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Rationale: Mitochondria have important roles in intracellular energy generation, modulation of apoptosis, and redox-dependent intracellular signaling. Although reactive oxygen species (ROS) participate in the regulation of intracellular signaling pathways, including activation of nuclear factor (NF)-kappaB, there is only limited information concerning the role of mitochondrially derived ROS in modulating cellular activation and tissue injury associated with acute inflammatory processes.Objectives: To examine involvement of the mitochondrial electron transport chain complex I on LPS-mediated NF-kappaB activation in neutrophils and neutrophil-dependent acute lung injury.Methods: Neutrophils incubated with rotenone or metformin were treated with bacterial lipopolysaccharide (LPS) to determine the effects of mitochondrial complex I inhibition on intracellular concentrations of reactive oxygen species, NF-kappaB activation, and proinflammatory cytokine expression. Acute lung injury was produced by intratracheal injection of LPS into control, metformin, or rotenone-treated mice.Measurements and Main Results: Inhibition of complex I with either rotenone or the antihyperglycemic agent metformin was associated with increased intracellular levels of both superoxide and hydrogen peroxide, as well as inhibition of LPS-induced I kappaB-alpha degradation, NF-kappaB nuclear accumulation, and proinflammatory cytokine production. Treatment of LPS-exposed mice with rotenone or metformin resulted in inhibition of complex I in the lungs, as well as diminished severity of lung injury.Conclusions: These results demonstrate that mitochondrial complex I plays an important role in modulating Toll-like receptor 4-mediated neutrophil activation and suggest that metformin, as well as other agents that inhibit mitochondrial complex I, may be useful in the prevention or treatment of acute inflammatory processes in which activated neutrophils play a major role, such as acute lung injury. [ABSTRACT FROM AUTHOR]

Meningeal hemangiopericytomas are rare vascular tumors that have a propensity for recurrence and metastasis. Intracranial hemangiopericytomas are rare vascular tumors. They account for 0.5% of primary central nervous system tumors and 2% of meningiomas. Unlike usual benign meningiomas, which rarely metastasize extracranially, meningeal hemangiopericytoma has a high rate of local recurrence and distant metastasis. The treatment paradigms for hemangiopericytomas and meningiomas differ based on their biological behaviors. Hemangiopericytomas have higher rates of recurrence and metastasis compared with meningiomas. Intracranial meningeal hemangiopericytoma is characterized by clinically repeated local recurrences at the primary site. Bone, liver, lung, central nervous system, and abdominal cavity are the most commonly reported sites of metastasis in hemangiopericytomas.This article describes a case of bone metastasis with extensive involvement of the scapula from intracranial hemangiopericytoma. Bone metastasis can be seen in a relatively late phase of the disease, with metastasis to other organs. Although radiation therapy is effective in controlling pain from bone metastases in unresectable disease and those with extensive visceral metastases, aggressive local surgical control of a solitary bone metastasis may be an option for patients with limited distant disease. The diagnosis may be initially confused with clear cell meningioma and benign meningiomas. The management of bone metastasis is not well reported in the orthopedic literature. [ABSTRACT FROM AUTHOR]

Purpose: The importance of a TP53 mutation has been demonstrated in several tumor types, including breast cancer (BC). However, the accuracy of p53 protein expression as a predictor of gene mutation has not been well studied in BC. Therefore, we evaluated p53 protein expression associated with TP53 mutations in breast cancers from 64 patients., Methods: TP53 mutation was examined using next-generation sequencing (NGS). p53 protein expression was examined using immunohistochemistry (IHC)., Results: Among the 64 BCs, 55% demonstrated abnormal expression patterns including 27% overexpression, 22% null, 6% equivocal with 45% having a wild-type pattern. A TP53 mutation was present in 53% (34/64) of tumors including 30% (19/64) demonstrating a missense mutation, 11% (7/64) with a frameshift mutation, 11% (7/64) with a nonsense mutation, and 3% (1/64) with a splice site mutation. Abnormal expression of p53 protein was present in 33 of 34 (97%) tumors carrying a TP53 mutation; conversely, a wild-type pattern was present in 28 of 30 (93%) tumors without a detectable mutation (p < 0.0001). The majority of BCs with a p53 IHC overexpression pattern (15/17, 88%) contained a missense TP53 mutation; while the majority of BCs with a null pattern (12/14, 86%) contained a truncating mutation (p < 0.0001). The BCs with a null pattern are associated with a high Nottingham histological grade and a triple-negative phenotype when compared to those demonstrating overexpression (p < 0.05)., Conclusion: These findings suggest that p53 IHC can be a potential surrogate for TP53 mutations in BC. Different p53 expression patterns may correlate with specific TP53 genetic mutations in BC., (© 2024. The Author(s).)

