Publications by authors named "Gregory W Charville"

53 Publications

Diagnosis of soft tissue tumors using immunohistochemistry as a surrogate for recurrent fusion oncoproteins.

Semin Diagn Pathol 2021 Nov 3. Epub 2021 Nov 3.

Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States of America. Electronic address:

Soft tissue neoplasms encompass a broad spectrum of clinicopathologic manifestations. In a subset of soft tissue tumors, spanning a wide range of clinical behavior from indolent to highly aggressive, recurrent genetic translocations yield oncogenic fusion proteins that drive neoplastic growth. Beyond functioning as primary mechanisms of tumorigenesis, recurrent translocations represent key diagnostic features insofar as the presence of a particular oncogenic gene fusion generally points to specific tumor entities. In addition to more direct methods for identifying recurrent translocations, such as conventional cytogenetics or fluorescence in situ hybridization, immunohistochemistry for a component of the fusion oncoprotein increasingly is being used as a surrogate marker, exploiting the tendency of these fusion components to be distinctively overexpressed by translocation-bearing tumor cells. Diagnostic immunohistochemistry can also be used to identify the characteristic gene expression changes that occur downstream of oncogenic fusions. Here, we review the use of immunohistochemistry to detect surrogate markers of recurrent translocations in soft tissue tumors, focusing on the practical applications and limitations of this diagnostic approach.
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http://dx.doi.org/10.1053/j.semdp.2021.10.005DOI Listing
November 2021

Well-differentiated lipomatous neoplasms with p53 alterations: A clinicopathologic and molecular study of eight cases with features of atypical pleomorphic lipomatous tumor.

Histopathology 2021 Nov 1. Epub 2021 Nov 1.

Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.

Aims: Well-differentiated lipomatous neoplasms encompass a broad spectrum of benign and malignant tumors, many of which are characterized by recurrent genetic abnormalities. Although a key regulator of p53 signaling, MDM2, is characteristically amplified in well-differentiated liposarcoma, recurrent abnormalities of p53 itself have not been reported in well-differentiated adipocytic neoplasms. Here, we present a series of well-differentiated lipomatous tumors characterized by p53 alterations and histologic features in keeping with atypical pleomorphic lipomatous tumor (APLT).

Methods And Results: We reviewed the morphologic, immunohistochemical, and molecular genetic features of eight lipomatous tumors with p53 alterations. Four tumors arose in the thigh, and one case each arose in the shoulder, calf, upper back, and subclavicular regions; six tumors were deep/subfascial and two were subcutaneous. Relevant clinical history included two patients with Li-Fraumeni syndrome. Morphologically, all cases demonstrated well-differentiated adipocytes with prominent nuclear pleomorphism, limited mitotic activity, and no tumor cell necrosis. All cases were negative for MDM2 overexpression and amplification by immunohistochemistry and fluorescence in situ hybridization, respectively. By immunohistochemistry, p16 was diffusely overexpressed in all cases; seven tumors (88%) showed abnormal loss of Rb and p53. TP53 mutation or deletion was identified in 4 of 6 tumors evaluated by exon-targeted hybrid capture-based massively parallel sequencing; RB1 mutation or deletion was present in 5 of 6 cases.

Conclusions: We present a series of eight well-differentiated lipomatous neoplasms characterized by p53 alterations in addition to Rb loss and histologic features of APLT. These findings suggest that impaired p53 signaling may contribute to the pathogenesis of APLT in a subset of cases.
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http://dx.doi.org/10.1111/his.14593DOI Listing
November 2021

Acinar cell clonal expansion in pancreas homeostasis and carcinogenesis.

Nature 2021 Sep 15;597(7878):715-719. Epub 2021 Sep 15.

Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer deaths worldwide. Studies in human tissues and in mouse models have suggested that for many cancers, stem cells sustain early mutations driving tumour development. For the pancreas, however, mechanisms underlying cellular renewal and initiation of PDAC remain unresolved. Here, using lineage tracing from the endogenous telomerase reverse transcriptase (Tert) locus, we identify a rare TERT-positive subpopulation of pancreatic acinar cells dispersed throughout the exocrine compartment. During homeostasis, these TERT acinar cells renew the pancreas by forming expanding clones of acinar cells, whereas randomly marked acinar cells do not form these clones. Specific expression of mutant Kras in TERT acinar cells accelerates acinar clone formation and causes transdifferentiation to ductal pre-invasive pancreatic intraepithelial neoplasms by upregulating Ras-MAPK signalling and activating the downstream kinase ERK (phospho-ERK). In resected human pancreatic neoplasms, we find that foci of phospho-ERK-positive acinar cells are common and frequently contain activating KRAS mutations, suggesting that these acinar regions represent an early cancer precursor lesion. These data support a model in which rare TERT acinar cells may sustain KRAS mutations, driving acinar cell expansion and creating a field of aberrant cells initiating pancreatic tumorigenesis.
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http://dx.doi.org/10.1038/s41586-021-03916-2DOI Listing
September 2021

Quantitative image features from radiomic biopsy differentiate oncocytoma from chromophobe renal cell carcinoma.

J Med Imaging (Bellingham) 2021 Sep 7;8(5):054501. Epub 2021 Sep 7.

Mayo Clinic Arizona, Department of Radiology, Phoenix, Arizona, United States.

: To differentiate oncocytoma and chromophobe renal cell carcinoma (RCC) using radiomics features computed from spherical samples of image regions of interest, "radiomic biopsies" (RBs). : In a retrospective cohort study of 102 CT cases [68 males (67%), 34 females (33%); mean age ± SD, ], we pathology-confirmed 42 oncocytomas (41%) and 60 chromophobes (59%). A board-certified radiologist performed two RB rounds. From each RB round, we computed radiomics features and compared the performance of a random forest and AdaBoost binary classifier trained from the features. To control for overfitting, we performed 10 rounds of 70% to 30% train-test splits with feature-selection, cross-validation, and hyperparameter-optimization on each split. We evaluated the performance with test ROC AUC. We tested models on data from the other RB round and compared with the same round testing with the DeLong test. We clustered important features for each round and measured a bootstrapped adjusted Rand index agreement. : Our best classifiers achieved an average AUC of . We found no evidence of an effect for RB round ( ). We also found no evidence for a decrease in model performance when tested on the other RB round ( ). Feature clustering produced seven clusters in each RB round with high agreement ( , ). : A consistent radiomic signature can be derived from RBs and could help distinguish oncocytoma and chromophobe RCC.
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http://dx.doi.org/10.1117/1.JMI.8.5.054501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423237PMC
September 2021

Hairless regulates heterochromatin maintenance and muscle stem cell function as a histone demethylase antagonist.

