American Journal of Surgical Pathology最新文献

Uterine placental site trophoblastic tumors (PSTTs) are rare trophoblastic neoplasms, presumed to be of gestational origin. Herein, using a comprehensive morphologic, immunohistochemical, and molecular approach, we describe 5 cases of primary uterine nongestational PSTTs. The median age at presentation was 32 years (range 25 to 45). All tumors were initially expected to be of gestational origin as all were located in the uterus and all patients had a history of pregnancy (5/5, 100%). The median size of the primary uterine tumors was 6.3 cm (range 4.8 to 7.5). Three patients (3/5, 60%) had metastatic disease at presentation or revealed during initial workup (1/5 [20%] patients with lymph node metastasis only and 2/5 [40%] with distant metastases). All tumors showed similar histopathologic and immunohistochemical features to those of gestational PSTTs. The tumor cells expressed hPL in 5/5 (100%) tumors, hCG in 5/5 (100%; focal in all tumors), and GATA3 in 5/5 (100%). However, short tandem repeat (STR) genotyping did not identify any nonpatient alleles in the tumors, indicating a nongestational origin. The median progression-free survival was 18 months (range: 0 to 85) and 2/5 (40%) patients died from disease, highlighting the potential poor prognosis of this nongestational tumor. Thus, in the same way as gestational and nongestational choriocarcinomas are recognized as different entities, nongestational PSTTs could be viewed as a distinct entity from their gestational counterparts, although further investigation and more cases are needed. Furthermore, we propose recommendations for diagnosing and staging of nongestational PSTTs to improve patient stratification and management.

Diffuse adult-type gliomas are delineated based on their molecular composition including the presence or absence of mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2), a key enzyme in the citric acid cycle. IDH-mutant tumors are associated with better survival than IDH-wildtype counterparts and can be further subdivided into astrocytoma or oligodendroglioma. Rare gliomas with fumarate hydratase (FH) deficiency have been reported. Given that FH is also a critical enzyme in the citric acid cycle, such tumors seem to be epigenetically similar to IDH-mutant tumors and, despite meeting criteria as IDH-wildtype gliomas per the current recommendations set forth by the World Health Organization, may behave in a manner akin to IDH-mutant neoplasms. Hereditary leiomyoma and renal cell cancer syndrome is associated with cutaneous and uterine leiomyomas and renal cell carcinoma caused by a germline FH alteration. To date, only rare examples of patients with known germline FH mutation subsequently diagnosed with a glioma have been reported. We report a case of a young patient with a glioma harboring features of IDH-mutant astrocytoma without evidence of IDH1/2 alterations. After the identification of cutaneous FH-deficient leiomyomas, a retrospective analysis of his brain tumor revealed FH deficiency and a germline FH alteration was ultimately identified after further molecular studies. Although rare, we conclude that FH mutations seem to be part of the spectrum of alterations in diffuse gliomas.

Sarcomatoid urothelial carcinoma (SUC) is a rare and aggressive subtype of bladder cancer. We retrospectively analyzed 136 patients diagnosed between 1993 and 2025. Clinicopathologic features, immunophenotype, PD-L1 expression, molecular alterations, and survival outcomes were assessed, with a focus on patients presenting with local low-stage (pT1) disease. The cohort included 96 males and 40 females (median age: 72). Most tumors (77%) were mixed with conventional urothelial carcinoma (UC), and 10% demonstrated heterologous differentiation. Tumor stage, lymphovascular invasion (LVI), and nodal metastasis were significantly associated with poor overall survival (OS; P <0.05). Fifty-four cases had CK5/6 and GATA3 immunohistochemical stains available; a mixed basal-luminal phenotype (CK5/6+/GATA3+) was most common (43%), though immunophenotypic grouping did not significantly impact survival. Twenty-two patients had PD-L1 immunostain performed at diagnosis, and most patients (82%) were PD-L1(+) with a CPS ≥10. Patients with CPS ≥50 trended toward improved OS. Panel-based sequencing was available for 6 patients and revealed heterogeneous mutations with few recurrent alterations. In our cohort, 10 patients had local low-stage (LLS/pT1) SUC, which is rare in SUC. The metastatic rate was 30%, and mortality was 40%. Findings in LLS patients with poor outcomes included large tumor, extensive invasion, tumor necrosis, and heterologous elements. LLS patients who underwent radical cystectomy (RC) had longer OS compared with those treated with transurethral resection of bladder tumor (TURBT) alone ( P =0.0269). 3/6 survival LLS patients had no residual tumor at RC. Our findings highlight the variable clinical courses of SUC, and call for more attention on this unique group of patients. The absence of residual disease in several pT1 patients following RC suggests that timely RC can have a favorable outcome in a subset of patients.

