Cementoblastoma Mimicking Pathology of Endodontic Origin: A Case Report.

Interdisciplinary care in the management of complex pathology is critical to ensure patients receive predictable, evidence-based treatment. The authors report the unique case of a healthy 38-year-old female patient who presented to a private endodontics practice with a radiopaque lesion associated with the root of tooth No. 20. The patient experienced mild and occasional palpation tenderness associated with the tooth. Extraoral examination and intraoral soft tissues presented without any abnormalities. Intraoral radiographs revealed a radiopacity overlying the apex of tooth No. 20. A cone-beam computed tomography scan of the region revealed a well-delineated bulbous radiopaque lesion attached to the lingual aspect of the apical third of the root of tooth No. 20. The lesion could not be distinguished from the root outline and presented with a radiolucent halo along its periphery. The differential diagnosis at the time consisted of cementoblastoma, condensing osteitis, hypercementosis, and periapical cemento-osseous dysplasia. The patient was referred to an oral and maxillofacial surgeon for evaluation and treatment. Tooth No. 20 was subsequently treated with an excisional biopsy and concurrent extraction of the tooth. Histologic examination of the lesion supported the diagnosis of cementoblastoma.

Atypical Spindle Cell/Pleomorphic Lipomatous Tumor With Sarcomatous Transformation: Clinicopathologic and Molecular Analysis of 4 Cases.

Atypical spindle cell/pleomorphic lipomatous tumor (ASPLT) is a recently described adipocytic tumor predominantly affecting the subcutaneous soft tissues of adults. Previous studies have shown that ASPLT follows a benign clinical course with a 4% to 12% local recurrence rate and no risk of dedifferentiation. Herein, we describe the clinicopathologic and molecular findings of 4 cases of ASPLT showing unequivocal sarcomatous transformation. Three patients were male and one was female, aged 65, 70, 74, and 78 years. Two cases presented as mass-forming lesions, while 1 case was incidentally discovered. The tumors measured 30, 55, 80, and 110 mm and occurred in the chest wall (n = 2) or arm (n = 2); all were subcutaneous. Microscopically, they showed a biphasic appearance comprising a low-grade ASPLT component and a high-grade sarcomatous component. The low-grade components showed features in the spectrum of either atypical pleomorphic lipomatous tumor (n = 2) or atypical spindle cell lipomatous tumor (n = 2). The high-grade components displayed leiomyosarcoma-like (n = 2), pleomorphic liposarcoma-like (n = 1) or undifferentiated sarcoma-like (n = 1) morphology. On immunohistochemistry, tumors were negative for MDM2 and showed loss of RB1 expression. In addition, the leiomyosarcoma-like areas seen in 2 cases were positive for smooth muscle actin and H-caldesmon. Single-nucleotide polymorphism array, performed in 3 cases, showed deletions of TP53, RB1, and flanking genes in both components. In contrast, the sarcomatous components showed more complex genomic profiles with rare segmental gains and recurrent loss of PTEN (n = 3), ATM (n = 2), and CDKN2A/B (n = 2) among other genes. Whole exome sequencing identified a TP53 variant in one case and an ATRX variant in another, each occurring in both tumor components. Limited clinical follow-up showed no recurrence or metastasis after 1 to 13 months (median, 7.5 months) postsurgical excision. Altogether, our data support that ASPLT can rarely develop sarcomatous transformation and offer insights into the molecular mechanisms underlying this event.

GLI1-Altered Mesenchymal Tumors.

GLI1-altered mesenchymal tumors comprise an emerging group of neoplasms characterized by fusions or amplifications involving GLI1, a gene that encodes a key regulator of the Hedgehog signaling pathway. In recent years, tumors with GLI1 alterations have been reported across a variety of anatomic sites and a broad age range. Although these tumors can exhibit a wide morphologic spectrum and a variable immunophenotype, they frequently present with monomorphic ovoid cells arranged in distinctive nests with a rich, arborizing vascular network. Recent evidence indicates that they have the potential to metastasize, which suggests that they may be best considered a sarcoma.