The diagnosis of low-grade fibroblastic/myofibroblastic tumors of acral sites can be challenging. These tumors encompass a diverse group of neoplasms with a spectrum of biologic potential ranges from benign to overtly malignant. They often demonstrate significant clinical, radiologic, and immunophenotypic overlap, in which the molecular phenotype may play an important diagnostic role to arrive at the final diagnosis. Herein, we report a case of soft tissue mass lesion presented on the palm of an adult patient for four months. Histologically, the tumor consisted of primarily low-grade spindle cells expressing smooth muscle actin. Molecular testing revealed a novel SREBF1::USP6 fusion gene, confirming the final diagnosis of nodular fasciitis and ultimately expanding its molecular profile. This case highlights the diagnostic value of single, cost-effective, targeted molecular panel to arrive at an accurate diagnosis and provide helpful therapeutic information., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: PD-L1 immunohistochemistry (IHC) is being used as a predictive marker of the benefit derived from immunotherapy in several cancer types, including breast cancer. However, the insight gleaned of the prognostic and predictive value of PD-L1 status and its correlation with molecular characteristics during breast cancer progression remains limited., Methods: We performed an PD-L1 (22C3) assay in pre-treatment primary and metastatic tumor sections from 33 patients with breast carcinoma, matched for post neoadjuvant chemotherapy (p-NACT). PD-L1 expression was evaluated using 3 scoring methods: immune cell (IC) and tumor cell (TC) with a 1% as the cutoff value, and combined positive scores (CPS) with a 1 as the cutoff value. Twenty-two samples from 11 patients had successful fluorescence in situ hybridization (FISH)-based molecular data available for analysis., Results: In the 33 pre-treatment primary tumors, PD-L1 IC, TC, and CPS showed positive correlation with stromal tumor infiltrate lymphocytes (sTIL), histological grade 3, and triple negative breast carcinoma (TNBC). In the matched metastatic tumors, only PD-L1 IC showed a positive correlation with sTIL. The primary tumors showed a higher PD-L1 expression than the matched metastatic tumors by IC and CPS. Negative to positive conversion by CPS was identified in the metastatic tumors from lung, pleura and liver. p-NACT tumors also showed a trend of lower PD-L1 expression compared to the pre-treatment tumors. Six patients had matched samples for molecular and PD-L1 comparison, and none of them showed consistent gene alterations or PD-L1 expression among the primary, p-NACT and metastatic tumors., Conclusion: Our study showed a decrease in PD-L1 expression and disconnected molecular features during breast cancer progression. Repeating PD-L1 IHC testing could be considered in some specific metastatic sites if primary tumors were negative. Further studies are needed to identify other predictive factors for immune checkpoint inhibitor (ICI) therapy in patients with breast carcinoma., Competing Interests: Disclosure No authors have any conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Low HER2 expression is emerging as an actionable target for the treatment of breast cancer (BC) with the antibody drug conjugate Trastuzumab deruxtecan. The aim of the study was to characterize the dynamics of HER2 expression during BC progression., Methods: We evaluated the evolution of HER2 expression in 171 paired primary and metastatic BCs (pBCs/mBCs) by including the HER2-low category., Results: The proportions of HER2-low cases were 25.7% in pBCs and 23.4% in mBCs, respectively, while those of HER2-0 cases were 35.1% and 42.7%, respectively. The overall conversion rate between HER2-0 and HER2-low was 31.7%. HER2-low switching to HER2-0 was more frequent than the reverse (43.2% vs. 23.3%; P = 0.03). Two (3.3%) and 9 (20.5%) cases of pBCs with a HER2-0 and a HER2-low status, respectively, were converted to HER2-positive mBCs. In contrast, 10 (14.9%) HER2-positive pBCs were converted to HER2-0 and an identical number to HER2-low mBCs, respectively, significantly higher than that when compared to the HER2-0 to HER2-positive (P = 0.03), but not HER2-low to HER2-positive conversion. No significant difference was found when comparing the conversion rates among the common organs of relapse. Of the 17 patients with multiorgan metastases, 41.2% had discordance among the different sites of relapse., Conclusions: HER2-low BCs constitute a heterogeneous group of tumors. Low HER2 expression is dynamic, with significant discordance between primary tumors and advanced disease as well as the distant sites of relapse. Repeat biomarker studies from advanced disease are warranted in making appropriate treatment plans in the pursuit of precision medicine., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Periosteal fasciitis is a subtype of nodular fasciitis originating from the periosteum. The diagnosis can be challenging and requires radiologic-pathologic correlation. Advances in molecular analysis confirmed that nodular fasciitis and its related lesions harbor a USP6 gene rearrangement with one of the several potential partners. Herein, we report a case of periosteal fasciitis with metaplastic bone formation detected incidentally during a radiologic survey for breast carcinoma. Radiologic examination revealed a 2.4 cm, heterogeneous, avidly enhancing lesion of the right femoral distal metaphysis concerning for low-grade periosteal chondrosarcoma. Histological examination of a core needle biopsy revealed a tumor composed of bland spindle cells with myofibroblastic and osteoblastic phenotypes admixed with immature bone and cartilaginous elements. Molecular analysis revealed a novel STAG1::USP6 fusion that helped arrive at the right diagnosis and further expands the molecular profile of USP6 -associated neoplasms., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Compelling data has demonstrated the prognostic significance of tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC), a subtype generally associated with a poor clinical outcome but highly heterogeneous in nature. There have been limited studies investigating the importance of subsets of T cells in TILs. Further, the significance of intratumoral versus peritumoral TILs remains controversial. We examined the prognostic value of tumor-associated CD8 + cytotoxic T cells and FOXP3 + regulatory T cells in 35 chemotherapy-naive TNBC cases with a tumor-host interface in the tissue sections. The CD8 + and FOXP3 + cell count was expressed by immunoreactive cells per high-power field in an average of 10 high-power fields. There was a wide range of CD8 + and FOXP3 + T cells within the peritumoral and intratumoral stroma. Both CD8 + and FOXP3 + TILs were significantly higher at the former location as compared with the latter ( P <0.0001 and 0.003, respectively). The numbers of CD8 + and FOXP3 + T cells, either within peritumoral or intratumoral stroma, were not significantly associated with distant relapse-free or disease-specific survival. However, the peritumoral CD8 + /FOXP3 + ratio of TILs was significantly associated with prolonged relapse-free survival ( P =0.04) and disease-specific survival ( P =0.02). This association was not observed with the CD8 + /FOXP3 + ratio of intratumoral TILs. These observations suggest that the immunologic balance in the tumor microenvironment might determine antitumor immunity. Further, the peritumoral TILs appear to play a more important role in the progression of TNBC when compared with the intratumoral TILs, thus reaffirming the necessity of revisiting the method for the assessment of TILs., Competing Interests: S.W. is a consultant on the Breast Pathology Faculty Advisory Board for Daiichi Sankyo Inc. and AstraZeneca (not relevant to this work). The remaining authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) have demonstrated antitumor activity in cancers with a homologous recombination deficiency (HRD) and have recently been approved by the FDA for the treatment of germline BRCA1/2- mutation-associated breast cancer. PARPis have also been found to be efficacious in BRCA wild-type ( BRCAwt ) lesions with high genomic loss of heterozygosity (LOH-high). The goal of this study was to retrospectively investigate the tumor mutations in homologous recombination (HRR) genes and the LOH score in advanced-stage breast carcinomas (BCs). Sixty-three patients were included in our study, 25% of whom had HRR gene mutations in their tumors, including 6% BRCA1/2 and 19% non- BRCA -containing gene mutations. An HRR gene mutation was associated with a triple-negative phenotype. Twenty-eight percent of the patients had an LOH-high score, which, in turn, was associated with a high histological grade, a triple-negative phenotype, and a high tumor mutational burden (TMB). Among the six patients who received PARPi therapy, one had a tumor with a PALB2 mutation other than BRCA and had a clinical partial response. Twenty-two percent of the LOH-low tumors had BRCAwt -HRR gene mutations, compared with 11% of the LOH-high tumors. Comprehensive genomic profiling revealed a subset of breast cancer patients with a BRCAwt -HRR gene mutation that would be missed by an LOH test. The necessity of next-generation sequencing coupled with HRR gene analysis for PARPi therapy requires further investigation in clinical trials.

