EWSR1-PATZ1 fusion renal cell carcinoma: a recurrent gene fusion characterizing thyroid-like follicular renal cell carcinoma.

Thyroid-like follicular renal cell carcinoma is an uncommon kidney tumor with no distinct molecular alteration described to date. This cohort of eight women with mean and median ages of 45 and 46 years, respectively (range 19-65 years), had unencapsulated, well-circumscribed tumors composed of tightly packed anastomosing follicle-like cysts filled with eosinophilic colloid-like material and lined by cuboidal cells with high nuclear to cytoplasmic ratios, oval to elongated nuclei with perpendicular arrangement toward the lumens, and prominent nuclear overlapping. The stroma between these was minimal with the exception of two tumors. Calcifications and necrosis were absent. Immunohistochemically, the tumors were positive for KRT19 (7/7), PAX8 (5/5), cyclin D1 (6/6), KRT7 (5/7), and AMACR (1/5; focal, weak), and were negative for WT1, TTF1 (transcription termination factor-1), and thyroglobulin. In three of three tumors tested molecularly, EWSR1-PATZ1 fusion was identified by RNA sequencing and confirmed by RT-PCR and Sanger sequencing. Over a follow-up period of 1-7 years, no evidence of recurrence or metastasis has been detected. The EWSR1-PATZ1 fusion has been recognized as a recurrent alteration in a subset of round to spindle cell sarcomas with EWSR1-non-ETS fusions (EWSR1-PATZ1 sarcoma) and in several central nervous system tumors. The finding of an EWSR1-PATZ1 fusion in all three of the thyroid-like follicular renal cell carcinomas for which sufficient tissue was available for genomic profiling provides the first distinct molecular abnormality in thyroid-like follicular renal cell carcinomas, supporting its designation as a distinct diagnostic entity.

Evaluation of SWI/SNF Protein Expression by Immunohistochemistry in Ovarian Clear Cell Carcinoma.

Ovarian clear cell carcinomas (OCCC) are known to harbor ARID1A mutations, and several recent studies have described immunohistochemical loss of SMARCA2, SMARCA4, and SMARCB1 in a subset of tumors. We performed ARID1A, SMARCA2, SMARCA4, and SMARCB1 immunohistochemistry on 105 OCCCs to identify possible associations with clinicopathologic features and assess their prognostic value in these tumors. ARID1A, SMARCA4, and SMARCB1 were considered retained if any tumor cell nucleus stained while for SMARCA2, >5% of tumor nuclei were required to be positive. Patients had a mean age of 56 yr and tumors averaged 13 cm in size. Most patients (63%) had stage I tumors with 47% being alive and well, 41% dead from disease, 10% dead from other causes, and 3% alive with disease at last follow-up (mean 72 mo). Tumors showed an admixture of architectural patterns, but papillary was most frequent (49%). Stromal hyalinization was detected in 83% of OCCCs and a background precursor in 78%. High-grade atypia and/or oxyphilic cells were noted in 45% and 29% of tumors, respectively. All OCCCs expressed SMARCA4 and SMARCB1, but the absence of ARID1A was noted in 30% of tumors and SMARCA2 in 8%. ARID1A-retained OCCCs were associated with a dominant tubulocystic or solid pattern, but no other clinicopathologic features reached statistical significance. No switch/sucrose non-fermentable protein expression was predictive of prognosis. Additional studies with known mutational status of these proteins are warranted to better assess their prognostic utility and develop a standardized immunohistochemical scoring system.

Quantitative next-generation sequencing-based analysis indicates progressive accumulation of microsatellite instability between atypical hyperplasia/endometrial intraepithelial neoplasia and paired endometrioid endometrial carcinoma.