GLI1-Altered Mesenchymal Tumors With ACTB or PTCH1 Fusion: A Molecular and Clinicopathologic Analysis.

Mesenchymal tumors with GLI1 fusions or amplifications have recently emerged as a distinctive group of neoplasms. The terms GLI1-altered mesenchymal tumor or GLI1-altered soft tissue tumor serve as a nosological category, although the exact boundaries/criteria require further elucidation. We examined 16 tumors affecting predominantly adults (median age: 40 years), without sex predilection. Several patients had tumors of longstanding duration (>10 years). The most common primary site was soft tissue (n = 9); other sites included epidural tissue (n = 1), vertebra (n = 1), tongue (n = 1), hard palate (n = 1), and liver (n = 1). Histologically, the tumors demonstrated multinodular growth of cytologically uniform, ovoid-to-epithelioid, occasionally short spindled cells with delicate intratumoral vasculature and frequent myxoid stroma. Mitotic activity ranged from 0 to 8 mitoses/2 mm2 (mean 2). Lymphovascular invasion/protrusion of tumor cells into endothelial-lined vascular spaces was present or suspected in 6 cases. Necrosis, significant nuclear pleomorphism, or well-developed, fascicular spindle-cell growth were absent. Half demonstrated features of the newly proposed subset, "distinctive nested glomoid neoplasm." Tumors were consistently positive for CD56 (n = 5/5). A subset was stained with S100 protein (n = 7/13), SMA (n = 6/13), keratin (n = 2/9), EMA (n = 3/7), and CD99 (n = 2/6). Tumors harbored ACTB::GLI1 (n = 15) or PTCH1::GLI1 (n = 1) fusions. The assays used did not capture cases defined by GLI1 amplification. We also identified recurrent cytogenetic gains (1q, 5, 7, 8, 12, 12q13.2-ter, 21, and X). For patients with available clinical follow-up (n = 8), half were disease free. Half demonstrated distant metastases (lungs, bone, or soft tissue). Of cases without follow-up (n = 8), 2 were known recurrences, and 1 was presumed metastasis. Our results imply a more aggressive biological potential than currently reported. Given the possibility for metastasis and disease progression, even in cytologically bland, nested tumors, close clinical surveillance, akin to that for sarcoma management, may be indicated. The term GLI1-altered mesenchymal tumor with malignant potential is proposed.

Metastatic Neuroendocrine Neoplasms to the Pancreas: Two Unusual Cases and a Review of the Literature.

Neuroendocrine tumor metastases to the pancreas are rare, and they share substantial overlap with the significantly more common primary pancreatic neuroendocrine neoplasms, representing a potential diagnostic pitfall. Elucidating whether a neuroendocrine tumor within the pancreas is a primary neoplasm versus a metastasis has significant prognostic and treatment implications. Correlation with clinical history and imaging as well as incorporating an appropriate immunohistochemical panel are essential to establish the correct diagnosis. Herein, we present 2 rare neuroendocrine tumors that metastasized to the pancreas: a medullary thyroid carcinoma and an atypical carcinoid tumor of lung origin. We also provide a brief review of the literature.

Gene of the month: DDIT3.

DNA damage-inducible transcript 3 (DDIT3) gene, mapped to the human chromosome 12q13.3, encodes a protein that belongs to the CCAAT/enhancer-binding protein family of transcription factors. DDIT3 is involved in the proliferative control that responds to endoplasmic reticulum stress in normal conditions, dimerising other transcription factors with basic leucine zipper (bZIP) structural motifs. DDIT3 plays a significant role during cell differentiation, especially adipogenesis, arresting the maturation of adipoblasts. In disease, FUS/EWSR1::DDIT3 fusion is the pathogenic event that drives the development of myxoid liposarcoma. The amplification of DDIT3 in other adipocytic neoplasms mediates the presence of adipoblast-like elements. Another fusion, GLI1::DDIT3, has rarely been documented in other tumours. This paper reviews the structure and function of DDIT3, its role in disease-particularly cancer-and its use and pitfalls in diagnostic testing, including immunohistochemistry as a tissue-based marker.