Point mutations in genes of the mitogen-activated protein kinase (MAPK) pathway are the most frequent oncogenic drivers of melanocytic neoplasms, whereas gene fusions are comparatively rare. Kinase fusions are among the molecular alterations that characterize Spitz neoplasms; however, not all melanocytic tumors that harbor one as the main oncogenic driver conform to clinical and/or histomorphologic parameters associated with Spitz neoplasms. In this study, we describe the clinical, histopathologic, and molecular characteristics of 7 RAF1 and 23 BRAF fusion-positive melanomas of patients who presented with or later developed regional and/or distant metastases. We report that most tumors in this series arose in adult patients and lacked Spitz-like microscopic features. Awareness of the varied clinical and histopathologic presentation of RAF1 and BRAF fusion-positive melanomas is important as the protein products of these kinase gene fusions constitute potentially actionable therapeutic targets.

Ten anaplastic juvenile granulosa cell tumors (JGCT) with architectural and cytologic features that differ from those seen in conventional JGCTs were identified from patients who ranged from 7 to 44 (median 13) years. The tumors measured from 8.3 to 28 (median 21) cm. FIGO stage was IA (n=3), IC3 (n=2), II (n=1), IIIA (n=3), or unknown (n=1). All tumors had conventional areas with solid/nodular growth usually punctuated by follicles. However, all demonstrated areas (median 50%, range: 10% to 90%) with effacement of this architecture, characterized by diffuse growth, marked cytologic atypia, and brisk mitoses (up to 40/10 HPFs). In contrast, the conventional component exhibited significantly less atypia and mitoses. Next-generation sequencing was performed in 7 tumors and all harbored TP53 mutations; the remaining 3 showed aberrant p53 expression by immunohistochemistry. MYC family ( MYC and MYCN ) amplifications were identified in 4 tumors, while other alterations included AKT1 in-frame duplications (n=4) and DICER1 mutations (n=2). Follow-up was available for 9 patients (median 22 mo); 4 died of disease (all stage II/III with MYC/MYCN amplifications), one was alive with disease (stage IA), and 4 were alive and well (stages IA/IC). Anaplastic JGCTs have a distinct morphologic appearance and consistently demonstrate TP53 inactivation, with MYC family amplification evident in advanced-stage tumors. Although it cannot be determined whether MYC family amplifications are an independent predictor of behavior, they are important to recognize as such patients may benefit from MYC inhibitors. Tumors with the features described herein should be distinguished from conventional JGCTs because of the prognostic implications. In addition, the architectural deviations from that usually encountered and pleomorphism further add to diagnostic challenges in evaluating JGCTs.

Inflammatory myofibroblastic tumors (IMTs) of the urinary bladder are rare mesenchymal neoplasms with an incompletely defined molecular spectrum. This integrated clinicopathologic and molecular study of 20 bladder IMTs utilized immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and targeted RNA sequencing to characterize their molecular drivers. Clinically, patients (mean age 45 y) presented with hematuria (85%) and cystoscopic polypoid/nodular masses; despite muscularis propria invovlement (55%) or perivesical soft tissue extension (5%), clinical outcomes were excellent (90% disease-free survival; mean follow-up 32.6 mo), with 2 recurrences managed by repeat resection. Histologically, the tumors exhibited mixed growth patterns: compact spindle cell (75%), myxoid (50%), and hypocellular fibrous (20%), with 45% showing combined features. IHC revealed ALK positivity in 90% (18/20) of cases, predominantly diffuse cytoplasmic staining (17/18), while keratins (AE1/AE3 and/or CAM5.2) were positive in 83.3%. Molecular analysis identified ALK rearrangements in 87.5% (14/16) of FISH-tested cases (signal separation: 13% to 42%) and gene fusions in 88.9% (16/18) of RNA-sequenced cases, with FN1::ALK being the predominant fusion (75%, 12/16). Rare fusions included VCL::ALK , DCTN1::ALK , PPFIBP1::ALK , and a novel TFG::ROS1 (confirmed by RT-PCR and Sanger sequencing). Distinct genotype-phenotype correlations emerged: myxoid morphology strongly associated with FN1::ALK (87.5%, 7/8), while hypocellular fibrous patterns enriched non- FN1 fusions (75%, 3/4). The predominance of FN1::ALK fusions, sharing identical breakpoints ( ALK exons 18 to 19) with pseudosarcomatous myofibroblastic proliferations of the urinary bladder, alongside expanded molecular diversity (non- FN1/ROS1 fusions), supports their classification as a biological continuum of ALK -driven bladder mesenchymal neoplasms. These findings broaden the molecular genetic spectrum of bladder IMTs and advocate for histology-guided molecular testing to identify kinase fusions, reinforcing conservative management for these typically indolent tumors.

