Clear cell papillary renal cell carcinoma (CCPRCC) is a low-grade, indolent neoplasm with no reported cases of death from disease or metastasis. These lesions can show clinical, morphologic, and ...immunophenotypic overlap with several aggressive forms of renal cell carcinoma (RCC), including clear cell RCC, translocation RCC, and papillary RCC with cytoplasmic clearing. Given the difference in behavior, it is important to reliably separate these entities. We retrospectively reviewed 47 tumors from 45 patients with morphologic features of CCPRCC. All cases were stained against cytokeratin 7 (CK7), carbonic anhydrase IX (CAIX), and GATA3. Cases inconsistent with CCPRCC were reclassified. In addition, we stained tissue microarrays with 103 typical clear cell RCCs and 62 papillary RCCs, each in triplicate. Twenty-five cases were morphologically and immunophenotypically consistent with CCPRCC; all of them showed diffuse CK7 expression and cup-like reactivity with CAIX. Of these, 19 (76%) showed strong nuclear reactivity for GATA3. Although some non-CCPRCC neoplasms showed at least partial CK7/CAIX coexpression, none were immunopositive for GATA3. All background normal kidneys studied showed GATA3 expression in the distal tubules, collecting ducts, and retention cysts of the distal nephron. On follow-up, none of the patients with CCPRCC had recurrences or metastasis. Sensitivity and specificity for GATA3 staining in the diagnosis of CCPRCC were 76% and 100%, with positive and negative predictive values of 100% and 74%. In conclusion, GATA3 is specific and sensitive for CCPRCC and can be used for accurate distinction from its main mimickers. Coexpression of GATA3 and CK7 in most CCPRCC provides evidence of their origin from distal nephron.
•GATA3 immunoreactivity is present in 74% of clear cell papillary renal cell carcinomas (CCPRCC).•None of the more aggressive morphologic mimics or CCPRCC showed immunoreactivity for GATA3.•The sensitivity and specificity of GATA3 for diagnosing CCPRCC are 76% and 100%, respectively.•GATA3 positivity in CCPRCC suggests a potential origin of this neoplasm in the distal nephron.
HEY1‐NCOA2 fusion is most described in mesenchymal chondrosarcoma. This is the first case report of a primary renal spindle cell neoplasm of uncertain malignant potential with a HEY1::NCOA2 fusion ...identified by Fusionplex RNA‐sequencing that is histologically distinct from mesenchymal chondrosarcoma. The neoplasm was identified in a 33‐year‐old woman without significant past medical history who underwent partial nephrectomy for an incidentally discovered renal mass. The histologic features of the mass included spindle cells with variable cellularity and monotonous bland cytology forming vague fascicles and storiform architecture within a myxoedematous and collagenous stroma with areas of calcification. The morphologic and immunophenotypic features were not specific for any entity but were most similar to low‐grade fibromyxoid sarcoma. To date, the patient has not had recurrence, and the malignant potential of the neoplasm is uncertain.
Detection of disease‐defining gene fusions in sarcoma has led to refining their classification, as well as to discover several new entities. The advent of anchored multiplex PCR/targeted RNA ...next‐generation sequencing (AMP/RNA‐seq) has allowed for the development of scalable platforms that can simultaneously examine multiple fusion transcripts without prior knowledge of specific fusion partners.In this study, we assess the utility of a FusionPlex sarcoma panel analysis by AMP/RNA‐seq to detect disease‐defining gene fusions in 16 cases of undifferentiated round cell sarcoma in which prior diagnostic work‐up could not establish a definitive diagnosis. The clinical and pathologic features of these cases were correlated with the molecular findings. Validation of the method using 41 cases with known diagnoses showed analytic sensitivity and specificity of 98% and 100%, respectively. Of the 16 cases of undifferentiated round cell sarcoma, gene fusions were found in 9 (56%). These included three cases with CIC‐DUX4 fusion, two cases with BCOR‐CCNB3, and four single cases with CIC‐NUTM2A, HEY1‐NCOA2, EWSR1‐NFATC2, and NUT‐MGA1 fusions. Overall, despite some degree of morphologic overlap, all fusion‐positive cases had distinct morphologic features, which can be helpful for their histologic classification. We also describe the first adult case of MGA‐NUTM1 fusion sarcoma, as well as cartilaginous differentiation in a BCOR‐CCNB3 fusion sarcoma, which has not been previously reported. Our study demonstrated that FusionPlex sarcoma panel analysis, in the appropriate morphologic context, is a sensitive and precise ancillary method for the detection of disease‐defining gene fusions in undifferentiated round cell sarcomas, aiding in their definitive classification.