The art of specimen orientation: Two-dimensional maps for oropharynx squamous cell carcinoma.

The goal of surgical treatment for oropharynx squamous cell carcinoma (SCCa) is resection to negative margins. Current methods of orienting resection specimens often do not give a comprehensive view, especially in oropharynx SCCa where specimens can lack anatomic landmarks. We created standardized two-dimensional maps of oropharynx anatomy drawn to scale to improve communication between surgeons and pathologists. Notes regarding surgery including anatomic landmarks, areas of concern, additional margins, and relevant clinical information were added to the map. The maps guided pathology work-up, and the pathologist could communicate details back to the surgeon on how the specimen was sectioned or locations of microscopic foci to direct future treatment and clinical monitoring. The use of two-dimensional maps for oropharynx SCCa specimens offers a standardized solution to address the challenges of anatomic orientation. These maps summarized key pathological information, preserved clinical details from the specimens, and guided multidisciplinary conferences when planning adjuvant treatment.

Pathologic Femur Fracture in an Immunocompetent Healthy Young Adult due to Acute Osteomyelitis.

An immunocompetent 33-year-old woman presented with a pathologic femur fracture after one month of progressively worsening right thigh pain. Open biopsy demonstrated acute suppurative osteomyelitis despite the lack of clinical risk factors. The polymicrobial infection was successfully treated with three operative procedures and culture-specific antibiotic agents. Acute osteomyelitis, while an uncommon cause of pathologic fracture, must always be on the differential diagnosis, even when no obvious predisposing factors are present. When investigating for an infectious etiology in cases such as our own, considering immunodeficiency syndromes alongside the more typical causes of osteomyelitis is encouraged.

Oligometastatic Melanoma Treated by Metastasectomy in Combination with Immune Checkpoint and BRAF Inhibitors: A Case Series.

BACKGROUND Early therapies for metastatic melanoma improved patient quality of life; however, median survival remained unaffected. Studies are showing that surgical excision with the combination of immune checkpoint inhibitor (ICI) therapy has better outcomes than systemic therapy alone. This single-center case series describes 7 patients with oligometastatic melanoma treated by metastasectomy in combination with ICI and BRAF inhibitors. CASE REPORT One female and 6 male patients are included in our study, with ages ranging from 34 to 82 years. Oligometastatic melanoma is defined was having no more than 5 metastatic regions. Each patient had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients received either ICI therapy with ipilimumab, nivolumab, and/or pembrolizumab, or targeted therapy with encorafenib and binimetinib, or a combination. Patients underwent metastasectomies with curative intent. The main outcome and measurements obtained were the duration of disease-free survival, based on radiographic evidence. The range of disease-free survival in our population was 13 to 67 months, with the lower end limited by patient death and the upper limit being the present day. CONCLUSIONS This case series reiterates survival benefit for patients who received metastasectomy after exhibiting good response to ICI therapy. ICI and/or BRAF inhibitor therapy combined with metastasectomy provides a possible curative option for patients who may have previously been relegated to palliative-focused care. By using a multimodal approach with oncologists and surgeons, we can challenge our understanding of what constitutes a resectable cancer.

Use of molecular testing results to analyze the overuse of atypia of undetermined significance in thyroid cytology.