Background: Ewing sarcoma (ES) can be confirmed by identifying the EWSR1-FLI1 fusion transcript. This study is to investigate whether immunostaining (IHC) of PRKCB-a protein directly regulated by EWSR1-FLI1 is a surrogate maker for diagnosing ES in routine practice. Methods: Microarray gene expression analyses were conducted. RKCB IHC was applied to 69 ES confirmed by morphology and molecular methods, and 41 non-Ewing small round cell tumors. EWSR1 rearrangement, EWSR1-FLI1 fusion or t(11;22)(q24;q12) were identified by fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, or cytogenetic analysis, respectively. Results: Gene array analyses showed significant overexpression of the PRKCB in ES. PRKCB IHC was positive in 19 cases of ES with EWSR1-FLI1 fusion, 3 cases with cytogenetic 11:22 translocation and 59 cases with EWSR1 rearrangement while negative in only one EWSR1 rearranged case. PRKCB IHC is sensitive (98%) and specific (96%) in detecting EWSR1 rearranged ES. Conclusions: PRKCB is a reliable antibody for diagnosing ES in routine practice.

Introduction: PD-L1 expression is the most widely used predictive marker for immune checkpoint inhibitor (ICI) therapy in patients with lung adenocarcinoma. However, the current understanding of the association between PD-L1 expression and treatment response is suboptimal. A significant percentage of patients have only a cytological specimen available for clinical management. Therefore, it is relevant to examine the impact of molecular features on PD-L1 expression in cytological samples and how it might correlate with a therapeutic response., Methods: We evaluated patients diagnosed with adenocarcinoma of the lung who had both in-house targeted next-generation sequencing analysis and paired PD-L1 (22C3) immunohistochemical staining performed on the same cell blocks. We explored the association between molecular features and PD-L1 expression. In patients who underwent ICIs therapy, we assessed how a specific gene mutation impacted a therapeutic response., Results: 145 patients with lung adenocarcinoma were included in this study. PD-L1-high expression was found to be more common in pleural fluid than in other sample sites. Regional lymph node samples showed a higher proportion of PD-L1-high expression (29%) compared with lung samples (6%). The predictive value of PD-L1 expression was retained in cytological samples. Mutations in KRAS were also associated with a PD-L1-high expression. However, tumors with TP53 or KRAS mutations showed a lower therapy response rate regardless of the PD-L1 expression., Conclusion: Cytological samples maintain a predictive value for PD-L1 expression in patients with lung adenocarcinoma as regards the benefit of ICI treatment. Specific molecular alterations additionally impact PD-L1 expression and its predictive value., (© 2023 S. Karger AG, Basel.)

