Expression of Forkhead Box M1 and Anticancer Effects of FOXM1 Inhibition in Epithelioid Sarcoma.

Epithelioid sarcoma (ES) is a rare aggressive sarcoma that, unlike most soft-tissue sarcomas, shows a tendency toward local recurrence and lymph node metastasis. Novel antitumor agents are needed for ES patients. Forkhead box transcription factor 1 (FOXM1) is a member of the Forkhead transcription factor family and is associated with multiple oncogenic functions; FOXM1 is known to be overexpressed and correlated with pathogenesis in various malignancies. In this study, we immunohistochemically analyzed FOXM1 expression levels and their clinical, clinicopathologic, and prognostic significance in 38 ES specimens. In addition, to investigate potential correlations between FOXM1 downregulation and oncologic characteristics, we treated ES cell lines with thiostrepton, a naturally occurring antibiotic that inhibits both small interfering RNA (siRNA) and FOXM1. In the analyses using ES samples, all 38 specimens were diagnosed as positive for FOXM1 by immunohistochemistry. We separated specimens into high (n = 19) and low (n = 19) FOXM1-protein expression groups by staining index score, and into large (n = 12), small (n = 25), and unknown (n = 1) tumor-size groups using a cutoff of 5 cm maximum diameter. Although there were significantly more samples with high FOXM1 expression in the large tumor group (P = .013), there were no significant differences with respect to age (P = 1.00), gender (P = .51), primary site of origin (P = .74), histologic subtypes (P = 1.00), depth (P = .74), or survival rate (P = .288) between the high and low FOXM1-protein expression groups. In the in vitro experiments using ES cell lines, FOXM1 siRNA and thiostrepton successfully downregulated FOXM1 mRNA and protein expression. Furthermore, downregulation of FOXM1 inhibited cell proliferation, drug resistance against chemotherapeutic agents, migration, and invasion and caused cell cycle arrest in the ES cell lines. Finally, cDNA microarray analysis data showed that FOXM1 regulated cIAP2, which is one of the apoptosis inhibitors activated by the TNFα-mediated NF-κB pathway. In conclusion, the FOXM1 gene may be a promising therapeutic target for ES.

Multiple Lymphaticovenular Anastomoses for Chyluria in Klippel-Trenaunay Syndrome.

ABSTRACT: Klippel-Trenaunay syndrome (KTS) is characterized by port-wine stains, mixed vascular malformations, and soft tissue and bone hypertrophy. Klippel-Trenaunay syndrome is occasionally complicated by chyluria, for which there is no effective treatment currently. We report a case of KTS complicated by intractable chyluria and hematuria due to a lymphatic-ureteral fistula. The patient was successfully treated with multiple lymphaticovenular anastomoses (LVAs).A 66-year-old woman with an enlarged left lower extremity since childhood was diagnosed with KTS. At 60 years of age, she developed chyluria (urine albumin, 2224 µg/mL) and hematuria. Lymphoscintigraphy showed a lymphatic-ureteral fistula near the ureterovesical junction. Conservative treatment was ineffective. She also developed left lower extremity lymphedema, which gradually worsened. Leg cellulitis and purulent pericarditis developed because of hypoalbuminemia (minimum serum albumin level, 1.3 g/dL).We performed 14 LVAs in 2 surgeries to reduce lymphatic fluid flow through the lymphatic-ureteral fistula. The chyluria and hematuria resolved soon after the second operation, and the urine albumin level decreased (3 µg/mL). After 28 months, she had no chyluria or hematuria recurrence and her serum albumin level improved (3.9 g/dL). Multiple LVAs can definitively treat chyluria caused by a lymphatic-ureteral fistula in patients with KTS.

A pathological complete response after immunotherapy with pembrolizumab for distal duodenal adenocarcinoma caused by Lynch syndrome: a case report.

