American Journal of Surgical Pathology最新文献

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.

TFEB -altered renal cell carcinoma (RCC) included TFEB -rearranged and TFEB -amplified RCC with unclear clinicopathological features and treatment options. Cases of TFEB -altered RCCs were collected. Fourteen cases showed TFEB rearrangement. Five MALAT1::TFEB fusions and one ACTB::TFEB fusion were verified. 8/14 TFEB -rearranged RCCs showed biphasic "pseudorosette" structure. All TFEB -rearranged RCC patients were alive without recurrence or metastasis after 3 to 122 months. Fifteen cases showed TFEB amplification, including 5 high-level amplifications (>10 copies) and ten low-level amplifications (5 to 10 copies), including 3 cases showing concomitant TFEB amplification and rearrangement. TFEB -amplified RCCs were high-grade, showing papillary, solid, nested, or alveolar arrangements of cells. In addition, 8 cases showed 3 to 4 TFEB signals were collected, indicating diverse morphologies. PDL1 membranous staining was observed in 9/10 TFEB -rearranged RCCs, and 11/13 TFEB -amplified RCCs. Copy number variation analysis revealed specific amplification of chromosome 6p21.1, where TFEB, VEGFA6 , and CCND3 were located, in one high- and 2 low-level amplification cases. Four cases with 3 to 4 TFEB signals did not show specific amplification of this region. Within the follow-up periods of 3 to 64 months, 8/13 TFEB -amplified RCC cases presented with metastasis, and 3/13 patients died in the 12th and 24th months. The treatment processes in several cases and the detailed therapeutic course of a TFEB -amplified case were documented, highlighting the efficacy of PD-1 inhibitors. Our research supported a cutoff of ≥5 TFEB copies for the diagnosis of TFEB -amplified RCCs, though further studies were needed regarding the threshold. The expression of PDL1 might indicate a potential benefit of PD-1 inhibitors.

Evaluation of T-cell receptor (TCR) β-chain constant region 1 (TRBC1) expression is an alternative T-cell clonality assessment method. However, evaluation of TRBC1 immunohistochemistry (IHC) for distinguishing mycosis fungoides (MF)/Sezary syndrome (SS) from reactive inflammatory infiltrates in skin is incomplete. We evaluated the utility of a novel dual TRBC1-CD3 IHC stain in skin biopsies with MF/SS (n=40), reactive (n=24), or atypical T-cell infiltrates indeterminant for MF/SS (n=9). Twenty of 24 reactive cases showed clear polytypic TRBC1 expression (median percent TRBC1 positivity among CD3-positive T cells [%TRBC1+] 50% in dermis, 42.5% in epidermis among all cases), while 34/40 MF/SS were clearly monotypic (%TRBC1+ either ≤20% or ≥85%) (sensitivity 85.0%, specificity 91.7%, positive predictive value 94.4%, negative predictive value 78.6%). Discordance between TRBC1 expression and diagnosis was associated with few neoplastic/monotypic T cells and/or lack of physical separation between neoplastic and non-neoplastic populations. Among patch/plaque MF/SS, TRBC1 showed similar diagnostic sensitivity (80.0% vs. 86.7%) and high categorical correlation (monotypic vs. not monotypic, 80%) with TCR gene rearrangement results. TRBC1 interpretation was reproducible, with ≥2/3 and 3/3 pathologists rendering identical interpretations in 100% and 86% of cases, respectively, after independent review and 100% agreement following collective review. Digital image analysis confirmed visual %TRBC1+ accuracy ( r =0.9749, P <0.0001). On the basis of these results, we propose %TRBC1+ cutoffs of <25% or >75% for establishing T-cell monotypia in skin. Considering such thresholds, TRBC1-CD3 evaluation facilitated diagnostic refinement in 7/9 (78%) atypical cases. Overall, TRBC1-CD3 IHC clearly and rapidly aids diagnosis of cutaneous T-cell proliferations.

Most salivary gland tumors are found to have genetic fusions driving their oncogenesis, with an explosion of such findings in recent years. They typically represent previously identified and well-characterized tumors and the fusions are generally not necessary for diagnosis but rather serve as diagnostic arbitrators in challenging cases. That said, occasional unexpected molecular findings are broadening our understanding of these common tumors and have led to the emergence of new entities, some of which were "hiding in plain sight" and are quite common, like secretory carcinoma. In contrast, others are sufficiently rare that molecular testing was required to identify them in small cohorts, combining cases from multiple institutions, such as microcribriform adenocarcinoma. Recently, we identified a rare case of tongue adenocarcinoma with EWSR1::BEND2 fusion with an unusual morphology, and 2 additional cases were subsequently briefly reported in the literature. In this study, we collected and analyzed a total of 7 cases that show variable but consistent morphology, including a fenestrating glandular appearance, occasional squamous or basaloid growth, and focal mucinous cells. The tumors showed a predilection for the pharynx with 4 cases in the base of the tongue, one case in the tonsil/oropharyngeal wall, one case in the nasopharynx, and only one nonpharyngeal case in the trachea. No oral cavity or major salivary gland tumors were found with this set of findings to date. The tumors showed some aggressive tendencies, with 2/4 with follow-up information having adverse outcomes, including lymph node metastases in 2 cases and 1 of these cases also having brain metastases, recurrence, and death from disease. All cases tested showed EWSR1::BEND2 fusion by NGS, as well as CK7/BEND2 positivity, and S100 negativity by immunohistochemistry. The tumors showed variable p63 staining depending on whether squamous or basaloid features were present. A tissue microarray (TMA) stained with an antibody directed against the BEND2 protein showed no significant staining in any other salivary tumor type. The constellation of findings in this cohort is highly suggestive of a specific entity, and we propose the appellation "Fenestrating Adenocarcinoma (FAC)" of the salivary gland.

Brain metastasis (BRM) of pancreatic ductal adenocarcinoma (PDAC) is rare. The clinicopathological characteristics of BRM have not been defined. We reviewed the clinicopathologic and molecular features of 18 PDAC patients who underwent resection of primary tumor (RPT) and developed BRM, along with 2 patients who had BRM resection without RPT and compared with 679 patients without BRM who received neoadjuvant therapy (NAT) and pancreatectomy. There were 11 males and 9 females (median age: 60.7 y). The median intervals to BRM were 47.0, 44.4, and 31.6 months from dates of diagnosis, surgery, and first metastasis to other sites, respectively. Five patients underwent resection for BRM and showed unique cystic papillary growth patterns with detached cell clusters. All BRMs had mutant p53 staining, 4 had retained SMAD4, and 3 were focally positive for CK17. Among 18 patients who underwent RPT, 12 received NAT. Patients with BRMs have lower tumor stage ( P <0.001) and better tumor response ( P =0.01) at RPT. The median overall survival (OS) for 18 patients with BRM after RPT was 62.3 months compared with 42.4 months for those without BRM (n=679, P =0.59). The median survival was 3.3 months from BRM diagnosis for all patients and 6.9 months for 5 patients who underwent brain surgery. In summary, BRM represents a late event in PDAC patients, occurs after patients developed metastasis to other organs, and has distinct cystic papillary growth pattern. The prognosis for patients who underwent RPT and developed BRM is similar to those who underwent RPT without BRM.