Introduction: Gene fusion identification by RNA-based next-generation sequencing (NGS) provides important information for cancer patients. NGS is commonly initiated by treating oncologists to identify therapeutic options. However, the implications of large fusion panels on tumor classification and diagnosis are underappreciated. We investigated the extent to which these tests aid diagnosis when ordered by pathologists., Methods: We retrospectively reviewed the results of a validated Archer FusionPlex panel ordered by surgical pathologists at our institution, excluding cases tested for therapeutic targets. One hundred thirty-five cases of solid tumors from October 2020 and September 2021 were included. We compared the initial diagnosis to the final diagnosis, which incorporated fusion gene results. We classified the cases into groups based on the degree of contribution of the RNA fusion panel to the final diagnosis., Results: Among 135 cases, a fusion event was identified in 47 cases, and no fusion event was identified in 88 cases. The results changed the diagnosis in 4 of 135 fusion positive cases (3%). Twenty-one cases (15%) provided a more specific diagnosis, and original diagnosis was confirmed in 17 cases (13%). In the remaining 5 cases (4%), the results identified fusion events of unknown clinical significance., Conclusions: RNA-based NGS provides significant benefit as an ancillary diagnostic tool. In our cohort, fusion analysis provided a more definitive diagnosis in 25 cases (19%). Our findings demonstrate an important role for pathologists in appropriate utilization of molecular testing, and diagnostic workflows integrating RNA-based NGS will lead to more accurate diagnosis and better patient care., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: While most estrogen receptor-positive (ER+) breast cancers express progesterone receptor (PR), a small subset of tumors exhibits an ER+/PR- phenotype despite the fact that PR is an ER-dependent gene product. Previous studies have shown that these tumors are generally associated with a worse clinical outcome when compared to the ER+/PR+ breast cancers, indicating that they are clinically and probably genetically different entities., Methods: We characterized the clinicopathologic features of ER+/PR- tumors from the Surveillance, Epidemiology and End Results (SEER) database and the authors' institutional cohort., Results: ER+/PR- tumors, constituting 12% of all breast cancers in both cohorts, less frequently occurred in Caucasians, were more likely to be of a higher histologic grade and presented with a higher stage when compared to ER+/PR+ tumors. Conversely, ER+/PR- neoplasms were more frequently seen in Caucasians, less likely to be of a higher histologic grade and less frequently presented with an advanced clinical stage when compared to ER-/PR- tumors. Further, the ER+/PR- tumors were associated with a disease-specific survival intermediate to that between ER+/PR+ and ER-/PR- tumors. An ER H-score of ≥270 was associated with a significantly superior relapse-free survival in the ER+/PR- tumors, suggesting that a near-maximal ER expression is needed to compensate for the altered ER signaling in these tumors. Pathologic stage and HER2 status were independent prognostic factors in the ER+/PR- tumors. These findings may provide additional insights in directing clinical decision making for individualized systemic therapy in the pursuit of precision medicine., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Tenosynovial giant cell tumors typically arise in the synovium of joints, bursae, or tendon sheaths. They may occur in an intra- or extra-articular location and can be divided into localized and diffuse types. The neoplastic nature of the lesion has been supported by a recurrent CSF1 gene rearrangement in a small subset of lesional cells, of which the most common fusion partner is COL6A3 . Herein, we report a case of intramuscular localized tenosynovial giant cell tumor harboring a novel CSF1-CD96 fusion transcript, thus expanding the molecular profile of this tumor.

Context.—: A number of fibro-osseous and osteocartilaginous lesions, especially common in the small bones of the hand and feet, pose a diagnostic challenge and have historically been thought to be reactive lesions. However, modern molecular techniques when supplementing clinical, radiographic, and histologic evaluation suggest they may, in fact, be neoplasms., Objective.—: To review the clinical presentation and histopathologic, molecular, and radiologic features of selective bone lesions, focusing most specifically on subungual exostosis, florid reactive periostitis, and bizarre periosteal osteochondromatous proliferation., Data Sources.—: Literature review and personal experience are the sources of this review., Conclusions.—: Some lesions previously thought to be reactive are locally aggressive and demonstrate reproducible molecular abnormalities, and thus may be neoplasms. Although most common in the bones of the fingers and toes, these lesions also occur in long and other bones. The clinical presentations, radiologic appearances, and histopathologic features often overlap, making the diagnosis challenging, and these lesions may require molecular evaluation to maximize accurate prognostication.

Context.—: Small round cell tumors of soft tissue and bone constitute a divergent group of neoplasms. These lesions often demonstrate overlapping clinical and radiologic characteristics and share histomorphologic and sometimes immunophenotypic similarities, but they typically have diverse prognostic outcomes, thus warranting different clinical management. Recent advances in molecular and cytogenetic techniques have identified a number of novel molecular alterations contributing to the diversity of these lesions. This state-of-the-art knowledge has enhanced our understanding of these diseases., Objective.—: To provide an overview of the current concepts in the classification and diagnosis of small round cell tumors of soft tissue and bone, focusing on salient histologic features, key immunophenotypic characteristics, and recent molecular genetic advancements., Data Sources.—: Data were obtained from pertinent peer-reviewed English-language literature and firsthand experience from the authors as practicing bone and soft tissue pathologists., Conclusions.—: Immunohistochemistry plays a vital role in rendering a specific diagnosis or narrowing the differential diagnosis in small round cell tumors of soft tissue and bone. Molecular genetic studies are often needed, especially for those lesions with unusual histologic features, an uncommon immunoprofile, and/or unusual clinical presentation. Accurate diagnosis of these tumors necessitates recognition of salient histologic features, judicious and astute use of ancillary studies, and correlation with the clinical and radiologic characteristics to guide clinical decision-making.

