A low-grade malignant soft tissue tumor with S100 and CD34 co-expression showing novel CDC42SE2-BRAF fusion with distinct features.

Recently, a novel group of spindle cell tumors defined by S100 and CD34 co-expression harboring recurrent fusions involving RET, RAF1, BRAF, and NTRK1/2 gene has been identified. Morphologically, they are characterized by monomorphic neoplasm cells, "patternless" growth pattern, stromal, and perivascular hyalinization, lacked necrosis. We reported a 52-year-old Chinese female patient with a S100 and CD34 co-expression sarcoma presenting in the right proximal forearm. The forearm mass initially emerged 19 months ago when it was misdiagnosed as a solitary fibrous tumor and was surgically removed without further treatment. Microscopically, the primary and the recurred tumors share the same features, resembling the morphology of the recently characterized group. Nevertheless, some distinct features, such as predominantly epithelioid tumor cells and focally staghorn vessels, were also present in our case. Genomic profiling with clinical next-generation sequencing was performed and revealed CDC42SE2-BRAF gene fusion, MET amplification, and CDKN2A/B deletion. Both FISH and nested RT-PCR were performed to confirm the gene fusion. The patient was treated with crizotinib for two cycles but showed no obvious benefit. The presented case adds to the spectrum of the novel, characterized solid tumors, and provides suggestions for emerging therapeutic strategies for precision medicine involving targeted kinase inhibitors.

Inflammatory myofibroblastic tumor arising from soft tissues of extremities harboring a novel CLIP2-ALK fusion.

A 34-year-old Chinese woman found a lump in her left leg for more than 3 weeks without any discomfort. Grossly, the tumor was relatively well delineated with focal infiltration. Histopathologic evaluation showed a compact fascicular spindle cell proliferation with variable myxoid and collagenous stroma and scattered inflammatory infiltrate. Immunohistochemically, the tumor cells showed positive expression of ALKD5F3 and SMA and negative expression of CD34, desmin, and cytokeretin. Fluorescence in situ hybridization analysis of the ALK locus showed break-apart signals in 20% of tumor cells, and DNA sequencing discovered a novel CLIP2-ALK fusion gene. The lesion was diagnosed as an inflammatory myofibroblastic tumor (IMT). To the best of our knowledge, this is the first case with CLIP2-ALK gene fusion in the somatic soft tissue IMTs.

Idiopathic isolated fibrotic atrial cardiomyopathy underlies unexplained scar-related atrial tachycardia in younger patients.

Aims: Unexplained scar-related atrial tachycardia (AT) has been frequently encountered in clinical practice. We hypothesized that idiopathic, isolated fibrotic atrial cardiomyopathy (ACM) underlies this rhythm disorder. This study was aimed to characterize the underlying substrate and to explore the aetiology of this unexplained scar-related AT. Methods and results: Twenty-six (11 men, aged 46 ± 13 years) of 52 non-surgical scar-related AT patients identified by three-dimensional voltage mapping were enrolled in this prospective observational study. Multimodality image examinations (echocardiography, cardiac magnetic resonance, 99Tc single-photon emission computed tomography), ventricular voltage mapping, and intracardiac pressure curve recording ruled out ventricular involvement. Catheter ablation was acutely successful for all the patients, and pacemaker implantation was performed in seven patients who presented sinus node dysfunction or atrial standstill after termination of the AT. In three patients with multiple AT recurrences, the diseased areas of the right atrium were resected and dechannelled via mini-invasive surgical interventions. Histological examinations revealed profound fibrosis without amyloidosis or adipose deposition. Viral and familial investigations yielded negative results. Fibrosis progression over a median of 45 (5-109) months of follow-up manifested as atrial arrhythmia recurrence in seven patients and atrial lead non-capture due to newly developed atrial standstill in two patients. Two patients suffered four ischaemic stroke events before receiving anticoagulation treatment. Conclusion: Isolated, fibrotic ACM may underlie the idiopathic scar-related ATs. This novel cardiomyopathy has unique clinical characteristics with high morbidity including stroke and warrants specific therapeutic strategies. Further investigations are required to determine the aetiology and mechanism.

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.

[Epithelioid hemangioendothelioma: a clinicopathologic analysis of 13 cases].

