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Những kết luận mới của luận án: - Đây là nghiên cứu đầu tiên tại Việt Nam áp dụng mô bệnh học, hóa mô miễn dịch trong chẩn đoán sarcôm mô mềm (SMM) ở các vị trí ngoại vi và trung tâm theo phân loại của tổ chức y tế thế giới năm 2013. - Nghiên cứu đã phân loại được típ mô bệnh học trên 363 trường hợp SMM, có 11/12 nhóm nguồn gốc, trong đó nhiều nhất là nhóm sarcôm nguyên bào xơ cơ (29,2%), tiếp đến là sarcôm mỡ (26,7%); sarcôm có nguồn gốc không chắc chắn 14,9%;…; không gặp trường hợp nào thuộc nhóm quanh mạch. U mô đệm dạ dày ruột ngoài tiêu hóa chiếm 2,2% (8/363) trong SMM nói chung và chiếm 5,9% (8/136) các SMM ở sau phúc mạc – trong ổ bụng. Hóa mô miễn dịch không những có vài trò quan trọng trong phân loại típ mô bệnh học của SMM mà một số dấu ấn còn có giá trị xác định bản chất phân tử của khối u như MDM2, CDK4, INI1, MUC4, TFE3, WT1, H3k27me3. - Độ mô học theo hệ thống phân độ SMM của Pháp và độ mô học theo Ki-67 càng cao càng làm tăng tỷ lệ diện cắt phẫu thuật dương tính (R1-R2) với p < 0,05. - Phân tầng nguy cơ di căn của u xơ đơn độc ác tính (≥ 4 nhân chia/10 vi trường) trên50 trường hợp: nguy cơ thấp 56%, nguy cơ trung bình 34%, nguy cơ cao 10%.
MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEALTH HANOI MEDICAL UNIVERSITY HO DUC THUONG INVESTIGATE HISTOPATHOLOGY, IMMUNOHISTOCHEMISTRY AND SOME PROGNOSTIC FACTORS OF COMMON SOFT TISSUE SARCOMAS Major : Biomedical Science (AnatomicalPathology-Forensic Pathology) Code : 9720101 SUMMARY OF MEDICAL PhD THESIS HANOI – 2022 THE WORK HAS BEEN COMPLETED AT HANOI MEDICAL UNIVERSITY Supervisor: Ass.Prof LE DINH DOANH Opponent 1: Opponent 2: Opponent 3: The thesis will be defended at Board of Examiners of Hanoi Medical University At: 14:00 Date: 10/ 09 / 20 The thesis can be found at: National library of Vietnam Library of Hanoi Medical University PUBLISHED RESEARCH PROJECTS RELATED TO THE CONTENT OF THE THESIS Ho Duc Thuong, Nguyen Thi Khuyen (2018), “Histopathological characteristics and TFE3 expression of niche soft tissue sarcoma: Four case studies at Viet Duc Hospital and reviewing medical literature”, Vietnam Cancer Journal, Issue No - 2018, pp 256-261 Ho Duc Thuong, Le Dinh Roanh (2020), “Histological type classification, expression of MDM2/CDK4 markers and some prognostic factors of fatty sarcoma at Viet Duc Hospital”, Medical Practice Journal, Issue No.1139, July 2020, pp 74-77 Ho Duc Thuong, Nguyen Thi Luan, Nguyen Sy Lanh, Le Dinh Roanh (2020), “Histological characteristics, expression of STAT6 and CD34 markers in 62 isolated fibroid cases at Viet Duc Hospital” , Medical Practice Journal, Issue No 1139, July 2020, pp 112-116 Ho Duc Thuong, Nguyen Thi Quynh, Dao Thi Luan, Nguyen Sy Lanh, Nguyen Duc Thang (2021), “Low-grade mucinous fibrosarcoma: A case study at Viet Duc Hospital and a review of the medical literature”, Vietnam Journal of Oncology, Issue No.1 - 2021, pp 367-372 INTRODUCTION Soft tissue sarcomas (STS) are cancers of the connective tissue in addition to bone except for lymphoid tissue, glial tissue, and supporting tissues of organs Compared with other cancers, STS are relatively rare Accurate diagnosis of histopathological type as well as subtype of STS is of great significance, deciding treatment attitude and predicting disease prognosis Previously, the histopathological diagnosis of STS was based only on routine histological techniques of Hematoxylin Eosin (HE) staining and some special staining methods Today, thanks to the help of modern techniques such as immunohistochemistry (IHC) and molecular biology, the diagnosis of STS has been improved diagnose The introduction of IHC is a revolution in the diagnosis of pathology in general and in the diagnosis of STS in particular In recent times, with the appearance of many new molecularly significant antibodies, IHC has shown an increasingly important role in diagnosing and determining the histopathological type of STS So far, there are many classifications of STS, in which the Fourth World Health Organization (WHO) classification of STS in 2013 has highlighted the role of IHC and molecular biology in stool histopathological type of STS In early 2020, the WHO's fifth classification of soft tissue and bone tumors was born, in addition to adding some new histopathological types and molecular biology, the classification also updated a new element has new prognostic significance of some common tumor types, dedifferentiated liposarcomas, solitary fibrous tumors In terms of treatment, surgery is the first indication for STS, however, it is difficult to remove the entire tumor, because the tumor often has extensive local invasion, the tumor size is often large and varies