Background: Human epidermal growth factor 2 (HER2) amplification and/or overexpression occurs in 12% to 25% of breast cancers. Accurate detection of HER2 is critical in predicting response to HER2-targeted therapy. Both immunohistochemistry (IHC) and in situ hybridization (ISH) are FDA-approved methods for detecting HER2 status because its protein overexpression is largely attributable to gene amplification. However, variable discordant results between IHC and ISH have been reported., Methods: We determined the frequency of HER2 IHC/ISH discordance in these patients and also performed a pooled literature review analysis., Results: Of the 1125 consecutive primary or metastatic breast cancers with HER2 IHC and ISH performed simultaneously between 2015 and 2020, 84.6% had an unequivocal HER2 status. Discordance was found in 30 cases from 26 patients, including 13 IHC - /ISH + and 17 IHC + /ISH - , representing 1.6% and 11.9% of IHC - and IHC + cases, respectively. Review of the literature between 2001 and 2020 identified 46 relevant studies, with a total of 43,468 cases with IHC and ISH performed. The IHC - /ISH+ and IHC + /ISH - discordances were seen in all antibody clones and ISH methods used. The IHC + /ISH - discordance was significantly higher than IHC - /ISH + (13.8% vs. 3%, P < .0001). The overall discordance constituted 4% of all cases and 5.4% of those with an unequivocal IHC status. Significantly lower incongruities for both IHC - /ISH + and IHC + /ISH - were found in those published after 2018. The discordances probably reflect altered biology of HER2 oncogene/oncoprotein. Routinely performing both IHC and ISH may uncover such cases to prevent denial of potentially beneficial targeted therapy., (Copyright © 2021. Published by Elsevier Inc.)

There have been many breast cancer prognostic models proposed in the last few decades, varying in their methods of development and validation, predictors, outcomes, and patients included. Most models were developed to assess prognostic outcomes for early breast cancers. In this study, we established a simplified prognostic score to predict survival outcomes in all breast cancer patients. A total of 36,152 breast cancer patients diagnosed between 2010 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were used as the training dataset. Multivariate analyses were performed to identify independent factors for disease-specific survival (DSS). A prognostic score was calculated by summing the point values based on the magnitude of the hazard ratio for all independent factors. The authors institutional cohort (n = 4982) was used as the validation dataset. The prognostic score model consisting of histologic grade, ER, PR, HER2, and TNM status demonstrated a similar predictive power when compared to the revised 8th AJCC Clinical Prognostic Staging system in both training and validation datasets, whereas the addition of age and race did not facilitate stratification of prognostic groups. Pairwise comparison of hazard ratios showed a significant difference in all categories when compared to their proximate groups in both prognostic schemes in the SEER database, while the prognostic score model demonstrated a slightly better discriminating power in the validation dataset. Thus, the proposed prognostic score showed at least a comparable predicting power for survival outcomes in breast cancer patients receiving standard-of-care treatment when compared to the AJCC Clinical Prognostic Stage. This prognostic model provides a convenient and alternative modality in clinical practice thus warranting further validation using larger cohorts with longer follow-up., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Gene knockout of the master regulator of mitochondrial fission, Drp1, prevents neoplastic transformation. Also, mitochondrial fission and its opposing process of mitochondrial fusion are emerging as crucial regulators of stemness. Intriguingly, stem/progenitor cells maintaining repressed mitochondrial fission are primed for self-renewal and proliferation. Using our newly derived carcinogen transformed human cell model, we demonstrate that fine-tuned Drp1 repression primes a slow cycling 'stem/progenitor-like state', which is characterized by small networks of fused mitochondria and a gene-expression profile with elevated functional stem/progenitor markers (Krt15, Sox2 etc) and their regulators (Cyclin E). Fine tuning Drp1 protein by reducing its activating phosphorylation sustains the neoplastic stem/progenitor cell markers. Whereas, fine-tuned reduction of Drp1 protein maintains the characteristic mitochondrial shape and gene-expression of the primed 'stem/progenitor-like state' to accelerate neoplastic transformation, and more complete reduction of Drp1 protein prevents it. Therefore, our data highlights a 'goldilocks' level of Drp1 repression supporting stem/progenitor state dependent neoplastic transformation., Competing Interests: BS, DP, MB, AH, SG, SL, GS, AG, AM, KM No competing interests declared, (© 2021, Spurlock et al.)