Proc Natl Acad Sci U S A 2021 09;118(37)

Paul F. Glenn Center for the Biology of Aging, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305;

Skeletal muscle possesses remarkable regenerative ability because of the resident muscle stem cells (MuSCs). A prominent feature of quiescent MuSCs is a high content of heterochromatin. However, little is known about the mechanisms by which heterochromatin is maintained in MuSCs. By comparing gene-expression profiles from quiescent and activated MuSCs, we found that the mammalian Hairless (Hr) gene is expressed in quiescent MuSCs and rapidly down-regulated upon MuSC activation. Using a mouse model in which Hr can be specifically ablated in MuSCs, we demonstrate that Hr expression is critical for MuSC function and muscle regeneration. In MuSCs, loss of Hr results in reduced trimethylated Histone 3 Lysine 9 (H3K9me3) levels, reduced heterochromatin, increased susceptibility to genotoxic stress, and the accumulation of DNA damage. Deletion of Hr leads to an acceleration of the age-related decline in MuSC numbers. We have also demonstrated that despite the fact that Hr is homologous to a family of histone demethylases and binds to di- and trimethylated H3K9, the expression of Hr does not lead to H3K9 demethylation. In contrast, we show that the expression of Hr leads to the inhibition of the H3K9 demethylase Jmjd1a and an increase in H3K9 methylation. Taking these data together, our study has established that Hr is a H3K9 demethylase antagonist specifically expressed in quiescent MuSCs.
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http://dx.doi.org/10.1073/pnas.2025281118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449361PMC
September 2021

PAX7 Is a Sensitive Marker of Skeletal Muscle Differentiation in Rhabdomyosarcoma and Tumors With Rhabdomyosarcomatous Differentiation in the Female Genital Tract.

Int J Gynecol Pathol 2021 Jun 9. Epub 2021 Jun 9.

Department of Pathology, Stanford University School of Medicine, Stanford, California (J.J.W., G.W.C., T.A.L.) Department of Pathology, Surrey Memorial Hospital, Surrey, British Columbia, Canada (D.K.).

In the female genital tract, rhabdomyosarcoma may occur in "pure" form or as a heterologous constituent of a biphasic neoplasm such as carcinosarcoma or adenosarcoma. Discriminating rhabdomyosarcoma from its histologic mimics relies on confirmation of skeletal muscle differentiation by morphology or immunohistochemistry (IHC), which can be challenging to interpret in some cases owing to limited expression. PAX7, a transcription factor expressed in mammalian muscle progenitor cells, has been reported in up to 86% of soft tissue rhabdomyosarcomas by IHC. To determine whether PAX7 IHC could augment current approaches to identify rhabdomyosarcoma in gynecologic malignancies, we assessed PAX7, myogenin, and MyoD1 IHC on whole tissue sections from 100 gynecologic tumors: 50 with rhabdomyosarcomatous differentiation and 50 with features mimicking rhabdomyosarcoma. PAX7 expression was present in 96% (48/50) of gynecologic tumors with rhabdomyosarcomatous differentiation and was absent in all rhabdomyosarcoma mimics; it was more diffusely expressed than myogenin in 16 cases and was positive in a greater percentage of tumor cells in 28 cases. PAX7 and myogenin were typically coexpressed, and no rhabdomyosarcoma exhibited complete absence of both markers; however, 2 myogenin-negative tumors were PAX7-postive. Morphologically, PAX7 localized to the nuclei of primitive-appearing cells, whereas myogenin was observed in maturing rhabdomyoblasts including strap cells. Our findings highlight the utility of PAX7 as a complementary diagnostic marker of rhabdomyosarcomatous differentiation in gynecologic tumors. PAX7 should be used in combination with other markers of skeletal muscle differentiation, namely myogenin, and may be particularly helpful in cases where myogenin and/or MyoD1 expression is limited.
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http://dx.doi.org/10.1097/PGP.0000000000000799DOI Listing
June 2021

Hereditary inflammatory fibroid polyps caused by germline pathogenic variants in PDGFRA: Refining PDGFRA-mutation syndrome.

Cancer Genet 2021 08 24;256-257:106-109. Epub 2021 May 24.

Cancer Genetics and Genomics, Stanford Health Care, United States; Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, United States.

A 35-year-old Filipino woman presented with epigastric pain and was found to have two large jejunal and ileal inflammatory fibroid polyps (IFPs) and dozens of subcentimeter small bowel submucosal nodules. Targeted exon sequencing of PDGFRA on the resected jejunum IFP identified a variant c.1664A>G that was subsequently confirmed in the germline. Family history was striking for three relatives with confirmed IFPs, including one with small bowel intussusception on five occasions. All relatives with IFPs were confirmed to have the same PDGFRA germline likely pathogenic variant, all were female, and all had IFPs by age 50 years that necessitated surgery. Two obligate carriers were reported to have had a similar phenotype while at least one obligate male carrier had no reported history of IFPs. This is the sixth reported family with a germline PDGFRA pathogenic variant and history of IFPs or gastrointestinal stromal tumor (GIST). This is the second report of the c.1664A>G likely pathogenic variant in a family that is unrelated to, and of different ethnic origin than, the first family. This second family exhibited a striking history of multiple IFPs without any reported GISTs, suggesting a possible genotype/phenotype association for this variant, and a possible female gender penetrance bias.
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http://dx.doi.org/10.1016/j.cancergen.2021.05.003DOI Listing
August 2021

Nodular fasciitis of the breast: clinicopathologic and molecular characterization with identification of novel USP6 fusion partners.

Mod Pathol 2021 Oct 7;34(10):1865-1875. Epub 2021 Jun 7.

Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.

