Expanding the Spectrum of NUTM1-Rearranged Sarcoma: A Clinicopathologic and Molecular Genetic Study of 8 Cases.

Apart from the lethal midline carcinoma (NUT carcinoma), NUTM1 translocation has also been reported in mesenchymal tumors, but is exceedingly rare. Here, we describe a series of 8 NUTM1-rearranged sarcomas to further characterize the clinicopathologic features of this emerging entity. This cohort included 2 males and 6 females with age ranging from 24 to 64 years (mean: 51 y; median: 56 y). Tumors occurred in the colon (2), abdomen (2), jejunum (1), esophagus (1), lung (1) and infraorbital region (1). At diagnosis, 6 patients presented with metastatic disease. Tumor size ranged from 1 to 10.5 cm (mean: 6 cm; median: 5.5 cm). Histologically, 4 tumors were composed of primitive small round cells to epithelioid cells intermixed with variable spindle cells, while 3 tumors consisted exclusively of small round cells to epithelioid cells and 1 tumor consisted predominantly of high-grade spindle cells. The neoplastic cells were arranged in solid sheets, nests, or intersecting fascicles. Mitotic activity ranged from 1 to 15/10 HPF (median: 5/10 HPF). Other features included rhabdoid phenotype (4/8), pronounced nuclear convolutions (2/8), prominent stromal hyalinization (2/8), focally myxoid stroma (1/8), foci of osteoclasts (1/8), and necrosis (1/8). By immunohistochemistry, all tumors showed diffuse and strong nuclear staining of NUT protein, with variable expression of pancytokeratin (AE1/AE3) (2/8), CK18 (1/8), CD99 (3/8), NKX2.2 (2/8), cyclin D1 (2/8), desmin (2/8), BCOR (2/8), S100 (1/8), TLE1 (1/8), and synaptophysin (1/8). Seven of 8 tumors demonstrated NUTM1 rearrangement by fluorescence in situ hybridization analysis. RNA-sequencing analysis identified MXD4::NUTM1 (3/7), MXI1::NUTM1 (3/7), and MGA::NUTM1 (1/7) fusions, respectively. DNA-based methylation profiling performed in 2 cases revealed distinct methylation cluster differing from those of NUT carcinoma and undifferentiated small round cell and spindle cell sarcomas. At follow-up (range: 4 to 24 mo), 1 patient experienced recurrence at 8.5 months, 4 patients were alive with metastatic disease (5, 10, 11, and 24 mo after diagnosis), 3 patients remained well with no signs of recurrence or metastasis (4, 6, and 12 mo after diagnosis). Our study further demonstrated that NUTM1-rearranged sarcoma had a broad range of clinicopathologic spectrum. NUT immunohistochemistry should be included in the diagnostic approach of monotonous undifferentiated small round, epithelioid to high-grade spindle cell malignancies that difficult to classify by conventional means. DNA-based methylation profiling might provide a promising tool in the epigenetic classification of undifferentiated sarcomas.

Primary NTRK -rearranged Spindle Cell Neoplasm of the Gastrointestinal Tract: A Clinicopathological and Molecular Analysis of 8 Cases.

NTRK-rearranged spindle cell neoplasm occurs predominantly in the superficial or deep soft tissues of extremities or trunk. Occurrence in the visceral organs is extremely rare. Herein, we describe 8 cases of NTRK-rearranged spindle cell neoplasm that arose primarily in the gastrointestinal tract. Patients included 5 males and 3 females with age at presentation ranging from 6 to 63 years (median: 29.5 years). Tumors occurred in the colon (n=3), small intestine (n=2), rectum (n=2), and stomach (n=1). Tumor size ranged from 3.5 to 9 cm (median: 5 cm). Morphologically, 4 tumors were low-grade, composed of haphazard or intertwining fascicles of spindle cells, with prominent interstitial collagen fibers and ring-like perivascular hyalinization being present in 2 tumors. The other 4 tumors were histologically high-grade sarcomas, consisting of sweeping fascicles of atypical spindle cells showing increased cellularity and brisk mitotic activity. Immunohistochemically, 6/6 cases (100%) showed diffuse and strong cytoplasmic staining of pan-TRK. Variable expression of TrkA, CD34, and S100 was noted in 5/5 (100%), 5/8 (62.5%), and 4/7 (57.1%) cases, respectively. Fluorescence in situ hybridization analysis showed NTRK1 rearrangement (n=7) and NTRK2 rearrangement (n=1). In cases with available materials, RNA sequencing identified LMNA::NTRK1 (n=3), TPM3::NTRK1 (n=2), and STRN::NTRK2 (n=1) fusions. At follow-up (range: 4 to 30 months; median: 12.5 months), 6 of 7 patients who underwent surgery had no evidence of disease at last follow-up. One patient was succumbed to the disease at 12 months despite adjunctive treatment with TRK inhibitor larotrectinib after surgery. One patient was treated with larotrectinib alone. He showed significant response at 7 months after treatment. NTRK-rearranged spindle cell neoplasm represents an exceptionally rare entity in the gastrointestinal tract. The presence of interstitial collagen fibers and ring-like perivascular hyalinization and co-expression of CD34 and S100 are diagnostic clues to low-grade neoplasms. However, high-grade sarcomas pose a considerable diagnostic challenge to pathologists owing to the lack of specific features. The final diagnosis relies on molecular assays. Patients with advanced disease may benefit from TRK inhibitor treatment.