Primary adenocarcinoma of the duodenum is a rare neoplasm that is often microsatellite instability-high (MSI-H). Pembrolizumab, a monoclonal antibody, has been recently approved in Japan for treatment of MSI-H solid tumors. Lynch syndrome is a frequent hereditary cancer predisposition syndrome. It is linked to an increased risk of various types of cancer, including colorectal and endometrial cancer, and is closely related to MSI-H. We present the case of a 55-year-old woman who was diagnosed with duodenal cancer. Biopsy findings revealed MSI-H, and pembrolizumab therapy was initiated because the tumor was in contact with the left renal vein and had metastasized to the mesenteric lymph nodes of the small intestine. Subsequently, after completing two courses of pembrolizumab therapy, the patient developed duodenal stenosis and underwent surgery. Pathological analysis of the resected specimen revealed no evidence of malignancy. Given the patient's previous cancer history and the occurrence of cancer in close relatives, genetic testing of peripheral blood was performed, which revealed the diagnosis of Lynch syndrome. Furthermore, the variant responsible for Lynch syndrome was found to be a mutation of NM_000251.3:c.211 + 1G > C in MSH2.

Cortical high-flow sign on arterial spin labeling: a novel biomarker for IDH-mutation and 1p/19q-codeletion status in diffuse gliomas without intense contrast enhancement.

This study aimed to investigate whether arterial spin labeling (ASL) features allow differentiation of oligodendroglioma, IDH-mutant and 1p/19q-codeleted (IDHm-codel) from diffuse glioma with IDH-wildtype (IDHw) or astrocytoma, IDH-mutant (IDHm-noncodel). Participants comprised 71 adult patients with pathologically confirmed diffuse glioma, classified as IDHw, IDHm-noncodel, or IDHm-codel. Subtraction images were generated from paired-control/label images on ASL and used to assess the presence of a cortical high-flow sign. The cortical high-flow sign was defined as increased ASL signal intensity within the tumor-affecting cerebral cortex compared with normal-appearing cortex. Regions without contrast enhancement on conventional MR imaging were targeted. The frequency of the cortical high-flow sign on ASL was compared among IDHw, IDHm-noncodel, and IDHm-codel. As a result, the frequency of the cortical high-flow sign was significantly higher for IDHm-codel than for IDHw or IDHm-noncodel. In conclusion, the cortical high-flow sign could represent a hallmark of oligodendroglioma, IDH-mutant, and 1p/19q-codeleted without intense contrast enhancement.

Prognostic implications of the immunohistochemical expression of perilipin 1 and adipophilin in high-grade liposarcoma.

AIMS: Liposarcoma is a malignant soft tissue tumour with adipocytic differentiation. Dedifferentiated liposarcoma (DDLS) and myxoid liposarcoma (MLS) are classified as high-grade liposarcomas. Lipid droplet-associated protein (also known as perilipin 1 (PLIN1)) is the predominant perilipin and has utility as a specific marker of adipogenic differentiation. Adipose differentiation-related protein (also known as adipophilin (ADRP)) is ubiquitously expressed in a range of tissues. High ADRP expression is reportedly a poor prognostic factor in several cancer types. However, no previous studies have examined the association between PLIN1 or ADRP expression and prognosis in sarcoma. This study therefore aimed to evaluate the association between PLIN1 or ADRP expression and prognosis in liposarcoma. METHODS: In total, 97 primary resection specimens (53 MLS and 44 DDLS) were examined in this study. PLIN1 and ADRP expression was evaluated by immunohistochemistry. Survival analyses were performed for MLS and DDLS. RESULTS: Of the 53 MLS specimens, 15 (28.3%) exhibited high PLIN1 expression. PLIN1 expression was not observed in DDLS specimens. High PLIN1 expression was significantly associated with increased disease-free survival (DFS) among patients with MLS (p=0.045). Distinct ADRP expression was observed in 13 of 53 (24.5%) MLS specimens and 5 of 44 (11.4%) DDLS specimens. High ADRP expression was associated with shorter overall survival (OS) in MLS (p=0.042) and DFS and shorter OS in DDLS (p=0.024 and p<0.001, respectively). CONCLUSIONS: PLIN1 and ADRP expression is associated with poor prognosis in high-grade liposarcoma.

Expression of SATB2, RUNX2, and SOX9 and possible osteoblastic and chondroblastic differentiation in chondroblastoma.