with anatomical position This is also one of the important factors in the prognosis of STS For the above reasons, the project titled “ Investigate histopathology, immunohistochemistry and some prognostic factors of common soft tissue sarcomas” has been carried out for the following purposes: Study on histopathology and immunohistochemistry of soft tissue sarcomas according to the classification of the WHO 2013 Analysis of some macroscopic and microscopic factors with prognostic significance of some common soft tissue sarcomas NEW CONTRIBUTIONS OF THE THESIS This is the first study in Vietnam to apply histopathology, IHC in the diagnosis of STS in peripheral and central locations according to the classification of the WHO 2013 2 The results from the study show that: The study classified the histopathological type on 363 cases of STS with 11/12 groups of origin, of which the most common group was fibroblastic /myofibroblastic sarcomas (29.2%), followed by adipocytic sarcomas (26,20%); sarcomas of uncertain differentiation 14.9%;…; There were no cases of perivascular tumour group Extra-digestive GIST accounts for 2.2% (8/363) of STSs in general and 5.9% (8/136) of retroperitonealintra-abdominal STSs IHC not only plays an important role in the histopathological classification of STSs, but some markers are also valuable in determining the molecular nature of the tumor such as MDM2, CDK4, INI1, MUC4, TFE3 , WT1, H3k27me3 - The higher histological grading of STS according to FNCLCC and Ki-67 grade is, the higher the rate of positive surgical resection (R1-R2) with p < 0.05 is increased - The stratification of the risk of metastasis of malignant solitary fibrous tumours (≥ mitoses/10 HPF) in more than 50 cases: low risk 56%, medium risk 34%, high risk 10% THE STRUCTURE OF THE THESIS The thesis consists of 147 pages, including the following parts: Introduction (2 pages), Chapter 1: Literature Overview (38 pages), Chapter 2: Research Subjects and Methods (21 pages); Chapter 3: Research results (35 pages); Chapter 4: Discussion (48 pages); Conclusion (2 pages); Recommendations (1 page) In the thesis, there are 36 tables, charts and figure References have 222 documents (8 documents in Vietnamese and 214 documents in English) The appendix includes a list of patients, illustrations, and sample research records CHAPTER LITERATURE OVERVIEW 1.1 Research situation on soft tissue sarcoma in the world and in Vietnam Recent studies on molecular biology and IHC in the field of STS have helped to diagnose the genetic nature of many histological types, discovering many new histologic types from undifferentiated/unclassified STSs, leading to the introduction of the new classification of STSs of the WHO 2013 and more recently the WHO 2020 Studies on biochemical markers IHC with molecular value is realized and increasingly applied in diagnostic practice 1.2 Histopathological classification of soft tissue sarcomas The first globally accepted histopathological classification for STS was the WHO classification (1969) Advances in IHC and molecular biology have led to the creation of new classifications that better serve the diagnosis, treatment, and prognosis Up to now, there have been 05 classifications of STS of the WHO, the latest 02 classifications were born in 2013 and 2020 1.2.1 Histological classification of soft tissue sarcomas of the 4th World Health Organization (2013) The WHO 2013 STS classification was born 11 years after the previous classification During that time there have been some changes in the classification of STS, mainly based on the discovery of new genes in differentiating tumor types In addition, several new distinct morphological types of tumor subtypes have been described along with novel alterations in the genetic problem Classification divides STS into 12 groups of origin: adipocytic, fibroblastic/myofibroblastic, so-called fibrohistiocytic, smoothmuscle, perivascular, skeletal-muscle, vascular, chondro-osseous, gastrointestinal stromal tumor (GIST), nerve sheath, uncertain differentiation and unclassified/undifferentiated Some new points of the 2013 classification compared to the previous ones: - Adipocytic tumours: The most notable change in this tumor category is the removal of the term round cell liposarcoma, and the classification of this tumor in the group of high-grade myxoid liposarcomas Mixed type liposarcomas have also been excluded from this classification and are classified as dedifferentiated liposarcomas - Fibroblastic/myofibroblastic tumours: Dermatofibrosarcoma Protuberans (DFSP) is closely related to giant cell fibroblastoma and is included in the WHO 2013, both tumors had rearrangements of chromosomes 17 and 22, which