A custom next-generation sequencing panel for 1p/19q codeletion and mutational analysis in gliomas.

The World Health Organization has updated their classification system for the diagnosis of gliomas, combining histological features with molecular data including isocitrate dehydrogenase 1 and codeletion of chromosomal arms 1p and 19q. 1p/19q codeletion analysis is commonly performed by fluorescence in situ hybridization (FISH). In this study, we developed a 57-gene targeted next-generation sequencing (NGS) panel including 1p/19q codeletion detection mainly to assess diagnosis and potential treatment response in melanoma, gastrointestinal stromal tumor, and glioma patients. Loss of heterozygosity analysis was performed using the NGS method on 37 formalin-fixed paraffin-embedded glioma tissues that showed 1p and/or 19q loss determined by FISH. Conventional methods were applied for the validation of some glioma-related gene mutations. In 81.1% (30 of 37) and 94.6% (35 of 37) of cases, 1p and 19q were found to be in agreement whereas concordance for 1p/19q codeletion and no 1p/19q codeletion was found in 94.7% (18 of 19) and 94.4% (17 of 18) of cases, respectively. Overall, comparing NGS results with those of conventional methods showed high concordance. In conclusion, the NGS panel allows reliable analysis of 1p/19q codeletion and mutation at the same time.

NR1D1-rearranged soft tissue tumour: A clinicopathological and molecular analysis of four additional cases.

AIMS: Nuclear receptor subfamily 1 group D member 1 (NR1D1)-rearranged soft tissue tumour is a newly described entity with an epithelioid morphology and a potential for aggressive behaviour. Largely due to under-recognition, this tumour type has not yet been widely acknowledged. Herein, we report four additional cases to further expand its clinicopathological and molecular spectrum. METHODS AND RESULTS: Four mesenchymal tumours with NR1D1 rearrangement were identified from our consultation files. There were one male and three females with ages ranging from 19 to 47 years (median = 28.5 years). Tumour occurred in the tongue, neck, hip and index finger, respectively. Histologically, two tumours were composed predominantly of epithelioid cells; one tumour had admixed epithelioid-spindle cells and one tumour consisted of monomorphic small round to ovoid cells. By immunohistochemistry, none of the tumours expressed lineage-specific markers. Targeted RNA-sequencing identified NR1D1 fusions in all four tumours, the partner genes being MAML2, MAML3, KMT2A and NCOA2, respectively. The novel MAML3 and NCOA2 rearrangements were confirmed by fluorescence in-situ hybridisation analysis. On follow-up (2-23 months), one patient experienced local recurrence due to incomplete resection and one patient developed lung metastasis. The other two patients were alive without disease. CONCLUSIONS: This study adds more support for NR1D1-rearranged soft tissue tumour as an emerging entity. The occurrence of two additional tumours in the head and neck region, description of a small round cell variant and identification of novel MAML3, KMT2A and NCOA2 partners further expand its clinicopathological and molecular spectrum. More studies on larger series are necessary to validate the fully malignant potential of NR1D1-rearranged soft tissue tumour.

Gastrointestinal Ewing Sarcoma: A Clinicopathological and Molecular Genetic Analysis of 25 Cases.