OBJECTIVE: To investigate the clinicopathologic characteristics of epithelioid hemangioendothelioma (EHE). METHODS: Thirteen cases of EHE were analyzed by gross examination, light microscopy and immunohistochemical staining. RESULTS: The patients included 6 males and 7 females. The age of patients ranged from 11 to 74 years (mean = 43 years). The tumors were located in soft tissue, liver, lung, mediastinum, sacrum, and pleura. The tumor cells were epithelioid, spindled or polygonal-shaped and exhibited cord-like or small nest growth pattern. Some tumor cells formed cytoplasmic vacuoles, which contained erythrocytes. The tumor cells showed abundant eosinophilic cytoplasm. The stroma varied from highly myxoid to hyaline. In 3 cases, the tumors contained areas with significant atypia, brisk mitotic activity and necrosis. Immunohistochemical study showed that the tumor cells were positive for CD31, ERG, FLI-1, CD34, factor VIII and CKpan to different extents. Follow-up information was available in 10 patients with duration ranging from 8 to 65 months. Seven patients were alive and three died. CONCLUSIONS: EHE is easily a rare maligant vascular tumor,occurs in many organs other than soft tissue.EHE is misdiagnosed as carcinoma for its significant epithelioid morphology. Recognizing its clinicopathologic characteristics and combined application of specific vascular endothelial immunohistochemical markers are important to avoid confusion with other lesions.

[Clinicopathologic observation of adenoid cystic carcinoma of esophagus].

OBJECTIVE: To study the clinicopathologic features and differential diagnosis of adenoid cystic carcinoma in the esophagus. METHODS: Ten cases of primary adenoid cystic carcinoma of the esophagus were retrieved from the archival file. The clinicopathologic and immunohistochemical features were studied. The differential diagnosis was analyzed. RESULTS: The male-to-female ratio was 9: 1. The age of patients ranged from 59 to 76 years. There were 4 cases with tumor located in mid esophagus, 4 cases with tumor located in mid to lower esophagus and the remaining 2 cases in lower esophagus. Low-power histologic examination showed mainly expansive growth pattern, with cribriform, solid and focal tubular architectures identified. The tumor cells showed nuclear hyperchromasia. Both ductal and myoepithelial differentiation was demonstrated. The stroma showed myxoid degeneration in areas. Comedo-type necrosis was observed in 8 cases and moderate to severe squamous dysplasia was present in one case. Three cases showed focal areas of squamous cell carcinoma. Immunohistochemical study showed that the tumor cells were positive for p63 (10/10), CD117 (10/10) and S-100 protein (9/10). There was focal staining for calponin (2/10) and smooth muscle actin (2/10). The ductal structures expressed CK7 (10/10). CONCLUSIONS: Adenoid cystic carcinoma of the esophagus demonstrates unique morphologic features with expression of S-100 protein and consistent expression of CD117. The above characteristics help to distinguish this entity from basaloid squamous cell carcinoma, mucoepidermoid carcinoma and small cell carcinoma of the esophagus.

[Interdigitating dendritic cell sarcoma/tumor: a clinicopathologic study].

OBJECTIVE: To study the clinicopathologic characteristics and diagnostic criteria of interdigitating dendritic cell sarcoma/tumor (IDCS/T). METHODS: The clinical features, histologic findings and results of immunohistochemical study in six cases of IDCS/T were analyzed, with review of literature. RESULTS: The age of patients ranged from 20 to 68 years. The sites of involvement included lymph node, tonsil and soft tissue. Histologically, the tumor cells were arranged in sheets, fascicles or whorls and intimately admixed with abundant lymphocytes and plasma cells. They were oval to spindly in shape and contained pale eosinophilic cytoplasm, oval nuclei and distinct nucleoli.Immunohistochemical study showed that the tumor cells were positive for S-100 protein and CD68. CONCLUSIONS: IDCS/T is a rare malignant tumor with poor prognosis. It carries distinctive histologic pattern and immunophenotype. The entity needs to be distinguished from follicular dendritic cell sarcoma/tumor, anaplastic large cell lymphoma and other spindle cell sarcomas in occurring soft tissue.

[Metanephric adenoma of kidney: a clinicopathologic study of eight cases].