Chondroblastoma (CB) is histologically characterized by oval to polygonal-shaped mononuclear neoplastic cells, multinucleated osteoclastic giant cells, and eosinophilic matrix with occasional calcification. Genetically, the majority of CBs harbor H3F3B p.K36M mutation. Despite the historical nomenclature, it has been reported that the matrix of CB is similar to osteoid rather than true cartilage; however, it remains unclear whether neoplastic cells in CB have the potential for osteoblastic differentiation. To clarify this issue, we immunohistochemically examined the expression of osteogenic and chondrogenic markers (SATB2, RUNX2, p63, and SOX9) as well as H3K36M mutant protein in 33 cases of CB. All 33 cases of CB were positive for H3K36M, while SATB2, RUNX2, p63, and SOX9 were expressed in 30/33 (91%), 33/33 (100%), 29/33 (88%), and 31/32 (97%) CB cases, respectively. Our immunohistochemical results suggest that neoplastic cells in CB frequently express both osteogenic and chondrogenic markers and may have an intermediate feature of osteoblastic and chondroblastic nature.

A new scoring system for the grading of conventional chondrosarcoma: Its clinicopathological significance.

BACKGROUND: Chondrosarcoma is the second most common primary malignant bone tumor, which produces cartilaginous matrix without neoplastic osteoid or bone formation. The histological grade in the WHO Classification of Soft Tissue and Bone (2020 edition) is the most important factor in predicting the clinical outcome of conventional chondrosarcoma, but the lack of clarity in its detailed definition is occasionally problematic. Here, we reviewed conventional chondrosarcoma cases and validated the significance of histological findings. Moreover, we proposed a new scoring system of conventional chondrosarcoma. MATERIAL AND METHODS: Clinicopathological features of 60 cases of conventional chondrosarcoma and 21 cases of dedifferentiated chondrosarcoma were reviewed. RESULTS: Moderate to severe nuclear atypia was correlated with distant metastasis. Moderate and severe nuclear atypia, high cellularity, and >1 % myxoid change were correlated with adverse overall survival. On the other hand, cases with mild nuclear atypia showed no tumor-related death and no metastases. Based on the above results, we proposed a new scoring system based on nuclear atypia (mild: 0, moderate: +1, severe: +2), cellularity (no and mildly increased cellularity: 0, moderately and diffusely increased cellularity: +1), necrosis [(-): 0, (+): + 1], and chondromyxoid area [(-): 0, (+): + 1]. Each grade was defined as follows: cases with only mild nuclear atypia as grade 1, cases with total score 1-3 excluding mild nuclear atypia as grade 2, and cases with total score 4 or 5 as grade 3. There were 18 cases (30 %) of grade 1 including 5 cases (28 %) of local recurrence, but no metastasis or tumor-related death; 26 cases (43 %) of grade 2 including 2 cases (8 %) of local recurrence, 3 cases (12 %) of metastasis, and 1 case (4 %) of tumor-related death; and 16 cases (27 %) of grade 3 including 4 cases (25 %) of local recurrence, 6 cases (38 %) of metastasis, and 5 cases (31 %) of tumor-related death. There was no statistically significant association between the histological findings and dedifferentiation. CONCLUSION: From this study, we propose a new histological scoring system for the grading of conventional chondrosarcoma, based on nuclear atypia, cellularity, necrosis, and myxoid change. Using this system, conventional chondrosarcoma may be clearly classified into three grades: grade 1, non-metastasizing; grade 2, metastasizing but rarely life-threatening; and grade 3, frequently metastasizing and life-threatening.

Myxoid type and non-myxoid type of intimal sarcoma in large vessels and heart: review of histological and genetic profiles of 20 cases.

Intimal sarcoma is one of the most common and well-known primary malignant neoplasms of the aorta and heart. The authors reviewed cases of intimal sarcoma from histological, immunohistochemical and genetic perspectives. Twenty cases of intimal sarcoma were retrieved. Immunohistochemistry and FISH of MDM2 and PDGFRA genes were performed. All 20 tumours were composed of spindle-shaped, stellate, oval or polygonal tumour cells with irregular hyperchromatic nuclei arranged in a haphazard pattern, accompanied by nuclear pleomorphism and frequent mitotic figures. Other histological findings were as follows: abnormal mitosis in 10 cases (50%), necrosis in 15 cases (75%), myxoid stroma in 12 cases (60%), cartilaginous formation in 1 case (5%), haemorrhage in 12 cases (60%) and fibrinous deposition in 14 cases (70%). The tumours were positive for MDM2 in 16 cases (80%), ERG in 4 cases (20%), alpha-smooth muscle actin in 6 cases (30%), desmin in 5 cases (25%) and AE1/AE3 in 4 cases (20%). Immunohistochemical positivity was focal in each case. Loss of H3K27me3 expression was noted in 2 cases (10%). MDM2 and PDGFRA gene amplifications were detected in 11 cases (55%) and 1 case (5%), respectively. Fisher's exact test revealed a significant correlation between MDM2 gene amplification and myxoid stroma (p = 0.0194). No parameters showed any association with the anatomical location of the tumours. It was suggested that myxoid histology of intimal sarcoma may be associated with MDM2 gene amplification and that intimal sarcoma may be divided into myxoid and non-myxoid types.