Occurrence of extraskeletal Ewing sarcoma (ES) in the gastrointestinal (GI) tract is extremely rare. Here, we report 25 cases of ES arising primarily in the GI tract with a focus on the clinicopathological and molecular features, differential diagnosis, and biological behavior. Thirteen patients (52%) were male, and 12 (48%) were female with age ranging from 9 to 59 years (mean: 36.2 years; median: 38 years). Twenty-one tumors (84%) occurred in the small intestine, 3 (12%) in the stomach, and 1 (4%) in the anal canal. At operation, 8/18 (44.4%) patients presented with abdominopelvic disseminated disease. Tumor size measured from 2 to 25 cm (mean: 8.2 cm; median: 6 cm) in maximum size. Microscopically, the tumors were composed of infiltrative small round, ovoid, or short spindle cells arranged mostly in lobular and solid sheet-like patterns with a rich capillary vasculature. Focal formation of Homer Wright-type rosettes and pseudoalveolar architecture was noted each in 2 (8%) cases and 3 (12%) cases. Besides CD99 (25/25; 100%), Fli-1 (15/15, 100%), and NKX2.2 (14/16; 87.5%), the tumor cells also showed variable staining of CD117 (14/17; 82.4%). Of 25 cases, 23 (92%) demonstrated EWSR1 rearrangement by fluorescence in situ hybridization analysis. The 2 cases with negative fluorescence in situ hybridization results were found to harbor EWSR1::ERG and EWSR1::FLI1 fusion by further RNA sequencing, respectively, with a median follow-up of 12 months (range: 1 to 42 months), 5/19 (26.3%) patients developed visceral metastasis and 12/19 (63.2%) patients died of the disease (range:1 to 33 months; median: 9 months). This study showed that GI ES had a predilection for the small intestine, although other sites of the GI tract could also be involved. GI ES had a poor prognosis with a high rate of mortality, particularly in patients with abdominopelvic disseminated disease. In light of appropriate therapeutic strategies and prognostic considerations, it is essential not to misdiagnose GI ES as gastrointestinal stromal tumor owing to the expression of aberrant CD117.

Epithelioid dedifferentiated liposarcoma: A clinicopathological and molecular study of 6 cases.

In this study, we present six cases of epithelioid dedifferentiated liposarcoma to further characterize its clinical and pathological features. The patients are all adult men with age at presentation ranging from 46 to 64 years (median 58.5 years). The patients presented with nonspecific symptoms of retroperitoneal mass, intermittent dull pain or discomfort. None of the patients had any prior history of a primary tumor. Radiological examinations revealed the presence of ill-demarcated heterogenous mass located in the deep soft tissue, including retroperitoneum (4 cases), pelvis and trunk (1 case each). Grossly, they appeared as solid tumors with focal areas of necrosis being presented in 2 cases. Histologically, all tumors were characterized by sheets of epithelioid cells that displayed marked cellular atypia and brisk mitotic activity. Variable portion of atypical lipomatous tumor/well-differentiated liposarcoma was present in 3 cases. By immunohistochemistry, the high-grade epithelioid component in all 6 cases showed strong and diffuse nuclear staining of MDM2, CDK4 and P16, with partial expression of AE1/AE3 in 3 cases. Fluorescence in situ hybridization analysis revealed high-level amplification of MDM2 in all 6 cases, with co-amplification of CDK4 in 3 cases. Follow up information showed that two patients died of the disease within one year despite multidisciplinary treatment. Due to the striking epithelioid appearance, this rare variant of dedifferentiated liposarcoma may be confused with undifferentiated epithelioid sarcoma, poorly differentiated carcinoma, mesothelioma or other malignancies with epithelioid phenotype. The study presented herein further highlights the aggressive clinical behavior of this unique tumor type. For patients with advanced disease, CDK4 inhibitor may provide an optional targeted treatment.

Desmoplastic Small Round Cell Tumor of the Head and Neck: A Clinicopathological, Immunohistochemical and Molecular Analysis of Three Cases with Literature Review.

Desmoplastic small round cell tumor (DSRCT) is a rare aggressive malignancy typically originating from the abdominal or pelvic cavity. DSRCT presenting as a primary head and neck tumor has rarely been described in the literature. We present three cases of DSRCT arising in the head and neck to further characterize its clinicopathological features. All three patients were male and aged 36, 30 and 17 years. The involved sites included the orbit (1 case) and submandibular gland (2 cases). The tumors ranged in size from 2.4 to 3.5 cm (mean, 2.1 cm). Histologically, all tumors showed irregular-shaped, variable-sized nests of small round cells deposited in an abundant desmoplastic stroma. Tumor cells contained scant amounts of eosinophilic cytoplasm and small hyperchromatic nuclei with inconspicuous nucleoli. Immunohistochemically, the tumors were positive for keratin (AE1/AE3) (3/3), desmin (3/3), vimentin (2/2), NSE (1/1) and EMA (1/1). Fluorescence in situ hybridization (FISH) analysis demonstrated the presence of EWSR1 and WT1 rearrangements in all three cases. All patients received surgery and adjuvant chemotherapy and/or radiotherapy. There was no evidence of recurrence and metastasis in two patients, and the third suffered lung metastasis. DSRCT arising in the head and neck represents an extremely rare condition. It is easily mistaken as poorly differentiated carcinoma due to similar morphology and expression of epithelial markers. Immunohistochemistry assay in conjunction with molecular detection of EWSR1::WT1 fusion will be helpful for arriving at an accurate diagnosis to avoid misdiagnosis and inappropriate treatment.