resulted in the formation of the mosaic gene PDGFB-COL1A DFSP is classified as a tumor that rarely metastasizes (intermediate), although it has the potential to metastasize in the presence of a fibrosarcomatous component (Dermatofibrosarcoma Protuberans- variant Fibrosarcomatous - DFSP-FS) The subtypes of hemangiopericytomas were eliminated and classified as solitary fibrous tumours due to the discovery of the same NAB2-STAT6 gene The WHO 2013 classification recognizes the close relationship between low-grade fibromyxoid sarcoma and a subtype of sclerosing epithelioid fibrosarcoma - So-called fibrohistiocytic tumours: The term “malignant fibrous histiocytomas” was dropped from the 2013 WHO classification The term is obsolete, it includes many types of tumors that now exist can be precisely classified as specific types of sarcomas Unclassified/undifferentiated sarcomas now have their own classification - Rhabdomyosarcoma: The classification of “sclerosing/spindle cell rhabdomyosarcoma” was separated from embryonal rhabdomyosarcoma due to the detection of genetic differences - Vascular tumours: A newly recognized term "pseudomyogenic haemangioendothelioma" (and also “epithelioid sarcoma-like haemangioendothelioma”) is included in this category - Gastrointestinal stromal tumour: For the first time, GIST was included in the soft tissue tumour classification of the WHO (2013), previously GIST belonged to the classification of digestive system tumours It is worth noting that in the GIST classification there is recognition of SDH deficiency GIST - Tumours of uncertainly differentiation: There are new groups added to the 2013 classification: "Haemosidrotic fibrolipomatous tumour" and “Phosphaturic mesenchymal tumor” The term "primitive neuroectodermal neoplasm" (PNET) (synonymous with Ewing's sarcoma) has been dropped from this classification This is to reduce complex histological and genomic differences, similarity of names, PNETs of the central nervous system, and female genital tract - Undifferentiated/unclassified sarcomas: This group of tumors is new to the WHO 2013 classification, and is referred to as a tumor that cannot be classified into any other class because it cannot be proven otherwise histological, IHC, or molecular biology 1.2.2 Histological classification of soft tissue sarcomas of the 5th World Health Organization (2020) The fifth edition of the WHO's Classification of Bone and Soft Tissue Tumors was published in early 2020, seven years after the fourth edition New updates on classification are based on new genetic databases, prompting the introduction of several new histopathological subtypes and regrouping of some tumor types The chapter on soft tissue tumors in particular includes the addition of recently described tumor types; In some cases, more and more molecular biology research results are used to inform the reclassification of soft tissue tumors or to change the nomenclature and management of the disease Despite the increasing contribution of molecular biology, new classifications continue to emphasize the central diagnostic role of morphology In addition to introducing “new” soft tissue tumor types, this classification also provides prognostic updates for familiar tumors such as dedifferentiated liposarcomas and solitary fibrous tumours The classification also includes discussions focusing on a range of genetic alterations recently described in soft tissue tumours The past decade has been full of new discoveries of gene fusions in rare soft tissue tumors These include genetic alterations that are relevant to diagnostic practice An example is the chapter on undifferentiated small round cell sarcomas; The discovery of new gene fusions has led to the subtype of formerly "Ewinglike" sarcomas into new types with distinct clinical, morphological and immunohistochemical manifestations 1.3 The role of immunohistochemistry in the diagnosis of soft tissue sarcoma IHC is a special staining technique that uses specific antibodies to determine the presence of antigens on a slice of tissue or on different types of cells present in the tissue The basic principle is that when applying a tissue-specific antibody, if the antigen is present in the tissue, an antigenantibody combination reaction will occur In the diagnosis of STS, IHC not only detects the differentiation of tumor cells, helps to accurately classify each histopathological type and distinguishes it from other cancers, but also detects abnormal proteins generated from combined genes due to tumorspecific translocations or abnormal proteins produced by mutations in some genes involved in tumorigenesis Therefore, although it is an immunological technique, it reflects the lesion