American Journal of Surgical Pathology最新文献

Penile squamous cell carcinoma (PSCC) and its established precursor, penile intraepithelial neoplasia (PeIN), are classified as HPV-associated and HPV-independent. However, there is a spectrum of precursor lesions, which presents diagnostic challenges due to morphologic overlap. Immunohistochemical loss of GATA3, a tumor suppressor gene, has recently been reported in vulvar neoplasia. In this study, we evaluate the expression and diagnostic utility of GATA3 immunohistochemistry (IHC) in penile neoplasia. GATA3, p53, and p16 IHC was performed on 97 penile lesions, including lichen sclerosus (LS, N=14), condyloma acuminatum (N=11), squamous hyperplasia (SH, N=9), verrucous lesions (N=3), HPV-independent (N=12) and HPV-associated (N=18) PeIN, invasive HPV-independent, (N=19) and HPV-associated (N=11) PSCC, and normal skin (NL, N=41). GATA3 expression was scored as >75% basal/parabasal staining (pattern 0), 25% to 75% (pattern 1), 5% to 25% (pattern 2), and <5% (pattern 3). GATA3 was retained in NL (90%) and condyloma (73%) (P=0.15). LS and SH combined had significant GATA3 loss (44% pattern 0, 17% pattern 1, and 39% patterns 2 to 3) (P<0.001 vs. NL). HPV-independent PeIN had decreased GATA3 expression compared to NL (100% patterns 1 to 3, 87% patterns 2 to 3) (P<0.001), and LS-SH (P=0.003), but had similar expression to HPV-independent PSCC (P=1.00). HPV-associated PeIN and invasive PSCC had similar GATA3 loss (patterns 1 to 3, P=0.096). HPV-associated PSCC had a more severe loss (91%) than HPV-associated PeIN (39%) (P=0.008). These findings suggest that GATA3 alterations may be an early event during tumorigenesis, and that this marker may represent a useful complement to p16 and p53 in the differential diagnosis of HPV-independent PeIN from benign mimickers.

Most primary retroperitoneal soft tissue tumors are malignant, with liposarcomas and leiomyosarcomas being the most common. However, other sarcomas and benign tumors can also occur in this location. Pathologic evaluation of retroperitoneal sarcomas (RPS) presents unique challenges. Sarcomas are a heterogeneous group with overlapping microscopic features, making accurate classification essential for prognosis and evolving targeted therapies. Core biopsies often capture only a small portion of the tumor, which may result in underestimation of key features such as differentiation, necrosis, and proliferation, leading to undergrading. Surgical management is complicated by the RPS's tendency to involve adjacent organs. Resections are often large and en bloc, and formalin fixation can obscure anatomic landmarks, making it difficult to identify and assess true surgical margins. In addition to the standard data elements required for cancer staging, specific pathologic features of RPS should be reported to aid in prognosis and treatment planning. This position paper/consensus statement was developed by members of the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) based on evidence and expert opinion. A detailed description of specimen handling, specimen sampling, and the inclusion of the key diagnostic elements required for an accurate pathology report are provided. The aim of this manuscript is to offer a comprehensive critical reappraisal of the role of pathologic evaluation of surgical specimens in RPS surgery, as well as to propose a standard pathology report to harmonize reporting and facilitate future data collection and interpretation for future research development.

