). The clinicopathologic significance of rearrangement types and factors related to recurrence and metastasis were statistically analyzed. In all, classic PDGFB rearrangement, cryptic COL1A1-PDGFB fusion, and PDGFD rearrangement were identified in 172 (91.4%), 8 (4.3%), and 8 (4.3%: 4 COL6A3-PDFGD, 4 EMILIN2-PDGFD) cases, respectively. In an index DFSP harboring the cryptic fusion, the COL1A1-PDGFB transcript was confirmed by both RNA sequencing and reverse transcription-polymerase chain reaction. In comparison with cases harboring classic PDGFB rearrangement, cryptic PDGFB-rearranged DFSPs usually exhibited higher 5'-COL1A1 copy numbers. In a combined reappraisal of published and current cases, COL6A3-PDGFD-positive DFSPs (n=16) predominated in females (n=14, 88%) and torso (n=14, 88%), especially the breast (n=7, 44%); EMILIN2-PDGFD-positive DFSPs (n=6) preferentially demonstrated near exclusively subcutaneous growth (n=5, 83%) and fibrosarcomatous transformation (n=5, 83%). In our cohort, local recurrence was related to fibrosarcomatous variant (P=0.029, odds ratio=3.478) and head and neck location (P=0.046, odds ratio=3.508). Distant metastasis only occurred in the fibrosarcomatous variant (9/73, 12.3%) but not in other cases. In conclusion, 8.6% of DFSPs are negative for PDGFB break-apart FISH, which, especially those with challenging subcutaneous and circumscribed manifestation, require complementary diagnosis by FISH assays targeting COL1A1 and PDGFD. The types of fusion gene rearrangements, head and neck location, and fibrosarcomatous transformation may account for clinicopathologic and prognostic variations in DFSPs and warrant future independent validation.
Subject(s)
Dermatofibrosarcoma , Fibrosarcoma , Skin Neoplasms , Collagen , Dermatofibrosarcoma/diagnosis , Dermatofibrosarcoma/genetics , Dermatofibrosarcoma/pathology , Female , Fibrosarcoma/genetics , Gene Rearrangement , Humans , In Situ Hybridization, Fluorescence , Oncogene Proteins, Fusion/genetics , Proto-Oncogene Proteins c-sis/genetics , Skin Neoplasms/pathologyABSTRACT
Malignant gastrointestinal neuroectodermal tumor (MGNET) is a sarcoma typically involving the gastrointestinal tract with neuroectodermal differentiation and EWSR1-ATF1/CREB1 fusions. Recently, rare MGNET cases were reported in extragastrointestinal sites. We identified 2 cases of MGNET arising in unprecedented laryngeal and intracranial locations, respectively. Both cases showed spindle and epithelioid tumor cells with amphophilic to clear cytoplasm and occasionally prominent nucleoli, arranged in solid, fascicular, and pseudoalveolar patterns. Case 1 exhibited moderate to marked nuclear atypia and focal intraepithelial component. In contrast, case 2 comprised predominantly low-grade epithelioid cells with extensive pseudopapillary structures. Both tumors showed an S100/SOX10-positive and HMB45/melan-A-negative immunoprofile as well as EWSR1-ATF1 fusion. A chief obstacle in diagnosing case 1 was the histologic and immunophenotypic resemblance to melanoma. The striking pseudopapillary architecture and the intracranial location of case 2 rendered differential diagnoses including meningioma and ependymoma. With the peculiar locations and morphology, these cases posed great diagnostic challenge.
Subject(s)
Gastrointestinal Neoplasms , Melanoma , Biomarkers, Tumor/genetics , Diagnosis, Differential , Gastrointestinal Neoplasms/pathology , Humans , Immunohistochemistry , In Situ Hybridization, FluorescenceABSTRACT
AIMS: Intracranial myxoid mesenchymal tumors (IMMTs) with fusions between EWSR1/FUS and CREB transcription factors have morphologic overlap with myxoid angiomatoid fibrous histiocytoma (mAFH) and myoepithelial tumor/carcinoma (MET/MEC). We aimed to study the clinicopathologic and genetic spectrum of extracranial IMMT-like tumors and their relationships with mAFH and MET/MEC. METHODS: Twelve extracranial tumors harboring EWSR1/FUS-CREB fusions across different histologic groups were characterized using RNA sequencing, FISH and/or RT-PCR. RESULTS: There were 4 IMMT-like neoplasms, 3 MET/MECs, and 5 mAFHs from the tibia (n=1), oral cavity (n=2), and soft tissues (n=9; 5 in the extremities), harboring EWSR1-ATF1 in 4 cases, FUS-CREM and EWSR1-CREM in 3 each, and EWSR1-CREB1 in 2. Multinodular growth, reticular/cording/trabecular arrangements, myxocollagenous matrix, and lymphocytic infiltrates variably prevailed among the 3 groups. mAFHs were characterized by cells with syncytial cytoplasm. IMMT-like neoplasms and MET/MECs shared cells with distinct boundaries, but only MET/MECs expressed GFAP and/or S100. MUC4 and ALK were expressed in some IMMT-like neoplasms (2/4; 2/4) and mAFH (2/5; 1/5). Pan-TRK reactivity was observed in two IMMT-like neoplasms with upregulated NTRK3 mRNA and one MEC. Local recurrences, typically ≥â¯12 months postoperatively, developed in 2/3 IMMT-like neoplasms, 1/2 MET/MECs, and 0/4 mAFHs with follow-up. No definite associations were found between fusion types and histology, immunoprofile or outcome. CONCLUSIONS: We demonstrated the similarities and differences among 3 extracranial myxocollagenous tumor groups sharing EWSR1/FUS-CREB fusions. Oral IMMT-like neoplasms harboring FUS-CREM or EWSR1-ATF1 and FUS-CREM-positive.