characteristics at the molecular level Nowadays, the introduction of automated IHC staining machines has improved the technical quality Many new studies on IHC and many new markers are significant in the diagnosis of STS In STS diagnostic practice, IHC can be used with main roles: - Distinguish with benign lesions (pseudo-STS) - Distinguish with non-sarcoma undifferentiated malignancies - Classification of sarcomas 1.4 Prognosis of soft tissue sarcomas 1.4.1 Significant factors in the prognosis of soft tissue sarcoma Prognostic factors include main groups: patient-related factors, tumor-related factors, and treatment-related factors Some factors are significant in the prognosis of STS such as: age, tumor location, tumor size, surgical resection margin (R), histopathological type, histological grade, TNM 1.4.2 Ki-67 marker in the prognosis of soft tissue sarcoma Several histological grading systems based on IHC have been proposed, of which Ki-67 - a protein involved in cell proliferation - is the most widely studied marker Furthermore, this method shows high validity and reproducibility in histological classification of STS by semiquantitative method In addition, several studies have demonstrated that Ki67 expression level is an independent predictor of survival in STS 1.4.3 Update on prognostic factors of some soft tissue sarcomas according to WHO 2020 Table 1.3 WHO 2020 Classification: New concepts in nomenclature, grade and risk factor stratification Tumor type What's new? Malignant melanotic Change in nomenclature (formerly melanoma nerve sheath tumour Schwann cell tumor) to indicate clinical malignancy Dedifferentiated Adverse effects of high histologic grade according liposarcoma to FNCLCC, as well as with muscle differentiation (especially rhabdomyolysis) were noted Solitary fibrous tumor Prognostic model predicts risk of metastasis, using patient age, mitotic rate, tumor size, and necrosis CHAPTER RESEARCH SUBJECTS AND METHODS 2.1 Research subjects 2.1.1 Research subjects The study was carried out on STS cases according to the classification of the WHO 2013, at the Department of Pathology - Viet Duc Hospital, from January 1, 2016 to December 31, 2020 2.1.2 Selection criteria The patient must meet all of the following criteria: - Primary STSs of head and neck, extremities, trunk, retroperitoneum intra-abdominal, pleura - mediastinum - Type of specimen: Surgical specimen - There are templates and paraffin blocks for storage - Tissue samples are sufficiently exploited, still have antigenicity (based on staining of negative and positive controls), and tumor tissue samples have enough IHC staining 2.1.3 Exclusion criteria - Tumors from bone, viscera or gastrointestinal tract invading soft tissue - Needle biopsies - Necrotic specimens not meet the criteria for histopathology, IHC or genetic analysis - No more paraffin blocks or poor quality paraffin blocks 2.2 Research Methods - Study design: The study was designed by cross-sectional descriptive method - Research sample size: Selected 363 cases suitable for research subjects - How to select research sample: All cases of STS satisfying the selection criteria (2.1.2) and exclusion criteria (2.1.3) were selected into the study sample 2.3 Research contents 2.3.1 Research variables and indicators 2.3.1.1 Some clinical features - Age: Percentage of age groups (5 to ≤10 cm; >10 to ≤15 cm; >15 cm Determine the percentage - Tumor depth: Determine the percentage of tumors in the superficial or deep (in large muscle mass, intra-abdominal, mediastinum, meninges ) - Surgical resection margin: Determine the percentage of R0, R1, R2 according to AJCC 10 2.6 Ethics in research The study was conducted on patient tumor specimens, from archival specimens and paraffin blocks, without performing procedures on patients The study was approved by the ethics committee in biomedical research – Hanoi Medical University, certificate No 219/HĐĐĐHYHN, December 30, 2016 CHAPTER RESEARCH RESULTS 3.1 Some general results on age, gender, tumour position 3.2 Histopathological and immunohistochemical features 3.2.1 Some common features Table 3.3 Subgroups of soft tissue sarcomas by origin Group of Soft tissue sarcoma origin Quantity (n) Ratio (%) Adipocytic 97 26,7 Fibroblastic and myofibroblastic 106 29,2 So-called fobrohistiocytic 0,3 Smooth muscle 30 8,3 Skeletal muscle 22 6,1 Nerve sheath 17 4,7 Vascular 1,4 Chondro-osseous 0,3 EGIST 2,2 Perivascular 0 Uncertain differentiation 54 14,9 Undifferentiated/unclassified 22 6,1 363 100 Total Comments: Fibroblastic and myofibroblastic sarcomas accounts for the highest proportion with 29.2%, followed by liposarcoma with 26.7%, sarcoma of uncertain differentiation group