Histological background of dedifferentiated solitary fibrous tumour.

AIMS: Dedifferentiation is a histological phenomenon characterised by abrupt transition of histology to a sarcomatous component with high-grade malignant potential in solitary fibrous tumour (SFT). The authors histologically reviewed SFT cases to reveal the histological background of dedifferentiated SFTs. METHODS: Clinicopathological and histopathological findings of 145 SFT cases were reviewed. Immunohistochemical staining and genetic analysis were also performed. RESULTS: The non-dedifferentiated components showed a cellular component in 45 of 145 (31%), high mitotic rate (≥4/10 high-powered field) in 12 of 145 (8.2%) tumours, necrosis in 7 of 145 (4.8%) tumours, multinodular growth pattern in 39 of 132 (29.5%) available tumours and intratumoural fibrous septa in 37 of 131 (28.2%). Immunohistochemically, the non-dedifferentiated components were positive for CD34 in 128 of 141 (90.7%), bcl-2 in 101 of 133 (75.9%), nuclear pattern of ß-catenin in 64 of 127 (50.3%) and p16 in 22 of 140 (15.7%). Loss of Rb protein expression was detected in 17 of 110 (15.4%) cases. Statistically, cellular component, multinodular structure, p16 overexpression and Rb protein loss were significantly associated with dedifferentiation. Moreover, cellular component and multinodular structure were significantly associated with p16 overexpression and Rb protein loss. All the non-deddifferentiated components showed wild type of p53 expression. The dedifferentiated components of all 10 dedifferentiated tumours presented positivity for p16 in 9 of 10 (90%) and mutational type of p53 in 5 of 10 (50%). Loss of Rb protein expression was detected in 6 of 10 (60%). CONCLUSIONS: The authors propose that cellular or multinodular transformation may be associated with dedifferentiation. They also suggest that cellular and multinodular transformation may be associated with p16 overexpression and Rb downregulation.

Histological and immunohistochemical features and genetic alterations in the malignant progression of giant cell tumor of bone: a possible association with TP53 mutation and loss of H3K27 trimethylation.

In rare cases, giant cell tumor of bone (GCTB) can undergo primary or secondary malignant transformation to malignant giant cell tumor of bone (MGCTB), but the details of the molecular alterations are still unclear. The present study aimed to elucidate the clinicopathologic and molecular features of MGCTBs based on immunohistochemistry, fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) of nine MGCTBs (five primary and four secondary). Seven (78%) of 9 MGCTBs were immunohistochemically positive for H3.3 G34W. In two (22%) patients, although GCTB components were focally or diffusely positive for H3.3 G34W, their malignant components were entirely negative for H3.3 G34W, which was associated with heterozygous loss of H3F3A by FISH. NGS on four MGCTBs revealed pathogenic mutations in TP53 (n = 3), EZH2 (n = 1) and several other genes. Immunohistochemical analysis of the nine MGCTBs confirmed the p53 nuclear accumulation (n = 5) and loss of H3K27me3 expression (n = 3) and showed that they were mutually exclusive. In addition, four (80%) of five cases of pleomorphic or epithelioid cell-predominant MGCTBs were positive for p53, while three (75%) of four cases of spindle cell-predominant MGCTBs were negative for trimethylation at lysine 27 of histone 3 (H3K27me3). The results suggested that p53 alteration and dysfunction of histone methylation as evidenced by H3K27me3 loss may play an important role in the malignant progression of GCTB, and might contribute to the phenotype-genotype correlation in MGCTB. The combined histologic, immunohistochemical and molecular information may be helpful in part for the diagnosis of challenging cases.