Myoepithelial tumors arising in soft tissue are uncommon and mostly manifest a benign clinical course, although a malignant form does exist. An EWSR1 gene rearrangement is a common event in these tumors. Ossifying fibromyxoid tumor, a rare soft tissue neoplasm of uncertain differentiation, may have overlapping histologic and immunophenotypic features with myoepithelial tumors, but frequently harbors a PHF1 gene rearrangement. Interestingly, a PHF1-TFE3 fusion has been recently reported in both entities. Here we report a case of a malignant soft tissue tumor demonstrating myoepithelial differentiation and harboring a PHF1-TFE3 fusion. Despite being slow-growing and lacking significant cytologic atypia at initial presentation, the patient deteriorated rapidly with local recurrence and distant metastases. A discussion of the potential clinicopathologic implications of a PHF1-TFE3 fusion in these entities is also developed., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Purpose: The biology of breast cancer with a low expression level (1-10%) of estrogen receptor (ER) remains a matter of confusion. The recent American Society of Oncology/College of American Pathologist Guidelines have recommended reporting such tumors as a new "ER-low-positive" category with a recommended comment to emphasize the possible overall benefit of endocrine therapies in these patients. The aim of the study was to analyze the clinicopathologic features and clinical outcomes of ER-low-positive breast cancers., Methods: We characterized the clinicopathologic features and survival outcomes of ER-low-positive breast cancers in our 4179 patients diagnosed from 1998 to 2018., Results: The ER-positive, ER-low-positive, and ER-negative cases in our cohort were 2982 (71.4%), 97 (2.3%), and 1100 (26.3%), respectively. ER-low-positive tumors showed similar clinicopathologic characteristics yet significantly superior prognosis when compared to ER-negative tumors, while demonstrated largely overlapping survival outcomes with ER-positive tumors in the entire cohort. In the subcohort of tumors with a PR-positive phenotype, the prognosis of ER-low-positive tumors was intermediate between that of the ER-positive and ER-negative groups. ER-low-positive/PR-positive tumors had a significantly worse prognosis than ER-positive tumors, and a trend toward favorable survival outcomes when compared to ER-negative tumors, although no significant difference was identified for the latter. In contrast, the ER-positive and ER-low-positive groups showed similar survival outcomes in the subset of tumors with a PR-negative status, both being significantly better than ER-negative tumors., Conclusions: PR status as a surrogate marker of functional ER signaling provides critical information in this regard. These findings suggest that while ER-low-positive tumors are themselves heterogeneous, they often respond to endocrine treatment. Analysis of molecular signatures and standardization of therapeutic strategies are important to understand the biology of ER-low-positive tumors and to enable optimal treatment in the pursuit of individualized medicine.

The anatomic stage groups (ASG) have been arguably the most powerful in predicting breast cancer (BC) outcomes. Recognizing the prognostic influence of histologic grade and receptor status, the 8th AJCC mandates their incorporation into the newly established prognostic stage groups (PSG). This staging scheme was subsequently revised to provide pathological and clinical prognostic stage tables (PPSG/CPSG) due to its incapability to categorize a significant subset of BCs, with the former only used for patients having surgical resection as the initial treatment, and the latter for all patients. Given the increasingly used neoadjuvant therapy, PPSG cannot be assigned in a significant proportion of higher staged BCs. In this study, we validated the CPSG in a cohort of 5321 BCs. Compared to ASG, the application of CPSG resulted in assigning 16.1% and 27.2% of cases to a higher or a lower stage group in non-stage IV BCs, respectively. The changes were seen mostly frequently in ASG IB, followed by IIIC, IIB, IIA, IIIA, IIIB, and IA. In 7.9% of cases, the assigned CPSG changed more than one stage group from the ASG. CPSG provided an improved overall discriminating power in predicting BC-specific survival when compared to ASG. Pairwise comparison using the Cox proportional hazard model demonstrated further advantages for CPSG as the latter showed a significant difference in all categories when compared to their proximate groups, except IIA vs. IB and IIIA vs. IIIB. In contrast, a significantly different hazard was only seen when comparing IIB vs. IIA, IIIA vs. IIB, and IV vs. IIIC for ASG. Thus, the revised 8th AJCC CPSG provided a superior overall staging scheme for predicting prognostic outcomes in BC patients receiving standard of care treatment. Further validation using the available data with larger populations and longer follow-up may be needed to refine and improve this table.

Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status provide clinical utility in guiding therapeutic decision-making in metastatic breast cancer (BC). Increasing data have shown substantial differences between the receptor profiles of primary BCs and their paired metastases. In this study, we provide a large single center cohort to assess the frequency of receptor conversion in metastatic BC. The overall discordant rates were 18.3%, 40.3%, and 13.7% for ER, PR, and HER2, respectively. The discordance was significantly higher for PR when compared with ER and HER2. The conversion occurred significantly as a switch from positive to negative receptor status when compared with that from negative to positive for all three receptors. Semiquantitative analyses revealed a significantly decreased expression of both ER (25%) and PR (57%) in the metastases. There was a higher rate of PR discordance in bone metastases when comparing to other common organs of relapse. Furthermore, in the subset of patients with a single primary and multiple distant metastases, the discordant rates among the distant sites were 27.5%, 39.4%, and 14.3% for ER, PR, and HER2, respectively. A positive ER status, be it in primary or metastatic BC, was associated with a prolonged metastasis-free survival when compared with ER-negative primary tumors without conversion. Furthermore, a positive ER status in metastatic BC regardless of primary was associated with a superior overall survival when compared with an ER-negative tumor without conversion. Thus, receptor conversion is a frequent event in the course of BC progression, and can also be seen between different metastatic sites. Moreover, some conversions are of prognostic significance. The findings may reflect tumor heterogeneity, sampling or treatment effect, but may also indicate alteration in tumor biology. Repeat biomarker testing is warranted in making appropriate treatment plans in the pursuit of precision medicine.