with 14.9% The group of socalled fibrohistiocytic tumour and chondro-osseous tumour had case (accounting for 0.3%) There are no cases in the perivascular group 3.2.2 Histopathological characteristics, immunohistochemistry of some histopathological subtypes ● Liposarcoma: - Histopathological type: Among the total 97 cases of liposarcoma, the dedifferentiated type had the highest rate (50.5%), followed by the Welldifferentiated type (37.1%), the myxoid type (12.4%) 11 - Immunohistochemical features: Table 3.5 Characterization of some IHC markers of liposarcoma Marker Type Positive foci N (rate) Diffuse positivity N (rate) 15 (34,9%) 21 (48,8%) (16,3%) 43 (100%) MDM2 (7%) 25 (43,9%) 28 (49,1%) 57 (100%) CDK4 (2,5%) 14 (35%) 25 (62,5%) 40 (100%) HMGA2 (7,1%) (19,1%) 31 (73,8%) 42 (100%) S100 Negative N (ratio) Total N (ratio) Comments: In the study, there was case of dedifferentiated liposarcoma with a focal point of differentiation with a rhabdomyoblast component positive for Desmin and Myogenin, with a spindle cell component that was positive for MDM2 and CDK4 ● Fibroblastic and myofibroblastic tumours Table 3.6 Histopathological types of Fibroblastic and myofibroblastic tumours Histopathological type Quantity (n) Ratio (%) DFSP DFSP-FS Malignant solitary fibrous tumor Low grade fibroblastic sarcoma Myxofibrosarcoma Low grade fibromyxoid sarcoma Malignant inflammatory myofibroblastic tumor Total 24 21 50 1 22,6 19,8 47,2 0,9 7,5 0,9 0,9 106 100 Table 3.7 The relationship between DFSP and DFSP-FS with CD34 Histopathological CD34 diffusely type positive 17 (89,5%) DFSP CD34 foci positive or negative (10,5%) 19 (100%) Total DFSP-FS (43,7%) (56,3%) 16 (100%) Total 24 (68,6%) 11 (31,4%) 35 (100%) p = 0,009 12 Comments: In the DFSP group, the rate of CD34 positive or negative was very low, only 10.5%; while in the DFSP-FS group, the rate of CD34 positive or negative increased to 56.25%; statistically significant relationship with p = 0.009 Immunohistochemistry of solitary fibrous tumors: - STAT6: 19 cases of solitary fibrous tumors were stained with STAT6, 18/19 positive cases accounted for 94.7% - CD34: Table 3.8 Relationship between solitary fibrous tumors site and CD34 Location of CD34 CD34 foci solitary diffusely positive or Total fibroids positive negative (22,6%) 24 (77,4%) 31 (100%) Meningitis (62,5%) (37,5%) (100%) Other 12 (30,8%) 27 (69,2%) 39(100%) Total P = 0,029 Comments: In malignant solitary fibrous tumours, the rate of CD34 positive or negative in meningeal sites (77.4%) is much higher than in other sites than meninges (37.5%) The difference is statistically significant with p=0.029 ● Rhabdomyosarcoma: Histopathological type: in 22 cases of rhabdomyosarcoma, the most common was the embryonal rhabdomyosarcoma (40.9% (9/22), followed by the alveolar rhabdomyosarcoma 27.3% (6/22), the spindle cell rhabdomyosarcoma 18.2% (4/22), polymorphic rhabdomyosarcoma 9.1% (2/22), epithelioid rhabdomyosarcoma 4.5% (1/22) Immunohistochemistry: Myogenin was positive in 17/19 cases (89.5%), Myo-D1 was positive in 11/13 positive cases (84.6%), Desmin was positive in 19/19 positive cases ( 100%) ● Malignant Peripheral Nerve sheath Tumor (MPNST): Histopathology: In this study, we recorded 17 cases of MPNST, in which 3/17 cases of malignant Triton tumor (17.6%), 14/17 cases of normal type MPNST (82.4%) (02 cases with differentiated osteosarcomatous component), no cases with epithelioid type MPNST Immunohistochemistry: 3/3 cases of malignant Triton tumor were positive for Desmin, Myogenin and Myo-D1 in regions with rhabdomyoblast; 5/5 cases of MPNST of normal type are negative for these markers Over 10 cases were stained with H3K27me3, 6/10 cases of complete loss of 13 expression accounted for 60%, 1/10 cases of loss of regional disclosure accounted for 10%, 3/10 cases of no loss of disclosure accounted for 30% MPNST is positive for S100 (9/16 – 56.23%), SOX10 (3/10 – 30%) ● EGIST: EGIST accounts for 2.2% (8/363) in all STS and 5.9% (8/136) in retroperitoneal and intra-abdominal STS 6/8 cases of simple spindle cell EGIST accounted for 75%, 2/8 cases of mixed spindle cell and epithelioid EGIST accounted for 25%, no cases of EGIST simple epithelium IHC: 8/8 cases were diffusely positive for CD117 and DOG1 ● Sarcoma of uncertain differentiation: Table 3.10 Classification of sarcomas of uncertain differentiation Histopathological type Quantity (n) Ratio (%) Synovial sarcoma 28 51,9 Epithelioid sarcoma 12,9 Alveolar soft part sarcoma 9,2 Clear cell sarcoma 5,6 Extraskeletal myxoid chondrosarcoma 5,6 Extraskeletal Ewing's sarcoma 5,6 Desmoplastic small round cell tumor 5,6 Extrarenal malignant pecoma 1,8 Extrarenal malignant teratoid tumor 1,8 Total 54 100 