Atypical hyperplasia/endometrial intraepithelial neoplasia is an accepted precursor to endometrioid-type endometrial carcinoma. Mismatch repair-deficient endometrial carcinomas are also known to be a biologically and clinically distinct subset of tumors. However, the development of microsatellite instability in endometrial carcinogenesis has not yet been evaluated by novel next-generation sequencing-based methods. We examined 17 mismatch repair-deficient endometrioid endometrial carcinomas and their paired atypical hyperplasia/endometrial intraepithelial neoplasia precursors using a next-generation sequencing panel with quantitative microsatellite instability detection at 336 loci. Findings were compared to histological features, polymerase chain reaction-based microsatellite instability testing, immunohistochemical expression of mismatch repair proteins, and tumor mutational burden calculations. All 17 endometrial carcinomas and 8/17 atypical hyperplasia/endometrial intraepithelial neoplasia showed microsatellite instability by next-generation sequencing-based testing. Endometrial carcinoma specimens showed significantly more unstable microsatellite loci than paired atypical hyperplasia/endometrial intraepithelial neoplasia (mean: 40.0% vs 19.9 unstable loci, respectively). Out of nine microsatellite-stable atypical hyperplasia/endometrial intraepithelial neoplasia specimens, four showed mismatch repair loss by immunohistochemistry. All atypical hyperplasia/endometrial intraepithelial neoplasia and endometrial carcinoma specimens with microsatellite instability were also mismatch repair-deficient by immunohistochemistry. Tumor mutational burden was significantly greater in endometrial carcinoma than in paired atypical hyperplasia/endometrial intraepithelial neoplasia specimens, and tumor mutational burden was significantly correlated with percent unstable microsatellite loci. Paired atypical hyperplasia/endometrial intraepithelial neoplasia and endometrial carcinoma specimens show progressive accumulation of unstable microsatellite loci following loss of mismatch repair protein expression. Comprehensive next-generation sequencing-based testing of endometrial carcinomas offers new insights into endometrial carcinogenesis and opportunities for improved tumor surveillance, diagnosis, and management.

High NPM1 mutant allele burden at diagnosis correlates with minimal residual disease at first remission in de novo acute myeloid leukemia.

Acute myeloid leukemia (AML) with mutated NPM1 is a newly recognized separate entity in the revised 2016 WHO classification, and is associated with a favorable prognosis. While previous studies have evaluated NPM1 in a binary fashion, we recently demonstrated a significant independent negative prognostic effect of high NPM1 mutant allele burden (VAF) at diagnosis in a cohort of de novo AML patients. Although the importance of minimal residual disease (MRD) monitoring in NPM1-mutated AML has been well characterized, the potential relationship between diagnostic allele burden and MRD is unknown. We retrospectively evaluated for MRD at first remission (CR1). We used either next-generation sequencing (NGS) [n = 71], and/or immunohistochemistry (IHC) for mutant NPM1 (NPM1c) [n = 60], in a subset of patients from our recently examined cohort. We identified a statistically significant positive correlation between the VAF at diagnosis, and at CR1 (Spearman r = 0.4, P = .006), and enrichment for MRD in high diagnostic VAF patients (P = .05), as previously defined. IHC-positivity also correlated significantly with a higher median diagnostic NPM1 VAF (0.42 vs 0.39, P = .02), and with the VAF at CR1 (Spearman r = 0.7, P = .003). In multivariable analyses, both high diagnostic VAF (P = .003) and MRD (P = .02) were independent predictors of shorter event-free survival (EFS). Our findings suggest a relationship between the NPM1 mutant allele burden at diagnosis, and the presence of MRD at first remission. Our findings support IHC as a potentially useful adjunctive tool for disease monitoring.

High prevalence of MiTF staining in undifferentiated pleomorphic sarcoma: caution in the use of melanocytic markers in sarcoma.

AIMS: The diagnosis of undifferentiated pleomorphic sarcoma (UPS) may be challenging, as other lesions with undifferentiated spindle cell morphology must be excluded, including melanoma. Microphthalmia-associated transcription factor (MiTF) stains naevi and epithelioid melanomas, as well as some mesenchymal neoplasms. The aim of this study was to evaluate the prevalence of MiTF and melanocytic markers in UPS and a subset of atypical fibroxanthoma (AFX). METHODS AND RESULTS: MiTF, SOX10, Melan-A, HMB45 and S100 immunostaining was performed on resection specimens from 19 UPSs and five AFXs. Next-generation sequencing of 50 genes was performed in UPSs to exclude dedifferentiated melanoma. In 17 of 19 UPSs (89%), tumour cells showed nuclear positivity for MiTF that was not eliminated by casein block. Three showed focal nuclear staining for HMB45, which was eliminated by casein block. One showed focal nuclear vacuole staining for S100 with red but not brown chromogen. None expressed SOX10 or Melan-A. Mutational analysis of 15 UPSs with adequate DNA showed no mutations within hotspot regions of BRAF, KIT, or NRAS. Four of five AFXs (80%) stained with MiTF; other markers were negative. CONCLUSION: There is a high prevalence of nuclear MiTF expression in UPSs (89%) and AFXs (80%). Rare UPSs showed non-specific nuclear HMB45 or S100 staining. These findings argue against using MiTF in isolation to differentiate between UPS or AFX and melanoma, and caution in interpreting focal staining for a single additional melanocytic marker. Casein block may eliminate non-specific staining. MiTF should be used to support a diagnosis of melanoma only if multiple melanocytic markers are positive.