Clinicopathological and histopathological review of dedifferentiated liposarcoma: a comprehensive study of 123 primary tumours.

AIMS: Dedifferentiated liposarcoma (DDLS) has varying histopathological features, but their significance for the biological behaviour of this disease has not been fully clarified. The aim of this study was to elucidate the prognostic factors for DDLS by clinicopathologically reviewing a large case series. METHODS AND RESULTS: We clinicopathologically reviewed 123 cases of primary de-novo DDLS without preoperative treatment, including 81 in the internal trunk (internal DDLS) and 42 in peripheral sites (peripheral DDLS). Univariate and multivariate analyses of their features were also performed for all cases, the internal DDLS group, and the peripheral DDLS group. The results showed that, in all three groups, distant metastasis was significantly associated with shorter overall survival (OS) (univariate analysis, P < 0.0001, P = 0.0011, and P = 0.0101, respectively), whereas local recurrence showed no significant effect on prognosis. Histopathologically, a high mitotic count and the presence of round tumour cells were significantly associated with shorter OS in multivariate analysis of the internal DDLS group [respectively: P = 0.0022, hazard ratio (HR) 4.39, 95% confidence interval (CI) 1.71-11.28; and P = 0.0014, HR 7.19, 95% CI 2.14-24.16]. In the peripheral DDLS group, necrosis and high-grade histological components were significantly associated with shorter OS (univariate analysis, P = 0.0068 and P = 0.0174, respectively). CONCLUSIONS: The presence of round tumour cells may be one of the histological factors associated with a worse prognosis of DDLS patients, as previous studies indicated. This study also suggests that distant metastasis may be predictive of prognosis for both internal and peripheral DDLS, rather than local recurrence.

Prognostic implication of desmoplastic stroma in synovial sarcoma: A histological review.

Synovial sarcoma (SS) is a malignant soft tissue neoplasm harboring SS18-SSX fusion gene and is histologically characterized by spindle cells and epithelial components. Some investigations have demonstrated that desmoplastic reaction (DR) is an independent prognostic factor of cancers. However, it remains unknown whether DR is of predictive value for the prognosis of synovial sarcoma patients. Here, we reviewed the clinical and histological findings of 88 patients with SS. We defined DR as hyalinized collagenous structures and classified the degree of DR as follows: none, mild, moderate, and severe. Overall, 23 SS cases (24%) showed moderate or severe DR histologically. Statistically, the cases with moderate or severe degree of DR showed poorer prognosis than those with no or mild DR (local recurrence: P = 0.0059, distant metastasis: P = 0.0002, tumor death: P = 0.0382). The findings of the study suggest that the DR of synovial sarcoma could be an important prognostic factor.

Lenvatinib for poorly differentiated carcinoma of the anterior mediastinum.

We describe a Case of a 74-year-old Japanese man with poorly differentiated carcinoma of the anterior mediastinum. The patient underwent anterior mediastinal tumor resection through median sternotomy. The tumor, 7.0 × 5.0 cm, had invaded surrounding tissues (pericardium, right lung, right and left brachiocephalic veins, and superior vena cava). Complete resection of the tumor was not performed. One month after the operation, the patient developed multiple pulmonary metastases, right pleural dissemination, and carcinomatous pleurisy. He was treated with lenvatinib, a novel multi-kinase inhibitor, to which the metastasis responded favorably. This case reports for the first time the clinical usefulness of lenvatinib for poorly differentiated carcinoma of the anterior mediastinum. Management of side effects by several methods, including suspending use of medication on weekends (called a weekends-off strategy), is another strong argument to continue lenvatinib administration.

Clinicopathological and prognostic significance of H3K27 methylation status in malignant peripheral nerve sheath tumor: correlation with skeletal muscle differentiation.