Synovial sarcoma: In 28 cases of synovial sarcoma, there were 15 cases of monophasic spindle cell type (53.6%), eight cases of biphasic type (28.6%), and 05 cases of poorly differentiated type (17.8%) 14/28 cases had collagen-rich stroma, 02 cases had calcifications between spindle cells IHC: TLE1 was positive in 23/23 cases (100%), of which was diffusely positive 95.6% in histopathological types, 01 case was focally positive in poorly differentiated type; EMA was positive in 16/24 cases (66.7%), diffusely positive in 3/24 cases (12.5%); negative in 5/24 cases (20.8%); CK was positive in 15/22 cases (68.2%), diffusely positive in 1/22 cases (4.5%), negative in 6/22 cases (27.3%) Alveolar soft part sarcoma: 05 patients have similar microscopic appearance, with epithelial tumor cells, bright-colored or eosinophilic cytoplasm, central nuclei, rare atypical nuclei and mitotic nuclei, arranged arranged in a cavity, alveolar structure with a dense structure, interspersed with a proliferative vascular system IHC staining with TFE3 and both gave positive results at levels 2+ to 3+ Other markers (CK, CD56, 14 ChrommograninA, S100, Synaptophysin, Myogenin, Desmin, RCC, Pax-8, HMB45, MelanA, Hepa-1, ERG, TTF1, Inhibin, GFAP) were negative for differential diagnosis Epithelioid sarcoma (ES): 07 cases of ES in the study had similar histopathological images, rhabdoid cells or epithelial cells, large nuclei, clear nuclei, variable mitotic ratio (from 12 to 28), cytoplasm wide, some acidophilic, cell boundaries unclear The tumor has a central cord, cluster, foci, and necrotic structure that produces a pseudo-granuloma image IHC: Ck was positive in 7/7 cases (100%); EMA is positive in 4/4 cases (100%); CD34 positive drive 6/6 cases (100%); ERG was positive in 3/4 cases (75%); 6/6 cases were negative for CD31; 7/7 cases of complete loss of expression with INI1 marker (nuclear negative) 1/3 of cases (33.3%) had p63 positive for the disease ● Undifferentiated/unclassified sarcoma: Table 3.11 Histopathological types of undifferentiated/unclassified sarcomas Quantity Ratio Histopathological type (n) (%) Unclassified spindle cell sarcoma 36,4 Undifferentiated polymorphic sarcoma 31,9 Unclassified epithelial and spindle cell sarcomas 9,1 Undifferentiated epithelial cell sarcoma 4,5 Unclassified spindle cell and myxoid sarcoma 9,1 Undifferentiated round and spindle cell sarcoma 4,5 Myogenic-differentiated polymorphic sarcoma 4,5 Total 22 100 Immunohistochemistry: 22 IHC staining cases did not have specific markers They were negative for epithelial line markers (CK-, EMA-), melanoma lineage markers (S100-, HMB45-, MelanA-) 3.3 Some macroscopic and microscopic factors have prognostic significance 3.3.1 Some macroscopic factors - Size of the tumor: the smallest is 1.5 cm; the largest 50 cm; on average 11.3cm, ≤5cm has 88/363 cases (24.2%); >5-≤10cm has 120/263 cases (33.1%); >10- ≤15cm with 53/363 cases (14.6%); >15cm has 102/363 (28.1%) - Tumor depth: 87/363 cases (24%) tumors are superficial (subcutaneous); 276/363 cases (76%) deep tumors In which in trunk, 15 extremities and head and neck, deep tumors accounted for 59.2% (126/213) and superficial tumors accounted for 40.8% (87/213) 3.3.2 Surgical resection margin The rate of R0 was 28.7% (104/363); R1-2 was 71.3% (259/363), of which R1 was 50.6% 3.3.3 Histological grade according to FNCLCC - Over 355 cases of STS (except 08 cases of EGIST), histological grade III accounted for the highest rate 46.5% (165/355), followed grade II 30.1% (107/255) and grade I was 23.4% (83/355) Table 3.16 The relationship between histological grade according to FNCLCC and R Histological grade R0 R1-2 Total according to FNCLCC 40(48,2%) 43(51,8%) 83(100%) Grade I Grade II 29(27,1%) 78(72,9%) 107(100%) Grade III 30(18,2%) 135(81,8%) 165(100%) Total 99(27,9%) 256(72,1%) 355(100%) p < 0,0001 Comments: The higher the histological grade according to FNCLCC is, the higher the rate of R1-2 with p cm (23,5%) 13 (76,5%) 17 (100%) Total 24 (53,3%) 21 (46,7%) 45 (100%) p = 0,002 Comments: The rate of DFSP-FS was 28.6% in the group of tumor size ≤ cm, increased to 76.5% in the group of tumor size > cm, the relationship was statistically significant with p = 0.002 - R: The percentage of R1-2 cut area was 50% in DFSP, increased to 66.7% in DFSP-FS, the relationship was not statistically significant with p = 0.366 ● Prognostic stratification of solitary fibrous tumours Table 3.22 Risk stratification of solitary fibrous tumours Risk stratification for Quantity (n) Ratio (%) metastasis Low risk (0-3 points) 28 56 Moderate risk (4-5 points) 17 34 High risk (6-7 points) 10 Total 50 100 Comments: Over 50 cases of malignancy alone, the low-risk group