Identifying Inherited and Acquired Genetic Factors Involved in Poor Stem Cell Mobilization and Donor-Derived Malignancy.

Analysis of the clinical characteristics of hematopoietic stem cell transplant (HSCT) donors has proven beneficial for identifying cases of heritable hematopoietic disorders. This study examines poor peripheral blood hematopoietic stem cell mobilization after granulocyte colony-stimulating factor administration among 328 donors as a potential marker for suspected familial predisposition to myeloid malignancies. Here, we present data comparing the clinical characteristics of poor-mobilizing versus nonpoor-mobilizing donors and the results of panel-based sequencing of hematopoietic genes in poor-mobilizing donors. From this analysis, we identified a novel case of a donor-derived myelodysplastic syndrome in an HSCT recipient that is consistent with clonal evolution of TET2-mutated clonal hematopoiesis of indeterminate potential (CHIP) within the donor. This study demonstrates the potential risk of using hematopoietic stem cells from a donor with CHIP and raises the question of whether there should be increased screening measures to identify such donors.

Polyglucosan bodies in intramuscular nerve branches are a poor predictor of GBE1 mutation and adult polyglucosan body disease.

INTRODUCTION: Adult polyglucosan body disease (APBD) is associated with formation of polyglucosan bodies in peripheral nerve branches. Some muscle biopsies show these inclusions in intramuscular nerve branches. It has not been established whether the presence of multiple polyglucosan bodies in intramuscular peripheral nerve branches could or should suggest testing for APBD. METHODS: Fifteen muscle biopsies from adults between the ages of 36 and 84 years, all showing polyglucosan bodies in intramuscular peripheral nerve twigs, were tested by sequencing of the GBE1 gene. RESULTS: In 4 patients, testing identified heterozygous missense mutations not previously described. No homozygous or compound heterozygous mutations were identified. CONCLUSIONS: The presence of polyglucosan bodies in intramuscular nerve twigs by itself, even if they are multiple, is not an indication of APBD. Further testing may only be indicated in patients with clinical disease manifestations.

Nfatc1 orchestrates aging in hair follicle stem cells.

Hair production is fueled by stem cells (SCs), which transition between cyclical bouts of rest and activity. Here, we explore why hair growth wanes with age. We show that aged hair follicle SCs (HFSCs) in mice exhibit enhanced resting and abbreviated growth phases and are delayed in response to tissue-regenerating cues. Aged HFSCs are poor at initiating proliferation and show diminished self-renewing capacity upon extensive use. Only modestly restored by parabiosis, these features are rooted in elevated cell-intrinsic sensitivity and local elevation in bone morphogenic protein (BMP) signaling. Transcriptional profiling presents differences consistent with defects in aged HFSC activation. Notably, BMP-/calcium-regulated, nuclear factor of activated T-cell c1 (NFATc1) in HFSCs becomes recalcitrant to its normal down-regulating cues, and NFATc1 ChIP-sequencing analyses reveal a marked enrichment of NFATc1 target genes within the age-related signature. Moreover, aged HFSCs display more youthful levels of hair regeneration when BMP and/or NFATc1 are inhibited. These results provide unique insights into how skin SCs age.

Clinical Utility and Benefits of Comprehensive Genomic Profiling in Cancer.

