Biomedical subjects

Pedram Argani

Publications and source records attributed to Pedram Argani.

3 recordsLinked to original sources

PubMed2026

Loss of Methylthioadenosine Phosphorylase (MTAP) Expression: A Potentially Useful Tool for Distinguishing Sarcomatoid Urothelial Carcinoma From Inflammatory Myofibroblastic Tumor.

Inflammatory myofibroblastic tumor (IMT) and sarcomatoid urothelial carcinoma (SarUC) can have striking histologic overlap but have significantly different prognoses and clinical management paradigms. Loss of methylthioadenosine phosphorylase (MTAP) protein expression by immunohistochemistry (IHC) serves as a useful surrogate for homozygous 9p21 deletion, a recurrent genomic alteration in urothelial carcinoma (UC). We analyzed MTAP expression by IHC in 65 SarUCs and 27 urinary tract IMTs to evaluate its utility in navigating this challenging differential diagnosis. Overall, MTAP loss was significantly more frequent in SarUC (55%) compared with IMT (4%) (P < .0001). Among 46 biphasic SarUCs with independently evaluable epithelial and mesenchymal components, divergent expression patterns were frequent. The most common pattern was retention of MTAP staining in both epithelial and mesenchymal components (19/46; 41% of cases), followed by selective retention of MTAP in the epithelial component and loss in the mesenchymal component (16/46; 35% of cases). MTAP loss was observed in both the epithelial and mesenchymal components in 11 out of 46 (24%) SarUC cases. None of the 46 biphasic SarUC cases showed selective MTAP loss in the epithelial component but retention in the mesenchymal component. MTAP IHC was also particularly valuable in assessing clonal relationships in 2 challenging biphasic cases in which the differential diagnosis included a collision between a noninvasive low-grade papillary UC and an IMT versus a subtle IMT-like SarUC arising in association with an overlying noninvasive low-grade papillary UC. Next-generation sequencing on a subset of cases (n = 11) was useful for confirming 9p deletion in cases with MTAP loss by IHC, and for demonstrating molecular hallmarks of urothelial neoplasia thereby providing additional diagnostic support for morphologically challenging SarUC cases with IMT-like morphology. Therefore, MTAP IHC can be useful in evaluating spindle cell lesions of the urinary tract, as loss is significantly more common in SarUC than in IMT, and enriched in the mesenchymal component of biphasic SarUC. However, MTAP loss can be seen in both entities, and the diagnosis of IMT-like spindle cell tumors in the urinary tract requires careful integration of morphologic, immunohistochemical, and molecular data.

Humans↗

PubMed2025

TRIM63 Overexpression in FISH-Negative MiTF Family Altered Renal Cell Carcinoma (MiTF RCC).

TFE3 and TFEB break-apart fluorescent in situ hybridization (FISH) assays are the "gold standard" for diagnostic confirmation of microphthalmia-associated transcription factor (MiTF) family-altered renal cell carcinoma (MiTF RCC), which includes TFE3-rearranged RCC and TFEB-altered RCC. However, FISH assays, for multiple reasons, may lead to equivocal or false-negative results, especially in cryptic fusions resulting from intrachromosomal inversions involving 5' partner genes, such as non-POU domain-containing octamer-binding protein (NONO); GRIPI-associated protein 1 (GRIPAP1); RNA-binding motif protein, X chromosome (RBMX); and RNA-binding motif protein 10 (RBM10). When FISH results are negative in cases with strong morphological suspicion of the listed tumor entities, pathologists may recommend targeted RT-PCR or panel-based RNA fusion sequencing for diagnostic confirmation. Our recent RNA in situ hybridization (RNA ISH)-based study demonstrated RNA expression of the tripartite motif containing 63 (TRIM63) to be highly enriched in TFE3-rearranged RCC and TFEB-altered RCC, including 2 FISH false-negative RCC cases harboring RBM10::TFE3 fusion. Based on these observations, we hypothesized that TRIM63 positivity could aid in diagnosing cases that are negative by conventional FISH assay but remain morphologically suspicious, representing an unmet clinical need in this area. We collected 20 RCC cases with morphological suspicion (with equivocal/indeterminate immunohistochemistry panel) of MiTF RCC, which were TRIM63 positive, negative/equivocal for TFE3/TFEB gene rearrangement by FISH, and underwent next-generation sequencing (NGS). On NGS correlation, 14 of 20 (70%) FISH-negative TRIM63-positive tumors harbored an MiTF gene rearrangement. In the remaining 6 cases, we were unable to fully ascertain the MiTF rearrangement status due to the inherent limitation of the NGS panel utilized. The cases with MiTF gene rearrangement include TFE3 rearrangement in 60% (12/20) and TFEB low-level copy gains (with an additional missense mutation in 1 case) in 10% (2/20) of samples. RBM10:TFE3 fusion was seen in 67% (8/12) of TFE3-rearranged RCC in this cohort. TRIM63 RNA ISH assay could aid in identifying cases that harbor TFE3 or TFEB rearrangement associated with false-negative or equivocal TFE3/TFEB FISH results, especially those involving gene fusions with a paracentric Xp11 inversion. Overall, employment of TRIM63 RNA ISH coupled with TFE3/TFEB FISH assays and follow-up genomic interrogation enhanced diagnostic accuracy for patients with MiTF RCC.

Carcinoma, Renal Cell↗

PubMed2025

Ossifying Spindled and Epithelioid Tumor: A Novel Soft Tissue Tumor.

This investigation describes the clinicoradiologic, pathologic, and molecular features of a unique soft tissue tumor characterized by a peripheral shell of bone and composed of bland myoid spindle and epithelioid cells that are keratin-positive. Our study cohort consists of 6 men and 6 women, with a mean age of 32 years. The tumors arose in the extremities (n = 9) and proximal limb girdle (n = 3) and were equally distributed between deep and superficial soft tissues. Patients reported dull painless masses of several months to >10 years duration (mean: 2.9 years). Imaging demonstrated a complete or partial peripheral shell of bone that could extend centrally, and the tumor's mean size was 5.7 cm. Histologically, the tumors were composed of uniform, eosinophilic myoid spindled cells growing in sheets and intersecting fascicles, surrounded by mature lamellar and/or woven bone. Also present was an admixed component of intermediate-sized epithelioid cells with eosinophilic cytoplasm. Mitotic activity was consistently low. Immunohistochemistry showed strong multifocal staining for keratins, and 50% (5/10) showed focal staining for S100; however, all were negative for SMA, desmin, SOX10, ERG, and CD34. Genetic analysis by multiple targeted RNA sequencing panels was negative (n = 10); however, whole transcriptome sequencing (n = 8) revealed a recurrent and novel in-frame SRSF7::NFATC3 fusion in 4 tumors. Dual fluorescence in situ hybridization probes for SRSF7::NFATC3 successfully confirmed this fusion and identified a fifth case, which had not undergone whole transcriptome sequencing but was negative by a targeted RNA fusion panel. Methylation profiling (n = 8) demonstrated a shared epigenetic profile distinct from other entities. Clinical follow-up (n = 11) showed no evidence of recurrence after primary excision with a mean of 41.6 months. In summary, we describe a novel soft tissue tumor designated "ossifying spindled and epithelioid tumor" as a descriptive histologic term that also emphasizes its close radiologic mimic, ossifying fibromyxoid tumor. All cases have behaved in a benign fashion without recurrence following simple excision. Awareness of this entity is important, so that it can be distinguished from other neoplasms that have more aggressive biological potential.

Humans↗