To describe the radiologic and clinicopathologic features of extranodal Rosai-Dorfman disease (RDD) in our patient population.
Via a data mining engine, we evaluated 13 cases of extranodal RDD in 10 ...patients treated at our institution from 2000 to 2014.
There was a marked female predominance (90%) in our series. The most common clinical presentation was a palpable, painless mass, which often simulated a neoplasm. Only two cases occurred in children. Multicentric and recurrent disease were uncommon. Histologically, all cases showed large histiocytes with emperipolesis in a mixed inflammatory background, with areas of dense, storiform collagen fibrosis. Positive S-100 and CD68 with negative CD1a in histiocytes are characteristic.
Extranodal RDD is rare and its manifestations varied. It may constitute a clinical and pathologic diagnostic challenge. Clinical suspicion and recognition of its histologic features are necessary for correct diagnosis and avoiding unnecessary treatment. Resection is curative in most cases.
Fibroma of tendon sheath (FTS) is an uncommon benign fibroblastic/myofibroblastic neoplasm that typically arises in the tenosynovial tissue of the distal extremities. Histologically, it is a ...well-circumscribed proliferation of spindle cells within collagenous stroma with peripheral slit-like vessels. Most examples are relatively hypocellular and more densely collagenous than nodular fasciitis; however, a cellular variant has been described, which has considerable morphologic overlap with nodular fasciitis and has been shown to harbor USP6 translocations in a subset of cases. The incidence of these rearrangements and the identity of the USP6 fusion partners have not been described in detail. In this study we evaluate 13 cases of cellular fibroma of tendon sheath by anchored multiplex PCR/next generation sequencing in order to detect potential gene fusions. Nucleic acids of adequate quality were obtained in 11 cases, demonstrating gene fusions in 7/11 (64%), all of which involve USP6 with a variety of partners, including PKM, RCC1, ASPN, COL1A1, COL3A1, and MYH9. Some unusual histomorphologic findings were present in a subset of cases including palisading growth pattern, epithelioid cells, and osteoclast-like multinucleated giant cells, particularly in the tumors with PKM and ASPN gene partners. Overall, the findings support a biologic relationship between cellular fibroma of tendon sheath and other lesions within the spectrum of USP6-rearranged neoplasms, particularly nodular fasciitis.
Liposarcoma is a malignant soft tissue tumor with several subtypes, the most common of which is well-differentiated liposarcoma (WDL) or atypical lipomatous tumor (ALT). WDL/ALTs are further divided ...into three histological subtypes, including lipoma-like, sclerosing, and inflammatory. While the majority of these tumors are predominantly fatty, the sclerosing variant demonstrates diverse histologic and radiographic characteristics, including variable amounts of fibrosis and fat. Because of this histological variability and relative rarity, the sclerosing WDL/ALT can present diagnostic dilemmas. We present two cases of sclerosing WDL/ALT, both of which demonstrated high degrees of fibrosis and a paucity of fat, mimicking desmoid fibromatosis and other fibrotic soft tissue tumors. Thus, it is important for radiologists to be aware of the subtypes of liposarcoma and their unique characteristics, and to consider sclerosing WDL/ALT in cases of fibrotic soft tissue tumors.
The classification of endometrial stromal sarcoma (ESS) has been refined and aided by the discovery of various recurrent gene translocations. Low‐grade ESS (LG‐ESS) is most commonly characterized by ...JAZF1‐SUZ12 fusions followed by rearrangements involving PHD finger protein‐1 (PHF1) and multiple fusion partners, including JAZF1, EPC1, EPC2, and MEAF6. In the present study, integrating anchored polymerase chain reaction and paired‐end next‐generation ribonucleic acid sequencing, we identified the presence of a novel malignant brain tumor domain‐containing 1 (MBTD1)‐PHF1 gene fusion in a case of LG‐ESS. MBTD1 belongs to the Polycomb gene group, and its fusion with PHF1 is predicted to mediate tumorigenesis through aberrant transcriptional repression. Histology and immunohistochemical studies demonstrated conventional morphology for LG‐ESS and clinical follow‐up showed no progression of disease after 6 months. These findings help expand the current knowledge on the spectrum of gene rearrangements in the diagnosis of ESS.