accounted for the most 28 cases (56%), the high-risk group accounted for at least 10% ● Some prognostic factors for dedifferentiated liposarcoma - Histological grade of dedifferentiated liposarcoma according to FNCLCC: In 49 cases of dedifferentiated liposarcoma, there were cases of grade I (14,3%), 26 cases of grade II (53.1%), 16 cases of grade III (32.6%) ● Prognostic factors of EGIST Table 3.25 EGIST risk classification by size and mitotic count Tumor size Number of Risk group Mitosis/5mm (cm) patients (ratio) according to NIH >5 to ≤10 ≤5 (12,5%) Intermediary >5 to ≤10 >5 (25%) High >10 >5 (62,5%) High Comments: 1/8 cases belong to intermediate risk group (12.5%); 7/8 cases belong to high risk group (87.5%) 17 CHAPTER DISCUSSION 4.1 Regarding the histopathological and immunohistochemical characteristics Results from Table 3.3 in our study showed that sarcomas belonging to the fibroblast/fibroblast group accounted for the highest percentage (106/363; 29.2%); liposarcoma ranked second (97/363; 26.7%), followed by group of uncertain origin (14.9%), leiomyosarcoma ranked 4th (8.3%), followed by undifferentiated/unclassified sarcoma and rhabdomyosarcoma (both 6.1%), MPNST (4.7%); 08 cases of EGIST (2.2%), 05 cases of vascular origin (1.4%) and 01 case of osteochondrosis (0.3%) This result is similar to some previous studies that tumors of fibroblast/fibroblast origin and adipose origin are the most common Research by Coindre (1994), liposarcoma accounts for 13.7%, ranking second after malignant fibrous histiocytoma Research by Yusuf et al on 264 STS in general showed that rhabdomyosarcoma was the most common (20.5%), followed by DFSP (19.7%), liposarcoma ranked 3rd (12%) In general, there is a large difference in the rate of histopathological subtypes between authors, both at home and abroad The difference in research results of the authors shows the complexity, diversity in histopathology and the lack of consensus in diagnostic criteria among pathologists Tumors in different tumor locations have different histopathological images, research by Nguyen Dai Binh and Bui Thi My Hanh on peripheral soft tissue sarcoma, liposarcoma only ranks 6th because these two studies did not STS are in the abdominal cavity and retroperitoneum where liposarcomas are most common On the other hand, the variation in the results of the studies by the authors is due to the studies carried out in different times, using different classifications Previous studies also abused the term malignant fibrous histiocytoma in the diagnosis of sarcomas of histiocytic and fibrous origin, after adjustment, the rate of this histological type gradually decreased, to about 12 ,6% and 5% The 2013 WHO classification does not exist for the term malignant fibrous histiocytoma, tumors that resemble this type are classified as undifferentiated polymorphic sarcoma Moreover, the continuous development of science and technology applied in medicine has brought a deeper understanding of the pathology of STS, applied in diagnosis and 18 treatment, especially the New findings in cytogenetics (moderately positive) and molecular shrinkage of unclassified/ undifferentiated tumors IHC not only plays a role in the differential diagnosis of STS from benign pseudosarcoma or non-sarcoma malignancies (lymphoma, malignant melanoma, poorly differentiated carcinoma), but is also valuable in classifying sarcomas according to different origins However, despite making many IHC markers at home and abroad, in our study there were still 22 cases (6.1%) in the undifferentiated/unclassified group The development of science and technology, especially the positive mean and molecular biology in cancer in general and STS in particular, has helped to discover many new genes, help diagnose the disease, and at the same time help to disease classification, prognosis and treatment It is thanks to the development of molecular biology that has helped give birth to new classifications of the WHO 2013 and 2020 When new genes are discovered, scientists also try to find and create IHC markers of equivalent molecular significance to ease day-to-day diagnosis, replace expensive genetic tests, this is the research trend of present and future In this study, we initially used some molecularly significant IHC markers, which were performed at the surgery department of Viet Duc hospital or some pathology centers in Vietnam such as the Center for Pathology - Cytology at K hospital IHC with MDM2 and CDK4 markers is used in the definitive diagnosis of welldifferentiated and dedifferentiated liposarcoma and can be an alternative to FISH It is thanks to these markers that some cases were initially diagnosed as pleomorphic liposarcoma, but when