Pulmonary microcystic fibromyxoma (PMF), a rare benign mesenchymal neoplasm first described in 2006, remains diagnostically challenging due to histologic overlap with a variety of primary/metastatic myxoid tumors of the lung and absence of lineage-specific markers. Its molecular pathogenesis has been undefined. In this study, we analyzed 3 PMF cases (2 males, 1 female; age 48 to 63 y) presenting as solitary peripheral lung nodules (1.5 to 3.5 cm), incidentally detected or associated with cough. Histologically, tumors showed microcystic architecture with bland stellate/spindled cells in fibromyxoid stroma, devoid of mitoses or necrosis. Immunohistochemistry uniformly excluded epithelial, myoepithelial, myogenic, neural, and vascular differentiation. Targeted DNA-sequencing identified recurrent PDGFRB mutations in all cases: 2 exon 12 in-frame deletions ( P .W566_I569del, P .R565_I569del) and 1 exon 14 missense mutation ( P .N666K), validated by Sanger sequencing. PDGFRB immunohistochemistry in one case revealed diffuse cytoplasmic/membranous reactivity, supporting constitutive signaling. Targeted RNA-based NGS revealed no evidence of pathogenic gene fusions. All patients remained recurrence-free after resection (mean follow-up: 81 mo). Our findings establish PDGFRB mutations as a molecular hallmark of PMF, further confirming the neoplastic nature of PMF and broadening the spectrum of PDGFRB -activating alterations in mesenchymal tumors. These mutations, clustering in regions critical for kinase autoinhibition, may serve as potential diagnostic tools to distinguish PMF from histologic mimics.

With the first series of PRRX1 -rearranged tumors published in 2019, the spectrum of these so-called fibroblastic tumors has been expanded. Since then, several smaller case series have been published; however, our understanding of them continues to be quite limited given their rarity. We herein studied 18 additional cases, the largest series to date. Eighteen tumors present in 9 male, 8 female, and 1 nonbinary patient with a median age of 35 years (range: 11 to 70 y) and involved the neck (5), the chest region (4), thigh (3), back (1), shoulder (1), forehead (1), lower leg (1), axilla (1), and the parapharyngeal region (1). Clinical follow-up (9/18 tumors; 50%; median: 10 mo; range: 4 to 40 mo) showed consistent indolent behavior without local recurrences or distant metastases. On morphology, these tumors were characterized by well-circumscription and distinctive peripheral crescent-shaped vessels. They were composed of uniform spindle and round cells growing in short fascicles within often densely hyalinized collagen lacking significant mitotic activity, necrosis, or cytologic atypia. Immunohistochemically, about half of the tested tumors expressed focal to rarely diffuse S100 with occasional co-expression of SOX10. Interestingly, almost half of the tested cases also showed complete loss of RB expression. All but 1 tumor harbored a PRRX1::NCOA1 fusion, while 1 case harbored a novel PRRX1::EP300 fusion. We herein provide additional data on these exceptionally uncommon tumors, expand their molecular spectrum, and compare them to their close morphologic mimics to aid in accurate diagnosis and avoid confusion with potentially more aggressive neoplasms.

Embryonic-type neuroectodermal tumor (ENT; previously referred to as primitive neuroectodermal tumor, PNET) of the testis and gynecologic tract share morphologic features with small round blue cell tumors, including Ewing sarcoma (ES), yet are biologically, therapeutically, and prognostically distinct. The diagnosis of ENT can be challenging, and it is unclear if there are reliable biomarkers that can be used to confirm this diagnosis. This study characterized 50 ENTs arising from the testis (n=38) and gynecologic tract (n=12; 7 ovary/5 uterus) with 27 biomarkers (AE1/AE3, ATRX, CD99, chromogranin-A, Cyclin D1, Fli-1, GFAP, GLUT-1, IDH1/2, INSM1, MTAP, NANOG, Nestin, neurofilament, NKX2.2, NSE, OCT3/4, OLIG2, p16, PAX6, PHOX2B, S100, SALL4, SOX2, SOX10, SOX17, synaptophysin). Expression was evaluated for extent (0, negative; 1, ≤10% positive; 2, 11% to 50% positive; 3, >50% positive) and intensity (1, weak; 2, moderate; 3, strong) of staining to obtain a combined score (CS) of 0-9; a CS ≥4 was considered "significant staining." SOX2 was the most sensitive biomarker for ENT, as 85% of the tumors demonstrated CS=9. GLUT-1, Fli-1, SALL4, and Cyclin D1 also showed CS ≥4 in more than half of the ENTs; however, only a minority demonstrated CS=9. All other biomarkers showed CS ≥4 in fewer than half of the ENTs, including synaptophysin (38%), GFAP (15%), S100 (15%), and chromogranin-A (14%). NKX2.2, CD99, and SOX17 showed CS ≥4 in 7%, 0%, and 3% of tumors, respectively. Overall, we found that in the appropriate clinicopathologic context, utilizing a panel of SOX2, OCT3/4 (to exclude embryonal carcinoma), AE1/AE3, NKX2.2, CD99, and SOX17 could be helpful in the diagnosis of ENT; many other traditional diagnostic biomarkers show limited utility.