Rare primitive neuroectodermal tumor of the uterus diagnosed through molecular exclusion

Deep in the wall of a 46-year-old woman’s uterus, a tumor was growing that defied every category her pathologists knew. It was built from primitive small round cells that looked nothing like the glandular tissue of ordinary endometrial cancers, yet it carried an immunological signature blending neuroendocrine and epithelial markers in a way that made its lineage ambiguous. When the first surgical specimens arrived at the laboratory, the diagnosis remained out of reach even after expert consultation. Only after two operations, next-generation sequencing, and a systematic molecular exclusion of Ewing’s sarcoma did the team settle on one of the rarest diagnoses in gynecological pathology: a central-type primitive neuroectodermal tumor of the uterus. The case, published in Frontiers in Oncology, documents roughly the thirtieth such tumor ever reported and exposes how little the field still understands about these aggressive neoplasms.

Primitive neuroectodermal tumors were first proposed by Hart and Earle in 1973 to describe highly malignant undifferentiated small round cell tumors derived from primitive neural tube embryonic cells with the potential for multidirectional differentiation. In 1986, Dehner split the group into central and peripheral types according to anatomical site. Central-type tumors originate from small round primitive neuroepithelial cells of the supratentorial region and spinal cord, while peripheral-type tumors arise from neural crest-derived mesenchymal components and typically appear in extracranial soft tissue, bone, and peripheral nerve trunks. The peripheral type belongs to the Ewing sarcoma family of tumors, sharing histological morphology, immunophenotype, and chromosomal translocations with Ewing’s sarcoma itself, with the peripheral form showing more prominent neural differentiation. Since 1993 the World Health Organization has included PNET in its CNS tumor classification, and in 2002 the entity was grouped under neuroectodermal tumors.

The central-peripheral division, however, is increasingly recognized as biologically insufficient. According to the fifth edition of the WHO Classification of Female Genital Tumors, the concept of PNET, particularly the central type, has been reconsidered owing to its limited biological specificity. Tumors previously labeled cPNET are now thought to represent a heterogeneous group of neoplasms with neuroectodermal differentiation that overlaps with embryonal CNS tumors. Peripheral-type tumors are closely tied to Ewing’s sarcoma and defined by rearrangements of the Ewing sarcoma breakpoint region 1 (EWSR1) gene, whereas the central type lacks EWSR1 fusion events and shows histological features of poorly differentiated small round blue cell tumors with varying degrees of neuroepithelial, glial, and ependymoid differentiation. Emerging molecular evidence suggests some cases show similarities to embryonic neuroectodermal tumors or other CNS-like tumors, making integrated morphological, immunohistochemical, and molecular assessment the current diagnostic standard.

Uterine cPNET is vanishingly rare. Approximately 30 cases have been reported in the literature, including a large cohort of 17 cases, and the ovaries remain the most common site for PNET in the female reproductive system. The age of onset shows a bimodal distribution, occurring mainly during adolescence and menopause, with cases also reported during pregnancy and the puerperium. Clinical manifestations include irregular vaginal bleeding, postmenopausal bleeding, lower abdominal pain, and a palpable pelvic mass, and on imaging the tumors are often misdiagnosed as uterine fibroids or endometrial carcinoma. Grossly they appear multinodular or lobulated with an ill-defined capsule, soft and fish-flesh-like, often accompanied by hemorrhage and necrosis. Because clinical presentation, imaging findings, and histopathological features overlap with uterine leiomyosarcoma, sex cord-stromal tumors, and neuroendocrine carcinoma, diagnosis remains highly challenging and no standardized treatment protocol exists.

The new case began with persistent left lower abdominal pain, a continuous dull ache with no identifiable precipitating factors. Pelvic computed tomography revealed a rounded soft-tissue mass in the left pelvic cavity with ill-defined boundaries, compressing the lower segment of the left ureter, alongside multiple nodular uterine lesions showing moderate-to-marked contrast enhancement. Imaging suggested a pelvic malignant neoplasm accompanied by a uterine leiomyoma. Because the tumor’s origin was unknown and local invasion was evident, the patient underwent exploratory laparotomy. Surgeons found a solid mass measuring approximately 9 by 6 centimeters within the left broad ligament, closely attached to and compressing the ureter, with an irregularly enlarged uterus bearing multiple nodular protrusions. Intraoperative frozen section showed short spindle-shaped and small round cells with dense arrangement and notable atypia, prompting preliminary consideration of a sex cord stromal origin whose malignant potential could not be confirmed.

Definitive histopathological examination of the pelvic mass revealed a well-circumscribed lesion with an intact capsule and a grey-white to grey-red cut surface with focal cystic degeneration. Microscopically the tumor displayed an infiltrative growth pattern composed of diffuse sheets of primitive cells, predominantly small, round to short spindle-shaped, with scant cytoplasm and high nuclear-to-cytoplasmic ratios. Marked nuclear atypia, hyperchromasia, and frequent mitotic figures were observed, along with focal rosette-like structures providing morphological evidence of neuroectodermal differentiation. Immunohistochemistry showed diffuse positivity for synaptophysin and insulinoma-associated protein 1 (INSM1), together with CD56 expression and focal perinuclear dot-like staining for chromogranin A, supporting neuroendocrine and neuroectodermal differentiation. Focal cytokeratin and CK8/18 expression indicated partial epithelial differentiation, while negative results for CD99 and NKX2.2 argued against Ewing’s sarcoma and peripheral PNET. The concurrently resected uterine lesion showed strikingly similar features, with a Ki-67 labeling index reaching approximately 40 percent in hotspot areas and conspicuous intravascular tumor emboli.