BACKGROUND: Comprehensive genomic profiling (CGP) with next-generation sequencing detects genetic alterations of hundreds of genes simultaneously and multiple molecular biomarkers with one test. In the personalized medicine era, CGP is increasingly used for cancer diagnosis, treatment selection, and prognosis prediction. CONTENT: In this review, we summarize the benefits of CGP, clinical utility of CGP, and challenges of setting up CGP in the clinical laboratories. Besides the genetic alterations identified in the cancer-related genes, other biomarkers such as tumor mutational burden, microsatellite instability, and homologous recombination deficiency are critical for initiating targeted therapy. Compared with conventional tests, CGP uses less specimen and shortens the turnaround time if multiple biomarkers need to be tested. RNA fusion assay and liquid biopsy are helpful additions to DNA-based CGP by detecting fusions/splicing variants and complementing tissue-based CGP findings, respectively. SUMMARY: Many previous hurdles for implementing CGP in the clinical laboratories have been gradually alleviated such as the decrease in sequencing cost, availability of both open-source and commercial bioinformatics tools, and improved reimbursement. These changes have helped to make CGP available to a greater population of cancer patients for improving characterization of their tumors and expanding their eligibility for clinical trials. Additionally, sequencing results of the hundreds of genes on CGP panels could be further analyzed to better understand the biology of various cancers and identify new biomarkers.

Acute Lymphoblastic Leukemia with Myeloid Mutations Is a High-Risk Disease Associated with Clonal Hematopoiesis.

Myeloid neoplasms arise from preexisting clonal hematopoiesis (CH); however, the role of CH in the pathogenesis of acute lymphoblastic leukemia (ALL) is unknown. We found that 18% of adult ALL cases harbored TP53, and 16% had myeloid CH-associated gene mutations. ALL with myeloid mutations (MyM) had distinct genetic and clinical characteristics, associated with inferior survival. By using single-cell proteogenomic analysis, we demonstrated that myeloid mutations were present years before the diagnosis of ALL, and a subset of these clones expanded over time to manifest as dominant clones in ALL. Single-cell RNA sequencing revealed upregulation of genes associated with cell survival and resistance to apoptosis in B-ALL with MyM, which responds better to newer immunotherapeutic approaches. These findings define ALL with MyM as a high-risk disease that can arise from antecedent CH and offer new mechanistic insights to develop better therapeutic and preventative strategies. SIGNIFICANCE: CH is a precursor lesion for lymphoblastic leukemogenesis. ALL with MyM has distinct genetic and clinical characteristics, associated with adverse survival outcomes after chemotherapy. CH can precede ALL years before diagnosis, and ALL with MyM is enriched with activated T cells that respond to immunotherapies such as blinatumomab. See related commentary by Iacobucci, p. 142.

The Genomics Organization for Academic Laboratories (GOAL): A vision for a genomics future for academic pathology.

Innovative and self-sustaining clinical genomics laboratories specializing in cutting-edge oncology testing are critical to the success of academic pathology departments and resident and fellow education in molecular pathology. However, the pressures and challenges facing these laboratories are numerous, including the complexities of validating comprehensive cancer next-generation sequencing (NGS) panels, competition from commercial laboratories, and the reimbursement and regulatory hurdles inherent in high-complexity testing. Cross-institutional collaborations, including shared assay content and interpretative frameworks, are a valuable element to academic laboratory success. To address these and other needs, the Genomics Organization for Academic Laboratories (GOAL) was conceived in 2018, incorporated in 2020 and has grown to include 29 participating institutions in 2022. Here, we describe the mission of GOAL, its structure, and the outcomes and projects undertaken in its first years.

Clonal cytopenia of undetermined significance (CCUS)-associated reversion of donor-derived, transient αß T-cell large granular clonal lymphocytosis, emerging post-transplant in a patient with a history of γδ T-cell large granular lymphocytic leukemia.

Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) has revolutionized the therapy of hematolymphoid malignancies. Yet, how to best detect or predict the emergence of HSCT-related complications remain unresolved. Here, we describe a case of donor-derived, transient Alpha Beta (αß) T-cell large granular clonal lymphocytosis and cytopenia that emerged post-HSCT in a patient with a history of gamma delta (γδ) T-cell large granular lymphocytic leukemia (T-LGLL). Clonal unrelatedness of post-transplant T-LGL lymphocytosis to the patient's pretransplant T-LGLL was first identified by T-cell receptor (TCR) PCR showing different sized fragments of rearranged gamma chains, in addition to shift from γδ to αß TCR expression by flow cytometry analyses. Donor-derivation of the patient's post-transplant clonal lymphocytosis was confirmed by serial chimerism analyses of recipient's blood specimens demonstrating 100% donor DNA. Moreover, oncogenic DNMT3A and RUNX1 mutations were detected by next-generation sequencing (NGS) only in post-transplant specimens. Intriguingly, despite continued increase in DNMT3A and RUNX1 mutation load, the patient's clonal lymphocytosis and anemia eventually largely resolved; yet, the observed mutation profile with persistent thrombocytopenia indicated secondary clonal cytopenia of undetermined significance (CCUS) in the absence of overt morphologic evidence of myeloid neoplasm in the marrow. This case illustrates the utility of longitudinal chimerism analysis and NGS testing combined with flow cytometric immunophenotyping to evaluate emerging donor-derived hematolymphoid processes and to properly interpret partial functional engraftment. It may also support the notion that driver mutation-induced microenvironmental changes may paradoxically contribute to reestablishing tissue homeostasis.

STK11 Inactivation Predicts Rapid Recurrence in Inoperable Early-Stage Non-Small-Cell Lung Cancer.

PURPOSE: Molecular factors predicting relapse in early-stage non-small-cell lung cancer (ES-NSCLC) are poorly understood, especially in inoperable patients receiving radiotherapy (RT). In this study, we compared the genomic profiles of inoperable and operable ES-NSCLC. MATERIALS AND METHODS: This retrospective study included 53 patients with nonsquamous ES-NSCLC (stage I-II) treated at a single institution (University of Chicago) with surgery (ie, operable; n = 30) or RT (ie, inoperable; n = 23) who underwent tumor genomic profiling. A second cohort of ES-NSCLC treated with RT (Stanford, n = 39) was included to power clinical analyses. Prognostic gene alterations were identified and correlated with clinical variables. The primary clinical end point was the correlation of prognostic genes with the cumulative incidence of relapse, disease-free survival, and overall survival (OS) in a pooled RT cohort from the two institutions (N = 62). RESULTS: Although the surgery cohort exhibited lower rates of relapse, the RT cohort was highly enriched for somatic STK11 mutations (43% v 6.7%). Receiving supplemental oxygen (odds ratio [OR] = 5.5), 20+ pack-years of tobacco smoking (OR = 6.1), and Black race (OR = 4.3) were associated with increased frequency of STK11 mutations. In the pooled RT cohort (N = 62), STK11 mutation was strongly associated with inferior oncologic outcomes: 2-year incidence of relapse was 62% versus 20% and 2-year OS was 52% versus 85%, remaining independently prognostic on multivariable analyses (relapse: subdistribution hazard ratio = 4.0, P = .0041; disease-free survival: hazard ratio, 6.8, P = .0002; OS: hazard ratio, 6.0, P = .022). STK11 mutations were predominantly associated with distant failure, rather than local. CONCLUSION: In this cohort of ES-NSCLC, STK11 inactivation was associated with poor oncologic outcomes after RT and demonstrated a novel association with clinical hypoxia, which may underlie its correlation with medical inoperability. Further validation in larger cohorts and investigation of effective adjuvant systemic therapies may be warranted.

Current clinical practices and challenges in molecular testing: a GOAL Consortium Hematopathology Working Group report.

While molecular testing of hematologic malignancies is now standard of care, there is variability in practice and testing capabilities between different academic laboratories, with common questions arising on how to best meet clinical expectations. A survey was sent to hematopathology subgroup members of the Genomics Organization for Academic Laboratories consortium to assess current and future practice and potentially establish a reference for peer institutions. Responses were received from 18 academic tertiary-care laboratories regarding next-generation sequencing (NGS) panel design, sequencing protocols and metrics, assay characteristics, laboratory operations, case reimbursement, and development plans. Differences in NGS panel size, use, and gene content were reported. Gene content for myeloid processes was reported to be generally excellent, while genes for lymphoid processes were less well covered. The turnaround time (TAT) for acute cases, including acute myeloid leukemia, was reported to range from 2 to 7 calendar days to 15 to 21 calendar days, with different approaches to achieving rapid TAT described. To help guide NGS panel design and standardize gene content, consensus gene lists based on current and future NGS panels in development were generated. Most survey respondents expected molecular testing at academic laboratories to continue to be viable in the future, with rapid TAT for acute cases likely to remain an important factor. Molecular testing reimbursement was reported to be a major concern. The results of this survey and subsequent discussions improve the shared understanding of differences in testing practices for hematologic malignancies between institutions and will help provide a more consistent level of patient care.