OBJECTIVE: To study the clinical and histopathologic features of metanephric adenoma (MA). METHODS: Eight cases of recently diagnosed MA were retrieved from archival file. Immunohistochemical study was carried out. The clinical characteristics, pathologic parameters, differential diagnosis, treatment options and prognosis of MA were analyzed, with literature review. RESULTS: The patients included 6 females and 2 males. The age of patients ranged from 12 to 70 years (mean=43.6 years). Eight cases were located in renal cortex and showed well-defined borders. Histologically, the tumor was composed of tubules lined by small basophilic cells and embedded in an edematous stroma. Papillary structures and psammoma bodies were focally seen. Immunohistochemical study showed that the tumor cells were positive for PAX2 and vimentin in all the 8 cases. WT-1 was positive in 2 cases, focal and weak in 5 cases, and negative in 1 case. CK-Pan was positive in 3 cases. CK7 staining was mostly negative, with focal and weak positivity only in 1 case. The proliferative index, as highlighted by Ki-67 staining, was less than 2% in 7 cases and focally around 5% in 1 case. The expressions of CK20, CD10, RCC, epithelial membrane antigen, CD56, synaptophysin and chromogranin A were negative. Follow-up information from 7 to 57 months was available in all patients; and none of them developed local recurrence or distant metastasis. CONCLUSIONS: The diagnosis of MA relies primarily on thorough histologic examination and immunohistochemical study (vimentin and PAX2 positive, WT-1 focally and weakly positive in some cases, and low proliferative index). Correlation with clinical and radiologic findings would also be helpful.

Case report: Primary pulmonary low grade fibromyxoid sarcoma progressing to dedifferentiation: probably due to TP53 driver mutation.

Low Grade Fibromyxoid Sarcoma (LGFMS), a rare entity characterized by bland histologic features, typically affects deep soft tissues of the trunk and lower extremities. Rare cases have been reported arising from the viscera and few demonstrating morphology of high-grade dedifferentiation. Here we report a 39-year-old Chinese woman presenting with primary lung LGFMS, which metastasized to the pancreas five years after diagnosis and then relapsed ten years later as a mediastinum mass. Microscopically, the lung and pancreatic lumps shared similar classical features of LGFMS, composed of bland spindle-shaped cells with low mitotic activity. However, the mediastinal mass had dedifferentiated morphology of dense sheets of round and epithelioid cells with high degree of nuclear pleomorphism and brisk mitosis. Molecular studies showed both classical and dedifferentiated areas had FUS::CREB3L2 rearrangement. However, the mediastinal dedifferentiated area presented with extra H193Y mutation of the TP53. Moreover, the mediastinal tumor displayed a strong and diffuse pattern of p53 expression immunohistochemically, but the primary lung and secondary pancreatic masses did not. Thus, we diagnosed the mediastinal mass as dedifferentiated LGFMS and proposed that TP53 mutation was probably the driver gene alteration in the process, which, to the best of our knowledge, has not been reported in the existing literature.

[Solid variant of angiomatoid fibrous histocytoma:report of 3 cases].

OBJECTIVE: To study the clinicopathologic features, immunophenotype, molecular genetics and differential diagnosis of solid variant of angiomatoid fibrous histocytoma. METHODS: The clinicopathologic features of 3 cases of solid variant of angiomatoid fibrous histocytoma were analyzed and the literature was reviewed. RESULTS: There were a total of 2 males and 1 female. The age of patients ranged from 9 to 12 years. The patients presented with a painless mass located in left forearm, left knee or back. The lesions were treated by complete surgical resection. On gross examination, the tumors varied from 1.6 cm to 4.5 cm in greatest dimension. They were well-circumscribed and had pale yellow to grayish-red solid cut surface. Histologically, the tumor was composed of histocytoid cells arranged in sheet-like pattern. A fibrous pseudocapsule surrounded by lymphocytes and plasma cells was identified. Immunohistochemical study showed that the tumor cells in all cases were positive for vimentin and CD68. They were negative for S100 protein, cytokeratin, CD34, CD31, smooth muscle actin, CD35, CD21 and CD30. Two cases also expressed CD99 and one of them was positive for desmin and epithelial membrane antigen. Fluorescence in-situ hybridization was positive for EWSR1 gene. CONCLUSIONS: Solid type represents a variant of angiomatoid fibrous histocytoma and is considered as tumor of borderline malignant potential. Definitive diagnosis requires thorough histologic examination and clinical correlation. Immunohistochemistry and EWSR1 gene study are helpful in further delineation and differential diagnosis. Complete resection or wide local excision with post-operative follow up is the main modality of treatment.

[Epithelioid hemangioma: a clinicopathologic analysis of 7 cases].