Background: Receptor activator of nuclear factor κB (RANK) and its ligand, RANKL, are essential for mammary gland development and play a vital role in breast carcinogenesis. RANKL-RANK signaling also drives thermoregulation and modulates inflammatory activation in the brain. The expression of RANKL in primary breast cancer (BC) has been negatively associated with brain metastases, while significantly higher levels of RANK are seen in BC with brain metastases. We examined the expression of RANK and RANKL in BC metastasis to the brain., Patients and Methods: We examined the expression of RANK and RANKL in 40 cases of BC metastasis to the brain., Results: RANK was variably expressed in BC cells but minimally expressed in the adjacent brain parenchyma. In contrast, the expression of RANKL was minimal in metastatic BC but highly variable in tumoral stroma. RANKL expression in normal brain stroma obtained during autopsy was negligible. Histologic grade and BC subtypes were not significantly associated with RANK expression in metastatic BC. A significant negative correlation between RANK in metastatic BC and RANKL in tumoral stroma was identified (P < .001)., Conclusion: RANK expressed by primary BC and RANKL detected in the tumor microenvironment together participate in cancer development, while the same principle may operate at distant sites. Further investigation is necessary to provide additional insight into the role of the RANKL-RANK pathway in BC progression and to investigate the potential efficacy of therapeutic strategies targeting these molecules in BC metastasis to the brain., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Undifferentiated pleomorphic sarcomas are one of the most common subtypes of soft tissue sarcomas. These are aggressive mesenchymal tumors and are devoid of the major known biomarkers except vimentin. Our objective was to establish and characterize a primary cell population from a mandibular UPS specimen., Methods: The tumor was surgically removed from the right mandible of a 24-year-old male with IRB approved signed consent. Tumor was dissected, cultured ex vivo, and a cell population, MUPS-1, were isolated from outgrowths. Gene and protein expression profiles of both the primary tumor and the derived there from cells were obtained by quantitative RT-PCR and immunohistochemistry and included markers of epithelial, endothelial, and mesenchymal differentiation. To better define potential biomarkers, MUPS-1 cells were additionally characterized by RNA sequencing analysis., Results: Pathological analysis of primary tumor tissue revealed a sarcoma demonstrating multiple pathways of differentiation simultaneously with myxoid, fibrous, and osseous tissue. The isolated cells had a spindle cell-like morphology, were maintained in culture for greater than 20 passages, and formed colonies in soft agar indicating tumorigenicity. The cells, similar to the primary tumor, were strongly positive for vimentin and moderately expressed alkaline phosphatase. RNA-seq analysis revealed the tumor over-expressed several genes compared to normal tissue, including components of the Notch signaling pathway, NOTCH3 and JAG1., Conclusions: We have successfully established an undifferentiated pleomorphic sarcoma cell population, which will provide a valuable resource for studying fundamental processes and potentially serving as a platform for exploring therapeutic strategies for sarcomas., (© 2020 The Authors. Clinical and Experimental Dental Research published by John Wiley & Sons Ltd.)

The recent movement toward returning individual research results to study subjects/participants generates ethical and legal challenges for laboratories performing research on human biospecimens. The concept of an individual's interest in knowing the results of testing on their tissue is pitted against individual and systemic risks and an established legal framework regulating the performance of laboratory testing for medical care purposes. This article discusses the rationale for returning individual research results to subjects, the potential risks associated with returning these results, and the legal framework in the United States that governs testing of identifiable human biospecimens. On the basis of these considerations, this article provides recommendations for investigators to consider when planning and executing human biospecimen research, with the objective of appropriately balancing the interests of research subjects, the need for ensuring integrity of the research process, and compliance with US laws and regulations., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Case: Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue malignancy that very seldomly presents in the foot or ankle and as a result is not commonly in the differential of patients presenting with foot pain. We cite a case of EMC presenting in the atypical location of the midfoot. Because of its location and similarities, this tumor was initially misdiagnosed and mistreated by multiple medical providers as midfoot Charcot arthropathy., Conclusions: Neoplastic etiologies, including EMC, should remain in the differential for atypical, refractory foot pain that presents in a manner similar to Charcot foot.

The incidence of bilateral breast cancer (BBC) reportedly ranges from 1.4 to 11.8%. Women with a first primary breast cancer are at a 2- to 6-fold increased risk of developing contralateral BC. However, there have been limited studies analyzing the clinicopathologic features of BBC and conflicting data exist on the prognostic significance of BBC. In this study, we sought to analyze the incidence of BBC in the era of modern medicine and assess the clinicopathologic characteristics and prognostic outcomes compared to unilateral BC (UBC). Of the 5941 patients with stage I-III BC diagnosed between 1998 and 2013 at our institution, 110 developed BBC, including 58 synchronous BBC (SBBC, interval between the first and the contralateral BC ≤3 months) and 52 metachronous BBC (MBBC, interval >3 months). The median time to the second tumor was 67.9 months among patients with MBBC. BBC was associated with a significantly lower rate of having a ductal type, high grade, HER2-positive or node-positive disease when compared to UBC, while no difference was found for age, race, ER/PR status, or pathologic tumor stage. When compared to MBBC, SBBC was strongly associated with a lobular phenotype, non-high grade, and ER/PR-positive disease; and further demonstrated a significantly higher concordant rate for ER, PR, and HER2 status. Patients with BBC had a significantly worse distant relapse-free survival (RFS) but a similar disease-specific survival (DSS) when compared to those with UBC. Being African American, having a high histologic grade and higher pathologic tumor or node stage was significantly associated with a worse prognosis, while SBBC was associated with a favorable RFS by multivariate analysis. Nodal status was the only independent prognosticator for DSS in patients with BBC. Further investigation into the complex biologic and clinical behavior of BBC may provide novel insights into the therapeutic strategies in the pursuit of precision medicine in this unique subset of patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Bone pathology can be challenging because the skeleton is a living tissue prone to developing a diverse array of inflammatory, metabolic, genetic, reactive, circulatory, and neoplastic abnormalities. Several areas of bone pathology are particularly difficult or problematic for hematopathologists given the close resemblance of some hematologic entities to primary/metastatic bone lesions; examples include plasmacytic disorders versus osteoblastic tumors and lymphoma/leukemia versus round cell tumors of bone. This article provides a conceptual and practical overview of selective bone disorders commonly encountered in the differential diagnosis of hematologic diseases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Inflammatory myofibroblastic tumor (IMT) is a neoplastic proliferation of myofibroblastic/fibroblastic cells with a variable admixture of inflammatory cells. It primarily affects soft tissue and viscera of children and young adults. IMT occurring in bone is extremely rare. Approximately 50% of IMTs carry a clonal rearrangement of the anaplastic lymphoma kinase (ALK) gene, while other receptor tyrosine kinase gene rearrangements have been seen in a small subset of IMT. Herein, we report the first case of IMT which harbors an ALK gene amplification rather than a rearrangement thus resulting in overexpression of the protein, arising from the femur of a 24-year-old man. Our case provides a novel pathogenesis for IMT. An overview of cytogenetic abnormalities of IMT is also integrated into this report., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