High Rates of Ultraviolet-Signature Mutations in Squamous Cell Carcinomas of the Parotid Gland and Prognostic Implications.

In the absence of clear pathologic differences, clinical history may differentiate potential primary parotid squamous cell carcinomas (SCC) from metastases. The presence of an ultraviolet (UV) signature can distinguish between tumors of cutaneous and non-cutaneous origin. This study aimed to investigate rates of UV signature mutations in squamous cell carcinomas of the parotid gland as well as differences in clinical features between tumors of cutaneous and non-cutaneous origin. Clinical and pathologic data were collected from 71 patients with SCC involving the parotid gland, of which 48 had cutaneous, 10 had mucosal, and 13 had no history of SCC. In 34 available cases, genomic DNA was isolated from formalin-fixed paraffin-embedded tissue specimens and sequenced using a targeted hybrid capture 1213 gene panel. Tumor mutational burden and COSMIC (Catalogue of Somatic Mutations in Cancer) mutational signatures were calculated. Most (74%) were UV-positive. Patients with UV-positive tumors were significantly older, white, and had higher rates of sun exposure. Patients with UV-negative tumors had a significantly higher mortality rate and shorter time to death: 6 (67%) died of disease with a median time to death of 9 months compared to 5 (20%) UV-positive patients who died of disease with a median time to death of 32 months. Pathologic features did not significantly vary by clinical history or UV status. The presence of a UV-signature combined with clinical history can be used to determine the primary source of SCC involving the parotid gland. UV-positivity may reflect a less aggressive disease course in an older population.

A Tale of 2 Morphologies: Diagnostic Pitfalls in TFEB-Associated Renal Cell Carcinomas, Including a Novel NEAT1-TFEB Fusion.

AIMS: Translocation-associated renal cell carcinomas (RCCs) have been extensively subcharacterized in recent years, such that each is largely recognized by the 2016 World Health Organization as categorical neoplastic entities in the genitourinary tract. Those belonging to the t(6;11) family of tumors classically have a fusion between TFEB and MALAT1/α, and display a particular histomorphology. Specifically, they show a biphasic population of both small and large epithelioid cells, the smaller component of which surrounds basement membrane-type material. Despite this apt description, the tumors have variable morphology and mimic other RCCs including those with TFE3 translocations. Therefore, a high degree of suspicion is required to make the correct diagnosis. METHODS: The 2 cases described in this article were of strikingly different appearance, and initially considered consistent with other non-translocation-associated renal tumors. These included clear cell RCC (CCRCC), perivascular epithelioid cell tumor (PEComa), and other eosinophilic RCCs (mainly papillary RCC type 2). RESULTS: Using RNA sequencing techniques, they were found to harbor distinct pathogenic rearrangements involving the TFEB gene, namely, fusions with CLTC and NEAT1 (the latter partnering heretofore never reported). CONCLUSIONS: These alterations manifested in 2 notably dissimilar lesions, underscoring the importance of including this family of carcinomas in the differential of any renal neoplasm that does not display immunophenotypic characteristics consistent with its morphology.

CDKN2A loss-of-function predicts immunotherapy resistance in non-small cell lung cancer.