INTRODUCTION: The suggested atypia of undetermined significance (AUS) rate for thyroid fine-needle aspiration biopsies is 10% or less. Prompted by a high institutional AUS rate, we examined using molecular testing results (MTR) as a potential quality metric tool to reduce the AUS rate. We correlated MTR with AUS cytologic findings, surgical pathology follow-up, and individual pathologist AUS rates. MATERIALS AND METHODS: Demographic data, cytologic diagnoses, MTR, and surgical pathology diagnoses were retrospectively obtained. MTR were classified as either positive or negative. AUS rates and MTR proportions were compared among pathologists. The cytomorphologic features of 143 AUS cases were assessed and correlated with MTR. RESULTS: Between 2017 and 2022, 710 of 3247 thyroid fine-needle aspirations were classified as AUS, with a yearly average rate of 22% (range = 19%-26%). AUS cases included: 331 (47%) with architectural atypia; 204 (29%) with oncocytic (Hürthle cell) atypia; 99 (14%) with combined architectural and cytologic atypia; and 76 (10%) with isolated cytologic atypia. Most AUS cases with molecular testing had negative MTR (360/492, 73%). AUS with cytologic atypia had higher positive MTR risk (logarithm of odds ratio = 1.27, 95% credible interval [0.5-2.04], P = 0.001). The average positive MTR rate by pathologist was 21.5% (range 0%-35%); higher positive MTR rates had better correlation with subsequent neoplastic/malignant histologic diagnoses. The MTR sensitivity for malignant disease was 89% and the negative predictive value was 91%. CONCLUSIONS: MTR analysis reveals the importance of cytologic atypia as a determinant of malignancy risk in AUS cases. Periodic analysis of MTR data alongside individual pathologist AUS rates can help refine diagnostic criteria and potentially reduce AUS overuse.

TRPS1 immunohistochemical expression in salivary gland tumors: A pilot study.

OBJECTIVES: TRPS1 is a new, sensitive marker for breast carcinoma (BC). Salivary glands and breasts are both exocrine glands; thus, their tumors may share similar morphology and immunophenotype. Among salivary gland-type BC, TRPS1 is reported to be positive in secretory carcinomas (SCs) but negative in acinic cell carcinomas (AciCCs) and most adenoid cystic carcinomas (AdCCs). A subset of salivary duct carcinomas (SDCs) is positive for TRPS1. Herein, we investigate TRPS1 immunohistochemical expression in salivary gland tumors (SGTs). METHODS: A retrospective search yielded 110 SGTs (97 primary and 13 metastatic). TRPS1 immunohistochemistry was scored as negative, low positive, intermediate positive, or strongly positive. RESULTS: TRPS1 was expressed in 78% (14/18) of pleomorphic adenoma (PA) cases but negative/low positive in all Warthin tumors (6/6 [100%]). In basal cell adenoma (BCA), TRPS1 expression was intermediate to strong (13/14 [92%]) in the stromal cells, whereas ductal or basal cells showed low expression. TRPS1 expression varied in malignant SGTs, with intermediate to strong staining in 100% (15/15) of AdCCs, 100% (5/5) of basal cell adenocarcinoma, 100% (3/3) of intraductal carcinoma, 89% (8/9) of polymorphous adenocarcinoma, and 89% (7/8) of SDCs; negative/low positive expression was observed in 100% (3/3) of SCs, 89% (8/9) of AciCCs, and 50% (3/3) of mucoepidermoid carcinomas. In addition, strong and intermediate TRPS1 expression was observed in metastatic SGT to the lungs, lymph nodes, and soft tissue. CONCLUSIONS: Overall, TRPS1 is strongly expressed in PA as well as malignant and metastatic SGT. In addition, TRPS1 is positive in stromal cells of BCA but negative or low positive in ductal and basal cells.

Small biopsies in the head and neck: Bone and soft tissue.

Bone and soft tissue lesions in the head and neck encompass not only a broad morphologic spectrum but also significant inherent clinicopathologic overlap. Epidemiology, radiology, and location - similar to the diagnostic assessment in other sites - are especially important considerations in the context of an established mesenchymal proliferation. Herein, the approach towards diagnosis is stratified by morphology (spindle, sarcomatoid, epithelioid, round cell), cellular lineage (fibroblastic, nerve sheath, rhabdomyogenic), and tumor grade (benign, low- to high-grade malignant) as the basis of further immunohistochemical or molecular investigation.