PAX8 is used as a diagnostic aid in classifying retroperitoneal (RP) spindle cell tumors. PAX8 positivity in a spindled RP tumor is typically associated with sarcomatoid renal cell carcinoma (SRCC). However, PAX8 expression in solitary fibrous tumor (SFT), a tumor not uncommon to the RP, has not been extensively studied. We investigated the expression of PAX8 in SFTs and other spindle cell RP tumors. We collected 30 SFT, 23 SRCC, 11 gastrointestinal stromal tumors, 2 synovial sarcomas, 6 dedifferentiated liposarcomas (DDLS), 4 well differentiated liposarcomas (WDLS), and select other tumors. We identified nuclear PAX8 expression in 13 of 30 (43%) SFT, 0 of 6 (0%) DDLS, and 1 of 4 (25%) WDLS. Twenty-eight of 30 (93%) SFT, 0 of 23 (0%) SRCC, 2 of 6 (33%) DDLS, and 1 of 4 (25%) WDLS showed nuclear STAT6 expression. All gastrointestinal stromal tumors were negative for both PAX8 and STAT6. Of the 13 SFT showing PAX8 expression, 8 showed diffuse expression and 5 expressed PAX8 focally. Extrapleural SFTs were more likely to express PAX8 compared with pleural SFTs (10/13; 77% vs. 3/17; 18%, respectively; P=0.00117). Twenty of 23 (87%) SRCC expressed PAX8; the sarcomatoid component of all 23 SRCC was negative for STAT6. Of the other spindle cell tumors studied, 1 of 2 synovial sarcomas and 1 of 2 histiocytic sarcomas showed PAX8 expression. Pathologists should be aware of the potential pitfall of the relatively frequent expression of PAX8 by SFT and STAT6 expression in liposarcoma. PAX8 expression by a spindle cell lesion of RP would not allow distinction between SFT, SRCC, or sclerosing liposarcoma by itself. A STAT6/PAX8 phenotype excludes SRCC.

Background: The American Joint Committee on Cancer anatomic stage/prognostic group template arguably is the most powerful in predicting breast cancer outcomes because it considers the primary tumor, regional lymph node involvement, and presence of distant metastasis. However, other tumor and host characteristics have also been proved to be of prognostic value, including histologic grade and estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status. Thus, the 8th edition of the American Joint Committee on Cancer consolidated these factors into clinical prognostic stage groups., Materials and Methods: We validated the clinical prognostic stage groups compared with the anatomic stage groups in a cohort of 3322 breast cancer patients., Results: Compared with the anatomic stage, application of the clinical prognostic stage assigned 27.7% and 24.7% of cases to higher and lower stage groups, respectively. In 14% and 2.8% of cases, the assignment of clinical prognostic stage varied by 2 and 3 anatomic stages up or down, respectively. The Cox proportional hazard model demonstrated superior discriminatory power for clinical prognostic stage (overall χ 2 , 464.5; P < .0001 vs. χ 2 , 363.9; P < .0001). A pairwise comparison revealed that significant improvement was especially observed for patients with clinically prognostic stage I and III disease compared with that of the anatomic stage groups., Conclusion: The new clinical prognostic stage provides a more powerful, yet imperfect, tool for predicting breast cancer outcomes. Further refinement of this system might be necessary in the pursuit of precision medicine., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that controls inflammatory responses and redox homeostasis; however, its role during pulmonary tuberculosis (TB) remains unclear. Using freshly resected human TB lung tissue, we examined the role of HO-1 within the cellular and pathological spectrum of TB. Flow cytometry and histopathological analysis of human TB lung tissues showed that HO-1 is expressed primarily in myeloid cells and that HO-1 levels in these cells were directly proportional to cytoprotection. HO-1 mitigates TB pathophysiology by diminishing myeloid cell-mediated oxidative damage caused by reactive oxygen and/or nitrogen intermediates, which control granulocytic karyorrhexis to generate a zonal HO-1 response. Using whole-body or myeloid-specific HO-1-deficient mice, we demonstrate that HO-1 is required to control myeloid cell infiltration and inflammation to protect against TB progression. Overall, this study reveals that zonation of HO-1 in myeloid cells modulates free-radical-mediated stress, which regulates human TB immunopathology., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)