Single-cell RNA sequencing reveals cellular and molecular reprograming landscape of gliomas and lung cancer brain metastases.

BACKGROUND: Brain malignancies encompass gliomas and brain metastases originating from extracranial tumours including lung cancer. Approximately 50% of patients with lung adenocarcinoma (LUAD) will eventually develop brain metastases. However, the specific characteristics of gliomas and lung-to-brain metastases (LC) are largely unknown. METHODS: We applied single-cell RNA sequencing to profile immune and nonimmune cells in 4 glioma and 10 LC samples. RESULTS: Our analysis revealed that tumour microenvironment (TME) cells are present in heterogeneous subpopulations. LC reprogramed cells into immune suppressed state, including microglia, macrophages, endothelial cells, and CD8+ T cells, with unique cell proportions and gene signatures. Particularly, we identified that a subset of macrophages was associated with poor prognosis. ROS (reactive oxygen species)-producing neutrophils was found to participant in angiogenesis. Furthermore, endothelial cells participated in active communication with fibroblasts. Metastatic epithelial cells exhibited high heterogeneity in chromosomal instability (CIN) and cell population. CONCLUSIONS: Our findings provide a comprehensive understanding of the heterogenicity of the tumor microenvironment and tumour cells and it will be crucial for successful immunotherapy development for brain metastasis of lung cancer.

The immune subtypes and landscape of sarcomas.

BACKGROUND: Considering the molecular heterogeneity of sarcomas and their immunologically quiet character, immunotherapy (e.g., immune checkpoint inhibitors) plays a viable role in only a subset of these tumors. This study aimed to determine the immune subtypes (IMSs) of sarcomas for selecting suitable patients from an extremely heterogeneous population. RESULTS: By performing consensus clustering analysis of the gene expression profiles of 538 patients with sarcomas in online databases, we stratified sarcomas into three IMSs characterized by different immune cell features, tumor mutational burdens (TMBs), gene mutations, and clinical outcomes. IMS1 showed an immune "hot" and immunosuppressive phenotype, the highest frequencies of CSMD3 mutation but the lowest frequencies of HMCN1 and LAMA2 mutations; these patients had the worst progression-free survival (PFS). IMS2 was defined by a high TMB and more gene mutations, but had the lowest frequency of MND1 mutations. IMS3 displayed the highest MDN1 expression level and an immune "cold" phenotype, these patients had the worst PFS. Each subtype was associated with different expression levels of immunogenic cell death modulators and immune checkpoints. Moreover, we applied graph learning-based dimensionality reduction to the immune landscape and identified significant intra-cluster heterogeneity within each IMS. Finally, we developed and validated an immune gene signature with good prognostic performance. CONCLUSIONS: Our results provide a conceptual framework for understanding the immunological heterogeneity of sarcomas. The identification of immune-related subtypes may facilitate optimal selection of sarcoma patients who will respond to appropriate therapeutic strategies.

GLI1-altered mesenchymal tumor: a clinicopathological and molecular analysis of ten additional cases of an emerging entity.

We report 10 additional cases of GLI1-altered mesenchymal tumor to further delineate its clinicopathological and molecular spectrum. There were seven males and three females with a median age of 31 years (range 1.3 ~ 75 years). Five tumors arose in the oral cavity, one each in the stomach, uterine cervix, elbow, groin, and thigh. Histologically, all cases except one were composed of monomorphic round to epithelioid cells showing an infiltrative multinodular growth pattern. The neoplastic cells were surrounded by a rich network of capillary vessels. Vessel invasion or subendothelial protrusion into the vascular space was commonly present. One tumor developed regional lymph node metastasis. The remaining case showed a predominantly spindle cell tumor. By immunohistochemistry, most tumors showed diffuse staining of CD56 (8/8) with variable expression of S100 protein (7/8). In three tumors harboring amplified genes, strong and diffuse nuclear staining of MDM2 (2/3) and CDK4 (3/3) were noted. Next-generation sequencing (NGS) studies revealed GLI1 fusions in 7 cases and GLI1 amplification in 2 cases, which were validated by fluorescence in situ hybridization (FISH) analysis in the majority of cases. One case did not show fusion gene by RNA-seq, but FISH revealed both amplification and break-apart of GLI1 gene. Follow-up information showed local recurrences in two patients. All other patients remained disease-free at the last follow-up. Our study further demonstrates that mesenchymal tumors with GLI1 alterations represent a distinctive clinicopathological entity. Although the tumor has a propensity for the tongue, it can also arise in somatic soft tissues as well as in visceral organs. Based on the characteristic morphological features and genomic profiles, we propose the term "GLI1-altered mesenchymal tumor" to describe this emerging entity.