Malignant peripheral nerve sheath tumor (MPNST) is a very aggressive peripheral nerve sheath-derived sarcoma, which is one of the most difficult tumors to diagnose due to its wide spectrum of histological findings and lack of specific immunohistochemical markers. Recently, it has been reported that losses of expression of H3K27me3 and H3K27me2 caused by PRC2 dysfunction may be useful diagnostic markers for MPNST, but there is no consensus on their clinicopathological significance. Here, we investigated the relationship between loss of H3K27 methylation and various parameters and clarified the clinicopathological significance of such loss. We analyzed the clinicopathological and immunohistochemical features in 84 MPNST cases. Complete losses of H3K27me3 and H3K27me2 were observed in 37 (44%) and 29 (35%) cases, respectively. Losses of H3K27me3 and H3K27me2 were significantly correlated with myogenic immunopositivity (H3K27me3 vs. desmin, P = 0.0051; H3K27me3 vs. myogenin, P = 0.0009; H3K27me2 vs. myogenin, P = 0.042). Meanwhile, there were significant correlations between preservation of immunohistochemical neurogenic markers and intact H3K27me3 and H3K27me2 (H3K27me3 vs. S-100 protein, P = 0.0019; H3K27me3 vs. SOX10, P = 0.014; H3K27me2 vs. S-100 protein, P = 0.0011; H3K27me2 vs. SOX10, P = 0.0087). In multivariate analysis, local recurrence, distant metastasis, high FNCLCC grade, and loss of SOX10 expression were independent prognostic factors for overall survival. H3K27me3 and H3K27me2 expression was retained in all 26 cases of rhabdomyosarcoma non-alveolar subtype. In conclusion, we suggest that H3K27me3 and H3K27me2 immunonegativity is useful but not definitive for diagnosing MPNST. Complete loss of H3K27 methylation may be involved in aggressive transdifferentiation from neural differentiation to skeletal muscle differentiation in MPNST.

Tumor microenvironment in giant cell tumor of bone: evaluation of PD-L1 expression and SIRPα infiltration after denosumab treatment.

Giant cell tumor of bone (GCTB) is an intermediate malignant bone tumor that is locally aggressive and rarely metastasizes. Denosumab, which is a receptor activator of nuclear factor kappa B ligand (RANKL) inhibitor, can be used to treat GCTB. We focused on potential immunotherapy for GCTB and investigated the tumor microenvironment of GCTB. Programmed death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) expression and signal-regulatory protein alpha (SIRPα), forkhead box P3 (FOXP3), and cluster of differentiation 8 (CD8) infiltration were assessed by immunohistochemical studies of 137 tumor tissues from 96 patients. Of the naive primary specimens, 28% exhibited PD-L1 expression and 39% exhibited IDO1 expression. There was significantly more SIRPα+, FOXP3+, and CD8+ cell infiltration in PD-L1- and IDO1-positive tumors than in PD-L1- and IDO1-negative tumors. The frequency of PD-L1 expression and SIRPα+ cell infiltration in recurrent lesions treated with denosumab was significantly higher than in primary lesions and recurrent lesions not treated with denosumab. PD-L1 expression and higher SIRPα+ cell infiltration were significantly correlated with shorter recurrence-free survival. PD-L1 and SIRPα immune checkpoint inhibitors may provide clinical benefit in GCTB patients with recurrent lesions after denosumab therapy.

Myxoepithelioid tumour with chordoid features: a clinicopathological, immunohistochemical and genetic study of 14 cases of SMARCB1/INI1-deficient soft-tissue neoplasm.

AIMS: Complete loss of SMARCB1/INI1 in soft-tissue tumours such as malignant rhabdoid tumour, epithelioid sarcoma, myoepithelial tumour of soft tissue and extraskeletal myxoid chondrosarcoma is often associated with high-grade malignancy and poor prognosis. The diagnosis is sometimes challenging, owing to histological similarities, so careful differential diagnosis is required. Therefore, soft-tissue tumours with complete SMARCB1/INI1 loss could potentially include an unknown entity. METHODS AND RESULTS: We analysed 160 cases of SMARCB1/INI1-deficient soft-tissue tumour, and found 14 cases that were not classifiable into already existing categories and had common clinical and histological features. These involved two male and 12 female patients, ranging in age from 20 years to 61 years. The tumours were located in the the puboinguinal region (n = 13) and pelvic cavity (n = 1). Histologically, the tumours showed relatively uniform epithelioid to spindle-shaped cells with myxoid stroma. All tumours showed immunoreactivity for brachyury, epithelial membrane antigen, and progesterone receptor, and 12 of 14 cases did so for oestrogen receptor. Variable positive staining for α-smooth muscle actin, S100 and glial fibrillary acidic protein (GFAP) was seen. NR4A3 and EWSR1 gene rearrangements were not detected in 13 and 11 examined cases, respectively. Clinical follow-up data for the 14 patients showed that 13 were alive without disease and one had been lost to follow-up; four patients developed local recurrence and/or metastases. CONCLUSION: The designation 'myxoepithelioid tumour with choroid features' (METC) was proposed as a tumour with intermediate malignancy controllable with appropriate treatment, including the entity of myoepithelioma-like tumour of the vulvar region. METC represents a novel and independent subset that is histologically, biologically and clinically distinct from already existing SMARCB1/INI1-deficient soft-tissue tumours.