The diagnostic ambiguity persisted. External pathological consultation concluded the lesion was malignant, with primary differential diagnoses including high-grade endometrial stromal sarcoma, sex cord-stromal tumor, and neuroendocrine neoplasms, but a definitive classification could not be established. Next-generation sequencing covering a wide range of mutations, amplifications, and structural variations was performed to facilitate subtyping. The analysis revealed an intergenic rearrangement between the neurofibromatosis type 2 (NF2) gene and BRCA1 A complex subunit 1 (ABRAXAS1), concurrent amplification of CRKL, ANTXR2, CXCL13, FGF5, and SLC34A2, and single-nucleotide variants in TNFRSF14, TRIO, ROS1, PTPRO, KLF5, ALOX12B, and ROCK1. None of these alterations carried a known definitive classification or established driver significance, and no harmful germline mutations were detected. The sequencing findings failed to provide definitive criteria for tumor classification, highlighting the molecular-level non-specificity and pronounced heterogeneity of the case.

Given the tumor’s highly invasive nature, unclear classification, and risk of residual lesions, a multidisciplinary team concluded the tumor likely originated from the uterus and recommended extended resection with adequate tissue sampling. Two months after the initial surgery, the patient underwent total hysterectomy, bilateral salpingo-oophorectomy, and pelvic plus para-aortic lymphadenectomy. The specimen revealed multiple grayish-white nodular lesions in the left myometrium, with densely packed tumor cells in sheet-like and nested patterns, focal collagenous stromal proliferation, and abundant vascular networks. The refined immunohistochemical profile showed positivity for synaptophysin, INSM1, and CD56 with perinuclear dot-like chromogranin A, and the Ki-67 proliferation index reached approximately 70 percent, indicating a high-grade neoplasm with prominent neuroendocrine differentiation. Negative expression of CD99, FLI1, and NKX2.2, together with the absence of EWSR1-associated rearrangements, argued against an Ewing’s sarcoma or peripheral PNET-type neoplasm, while preserved INI-1 and BRG1 expression excluded SMARCB1 and SMARCA4-deficient tumors.

The final diagnosis was not based solely on excluding Ewing’s sarcoma. It rested on integrated assessment of the tumor’s primitive morphology, focal rosette-like structures, neuroendocrine and neuroectodermal immunophenotype, absence of an EWSR1-associated rearrangement, systematic exclusion of major mimics through negative staining for SOX-10, HMB-45, CD3, CD20, CD117, SMA, ER, GATA-3, CDX-2, and Villin, and comprehensive findings across extensively sampled specimens from multiple procedures. The tumor was classified as FIGO stage IIIC2 under the current FIGO 2023 framework, based on metastatic involvement of para-aortic lymph nodes below the renal vessels. Postoperatively, the patient received seven cycles of adjuvant combination therapy consisting of liposomal doxorubicin and ifosfamide on day 1, cisplatin and ifosfamide on day 2, and cadonilimab with ifosfamide on day 3, followed by maintenance cadonilimab. At the 24-month follow-up, she remained alive with no evidence of disease.

The molecular findings may hint at a unique biology. NF2, located on chromosome 22q, encodes the Merlin protein, a cytoskeletal tumor suppressor whose activation inhibits several proliferation-critical signaling pathways, including PIKE-L/PI3K, mTORC1, Src/Fak, and the Hippo cascade. NF2 mutations have been associated with more than 11 cancer types, and studies of pediatric brain tumors report that somatic structural variations disrupt the NF2/Hippo axis. ABRAXAS1 encodes a key subunit of the BRCA1 complex involved in homologous recombination repair, and structural alterations may cause BRCA1 complex dysfunction, exacerbating genomic instability and possibly cooperating with the NF2 pathway. The authors propose that uterine cPNET may involve a cross-regulatory network of the DNA damage response and Hippo pathways, though this requires validation. As a single case with 24-month follow-up, the findings cannot be generalized, and the authors call for multicenter consensus studies to clarify whether cPNET represents a homogeneous entity or a heterogeneous group of primitive neoplasms.

Subject of Research: Central-type primitive neuroectodermal tumor of the uterus: case report and literature review

Article Title: Central-type primitive neuroectodermal tumor of the uterus: Case report and literature review

Article References: Lin, Y.-Y., Xie, M.-Y., Mao, R.-J., Luo, B.-T., & Qi, Y. (2026). Central-type primitive neuroectodermal tumor of the uterus: Case report and literature review. Frontiers in Oncology, 16, Article 1926715. https://doi.org/10.3389/fonc.2026.1926715

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1926715

Keywords: central-type primitive neuroectodermal tumor, uterus, Ewing sarcoma, EWSR1, next-generation sequencing, NF2, ABRAXAS1, immunohistochemistry, small round cell tumor, differential diagnosis, gynecological oncology, case report