The clinicopathological spectrum of pseudomyogenic hemangioendothelioma: report of an additional series with review of the literature.

We present here our experience with 24 cases of pseudomyogenic hemangioendothelioma (PMHE) to further delineate its clinicopathological spectrum. There were 18 males and 6 females with a median age of 28 years (range 10~64 years). Most patients presented with erythematous nodules or papules, with or without pain. The majority (63%) occurred in the lower extremities, whereas a minority involved the trunk (25%), upper extremities (8%), and head and neck (4%). Six cases (25%) had a primary bone origin. With physical and radiological examinations, 16 cases (67%) manifested as multifocal disease, involving multiple tissue planes or different bones within the anatomic region. Six cases (25%) involved skin, soft tissue, and bone simultaneously. Histologically, all cases showed features consistent with a PMHE characterized by loose fascicles or sheets of plump spindled to epithelioid cells harboring brightly eosinophilic cytoplasm and vesicular nuclei. In addition, five cases (21%) contained a prominent myxoid matrix, and one case displayed perineural and intravascular invasion. The follow-up information available in 18 patients revealed local recurrence in 4 patients (22%) and persistent disease in 8 patients (44%), respectively. One patient developed bilateral pulmonary metastases which showed significant remission after systemic chemotherapy. None of the patients died of the disease. As the clinical appearance of PMHE can be deceptive, a radiological examination is essential in identifying an insidious multifocal disease. Although PMHE has a predilection for the distal extremities of young males, this rare tumor type could also occur in unusual sites and affect middle-aged adults of both genders. The striking myoid appearance in association with myxoid stromal change may represent a potential diagnostic pitfall. Biologically, PMHE has an indolent clinical behavior, albeit metastatic disease may occur in rare instance.

EWSR1-SMAD3 positive fibroblastic tumor.

We present a case of EWSR1-SMAD3 positive fibroblastic tumor that occurred in a 24-year-old man who presented with a recurrent tumor in the dorsum of his right foot. Magnetic resonance imaging (MRI) demonstrated a subcutaneous nodule located in the third metatarsophalangeal joint region, measuring 10 × 8 × 5 mm in size. Histological examination revealed a monomorphic spindle cell tumor composed of cellular fascicles of bland fibroblasts with hyalinization. Immunohistochemically, the tumor showed diffuse nuclear staining of ERG. Fluorescence in situ hybridization (FISH) assessment demonstrated an unbalanced rearrangement of the EWSR1 gene. Further next-generation sequencing (NGS) analysis identified EWSR1-SMAD3 gene fusion. Molecular detection may be helpful for identifying new entities, in particular to those that lack lineage-specific differentiation by conventional pathological examinations.