OBJECTIVE: To study the clinicopathologic features, diagnosis and differential diagnosis of epithelioid hemangioma. METHODS: The morphologic features of 7 cases of epithelioid hemangioma of skin, bone and venous vessels were studied. RESULTS: There were altogether 4 male and 3 female patients (median age = 34 years; age range from 14 to 54 years). The 3 skin cases presented as single or multiple erythematous to bluish nodules or papules, with or without itchiness. The 2 bone cases appeared as osteolytic expansile lesions on radiologic examination. The remaining 2 cases involved medium-sized venous structures and presented as small isolated nodules in soft tissue. Histologically, the lesions were characterized by the presence of exuberant endothelial proliferations with various degree of inflammatory reaction. The neoplastic endothelial cells were plump, eosinophilic and polygonal, forming vascular channels. Occasional solid sheet-like arrangement was demonstrated. Intracytoplasmic vacuoles were commonly identified, indicating formation of primary lumen. The surrounding stroma contained various number of eosinophils and lymphoplasmacytic cells. Immunohistochemical study showed that the tumor cells were positive for endothelial markers (CD31 and CD34) and negative for epithelial marker (cytokeratin). Follow-up information was available in 6 cases. The duration of follow-up ranged from 5 to 36 months (median = 14 months). There was no evidence of recurrence or distant metastasis. CONCLUSIONS: Epithelioid hemangioma is a rare benign curable lesion which can be multifocal, involving skin, soft tissue and bone. It needs to be distinguished from Kimura's disease and epithelioid hemangioendothelioma.

Prognostic analysis of extrameningeal solitary fibrous tumor using the modified Demicco model: a clinicopathologic study of 111 Chinese cases.

Introduction: Solitary fibrous tumor (SFT) represents a fibroblastic neoplasm exhibiting NAB2::STAT6 gene rearrangement, displaying diverse clinical manifestations, spanning from benign to malignant. To predict prognosis, the modified (four-variable) Demicco (mDemicco) model was introduced. This investigation aims to authenticate the mDemicco risk model's precision in Asian patients while investigating the clinicopathological and molecular factors linked to the prognosis of extrameningeal SFTs. Methods: Clinicopathological data from 111 extrameningeal SFT cases in East China, covering the period from 2010 to 2020, were thoroughly analyzed. The tumors were classified using the mDemicco model. Immunohistochemical evaluation of P16 and P53, molecular detection of TP53 and TERT promoter mutation, and fluorescence in situ hybridization for CDKN2A gene alterations were performed. Statistical methods were utilized to assess the associations between clinicopathological or molecular factors and prognosis. Results: Histologically, only one parameter, the mitotic count, exhibited a statistical correlation with progression-free survival (PFS) and overall survival (OS). During the Kaplan-Meier analysis, the variation in PFS among the different risk groups exhibited a notable trend towards statistical significance. Nevertheless, 3 out of 74 patients classified as low-risk SFTs and 7 out of 21 patients classified as intermediate-risk exhibited disease progression. Among the 5 patients with TP53 mutations and/or mutant-type P53 immunophenotype, 3 experienced disease progression, including 2 intermediate-risk patients. Additionally, among the 4 patients with TERT promoter mutations who were followed up, 3 showed progression, including 2 intermediate-risk patients. Moreover, it was observed that hemizygous loss of CDKN2A was detected in more than 30% of one case, yet the patient exhibited a favorable survival outcome. Conclusion: The mDemicco risk model exhibits certain limitations when dealing with smaller tumor sizes, younger age groups, and occurrences of malignant and dedifferentiated SFTs. Furthermore, molecular factors, such as TP53 or TERT promoter mutations, may identify intermediate-risk SFTs with poorer prognoses.

Primitive myxoid mesenchymal tumor of infancy: report of two cases and review of the literature.

Primitive myxoid mesenchymal tumor of infancy is a recently recognized soft tissue tumor with only a few cases reported. Here, we reported another two cases of the lesion, a 5-month-old boy presenting with a soft tissue mass in the neck region that recurred 2 months later and a 3-day-old girl with a congenital superficial dorsal lumbar mass that extended to the spinal canal 1 month later. They shared similar histological patterns, such as unusual diffuse myxoid background, delicate vascular network, small cystic spaces, low to moderate cellularity, and primitive mesenchymal tumor cells. Immunohistochemically, the tumor cells showed positive for vimentin, CD99, CD117 and nestin, negative for myoid, lipoblastic, histiocytic, and neural markers. In conclusion, primitive myxoid mesenchymal tumor of infancy is a distinctive entity with its own clinical pathological features. Expression of CD99, CD117 and nestin may be consistent with the primitive nature of the tumor and may serve as ancillary markers for differential diagnosis from the other infantile tumors.