IHC staining showed that tumor cells were positive for MDM2 or CDK4, it was re-diagnosed as dedifferentiated liposarcoma The rate of these markers in our study is similar to other studies The STAT6 marker has high sensitivity and specificity in solitary fibrous tumours INI1 was lost to expression in epithelioid sarcoma (7/7 cases) and malignant extrarenal teratoid tumour (1/1 case) MUC4 was positive for cytoplasm in low-grade fibromyxoid sarcoma (1/1 cases) TFE3 is positive for tumor cell nuclei in alveolar soft part sarcoma TLE1 is positive in all types of synovial sarcoma In addition, a number of other new IHC markers made at the Anatomy Pathology Center (USA) such as H3K27me3, ETV4, NKX2.2, BCOR, CCNB3 These markers really helped for Diagnosis and identification of histopathological type, thereby classifying the disease, helping to predict 19 and treat the disease Molecular biology techniques (FISH) are also used in some specific cases (difficult, rare cases) or immunohistochemistry shows weak, atypical due to poor fixation FISH technique is used to identify some genes such as: DDIT3, MDM2, PGDFB, EWSR1 Although the number is not much, the research is a premise for pathology departments in Vietnam to develop more molecularly significant immunohistochemical markers, deploy molecular biology techniques in the diagnosis of STS in particular and cancer in general 4.2 Regarding some macroscopic and microscopic factors with prognostic significance ● Tumor size The larger the tumor is, the more difficult it is to perform conservative surgery and often have distant metastases when first diagnosed The results of this study showed that: tumors > 5cm (75.8%), tumors >10 cm (42.7%) The study of Alexander S et al on 2084 primary soft tissue sarcoma in adults also showed similar tumor size with 759 cases (36.7%) tumor ≤ cm, 631 cases (30.4%) tumor 5.1- 10 cm and 680 cases (32.4%) with tumors > 10 cm; When considering the rate of R1 according to the primary tumor size: ≤ cm (13%); 5.1 - 10 cm (19%); 10.1 - 15 cm (26%); 15.1 - 20 cm (37%); and > 20 cm (43%) (P < 0.001) From the results of studying prognostic factors for soft tissue sarcoma in the trunk and retroperitoneum, author Singer S and colleagues came to the conclusion that tumors with large size > cm (p = 0.018) are the important independent prognostic factor for survival ● Surgical resection margin In order to avoid local recurrence and distant metastases, the surgical resection must be "clean" i.e free of tumor cells and at least mm from healthy tissue Negative surgical resection after surgery had a low local recurrence rate (9%) despite not receiving adjuvant radiotherapy Positive surgical resection is a poor prognostic factor for both recurrence and survival In this study, the rate of negative microscopic section was very low 28.7% (104/363); the positive section rate is high 71.3% (259/363) (of which the microscopic positive (R1) is 50.6% (184/363)) Studies analyzing the prognostic factors of deep and retroperitoneal soft tissue sarcoma have shown that a significant prognostic factor in metastatic survival is local disease control The 5-year metastasis-free survival was 73% for locally 20 controlled soft tissue sarcomas compared with 19% for locally recurrent soft tissue sarcomas at years (p=0.0013) ● Histological grade Over time, many histological grading tables have been proposed, but currently the FNCLCC is the most widely applied and has been recommended by the WHO for use in clinical new type of STS This system is more precisely defined, clearer, and potentially more repeatable in the practice of pathologists Histological grading of STSs according to FNCLCC is based on necrosis, mitotic index and tumor differentiation When grading histology according to FNCLCC on 355 STSs, our study results showed that grade III is the most common (46.5%), followed by grade II (30.1%) and low grade especially grade I (23.4%) This result is quite similar to the results of Bui Thi My Hanh (2010): Grade III STS is the most common (43.1%), followed by grade II (39.4%) and the lowest is grade II I (17.5%) but it is much different from the study of Nguyen Dai Binh (2003) who also ranks peripheral soft tissue sarcomas according to the FNCLCC, grade I is the most common (44%) and the lowest is grade III (15.7%) Studying the relationship between histological grade according to FNCLCC and surgical resection on 355 patients (except GIST) found that histology grade I has a positive rate of 51.8%, this rate is high in the grade I group Histological grade II was 72.9% and histology grade III was 81.8% Thus, the higher the histology, the higher the percentage of surgical resection and the higher the tumor with p