CIC-rearranged sarcoma:a clinicopathological analysis of 10 cases / 中华病理学杂志

Objective@#To investigate the clinicopathologic features, immunophenotype and prognosis of CIC-rearranged sarcoma (CRS).@*Methods@#The clinical and pathological data of 10 cases of CRS diagnosed between January 2017 and December 2018 at the Department of Pathology,Fudan University Shanghai Cancer Center were analyzed. Immunohistochemical study and fluorescence in situ hybridization (FISH) were performed. The literature was reviewed.@*Results@#There were five males and five females with a mean age of 28 years (range, 5 to 63 years). Eight tumors developed in the somatic soft tissues, including trunk (n=3),head and neck (n=3),and extremities (n=2). One case each arose in the small intestine and the occipital lobe. The average size was 4.9 cm (range,1.5-8.0 cm). Microscopically,all cases were composed of small to medium-sized round, oval to short spindled cells, showing nodular or lobular architecture, or were arranged in sheets. Compared with Ewing sarcoma, tumor cells of CRS usually showed irregular nuclear outline, coarse chromatin with prominent nucleoli and brisk mitotic activity. Necrosis was present in four cases with one showing geographic necrosis. Immunohistochemically, tumor cells usually showed focal or patch staining of CD99 (9/10),diffuse and strong nuclear expression of WT1 in half cases (2/4),and a high Ki-67 index (median 70%). By FISH, nine cases demonstrated convincing break-apart signal of CIC gene. Follow-up data available in seven cases (mean 12.1 months); of these two patients died of disease (2/7), whereas one patient was alive with unresectable recurrent tumor,the remaining four patients were alive with no evidence of disease. Five patients (5/7) experienced local recurrence and two patients (2/7) developed metastasis. The mean and median intervals to recurrence/metastasis were eight months and four months, respectively.@*Conclusions@#CRS is the most common type of EWSR1-negative small round cell sarcoma (SRCS). Although it has clinical and pathological overlapping features with Ewing sarcoma,the prognosis is comparatively poor. Focal or patch staining of CD99 but diffuse staining of WT1 in a case of small RCS should raise the possibility of CRS. FISH assay is required for the final diagnosis.

Lipofibromatosis-like neural tumour: a clinicopathological study of ten additional cases of an emerging novel entity.

We present our experience with ten cases of lipofibromatosis-like tumour (LPF-NT) to further characterise this newly described neoplasm. There were six males and four females with a mean age of 12.8 years (range 2-37 years). Tumours occurred in the neck (n = 3), buttock (n = 2), chest wall, flank, hip, hand and foot (n = 1). Histologically, they were composed of cellular fascicles of mildly to moderately atypical spindle cells displaying an infiltrative pattern reminiscent of lipofibromatosis or dermatofibrosarcoma protuberans. Immunohistochemically, all cases co-expressed S100 protein and CD34. FISH analysis revealed NTRK1 gene rearrangement in four of five cases tested. Clinical follow-up showed local recurrence in three cases but no evidence of metastasis. This study further supports that LPF-NT represents a novel entity of NTRK1-associated neoplasms. Awareness of its clinicopathological features, immunophenotypes and cytogenetic abnormalities helps pathologists arrive at the correct diagnosis.

Pleomorphic and dedifferentiated leiomyosarcoma: a clinicopathologic analysis / 中华病理学杂志

Objective@#To investigate the clinicopathologic features, differential diagnosis and biological behavior of pleomorphic leiomyosarcoma (PLMS) and dedifferentiated leiomyosarcoma (DLMS).@*Methods@#Forty-nine cases were collected from November 2007 to December 2016, including eight that diagnosed at Fudan University Shanghai Cancer Center, and 41 consultation cases. The clinical findings and pathologic features were reviewed. Immunophenotype was obtained in 33 cases and follow-up information was available in 38 cases.@*Results@#There were 22 males and 27 females with ages ranging from 24 to 83 years (mean 52.5 years). Fifteen cases occurred in extremities, 14 in deep body cavity, 11 in the trunk, 4 in the head and neck, 2 in the bladder, and 1 each in the inguinal region, perineum and femoral vein, respectively. Tumor sizes ranged from 3 to 30 cm (mean 9.1 cm). The tumors were composed of at least small foci of typical leiomyosarcoma (LMS) and areas of high-grade pleomorphic/undifferentiated sarcoma. The typical LMS component showed the characteristic morphology of smooth muscle differentiation and was low to intermediate grade in most cases. Pleomorphic areas were mainly composed of atypical spindle and polygonal cells admixed with variable large, bizarre atypical cells and multinuclear giant cells, mostly mimicking undifferentiated pleomorphic sarcoma. The pleomorphic and leiomyosarcomatous areas were usually intermixed, but the demarcation may be distinct or gradual in some cases. The classical LMS component was positive for at least one myogenic marker: α-SMA in 97.0%(32/33), desmin in 72.7%(24/33), H-caldesmon in 90.9% (20/22), MSA in 14/16, and calponin in 15/15 of cases. The pleomorphic sarcoma component was reactive for at least one myogenic marker in 87.9% (29/33) of cases, usually showing focal and less intense immunoreactivity than classical LMS component: α-SMA was positive in 81.8%(27/33), desmin in 48.5%(16/33), H-caldesmon in 72.7% (16/22), MSA in 12/16, and calponin in 11/15 of cases. Based on staining for muscle markers in the pleomorphic component, 29 cases were designated as PLMS, 4 as DLMS. Ki-67 index ranged from 15% to 70% (mean 40%). Follow-up data was available in 38 cases (77.6%), of which 11 patients (28.9%) died of disease, 12 patients were alive with unresectable or recurrent disease, 14 patients were alive with no evidence of disease and another one died of unrelated cause. The median disease-free and overall survival was 6 and 10 months respectively. Twelve patients exhibited local recurrence and 11 developed metastases. The median interval to progression was 8 months.@*Conclusions@#The identification of areas of typical LMS is crucial for accurate diagnosis of PLMS and DLMS. Both PLMS and DLMS show more aggressive behavior and poorer prognosis than ordinary LMS.