Nodular fasciitis is a benign, self-limited, pseudosarcomatous neoplasm that can mimic malignancy due to its rapid growth, cellularity, and mitotic activity. Involvement of the breast is rare and diagnosis on biopsy can be challenging. In this largest series to date, we examined the clinicopathologic and molecular characteristics of 12 cases of nodular fasciitis involving the breast/axilla. All patients were female, with a median age of 32 years (range 15-61). The lesions were 0.4 to 5.8 cm in size (median 0.8). All cases presented as palpable masses, and two patients had overlying skin retraction. Microscopically, lesions were relatively well-circumscribed nodular masses of bland myofibroblastic spindle cells within a variably myxoid stroma. Infiltrative growth into adipose tissue or breast epithelium was frequent. Mitotic figures were present in all cases, ranging from 1 to 12 per 10 high-power fields (median 3). Immunohistochemically, all cases expressed smooth muscle actin and were negative for pan-cytokeratin, p63, desmin, CD34, and nuclear beta-catenin. Targeted RNA sequencing performed on 11 cases identified USP6 gene fusions in eight; one additional case was positive by break-apart fluorescence in situ hybridization. The common MYH9-USP6 rearrangement was detected in four cases; another case had a rare alternative fusion with CTNNB1. Three cases harbored novel USP6 gene fusions involving NACA, SLFN11, or LDHA. All fusions juxtaposed the promoter region of the 5' partner gene with the full-length coding sequence of USP6. Outcome data were available for eight patients; none developed recurrence or metastasis. Five patients elected for observation without immediate excision, and self-resolution of the lesions was reported in three cases. Albeit uncommon, nodular fasciitis should be considered in the differential diagnosis of breast spindle cell lesions. A broad immunohistochemical panel to exclude histologic mimics, including metaplastic carcinoma, is important. Confirmatory detection of USP6 rearrangements can aid in classification, with potential therapeutic implications.
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http://dx.doi.org/10.1038/s41379-021-00844-4DOI Listing
October 2021

Management Strategies for Patients With Epithelioid Hemangioendothelioma: Charting an Indolent Disease Course.

Am J Clin Oncol 2021 08;44(8):419-422

Department of Medicine, Division of Oncology.

Background: Epithelioid hemangioendothelioma (EHE) is a malignant vascular neoplasm representing ∼1% of sarcomas. Due to its rarity, its clinical course is not well characterized and optimal treatment remains unknown.

Materials And Methods: This was a retrospective review of patients with EHE treated at Stanford University between 1998 and 2020. Demographic characteristics, pathology results, treatment modalities, and clinical outcomes were collected from the electronic medical records.

Results: A total of 58 patients had a mean age of 50.6 years and a slight female predominance (52%). Primary disease sites were liver (33%), soft tissue (29%), lung (14%), bone (9%), and mediastinum (9%). A majority (55%) had advanced or metastatic disease. Median overall survival (OS) was 16.9 years, with OS 89% at 1 year, 68% at 5 years, and 64% at 10 years. The longest median OS was associated with soft tissue sites and shortest with lung and mediastinal disease (P=0.03). The localized disease had improved median OS compared with metastatic disease (P=0.02). There was no OS difference between tumors >3 cm and those equal or smaller (P=0.85). Surgery was a common treatment (71%), while radiation and ablation were sometimes used (28% and 9%, respectively). The median time to initiating therapy of any kind was 68 days. The median time to systemic therapy was 114 days.

Conclusions: We report on the clinical characteristics and outcomes of patients with EHE at a large academic center. Treatment options included surgical excision, liver transplant, ablation, radiation, and systemic therapy. A subset of patients had indolent disease not requiring treatment upfront.
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http://dx.doi.org/10.1097/COC.0000000000000827DOI Listing
August 2021

PDGFRA Immunohistochemistry Predicts PDGFRA Mutations in Gastrointestinal Stromal Tumors.

Am J Surg Pathol 2021 Apr 12. Epub 2021 Apr 12.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA Department of Pathology, Stanford University School of Medicine, Stanford, CA.

Platelet-derived growth factor receptor A (PDGFRA) is a receptor tyrosine kinase that is activated by mutations in 10% of gastrointestinal stromal tumors (GISTs) and 55% to 70% of inflammatory fibroid polyps. PDGFRA-mutant GISTs are usually epithelioid and occur predominantly in the stomach. Succinate dehydrogenase-deficient GISTs also arise in the stomach and are usually epithelioid, as are some KIT-mutant GISTs. Recently, avapritinib was approved to treat PDGFRA D842V-mutant GISTs, which do not respond to conventional targeted therapy. Here, we evaluate the utility of PDGFRA immunohistochemistry (IHC) to predict PDGFRA mutations to direct targeted therapy. PDGFRA IHC was performed at 1:3000 and 1:10,000 dilutions on a tissue microarray containing 153 GISTs (126 KIT-mutant, 17 PDGFRA-mutant, and 10 succinate dehydrogenase-deficient). The "positive" staining threshold was defined as 50% of neoplastic cells staining at moderate intensity. PDGFRA IHC was 75.0% and 80.9% specific for PDGFRA mutations at 1:3000 and 1:10,000 dilutions, respectively, and it was 100% sensitive at both. On the basis of its higher specificity, a 1:10,000 dilution was used to stain whole-tissue sections of GISTs and other gastric tumor types. Combining tissue microarray and whole-tissue data, PDGFRA IHC was 94.4% sensitive and 81.0% specific for PDGFRA-mutant GIST among all 210 GISTs, and it was 84.1% specific among 149 GISTs with an epithelioid component. PDGFRA was positive in a subset of inflammatory fibroid polyps (15/30; 50%), monophasic synovial sarcomas (5/10; 50%), inflammatory myofibroblastic tumors (5/10; 50%), and plexiform fibromyxomas (2/8; 25%). It was negative in poorly differentiated adenocarcinoma (0/20), diffuse large B-cell lymphoma (0/10), glomus tumor (0/10), gastrointestinal neuroectodermal tumor (0/10), leiomyoma (0/10), gastric schwannoma (0/8), and gastroblastoma (0/3). Among GISTs, PDGFRA IHC is highly sensitive and moderately specific for PDGFRA-mutant tumors; it also can be positive in inflammatory fibroid polyp and some other mesenchymal tumor types. PDGFRA positivity could be used to triage epithelioid GISTs for PDGFRA sequencing to determine optimal therapy.
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http://dx.doi.org/10.1097/PAS.0000000000001720DOI Listing
April 2021

PDGFB RNA in situ hybridization for the diagnosis of dermatofibrosarcoma protuberans.