Immune checkpoint blockade (ICB) improves outcomes in non-small cell lung cancer (NSCLC) though most patients progress. There are limited data regarding molecular predictors of progression. In particular, there is controversy regarding the role of CDKN2A loss-of-function (LOF) in ICB resistance. We analyzed 139 consecutive patients with advanced NSCLC who underwent NGS prior to ICB initiation to explore the association of CDKN2A LOF with clinical outcomes. 73% were PD-L1 positive (≥ 1%). 48% exhibited high TMB (≥ 10 mutations/megabase). CDKN2A LOF was present in 26% of patients and was associated with inferior PFS (multivariate hazard ratio [MVA-HR] 1.66, 95% CI 1.02-2.63, p = 0.041) and OS (MVA-HR 2.08, 95% CI 1.21-3.49, p = 0.0087) when compared to wild-type (WT) patients. These findings held in patients with high TMB (median OS, LOF vs. WT 10.5 vs. 22.3 months; p = 0.069) and PD-L1 ≥ 50% (median OS, LOF vs. WT 11.1 vs. 24.2 months; p = 0.020), as well as in an independent dataset. CDKN2A LOF vs. WT tumors were twice as likely to experience disease progression following ICB (46% vs. 21%; p = 0.021). CDKN2A LOF negatively impacts clinical outcomes in advanced NSCLC treated with ICB, even in high PD-L1 and high TMB tumors. This novel finding should be prospectively validated and presents a potential therapeutic target.

The phenotypic profile of dermatomyositis and lupus erythematosus: a comparative analysis.

BACKGROUND: The mechanisms which regulate cutaneous inflammation in the setting of collagen vascular disease have been a topic of recent interest; emphasis has been placed on type I interferon-associated recruitment of CXCR3+ lymphocytes in dermatomyositis (DM). METHODS: On a total of 42 biopsies from patients with DM, systemic lupus erythematosus (SLE), discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE) comprehensive phenotypic studies were performed to explore the practical value of phenotypic analysis in the subclassification of lesions of collagen vascular disease. RESULTS: The infiltrate in DM was of mild intensity compared to lupus erythematosus (LE). The dominant mononuclear cell in DM exhibited a CD4/CXCR3-positive phenotype while biopsies of SLE typically showed a dearth of CXCR3-positive cells. CD8 and CD20 lymphocytes were greatest in SLE and DLE, respectively. CD123 plasmacytoid dendritic cells, seen in most cases, were most frequent in cases of SCLE; CD83 expression was minimal. Endothelial MXA expression was a characteristic feature of DM. CD123 and MXA expression within inflammatory cells and keratinocytes was most conspicuous in areas of interface injury. Cutaneous lymphocyte antigen (CLA) expression was diminished in the dermal infiltrate in most cases of DM and LE. T regulatory cells never exceeded 15% of the infiltrate and were the least in the setting of DM and LE. CONCLUSIONS: An interferon-alpha-inducible cytokine milieu is common in SLE, DLE, SCLE and DM. In addition, there are phenotypic differences as alluded to above that may be of some practical value in separating these distinctive subsets. Features not previously emphasized such as MXA endothelial cell staining in DM and the lack of staining for CD83 and CLA in lesions of collagen vascular disease may be of diagnostic value.

Follicular Thyroid Neoplasms: Comparison of Clinicopathologic and Molecular Features of Atypical Adenomas and Follicular Thyroid Carcinomas.

In follicular thyroid neoplasms without invasion, a diagnosis of atypical adenoma (AA) (follicular tumor of uncertain malignant potential) may be rendered if atypical features (indefinite capsular/vascular invasion, necrosis, solid growth, increased mitoses) are present. This study compares clinical, histologic, and molecular features of patients with AAs (n=31), nonmetastatic follicular thyroid carcinoma (nmFTC) (n=18), and metastatic follicular thyroid carcinoma (mFTC) (n=38). Patients with mFTC were older. Mitotic activity in areas of solid growth was greatest in mFTC (P=0.05). Oncocytic tumors tended to show solid growth (P=0.04). The presence or frequency of capsular and/or vascular invasion was not different between nmFTC and mFTC. TERT promoter mutations were higher in patients with mFTC (50%) than nmFTC (25%) and AA (10%) (P=0.02). TERT promoter mutation was associated with necrosis (P=0.01) and solid growth plus increased mitoses (P=0.03). Necrosis and TERT promoter mutations were identified in all groups, most frequently in mFTC. The combination of solid growth with increased mitoses, necrosis, and TERT promoter mutation was only seen in follicular carcinomas. Poorly differentiated features, vascular invasion, and TERT promoter mutation correlated with metastasis in FTC. Given the low frequency of necrosis and TERT promoter mutation in AAs, close clinical follow-up is recommended in patients with these findings, especially if additional atypical features (such as solid growth plus mitoses) are present.