A Subset of Thoracic SMARCA4-Deficient Undifferentiated Tumors Express GATA3.

Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a rare and highly aggressive malignant neoplasm characterized by high-grade undifferentiated morphologic features and recurrent inactivating mutations of SMARCA4. These tumors consistently exhibit loss of SMARCA4 (BRG1) while displaying variable expression of other nonspecific markers. Recently, we encountered a SMARCA4-UT demonstrating immunoreactivity for GATA3, and we sought to characterize this phenomenon in a larger series.A total of nine SMARCA4-UTs were examined from 3 large academic institutions. The clinicopathologic and molecular characteristics were studied and GATA3 immunohistochemistry was performed.The cohort included 5 male and 4 female patients, with a median age of 54 years and a median smoking history of 37 pack-years. At initial diagnosis, mediastinal lymph node involvement was observed in 5 patients (56%) while distant metastases were present in 7 patients (78%). The median survival was 6 months. Histologically, the tumors were characterized by sheets of undifferentiated epithelioid and/or rhabdoid cells, accompanied by frequent mitotic figures and necrosis. Immunohistochemically, all tumors displayed a complete loss of BRG1 expression. Notably, 4 of 9 tumors (44%) were positive for GATA3 expression, including one tumor that exhibited strong and diffuse immunoreactivity.GATA3 expression in SMARCA4-UT may pose diagnostic challenges, requiring differentiation from other GATA3-positive tumors. This distinction is crucial for accurate prognostication and treatment decisions.

Large-scale validation study of an improved semiautonomous urine cytology assessment tool: AutoParis-X.

BACKGROUND: Adopting a computational approach for the assessment of urine cytology specimens has the potential to improve the efficiency, accuracy, and reliability of bladder cancer screening, which has heretofore relied on semisubjective manual assessment methods. As rigorous, quantitative criteria and guidelines have been introduced for improving screening practices (e.g., The Paris System for Reporting Urinary Cytology), algorithms to emulate semiautonomous diagnostic decision-making have lagged behind, in part because of the complex and nuanced nature of urine cytology reporting. METHODS: In this study, the authors report on the development and large-scale validation of a deep-learning tool, AutoParis-X, which can facilitate rapid, semiautonomous examination of urine cytology specimens. RESULTS: The results of this large-scale, retrospective validation study indicate that AutoParis-X can accurately determine urothelial cell atypia and aggregate a wide variety of cell-related and cluster-related information across a slide to yield an atypia burden score, which correlates closely with overall specimen atypia and is predictive of Paris system diagnostic categories. Importantly, this approach accounts for challenges associated with the assessment of overlapping cell cluster borders, which improve the ability to predict specimen atypia and accurately estimate the nuclear-to-cytoplasm ratio for cells in these clusters. CONCLUSIONS: The authors developed a publicly available, open-source, interactive web application that features a simple, easy-to-use display for examining urine cytology whole-slide images and determining the level of atypia in specific cells, flagging the most abnormal cells for pathologist review. The accuracy of AutoParis-X (and other semiautomated digital pathology systems) indicates that these technologies are approaching clinical readiness and necessitates full evaluation of these algorithms in head-to-head clinical trials.

Probability of malignancy and molecular alterations as determined by ThyroSeq v3 genomic classifier in Bethesda Category IV.