•Class imbalance is common issue in the application of machine learning (ML) to neuroscience and can have severe consequences if not handled properly.•The impact of increasing data imbalance on ML ...performance is assessed for various levels of imbalance using simulated data, as well as EEG, MEG and fMRI recordings.•In highly imbalanced data, the commonly used Accuracy metric yields misleadingly high performances that result from systematically predicting the majority class.•The balanced accuracy (BAcc) metric is recommended as a default evaluation metric for ML, when seeking to minimize overall classification error.•A list of recommendations for dealing with imbalanced data is provided, and open-source code is made available to allow for further investigation.
Machine learning (ML) is increasingly used in cognitive, computational and clinical neuroscience. The reliable and efficient application of ML requires a sound understanding of its subtleties and limitations. Training ML models on datasets with imbalanced classes is a particularly common problem, and it can have severe consequences if not adequately addressed. With the neuroscience ML user in mind, this paper provides a didactic assessment of the class imbalance problem and illustrates its impact through systematic manipulation of data imbalance ratios in (i) simulated data and (ii) brain data recorded with electroencephalography (EEG), magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI). Our results illustrate how the widely-used Accuracy (Acc) metric, which measures the overall proportion of successful predictions, yields misleadingly high performances, as class imbalance increases. Because Acc weights the per-class ratios of correct predictions proportionally to class size, it largely disregards the performance on the minority class. A binary classification model that learns to systematically vote for the majority class will yield an artificially high decoding accuracy that directly reflects the imbalance between the two classes, rather than any genuine generalizable ability to discriminate between them. We show that other evaluation metrics such as the Area Under the Curve (AUC) of the Receiver Operating Characteristic (ROC), and the less common Balanced Accuracy (BAcc) metric - defined as the arithmetic mean between sensitivity and specificity, provide more reliable performance evaluations for imbalanced data. Our findings also highlight the robustness of Random Forest (RF), and the benefits of using stratified cross-validation and hyperprameter optimization to tackle data imbalance. Critically, for neuroscience ML applications that seek to minimize overall classification error, we recommend the routine use of BAcc, which in the specific case of balanced data is equivalent to using standard Acc, and readily extends to multi-class settings. Importantly, we present a list of recommendations for dealing with imbalanced data, as well as open-source code to allow the neuroscience community to replicate and extend our observations and explore alternative approaches to coping with imbalanced data.
We describe a case of a myoepithelial carcinoma of the superficial parotid gland in a 46‐year‐old male harboring a novel CTCF::NCOA2 gene fusion. To our knowledge, this novel gene fusion has not been ...described previously in myoepithelial carcinoma. A 46‐year‐old male patient presented with a mass involving the superficial left parotid gland with extension into the external auditory canal (EAC) and erosion of the conchal cartilage. Histologically, the neoplasm was composed of uniform spindled, epithelioid/ovoid cells arranged in cords and nests within hyalinized to myxoid stroma. On immunohistochemistry (IHC), the tumor cells demonstrated patchy and variable staining for low molecular weight cytokeratin (CAM5.2), pan‐cytokeratin (OSCAR), and S‐100. Overall, the morphological and immunohistochemical attributes supported a locally aggressive tumor of myoepithelial differentiation consistent with myoepithelial carcinoma. Molecular analysis using a custom 115‐gene gene panel by targeted RNA sequencing, showed an in‐frame CTCF::NCOA2 fusion. In addition to reporting this novel fusion in myoepithelial carcinoma, we also discuss relevant differential diagnosis, and provide a brief review of NCOA2 gene function in both normal and neoplastic contexts.
The 2020 release of the WHO Classification of Soft Tissue and Bone Tumors, 5th edition, contains several changes driven by new knowledge in the field. These include reclassification of some entities, ...refinement of risk classification systems, and the inclusion of novel disease processes, many of which are driven by recurrent gene fusions. The most notable changes are described here.
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