Clinicopathological features and prognostic factors in angiosarcoma: A retrospective analysis of 200 patients from a single Chinese medical institute.

Angiosarcoma is a rare soft tissue sarcoma, and the data about its clinicopathological features and prognostic factors are limited. The purpose of the present study was to report a large series of angiosarcoma at a single institution. Clinical data from 200 cases of angiosarcoma from the Shanghai Cancer Center (Shanghai, China) between March 2006 and March 2014 were retrospectively analyzed. The study population included 97 males and 103 females with ages between 4 and 91 years (median, 53 years). According to the tumor location, 200 cases were divided into 4 groups: i) Tumors involving the head and neck; ii) breast; iii) viscera (including internal organs and bone); and iv) soft tissue (including trunk and extremities). Of the 113 patients with follow-up data, 46 patients succumbed to the disease with a median interval of 10 months. Tumor recurrence/metastasis was identified in 66 patients with a median interval of 4 months. The disease-free survival (DFS) rate at 5-years was 19.3% and the overall survival (OS) rate at 5-years was 40.8%. Site of tumor origin, size (≥5 cm) and histological differentiation influenced DFS (P=0.032, 0.038 and <0.001, respectively), and OS (P<0.001, 0.008 and <0.001, respectively) rates. Age (<65 years) and multimodal treatment correlated with improved OS (P=0.003 and <0.001, respectively). Tumor differentiation and treatment modality were identified to be independent determinants of OS (P<0.001 and 0.038, respectively). Tumor recurrence/metastasis was an independent predictor of DFS (P<0.001). The prognosis of angiosarcoma is poor and the mortality rate is high. The site of tumor origin, size, histological differentiation, age, treatment modality and tumor recurrence/metastasis are all significant prognostic factors. In the present study, multimodal treatment may improve the clinical outcome of patients with angiosarcoma.

Primary Breast Angiosarcoma: A Retrospective Study of 36 Cases from a Single Chinese Medical Institute with Clinicopathologic and Radiologic Correlations.

The aim of this study was to present our experience with primary breast angiosarcoma (PBA) by describing a large series of cases with an emphasis on clinicopathologic and radiologic correlations. Thirty-six cases of PBA diagnosed at our institution between 2006 and 2014 were retrospectively evaluated. All but one case occurred in women with a median age of 35.5 years. The majority of patients presented with a deeply located painless mass, whereas a minority manifested as diffuse enlargement or swelling of the breast. Magnetic resonance imaging showed poorly demarcated lesions with low signal intensity on T1-weighted images, markedly high intensity on T2-weighted images, and prolongation of enhancement upon dynamic study. Histologically, 19 cases (52.8%) were low grade, 12 cases (33.3%) were intermediate grade, and 5 cases (13.9%) were high grade. Follow-up information was available for 27 patients and revealed local recurrence and/or metastasis in 16 patients (59.3%). Five patients (18.5%) died of the disease at a median interval of 20 months. Univariate analysis showed that tumor differentiation had effect on disease-free survival (DFS) (p = 0.005) but failed to predict overall survival (OS) (p = 0.645). The treatment modality was related to OS (p = 0.042) but not DFS (p = 0.131). The Cox proportional hazards regression model suggested that tumor differentiation was an independent predictor of DFS (p = 0.015). We hypothesize that tumor differentiation may be used as a prognostic factor for this rare malignancy. Clinicopathologic and radiologic correlation may help pathologists to arrive at the correct diagnosis of PBA.

Superficial CD34-positive fibroblastic tumour: a clinicopathological and immunohistochemical study of an additional series.