Mod Pathol 2021 08 24;34(8):1521-1529. Epub 2021 Mar 24.

Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.

Dermatofibrosarcoma protuberans (DFSP) is a spindle cell neoplasm of the skin and superficial soft tissue with a tendency for locally aggressive behavior; metastatic potential coincides with fibrosarcomatous transformation. The vast majority of DFSPs harbor the t(17;22) translocation resulting in a COL1A1-PDGFB fusion that drives autocrine growth stimulation via PDGFB overexpression. Here, we examined the utility of PDGFB RNA chromogenic in situ hybridization (CISH) for the diagnosis of DFSP. A total of 337 tumors represented in whole tissue sections and tissue microarrays, including 37 cases of DFSP and 300 histologically similar spindle cell tumors, were subjected to PDGFB RNA CISH using commercially available probes. PDGFB overexpression was observed by light microscopy in 24 of 26 conventional DFSPs (92%) and 11 of 11 fibrosarcomatous DFSPs (100%). One of two DFSPs negative for PDGFB by RNA CISH was found to harbor an uncommon alternative rearrangement involving PDGFD. All examined cases of histologic mimics were negative for PDGFB overexpression; limited PDGFB expression, not reaching an empirical threshold of greater than 5 puncta or one aggregate of chromogen in more than 25% of cells, was observed in 7 of 300 mimics (2.3%), including desmoplastic melanoma, malignant peripheral nerve sheath tumor, angiosarcoma, and pleomorphic dermal sarcoma. Vascular PDGFB expression was seen in several tumor types. We conclude that PDGFB RNA CISH, with careful interpretation and the use of appropriate thresholds, may serve as a surrogate marker of PDGFB rearrangement and a useful ancillary tool for the diagnosis of DFSP.
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http://dx.doi.org/10.1038/s41379-021-00800-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298273PMC
August 2021

Nuclear expression of DDIT3 distinguishes high-grade myxoid liposarcoma from other round cell sarcomas.

Mod Pathol 2021 07 17;34(7):1367-1372. Epub 2021 Mar 17.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Myxoid liposarcoma (MLPS) is a malignant adipocytic neoplasm with predilection for the extremities. MLPS is genetically defined by a t(12;16) translocation leading to FUS-DDIT3 (95%) or more rarely t(12;22) leading to EWSR1-DDIT3. Low-grade MLPS is characterized by bland spindle cells within a myxoid matrix containing delicate "chicken-wire" vasculature, whereas high-grade ("round cell") MLPS may be indistinguishable from other round cell sarcomas. In many cases, cytogenetic or molecular genetic techniques are applied to confirm the diagnosis. A recent study documented the utility of DDIT3 immunohistochemistry (IHC) in the differential diagnosis of adipocytic and myxoid soft tissue tumors. The purpose of this study was to evaluate DDIT3 IHC as a surrogate for molecular testing in high-grade MLPS. IHC was performed using a mouse monoclonal antibody directed against the N-terminus of DDIT3 on whole tissue sections from 50 high-grade MLPS cases and 319 histologic mimics used as controls (170 on whole tissue sections and 149 on a tissue microarray). Histologic mimics included Ewing sarcoma, CIC-rearranged sarcoma, sarcomas with BCOR genetic alterations, poorly differentiated synovial sarcoma, alveolar and embryonal rhabdomyosarcomas, mesenchymal chondrosarcoma, desmoplastic small round cell tumor, and neuroblastoma. Nuclear staining in >5% of cells was considered positive. By IHC, 48 (96%) high-grade MLPS showed strong diffuse nuclear staining for DDIT3. Of the controls, 2% of cases were positive, with no more than 25% nuclear staining. An additional 19% of control cases displayed less than 5% nuclear staining. Overall, DDIT3 IHC showed 96% sensitivity and 98% specificity for high-grade MLPS; strong, diffuse staining is also 96% sensitive but is 100% specific. IHC using an antibody directed against the N-terminus of DDIT3 is highly sensitive and specific for high-grade MLPS among histologic mimics and could replace molecular genetic testing in many cases, although limited labeling may be seen in a range of other tumor types.
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http://dx.doi.org/10.1038/s41379-021-00782-1DOI Listing
July 2021

Sinonasal FUS-ERG-Rearranged Ewing's Sarcoma Mimicking Glomangiopericytoma.

Case Rep Oncol 2020 Sep-Dec;13(3):1393-1396. Epub 2020 Nov 30.

Department of Medicine (Oncology), Stanford University School of Medicine, Stanford, California, USA.

Ewing's sarcoma is a rare and aggressive tumor that typically arises in the long bones of the extremities. It belongs in the family of small round blue cell tumors and is characterized immunohistochemically by diffuse CD99 expression and molecularly by one of several oncogenic translocations, most commonly t(11;22)(q24;q12) between the gene and the gene. Here we present a rare case of Ewing's sarcoma in the sinonasal tract with gene arrangement that was regarded for almost a decade as a sinonasal-type hemangiopericytoma (glomangiopericytoma). This case illustrates the surprisingly prolonged natural history of Ewing's sarcoma that did not receive therapy for many years and the importance of considering alternative genetic translocations. Our experience suggests that the presence of diffuse CD99 membranous staining pattern in a small blue round cell tumor with morphology typical for Ewing's sarcoma but FISH negative for rearrangement should prompt consideration of fusion.
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http://dx.doi.org/10.1159/000511415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772862PMC
November 2020

MUC4 is expressed in alveolar rhabdomyosarcoma.

Histopathology 2021 May 16;78(6):905-908. Epub 2021 Mar 16.

Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.

Aims: Mucin 4 (MUC4) is a transmembrane glycoprotein normally expressed by several human epithelial surfaces, including those of the colon, vagina, and respiratory tract. Although MUC4 overexpression is seen in various carcinomas, its expression among mesenchymal neoplasms is fairly specific to low-grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma. Having observed unanticipated anti-MUC4 immunoreactivity in rhabdomyosarcoma, we aimed to further characterise its expression.