[Primary intermediate hemangioendothelioma of bone: a study of 5 cases].

OBJECTIVE: To study the radiologic and pathologic features of primary intermediate hemangioendothelioma of the bone. METHODS: Five cases of primary intermediate hemangioendothelioma of bone encountered in the past three years were enrolled into the study. The clinical, radiologic, pathologic and immunohistochemical features of the tumors were reviewed. RESULTS: The patients included 3 children with Kaposiform hemangioendothelioma and 2 elderly with retiform hemangioendothelioma. Four of the cases affected long bones and the remaining case affected the clavicle. One case showed multifocal involvement of the humerus. Radiologically, the tumors showed borderline to low-grade bony destruction, with various degrees of cortical defect. Intralesional or perilesional bone formation was demonstrated in 4 cases and radial spicules were seen in 1 case. The histopathologic features of primary intermediate hemangioendothelioma of bone were similar to those of soft tissue, except for the presence of reactive bone formation. Immunohistochemically, the tumor cells were positive for CD31 (5/5), CD34 (5/5), vimentin (5/5) and smooth muscle actin (3/5) but negative for cytokeratin and epithelial membrane antigen. CONCLUSIONS: Primary intermediate hemangioendothelioma of bone is a distinct entity and similar histologic classification applies as in its soft tissue counterparts. Comparison of the biologic behavior requires long-term follow-up studies.

Case report: ALK-rearranged spindle and epithelioid cell neoplasms with S100 and CD34 co-expression: Additional evidence of kinase fusion-positive soft tissue tumors.

ALK rearrangements have rarely been reported in S100- and CD34-co-expressing soft tissue neoplasms with lipofibromatosis-like neural tumor (LPFNT) pattern or stromal and perivascular hyalinization, mimicking NTRK-rearranged spindle cell tumors. Here, we reported ALK fusions involving related partner genes in two adult soft tissue tumors with S100 and CD34 co-expression, and conducted a literature review of mesenchymal tumors harboring ALK or other kinase fusions. Case 1 was a 25-year-old female who underwent excision of a soft tissue mass in the anterior thigh region. Morphologically, the tumor was composed of spindle cells adjacent to epithelioid cells embedded in myxedematous and hyalinized stroma, with infiltrative boundary. Spindle cells mixed with inflammatory infiltration resembling inflammatory myofibroblastic tumor (IMT) were seen sporadically. However, brisk mitosis and focal necrosis was also observed, indicating an intermediate-grade sarcoma. In case 2, the left side of the neck of a 34-year-old man was affected. The tumor was composed of monomorphic spindle cells arranged in fascicular growth or patternless pattern, with stromal and perivascular hyalinization. Sparse inflammatory cell infiltration was also observed. Both tumors showed CD34, S100, and ALK-D5F3 immunoreactivity. Next generation sequencing (NGS) test identified a PLEKHH2::ALK fusion in case 1, which was confirmed by RT-PCR and Sanger sequencing, whereas the RT-PCR (ARMS method) test detected an EML4::ALK fusion in case 2. In conclusion, this study expands the morphological and genetic landscape of tumors with S100 and CD34 co-expression harboring kinase fusions, and suggests that kinase fusion-positive mesenchymal neoplasms are becoming an enlarging entity with a variety of morphological patterns.

[Adult prostate sarcoma: a clinicopathologic study of 15 cases].

OBJECTIVE: To clarify the clinical and morphological features of adult prostate sarcoma (APS) and to further improve the knowledge and diagnostic accuracy for APS. METHODS: Fifteen cases of APS were observed and analyzed on the clinical symptom, pathological features, treatment and prognosis. RESULTS: Age of onset ranged from 22 to 77 years (mean 46.3 years). The majority of cases were presented with dysuresia. By digital rectal examination and imaging of the prostate, APS was often identified as a large tumor mass. There were 6 cases of leiomyosarcomas, 6 embryonal rhabdomyosarcomas, and 3 fibrosarcomas in this series. Follow-up data were available for 12 cases: 7 cases died of the disease between 9 days and 360 days after surgery. Among 5 survived patients, 3 cases had recurrence after 2 to 24 months follow-up. CONCLUSIONS: APS is a rare tumor that typically has clinical features: earlier age of onset, fast-appeared urinary tract symptoms, significant mass effects, and poor outcome. Level of prostate specific antigen (PSA) is usually normal or lower. Final diagnosis relies on the features of histology and immunohistochemistry expression profile.