AIMS: To describe an additional series of superficial CD34-positive fibroblastic tumour, a newly described neoplasm, in order to enhance the recognition of an emerging novel entity. METHODS AND RESULTS: The clinicopathological features and immunophenotypes of 11 cases of superficial CD34-positive fibroblastic tumour were studied. There were eight males and three females, with a median age of 36 years. Tumours occurred in the thigh (n = 4), buttock (n = 3), shoulder (n = 2), upper arm (n = 1), and waist (n = 1). Histologically, all tumours were characterized by relative circumscription, pleomorphic spindled to polygonal cells with variably enlarged bizarre-appearing cells, intranuclear cytoplasmic pseudoinclusions, and extremely low mitotic activity. Immunohistochemically, neoplastic cells showed diffuse and strong expression of CD34 and focal staining of cytokeratin. Follow-up thus far has revealed an indolent clinical behaviour. CONCLUSIONS: Superficial CD34-positive fibroblastic tumour represents a new member of the family of cutaneous CD34-positive spindle-cell tumours. Familiarity with its clinicopathological characteristics is helpful in avoiding confusion with a variety of cutaneous mesenchymal tumours with overlapping features.

Epithelioid inflammatory myofibroblastic sarcoma: a clinicopathological, immunohistochemical and molecular cytogenetic analysis of five additional cases and review of the literature.

BACKGROUND: To explore the clinical characteristics and pathological features of epithelioid inflammatory myofibroblastic sarcoma (EIMS) with emphasis on the diagnostic spectrum. METHODS: The clinical data and histological features in 5 additional cases of EIMS were retrospectively reviewed. Immunohistochemical study and interphase fluorescence in situ hybridization (FISH) analysis were carried out. RESULTS: There were 2 males and 3 females with age at presentation ranging from 15 to 58 years (mean, 37 years). All 5 tumors were intra-abdominal with 2 arising in the mesentery and 1 each in the omentum, rectum and transverse colon. The tumor size ranged from 5 to 20 cm in maximum diameter (mean, 10.7 cm). Histologically, all 5 tumors were composed predominantly of large epithelioid cells possessing vesicular nuclei, prominent nucleoli, and amphophilic cytoplasm. Mitotic figures were easily identified (mean, 20/10HPF). Tumor cells were arranged in clusters or sheets embedded in a myxoid stroma containing prominent neutrophils. A minor component of spindle cells was present in focal areas. By immunohistochemistry, all 5 cases were positive for anaplastic lymphoma kinase (ALK) with a nuclear membrane pattern in 4 and cytoplasmic staining with perinuclear accentuation in 1. Besides ALK, tumor cells stained variably for desmin (4/5), alpha smooth muscle actin (2/5), muscle-specific actin (1/2) and pan-cytokeratin (1/4). FISH analysis demonstrated the presence of ALK rearrangement in all 5 cases. Of 5 patients, 3 developed local recurrence, 1 died of disease 8 months after surgery. CONCLUSION: EIMS represents a highly aggressive variant of inflammatory myofibroblastic tumor characterized by epithelioid morphology, prominent neutrophilic infiltrate, and nuclear membrane staining of ALK with ALK rearrangement. As patients with ALK-rearrangement tumors may benefit from targeted therapy, accurate diagnosis of EIMS is very important. Familiar with the characteristic features of EIMS will help pathologists avoid misdiagnosing the tumor as other malignancies.

Clinicopathologic and radiologic features of extraskeletal myxoid chondrosarcoma: a retrospective study of 40 Chinese cases with literature review.

The aim of this study is to describe the clinicopathologic and radiologic features of 40 cases of extraskeletal myxoid chondrosarcoma (EMC) from China. There were 25 males and 15 females (sex ratio, 1.7:1). Apart from an adolescent, all patients were adults with a median age of 49years. Twenty-four tumors (60%) occurred in the lower limb and limb girdles, especially the thigh, followed by the upper limb and limb girdles (20%) and trunk (10%). Other less commonly involved locations included the head and neck, sacrococcygeal region, and perineum. Tumors ranged in size from 1.5 to 19cm (mean, 7cm). By radiology, they appeared as hypoattenuated or isoattenuated masses on computed tomography with hyperintense signal on T2-weighted magnetic resonance imaging. Intralesional hypointense septa were present in most cases. Of the 40 tumors, 30 belonged to the classic subtype, whereas 9 cases were cellular, and 1 case had a rhabdoid phenotype. Tumor cells showed variable expression of synaptophysin (36%), S-100 protein (29%), epithelial membrane antigen (11%), and neuron-specific enolase (7%). Ki-67 index was remarkably higher in the cellular variant (mean, 30%). EWSR1-related rearrangement was detected in 12 of 14 cases tested by fluorescence in situ hybridization using break-apart probes. The overall 5- and 7-year survival was 71% and 60%, respectively. Awareness of the imaging features may help pathologists in the diagnosis of EMC. Fluorescence in situ hybridization also serves as a useful diagnostic tool for EMC, especially in the distinction from its mimics.