Methods And Results: Expression of MUC4 was assessed by immunohistochemistry in a total of 97 rhabdomyosarcomas using formalin-fixed paraffin-embedded tissue sections. MUC4 was expressed by 21 of 26 PAX3/7-FOXO1 fusion-positive cases, wherein immunoreactivity, varying from weak to strong, was present in 20-100% of neoplastic cells. With the exception of one sclerosing rhabdomyosarcoma showing immunoreactivity in 20% of cells, MUC4 was not expressed by embryonal (n = 28), sclerosing (n = 20), or pleomorphic (n = 23) rhabdomyosarcomas. Analysing published gene expression microarray data from a separate cohort of 33 fusion-positive and 25 fusion-negative rhabdomyosarcomas, we found on average a 11.4-fold increased expression in fusion-positive tumours (P = 0.0004).

Conclusions: MUC4 is expressed to a variable extent in the majority of PAX3/7-FOXO1 fusion-positive (alveolar) rhabdomyosarcomas, while expression in other rhabdomyosarcoma subtypes is rare.
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http://dx.doi.org/10.1111/his.14321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058254PMC
May 2021

"Inflammatory Leiomyosarcoma" and "Histiocyte-rich Rhabdomyoblastic Tumor": a clinicopathological, immunohistochemical and genetic study of 13 cases, with a proposal for reclassification as "Inflammatory Rhabdomyoblastic Tumor".

Mod Pathol 2021 04 22;34(4):758-769. Epub 2020 Oct 22.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Inflammatory leiomyosarcoma (ILMS), defined as "a malignant neoplasm showing smooth muscle differentiation, a prominent inflammatory infiltrate, and near-haploidization", is a very rare soft tissue tumor with a generally favorable prognosis. The morphologic features of "histiocyte-rich rhabdomyoblastic tumor" (HRRMT) are similar to those of ILMS, although this lesion shows by definition a skeletal muscle phenotype. Recent gene expression profiling and immunohistochemical studies have also suggested that ILMS and HRRMT may be related. We studied the clinicopathologic, immunohistochemical and genetic features of four cases previously classified as ILMS and nine classified as HRRMT. Tumors from both groups tended to occur in the deep soft tissues of the extremities of young to middle-aged males and exhibited indolent behavior. Morphologically, all were well-circumscribed, often encapsulated, and showed a striking histiocyte-rich inflammatory infiltrate admixed with variably pleomorphic tumor cells showing spindled and epithelioid to rhabdoid morphology, eosinophilic cytoplasm, and prominent nucleoli, but few, if any, mitotic figures. Immunohistochemically, the tumor cells expressed desmin, alpha-smooth muscle actin, and the rhabdomyoblastic markers PAX7, MyoD1, and myogenin. H-caldesmon expression was absent in all cases, using the specific h-CD antibody. Karyotypic study (1 HRRMT) and genome-wide copy number analysis (7 HRRMT, OncoScan SNP assay), revealed near-haploidization in four cases, with subsequent genome doubling in one, an identical phenotype to that seen in ILMS. We propose reclassification of ILMS and HRRMT as "inflammatory rhabdomyoblastic tumor", a name which accurately describes the salient morphologic and immunohistochemical features of this distinctive tumor, as well as its intermediate (rarely metastasizing) clinical behavior.
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http://dx.doi.org/10.1038/s41379-020-00703-8DOI Listing
April 2021

Distantly Metastatic Retinoblastoma to Soft Tissue and Bone: A Challenging Diagnosis Highlighting the Utility of CRX.

Am J Surg Pathol 2021 06;45(6):820-824

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Distant metastasis of retinoblastoma to sites outside the central nervous system is rare; such cases may present years following primary treatment. Diagnosis may be difficult given the rarity of such events and considerable histologic mimics. We describe the clinicopathologic features of 6 cases of metastatic retinoblastoma to distant bone and soft tissue sites from 2 large academic centers. Patients were 3 female and 3 male children; median age was 9.5 years (range: 5 to 15 y) with a mean interval from primary disease diagnosis of 8.0 years (range: 0.75 to 14 y). Metastasis to bones of the lower extremities was most common, occurring in 4 of 6 cases. Tumors showed typical histologic features of retinoblastoma, with sheets of primitive round cells with minimal cytoplasm and indistinct nucleoli; however, characteristic Flexner-Wintersteiner rosettes were absent. A subset of cases demonstrated an alveolar growth pattern, and 2 cases showed higher grade cytology with nuclear anaplasia and prominent nucleoli. Immunohistochemistry for CRX and RB1 showed uniform positivity and loss of expression, respectively. Metastatic retinoblastoma outside the central nervous system may present following long disease-free intervals. Immunohistochemistry for CRX is helpful to confirm this challenging diagnosis.
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http://dx.doi.org/10.1097/PAS.0000000000001620DOI Listing
June 2021

Angiosarcoma of the Breast: Management and Outcomes.

Am J Clin Oncol 2020 11;43(11):820-825

Department of Radiation Oncology.

Objective: Angiosarcoma of the breast is rare and has a poor prognosis. We reviewed our institution's experience with this disease to characterize presentation, identify management patterns, and report outcomes.

Methods: Fifty-eight patients with nonmetastatic angiosarcoma were identified from 1998 to 2019 and retrospectively reviewed. Overall survival (OS) and recurrence-free survival (RFS) were calculated using the Kaplan-Meier analysis and log-rank test.

Results: The median follow-up was 43.4 months (range: 1.8 to 203.3 mo). Twenty-four patients had primary angiosarcoma (PAS) and 34 patients had secondary angiosarcoma (SAS). Patients with PAS were significantly younger than those with SAS (P<0.0001). Mastectomy was the main surgical treatment in our cohort (n=47) and 3 underwent a lumpectomy. The multifocal disease was found in 5/23 patients with PAS and 11/35 patients with SAS. Twenty-eight patients received chemotherapy. Radiation was administered to 13 patients with PAS and 3 patients with SAS. Five-year OS was 73.7% for PAS and 63.5% for SAS. Local recurrence occurred in a greater proportion of patients with margins <5 mm than those with margins ≥5 mm. Chemotherapy did not impact RFS and was not associated with OS in PAS (P=0.35). Those with SAS treated with chemotherapy had significantly greater OS than those who did not receive chemotherapy (P=0.043). Radiation did not significantly influence RFS or OS.