The association between the expression of PD-L1 and CMTM6 in undifferentiated pleomorphic sarcoma.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a sarcoma with a poor prognosis. A clinical trial, SARC028, revealed that treatment with anti-PD-1 drugs was effective against UPS. Studies have reported that UPS expresses PD-L1, sometimes strongly (≥ 50%). However, the mechanism of PD-L1 expression in UPS has remained unclear. CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) was identified as a novel regulator of PD-L1 expression. The positive relationship between PD-L1 and CMTM6 has been reported in several studies. The aim of this study was thus to examine CMTM6 expression in UPS and evaluate the relationship between PD-L1 and CMTM6 in this disease. MATERIALS AND METHODS: Fifty-one primary UPS samples were subjected to CMTM6 and PD-L1 immunostaining. CMTM6 expression was assessed using proportion and intensity scores. CMTM6 gene copy number was also evaluated using a real-time PCR-based copy number assay. We also analyzed the mRNA expression and copy number variation of PD-L1 and CMTM6 in The Cancer Genome Atlas (TCGA) data. RESULTS: TCGA data indicated that the mRNAs encoded by genes located around 3p22 were coexpressed with CMTM6 mRNA in UPS. Both proportion and intensity scores of CMTM6 positively correlated with strong PD-L1 expression (≥ 50%) (both p = 0.023). CMTM6 copy number gain increased CMTM6 expression. Patients with UPS with a high CMTM6 intensity score had a worse prognosis for overall survival. CONCLUSIONS: UPS showed variation in CMTM6 copy number and CMTM6 expression. CMTM6 expression was significantly correlated with PD-L1 expression, especially with strong PD-L1 expression.

Brachyury expression in intracranial SMARCB1-deficient tumors: important points for distinguishing poorly differentiated chordoma from atypical teratoid/rhabdoid tumor.

Loss of SMARCB1 protein expression has recently been identified in a variety of tumor types such as poorly differentiated chordoma (PCh) and malignant rhabdoid tumor (MRT) including atypical teratoid/rhabdoid tumor (AT/RT). PCh is characterized by poorly differentiated epithelioid tumor cells, sheet arrangement, and coexpression of nonepithelial and epithelial markers. Rhabdoid cells are sometimes present. Therefore, the differentiation of these tumors is often difficult. Brachyury is a transcription factor within the T-box family typically expressed in notochord tissue and chordomas. Some studies have reported high specificity and sensitivity of brachyury expression in chordomas. In the present study, we analyzed immunohistochemical brachyury expression in SMARCB1-deficient tumors and discuss important clinicopathological and diagnostic points, especially in cases of intracranial SMARCB1-deficient tumors with brachyury expression. Brachyury and cytokeratin immunoexpression status was examined in 42 formalin-fixed paraffin-embedded SMARCB1-deficient tumor specimens (PCh, 6 cases; extra-central nervous system [CNS] MRT, 26 cases; AT/RT, 10 cases) and 25 cases of conventional chordoma (CCh). All cases of PCh and CCh showed diffuse immunopositivities for cytokeratin 8, pan-cytokeratin, and brachyury. Brachyury immunoexpression was present in 2 extra-CNS MRT (8%) and 5 AT/RT (50%) cases, but immunopositivity was focal not diffuse. Indeed, in almost all cases of AT/RT (cytokeratin 8, 7/10 cases; pan-cytokeratin, 7/10 cases) and extra-CNS MRT (cytokeratin 8, 23/26 cases; pan-cytokeratin, 25/26 cases), fewer than 50% of cells showed immunoreactivity. Although the histological and clinical features of PCh resemble those of AT/RT, semiquantitative evaluations of the degree of brachyury and cytokeratin immunoexpressivity may help to distinguish PCh from AT/RT.