Inflammatory spindle cell PEComa is a rare PEComa variant with rare cases harboring YAP1::TFE3 fusion recently reported in the lungs. These tumors share identical YAP1::TFE3 fusion breakpoints and overlapping morphology with clear cell stromal tumor of the lung (CCST-L), but differ by demonstrating a myomelanocytic immunophenotype. We report the first 3 nonvisceral cases of inflammatory spindle cell PEComa with YAP1::TFE3 fusion. All occurred in female patients, aged 51 to 76 years, involving the vulva, presacral region, and thigh, and ranged from 3.8 to 5.0 cm (median: 4.0 cm). Histologically, all were well circumscribed with a fibrous capsule containing lymphoid cuffs, and were composed of fusiform to plump spindle cells arranged in short fascicles and vaguely storiform patterns, admixed with prominent inflammatory infiltrates. Extensive stromal calcifications, focal necrosis and occasional mitotic figures, including one atypical mitosis, were present in one case. Immunohistochemically, all cases were positive for smooth muscle actin and HMB45, and negative for cytokeratins, ERG, CD31, S100, and ALK. Targeted RNA sequencing identified YAP1::TFE3 fusions in all tumors, with 2 showing identical breakpoints to CCST-L (YAP1 exon 4-TFE3 exon 7), and 1 showing a breakpoint involving YAP1 exon 3-TFE3 exon 7. We report the first 3 cases of YAP1::TFE3-rearranged, nonvisceral inflammatory spindle cell PEComa occurring in somatic soft tissue sites, expanding the anatomic spectrum of this recently characterized entity. Inflammatory spindle cell PEComa should be considered in the differential diagnosis of spindle cell neoplasms with prominent admixed inflammation.

The 5th edition of the WHO classification of haematolymphoid tumours introduces the concept of hyperplasias arising in immune deficiency and dysregulation (IDD), which are frequently associated with Epstein-Barr virus (EBV). These lesions can be histologically classified as follicular hyperplasia (FH), infectious mononucleosis-like hyperplasia (IMH), or plasmacytic hyperplasia. Although EBV-associated reactive lymphoid hyperplasia (EBV-RLH) has been recognized in various IDD settings, comprehensive clinicopathologic analyses remain limited. We analyzed 34 Japanese patients with EBV-RLH. The IDD settings primarily included autoimmune diseases (with or without immunosuppressive therapy), chemotherapy for prior malignancies, aging, post-hematopoietic stem cell transplantation, and HIV infection. No patient exhibited histologic transformation or died due to EBV-RLH. Three patients had concurrent hematologic malignancies, and 12 had immune dysregulation related to prior chemotherapy. Histologically, 20 cases showed FH, 6 IMH, and 8 nonspecific patterns. EBER-positive cells were distributed in both interfollicular areas and germinal centers (GCs) in 27 cases (79%) and confined to interfollicular areas in 7. Six cases exhibited intensive aggregation of EBER-positive cells in one or a few GCs. Double staining confirmed that most EBER-positive cells expressed CD79a but not CD3. IGH and TCRG PCR analyses were successful in 24 cases: 21 were negative for both rearrangements, and 3 showed clonal rearrangements (1 double, 1 IGH-only, and 1 TCRG-only). EBV-RLH generally followed an indolent course; however, it may coexist with hematologic malignancies or develop after multichemotherapy. Careful histopathologic evaluation is essential to avoid overlooking concurrent malignancy or unnecessary treatment.

Erdheim-Chester disease (ECD) is a rare disease characterized by the accumulation of neoplastic histiocytes in various extra-nodal tissues. Tissue biopsies involved by ECD are difficult to distinguish from reactive inflammatory infiltrates given the bland appearance of the neoplastic histiocytes. Confirmation of the ECD diagnosis often relies on molecular studies to confirm BRAF V600E mutation or other activating mutations involving MAPK pathway genes. In this study, we examined the diagnostic utility of cyclin D1 and pERK as immunohistochemical markers of MAPK pathway activation in ECD compared with its histopathologic mimics. The cohort included 41 clinically confirmed ECD patients, most with known genetic alterations in MAPK pathway genes (n=38). In 3 cases no mutation was identified. 37 of 41 (90%) of ECD cases showed cyclin D1 overexpression, with frequent staining in the cytoplasm as well as the nucleus. pERK expression was observed in 32 of 39 (82%) cases. Cyclin D1 staining was negative in histopathologic mimics of ECD, apart from weak patchy staining in fat necrosis and uniform staining in a subset of cases of juvenile/adult xanthogranuloma. While not entirely sensitive or specific, in the proper clinical and radiologic context strong nuclear and cytoplasmic cyclin D1 expression within histiocytic infiltrates helps to support a diagnosis of ECD.

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.