Conclusions: Five-year OS was higher than anticipated. Margins >5 mm appear important for local control. Patients with SAS, but not PAS, may achieve improved survival with chemotherapy. National trials using prespecified agents may be needed to identify an optimal chemotherapy regimen for women with SAS.
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http://dx.doi.org/10.1097/COC.0000000000000753DOI Listing
November 2020

DDIT3 Immunohistochemistry Is a Useful Tool for the Diagnosis of Myxoid Liposarcoma.

Am J Surg Pathol 2021 02;45(2):230-239

Department of Pathology, Stanford University School of Medicine, Stanford, CA.

Myxoid liposarcoma is a malignant adipogenic neoplasm characterized by prominent arborizing capillaries, occasional lipoblasts, and primitive-appearing spindle cells in a myxoid background. A recurrent translocation in myxoid liposarcoma results in an oncoprotein consisting of full-length DDIT3 (CHOP) fused to an N-terminal segment of either FUS (TLS) or, less often, EWSR1. Here, we explore the diagnostic significance of DDIT3 expression in myxoid liposarcoma using a mouse monoclonal antibody recognizing an epitope in the N-terminal region. Studying a total of 300 tumors, we find diffuse, moderate-to-strong nuclear-localized anti-DDIT3 immunoreactivity in all 46 cases of myxoid liposarcoma representing 36 unique tumors, including 6 cases with high-grade (round cell) morphology. DDIT3 immunohistochemistry also highlighted a distinctive vasculocentric growth pattern in 7 myxoid liposarcomas treated with neoadjuvant radiation. In contrast, the vast majority of other examined lipomatous and myxoid neoplasms exhibited no DDIT3 expression; limited, weak immunoreactivity in <10% of cells was infrequently observed in dedifferentiated liposarcoma (6/39, 15%), solitary fibrous tumor (3/12, 25%), pleomorphic liposarcoma (1/15, 7%), and high-grade myxofibrosarcoma (2/17, 12%). Although this minimal DDIT3 expression did not correlate with DDIT3 amplification or myxoid liposarcoma-like morphology in dedifferentiated liposarcoma, there was evidence among sarcomas (excluding myxoid liposarcoma) of a relationship between expression and exposure to neoadjuvant radiation or cytotoxic chemotherapy. The constellation of findings indicates that DDIT3 immunohistochemistry may have utility in the evaluation of myxoid and lipomatous neoplasms to support the diagnosis of myxoid liposarcoma.
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http://dx.doi.org/10.1097/PAS.0000000000001564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796975PMC
February 2021

Diffuse PRAME expression is highly specific for malignant melanoma in the distinction from clear cell sarcoma.

J Cutan Pathol 2020 Dec 10;47(12):1226-1228. Epub 2020 Sep 10.

Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.

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http://dx.doi.org/10.1111/cup.13812DOI Listing
December 2020

AGER1 downregulation associates with fibrosis in nonalcoholic steatohepatitis and type 2 diabetes.

J Clin Invest 2020 08;130(8):4320-4330

Gastroenterology and Hepatology, Stanford University, Stanford, and VA Palo Alto, California, USA.

Type 2 diabetes is clinically associated with progressive necroinflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Advanced glycation end-products (AGEs) accumulate during prolonged hyperglycemia, but the mechanistic pathways that lead to accelerated liver fibrosis have not been well defined. In this study, we show that the AGEs clearance receptor AGER1 was downregulated in patients with NASH and diabetes and in our NASH models, whereas the proinflammatory receptor RAGE was induced. These findings were associated with necroinflammatory, fibrogenic, and pro-oxidant activity via the NADPH oxidase 4. Inhibition of AGEs or RAGE deletion in hepatocytes in vivo reversed these effects. We demonstrate that dysregulation of NRF2 by neddylation of cullin 3 was linked to AGER1 downregulation and that induction of NRF2 using an adeno-associated virus-mediated approach in hepatocytes in vivo reversed AGER1 downregulation, lowered the level of AGEs, and improved proinflammatory and fibrogenic responses in mice on a high AGEs diet. In patients with NASH and diabetes or insulin resistance, low AGER1 levels were associated with hepatocyte ballooning degeneration and ductular reaction. Collectively, prolonged exposure to AGEs in the liver promotes an AGER1/RAGE imbalance and consequent redox, inflammatory, and fibrogenic activity in NASH.
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http://dx.doi.org/10.1172/JCI133051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410084PMC
August 2020

Tenosynovial giant cell tumor of the suboccipital region - A rare, benign neoplasm in this location.

J Clin Neurosci 2020 Aug 4;78:413-415. Epub 2020 Jul 4.

Department of Neurosurgery, Stanford University, Stanford, CA, United States.

Tenosynovial giant cell tumors (TGCTs) are benign neoplasms that arise from the synovium of tendon sheaths, bursae, and joints. We report a rare presentation of TGCT involving the suboccipital spine.
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http://dx.doi.org/10.1016/j.jocn.2020.05.022DOI Listing
August 2020

Clinicopathologic characterization of malignant chondroblastoma: a neoplasm with locally aggressive behavior and metastatic potential that closely mimics chondroblastoma-like osteosarcoma.

Mod Pathol 2020 11 29;33(11):2295-2306. Epub 2020 Jun 29.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Chondroblastoma is currently classified as a benign neoplasm; however, chondroblastoma and chondroblastoma-like osteosarcoma have morphologic overlap, raising the possibility that some tumors diagnosed as chondroblastoma-like osteosarcoma might actually represent malignant chondroblastoma. The H3F3B K36M point mutation, which has not been reported in osteosarcoma, is identified in 95% of chondroblastomas and is reliably detectable by immunohistochemistry (IHC). We reviewed 11 tumors diagnosed as atypical chondroblastoma, malignant chondroblastoma, or chondroblastoma-like osteosarcoma (median follow-up: 8.8 years; range: 4 months-26.4 years). Seven chondroblastomas with cytologic atypia and permeative growth were designated "malignant chondroblastoma"; six were H3K36M-positive by IHC. Relative to conventional chondroblastoma, malignant chondroblastoma occurred in older individuals (median: 52 years; range: 29-57 years) and arose at unusual sites. Three of four tumors with long-term follow-up recurred, and one patient died of widespread metastases. One was found to have chromosomal copy number alter4ations and a SETD2 mutation in addition to H3F3B K36M. The four remaining tumors were classified as chondroblastoma-like osteosarcoma. Chondroblastoma-like osteosarcoma occurred in younger patients (median: 21 years; range: 19-40 years) than malignant chondroblastoma. In contrast to malignant chondroblastoma, all had regions of malignant cells forming bone. Two of three patients with long-term follow-up developed recurrences, and two died of disease, one with widespread metastases. No mutations in H3F3A/H3F3B were detected by Sanger sequencing. While malignant chondroblastoma and chondroblastoma-like osteosarcoma show significant morphologic overlap, they have distinct clinical presentations and genetic findings. When considering this challenging differential diagnosis, IHC using histone H3 mutation-specific antibodies is a critical diagnostic adjunct.
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http://dx.doi.org/10.1038/s41379-020-0604-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007083PMC
November 2020

Disseminated Pneumocystis jirovecii Infection with Osteomyelitis in a Patient with CTLA-4 Haploinsufficiency.