Subject(s)
Brain Neoplasms/diagnosis , Brain Neoplasms/etiology , CREB-Binding Protein/physiology , Neoplasms, Connective and Soft Tissue/diagnosis , Neoplasms, Connective and Soft Tissue/etiology , Adult , Aged , Brain Neoplasms/pathology , Female , Humans , Male , Middle Aged , Neoplasm Invasiveness , Neoplasms, Connective and Soft Tissue/pathology , Young AdultABSTRACT
INTRODUCTION: Platelet-rich plasma (PRP) therapy has been used in different medical fields, but its effectiveness in burn wound healing remains debatable. In this study, we performed a systematic review and meta-analysis of the available evidence on burn patients treated with PRP to evaluate the safety and efficacy of the treatment. METHODS: Randomized controlled trials evaluating the efficacy of PRP in patients with burn injuries were selected. Eligible retrospective studies were abstracted and assessed for the risk of bias by two reviewers and results of mean time to complete epithelization and wound closure rate in the included studies were analyzed. Studies on the correlation between PRP and burn wound healing published in English or Chinese before March 2020 were retrieved from PubMed. RESULTS: Eight studies (including 449 patients) met our inclusion criteria. Qualitative analysis revealed that compared with the control group, the PRP group had significantly better wound closure rates at weeks 2 (mean difference (MD): 12.79 [95% confidence interval (CI): 7.08, 18.49]; I2: 0%; p < 0.0001) and 3 (MD: 12.66 [95% CI: 5.97, 19.34]; I2: 55%; p = 0.0002) and time to complete epithelialization (MD: -3.45 [95% CI: -4.87, -2.04] (days); I2: 0%; p < 0.00001). There was no significant difference in infection rate or graft take rate. CONCLUSIONS: PRP application can accelerate wound closure, however, it has no effect on the rates of wound infection and graft take rate.
Subject(s)
Burns , Platelet-Rich Plasma , Burns/therapy , Humans , Randomized Controlled Trials as Topic , Re-Epithelialization , Retrospective Studies , Wound HealingABSTRACT
Sarcomas with MEIS1-NCOA2 fusions have been so far reported in 2 cases each of primitive renal sarcomas and intraosseous pelvic rhabdomyosarcomas. Their histologic spectrum, anatomic distribution, and clinical behavior remain poorly defined. In this study, we report 6 additional spindle cell sarcomas with MEIS1-NCOA2 or NCOA1 fusions that fall into the same disease spectrum with the previously reported renal sarcomas. The patients' age range was wide (20-76 years, mean 46) and all except one were female. The tumors arose in the kidney (n = 2), and one each in the uterine corpus, vagina, scrotum, and para-rectal region. The consistent morphology was that of monomorphic spindle to ovoid cells in a storiform, whorling, or solid pattern. Alternating cellularity, myxoid stroma, and microcystic changes were seen in some cases. Mitotic activity varied greatly (<1-33/10 high power fields). The immunophenotype was nonspecific, with most cases expressing variable degrees of TLE1, WT1, cyclin D1, CD56, and CD10. Using various platforms of RNA-based targeted sequencing, MEIS1-NCOA2 fusions were recurrently identified in 5 cases, and a novel MEIS1-NCOA1 fusion was found in one renal tumor. The gene fusions were validated by fluorescence in situ hybridization using custom BAC probes. Of the 5 patients with available follow-up (5 months to 8 years), all experienced local recurrences, but no distant spread or death from disease. Our results expand the clinicopathologic spectrum of sarcomas with MEIS1-NCOA2/1 fusions, providing evidence of an undifferentiated spindle cell phenotype with nonspecific immunoprofile and low-grade clinical behavior.