BACKGROUND: ThyroSeq molecular testing assesses the probability of malignancy (POM) in thyroid fine-needle aspiration cytology (FNAC) with indeterminate cytology. The aim was to investigate whether Bethesda category IV (BIV) subcategories are associated with specific molecular alterations, molecular-derived risk of malignancy (MDROM), and risk of malignancy (ROM). METHODS: FNAC slides, associated ThyroSeq, version 3, Genomic Classifier results, and surgical follow-up were retrieved for BIV nodules. Nodules were subcategorized as follicular neoplasm (FN) with or without cytologic atypia or oncocytic follicular neoplasm (OFN). The MDROM, ROM, and frequency of molecular alterations in FN and OFN were analyzed. p < .05 was considered significant. RESULTS: A total of 92 FNAC were identified and subcategorized into 46 FN (15 with and 31 without cytologic atypia) and 46 OFN. The benign call rate and the positive call rate were 49% and 51%, respectively. The MDROM in BIV was 34.3%, trending lower in OFN than in FN. RAS mutations were significantly more frequent in FN when compared to OFN (p = .02). Chromosomal copy number alterations were more often present in OFN than in FN (p < .01). On histologic follow-up, ROM in OFN was trending lower than in FN (p = .1). The most common diagnosis in OFN was oncocytic adenoma, whereas follicular variant papillary thyroid carcinoma was most common in FN. CONCLUSIONS: The MDROM and ROM were trending lower in OFN compared with FN, and the molecular alterations differed between OFN and FN subcategories.

Examining longitudinal markers of bladder cancer recurrence through a semiautonomous machine learning system for quantifying specimen atypia from urine cytology.

BACKGROUND: Urine cytology is generally considered the primary approach for screening for recurrence of bladder cancer. However, it is currently unclear how best to use cytological examinations for assessment and early detection of recurrence, beyond identifying a positive finding that requires more invasive methods to confirm recurrence and decide on therapeutic options. Because screening programs are frequent, and can be burdensome, finding quantitative means to reduce this burden for patients, cytopathologists, and urologists is an important endeavor and can improve both the efficiency and reliability of findings. Additionally, identifying ways to risk-stratify patients is crucial for improving quality of life while reducing the risk of future recurrence or progression of the cancer. METHODS: In this study, a computational machine learning tool, AutoParis-X, was leveraged to extract imaging features from urine cytology examinations longitudinally to study the predictive potential of urine cytology for assessing recurrence risk. This study examined how the significance of imaging predictors changes over time before and after surgery to determine which predictors and time periods are most relevant for assessing recurrence risk. RESULTS: Results indicate that imaging predictors extracted using AutoParis-X can predict recurrence as well or better than traditional cytological/histological assessments alone and that the predictiveness of these features is variable across time, with key differences in overall specimen atypia identified immediately before tumor recurrence. CONCLUSIONS: Further research will clarify how computational methods can be effectively used in high-volume screening programs to improve recurrence detection and complement traditional modes of assessment.

Benign and low-grade superficial endothelial cell neoplasms in the molecular era.

Vascular tumors are the most common mesenchymal neoplasms of the skin and subcutis, and they encompass a heterogeneous group with diverse clinical, histological, and molecular features, as well as biological behavior. Over the past two decades, molecular studies have enabled the identification of pathogenic recurrent genetic alterations that can be used as additional data points to support the correct classification of these lesions. The purpose of this review is to summarize the available data related to superficially located benign and low-grade vascular neoplasms and to highlight recent molecular advances with the role of surrogate immunohistochemistry to target pathogenic proteins as diagnostic biomarkers.

Cutaneous myoepithelioma with EWSR1 gene rearrangement and its differentials: A diagnostic challenge.

Cutaneous myoepithelioma is a rare benign soft tissue neoplasm of myoepithelial cells involving the skin and subcutis. These tumors can be diagnostically challenging. The plasticity of myoepithelial cells leads to wide variability in the cytomorphology, immunophenotype, and genetic features of myoepithelioma. Their protean presentations may mimic malignant neoplasms. Therefore, distinction from malignancy is essential. Herein, we report a case of cutaneous myoepithelioma presenting similarly to Ewing sarcoma, with small round blue cells and an EWSR1 rearrangement. Our case highlights the important morphologic, immunohistochemical, and cytogenetic features of this benign basaloid cutaneous tumor.