J Clin Immunol 2020 02 18;40(2):412-414. Epub 2020 Jan 18.

Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Stanford School of Medicine, 269 Campus Drive, CCSR Suite 3215, Stanford, CA, 94305-5366, USA.

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http://dx.doi.org/10.1007/s10875-020-00748-zDOI Listing
February 2020

Nonphagocytic Activation of NOX2 Is Implicated in Progressive Nonalcoholic Steatohepatitis During Aging.

Hepatology 2020 10 9;72(4):1204-1218. Epub 2020 Oct 9.

Gastroenterology and Hepatology, Stanford University, Stanford, CA.

Background And Aims: Older patients with obesity/type II diabetes mellitus frequently present with advanced NASH. Whether this is due to specific molecular pathways that accelerate fibrosis during aging is unknown. Activation of the Src homology 2 domain-containing collagen-related (Shc) proteins and redox stress have been recognized in aging; however, their link to NASH has not been explored.

Approach And Results: Shc expression increased in livers of older patients with NASH, as assessed by real time quantitative PCR (RT-qPCR) or western blots. Fibrosis, Shc expression, markers of senescence, and nicotinamide adenine dinucleotide phosphate, reduced form oxidases (NOXs) were studied in young/old mice on fast food diet (FFD). To inhibit Shc in old mice, lentiviral (LV)-short hairpin Shc versus control-LV were used during FFD. For hepatocyte-specific effects, floxed (fl/fl) Shc mice on FFD were injected with adeno-associated virus 8-thyroxine-binding globulin-Cre-recombinase versus control. Fibrosis was accelerated in older mice on FFD, and Shc inhibition by LV in older mice or hepatocyte-specific deletion resulted in significantly improved inflammation, reduction in senescence markers in older mice, lipid peroxidation, and fibrosis. To study NOX2 activation, the interaction of p47 (NOX2 regulatory subunit) and p52Shc was evaluated by proximity ligation and coimmunoprecipitations. Palmitate-induced p52Shc binding to p47 , activating the NOX2 complex, more so at an older age. Kinetics of binding were assessed in Src homology 2 domain (SH2) or phosphotyrosine-binding (PTB) domain deletion mutants by biolayer interferometry, revealing the role of SH2 and the PTB domains. Lastly, an in silico model of p52Shc/p47 interaction using RosettaDock was generated.

Conclusions: Accelerated fibrosis in the aged is modulated by p52Shc/NOX2. We show a pathway for direct activation of the phagocytic NOX2 in hepatocytes by p52Shc binding and activating the p47 subunit that results in redox stress and accelerated fibrosis in the aged.
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http://dx.doi.org/10.1002/hep.31118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478166PMC
October 2020

OLIG2 is a marker of the fusion protein-driven neurodevelopmental transcriptional signature in alveolar rhabdomyosarcoma.

Hum Pathol 2019 09 9;91:77-85. Epub 2019 Jul 9.

Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA. Electronic address:

Alveolar rhabdomyosarcoma (RMS) is associated with an underlying pathogenic translocation involving either PAX3 or PAX7 and FOXO1. The presence or absence of this fusion defines the biology and clinical behavior of this subtype of RMS and its identification in tumors is relevant to prognostication and treatment planning. To further explore the unique characteristics of fusion-driven RMS, we leveraged a published gene expression data set to perform an unbiased comparison of 33 fusion-positive and 25 fusion-negative RMS cases. Our analyses revealed 1790 expressed loci with more than two-fold differential expression at a threshold of P < .05. Genes with increased expression in fusion-positive relative to fusion-negative RMS were significantly enriched for those involved in "nervous system development," "neuron differentiation," and "neurogenesis," highlighting a neurodevelopmental gene expression signature driven by the alveolar RMS-associated fusion protein. We show that neurodevelopmental genes are enriched near PAX3-FOXO1 fusion protein binding sites, suggesting a genome-wide fusion protein-mediated activation of cis regulatory elements. Among the genes with differential expression in fusion-positive versus fusion-negative RMS, we identified expression of the transcriptional regulator of motor neuron and oligodendrocyte development, OLIG2, as a marker of the fusion protein-dependent neurodevelopmental signature. Immunohistochemical analysis of a cohort of 73 RMS specimens revealed OLIG2 expression in 96.4% of fusion-positive RMS (N = 27/28), but only in 6.7% of fusion-negative RMS (N = 3/45; P < .001). The proportion of OLIG2-expressing cells in fusion-negative cases did not exceed 5%, while 92.9% of fusion-positive cases showed expression in at least 5% of cells. Our findings identify OLIG2 expression as a unique manifestation of a neurodevelopmental gene expression signature driven by the oncogenic fusion protein characteristic of alveolar RMS, which may aid in the diagnostic and prognostic distinction of fusion-positive cases.
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http://dx.doi.org/10.1016/j.humpath.2019.07.003DOI Listing
September 2019

Diagnostic classification of soft tissue malignancies: A review and update from a surgical pathology perspective.

Curr Probl Cancer 2019 08 28;43(4):250-272. Epub 2019 May 28.

Department of Pathology, Stanford University School of Medicine, Stanford, CA. Electronic address:

Soft tissue sarcomas encompass a broad spectrum of histologically, clinically, and molecularly diverse neoplasms that present unique diagnostic and therapeutic challenges. Accurate classification is essential both for appropriate risk stratification and for guiding clinical management. Once classified almost exclusively based on the morphologic appearance of the tumor by light microscopy, many soft tissue sarcomas are now known to manifest recurrent patterns of genetic alterations. In addition to enabling molecular confirmation of histologic diagnoses, discovery of these recurrent genetic alterations has helped to refine existing morphologic definitions of sarcoma subtypes and even prompted the discovery of new subtypes. As therapy for sarcoma has become increasingly tailored to a specific entity, the integration of molecular data has assumed added importance in diagnostic decision making. In this article, we summarize principles of the histologic evaluation of soft tissue sarcomas, discuss specific diagnostic features of several of the most common sarcoma subtypes, and describe our vision for a future of soft tissue sarcoma diagnosis that merges morphologic, genetic, and epigenetic features to arrive at diagnoses that are aligned with tumor-specific, biologically targeted treatment approaches.
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http://dx.doi.org/10.1016/j.currproblcancer.2019.05.006DOI Listing
August 2019

INSM1 Expression in Peripheral Neuroblastic Tumors and Other Embryonal Neoplasms.

Pediatr Dev Pathol 2019 Oct 11;22(5):440-448. Epub 2019 Apr 11.

Department of Pathology, Stanford University School of Medicine, Stanford, California.

Insulinoma-associated protein 1 (INSM1) is a transcription factor that functions in neuroepithelial tissue development and shows expression in neuroendocrine neoplasms. Given the role of INSM1 in controlling differentiation of the sympatho-adrenal lineage, we hypothesized that INSM1 expression would define a subset of neuroblastic tumors. This study aimed to characterize the immunohistochemical profile of INSM1 in a cohort of peripheral neuroblastic tumors and compare INSM1 expression in these tumors to that seen in other embryonal neoplasms, using both tissue microarrays and whole-slide histologic sections. INSM1 showed nuclear expression in 39/50 (78%) peripheral neuroblastic tumors, including 27/32 (84%) neuroblastomas, 9/9 (100%) ganglioneuroblastomas, and 3/9 (33%) ganglioneuromas. Altogether, 70% of peripheral neuroblastic tumors showed anti-INSM1 immunoreactivity in more than 20% of tumor nuclei. Although no non-neuroblastic tumors in this study exhibited INSM1 expression in more than 20% of nuclei, focal or patchy staining was identified in 7/14 (50%) rhabdomyosarcomas, 7/22 (32%) nephroblastomas, and 4/20 (20%) Ewing sarcomas. The absence of INSM1 expression in peripheral neuroblastic tumors was restricted to undifferentiated and poorly differentiated neuroblastomas, as well as mature ganglioneuromas, mimicking the transient INSM1 expression seen in sympatho-adrenal differentiation during normal development. No significant association between amplification status and INSM1 expression was observed. We found that all 3 INSM1-negative neuroblastoma patients with available follow-up were alive at a median of 15 years, in comparison to 9 of 13 INSM1-positive neuroblastoma patients living at a median of 5 years. Additional studies are needed to determine whether INSM1 expression is indicative of a clinically significant differentiation state in neuroblastoma.
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http://dx.doi.org/10.1177/1093526619843725DOI Listing
October 2019

Immune checkpoint blockade as a potential therapeutic strategy for undifferentiated malignancies.

Hum Pathol 2018 12 7;82:39-45. Epub 2018 Jul 7.

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Undifferentiated malignancies (UMs) encompass a diverse set of aggressive tumors that pose not only a diagnostic challenge but also a challenge for clinical management. Most tumors in this category are currently treated empirically with nonspecific chemotherapeutic agents that yield extremely poor clinical response. Given that UMs are inherently genetically unstable neoplasms with the potential for immune dysregulation and increased neoantigen production, they are likely to be particularly amenable to immune checkpoint inhibitors, which target programmed cell death protein 1 (PD-1) or its ligands, PD-L1 and PD-L2, to promote T-cell antitumor activity. Aberrant expression of PD-L1 and, more recently, chromosomal 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) alterations can be used as biomarkers to predict responsiveness to checkpoint inhibitors. Here we evaluated 93 cases previously diagnosed as an "undifferentiated" malignancy and found that 56% (52/93) of UMs moderately to strongly express PD-L1 by immunohistochemistry (IHC). Concurrent CD274(PD-L1) and PDCD1LG2(PD-L2) fluorescence in situ hybridization (FISH) was performed on 24 of these cases and demonstrates a genetic gain at both loci in 62.5% of UMs. Genetic alterations at the CD274(PD-L1) and PDCD1LG2(PD-L2) loci were found to be completely concordant by FISH. Overall, we found that a significant proportion of UMs express PD-L1 and provide molecular support for using checkpoint inhibitors as a treatment approach for this class of tumors.
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http://dx.doi.org/10.1016/j.humpath.2018.06.034DOI Listing
December 2018

A Chance to Cut Is a Chance to Cure: Endoscopic Submucosal Dissection for Early Gastric Cancer.

Dig Dis Sci 2019 05;64(5):1129-1132

Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA.

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http://dx.doi.org/10.1007/s10620-018-5317-8DOI Listing
May 2019

Impaired Notch Signaling Leads to a Decrease in p53 Activity and Mitotic Catastrophe in Aged Muscle Stem Cells.

Cell Stem Cell 2018 10 20;23(4):544-556.e4. Epub 2018 Sep 20.

Paul F. Glenn Center for the Biology of Aging and Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Neurology Service and Rehabilitation Research and Development Center of Excellence, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA. Electronic address:

The decline of tissue regenerative potential with age correlates with impaired stem cell function. However, limited strategies are available for therapeutic modulation of stem cell function during aging. Using skeletal muscle stem cells (MuSCs) as a model system, we identify cell death by mitotic catastrophe as a cause of impaired stem cell proliferative expansion in aged animals. The mitotic cell death is caused by a deficiency in Notch activators in the microenvironment. We discover that ligand-dependent stimulation of Notch activates p53 in MuSCs via inhibition of Mdm2 expression through Hey transcription factors during normal muscle regeneration and that this pathway is impaired in aged animals. Pharmacologic activation of p53 promotes the expansion of aged MuSCs in vivo. Altogether, these findings illuminate a Notch-p53 signaling axis that plays an important role in MuSC survival during activation and is dysregulated during aging, contributing to the age-related decline in muscle regenerative potential.
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http://dx.doi.org/10.1016/j.stem.2018.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173623PMC
October 2018
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