The determination of the extent and margins of precancerous or cancerous lesions is still a problem in oncological surgeries today. This is more so with the 'holy grail' goal of optimal excision requiring total lesion removal and maximal neighboring tissue conservation especially for an important organ like the cervix. Although frozen section is the gold standard method available for aiding intraoperative diagnosis and surgery decision management, in dysplasia of the cervix where precancer cases are treated, it is not applicable due to various reasons, mainly to avoid over treatment. Still an optimal surgery is highly advocated and currently applying LUGOL dye to cervix is the accepted technique although not always accurate. Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy can complement visual inspection after LUGOL application, and several efforts have shown its potential in this regard. Research efforts on the subject, however, have not explored the use of ATR-FTIR spectroscopy for determining the extent of precancer on fresh cervical biopsies. This work therefore sets out to investigate ATR-FTIR spectroscopy for estimating the extent of precancer on fresh cervical samples using discriminatory features from the fingerprint region, as well as entropy and bound water related markers. Our results show that posterior probabilities were statistically different for precancer and healthy sampling points, with an area under the receiver operating characteristic curve value of 0.678 ± 0.094. At a cut-off probability of 0.550, sensitivity and specificity were 70% and 59%, respectively. These results show that ATR-FTIR spectroscopy on fresh tissue can aid spatially resolved determination of the extent of precancer, and that bound water and entropy related spectral biomarkers can provide additional diagnostic information for the ultimate goal of aiding intraoperative decision management.

Chromosomal instability is a common feature of malignancies that arises from persistent defects in chromosome segregation during mitosis. The resulting genetic heterogeneity and acquired malignant traits often characterize advanced disease. However, little is known about the mitotic processes underlying the acquisition of chromosomal instability and whether or how they might contribute to the early stages of cancer initiation. Here, we focused on a characteristic chromosome congression defect termed ECAC (Ectopic Chromosome Around Centrosome), which is observed in human papillomavirus (HPV)-positive cervical dysplasia, a premalignant lesion of the cervix. The expression of the HPV oncoprotein E6 induced proteasome-dependent degradation of the kinetochore motor CENP-E in addition to p53. We then identified the region of CENP-E required for E6-dependent degradation and conducted rescue experiments using a degradation-resistant mutant. These experiments demonstrated that CENP-E degradation is the main cause of the ECAC phenotype. Remarkably, the E6-mediated CENP-E destabilization and the resulting induction of ECAC were observed across multiple high-risk HPV genotypes, indicating that these defects represent a broadly shared pathological feature of oncogenic HPV infection. We also found that sustained E6 expression led to the accumulation of aneuploid cell populations during long-term culture. These findings define the molecular basis of ECAC and suggest that persistent chromosome congression defects can initiate chromosomal instability in premalignant cervical lesions.

Cervical cancer screening with high-risk human papillomavirus (HR-HPV) testing requires effective triage of HPV-positive women. Koilocytosis is a classic cytopathic effect of HPV infection, but its clinical significance in low-grade squamous intraepithelial lesions (LSILs) remains unclear. We retrospectively evaluated 157 HPV-positive women with LSIL cytology and follow-up data, including 140 women with concurrent biopsy results. Koilocytes were identified in 93/157 cases (59.2%) and were less frequent in HPV16/18-positive cases. Cervical intraepithelial neoplasia ≥ grade 2 (CIN2+) was detected in 9/84 koilocyte-positive cases (10.7%) and 16/56 koilocyte-negative cases (28.6%), whereas non-CIN findings were more common in koilocyte-positive cases. Koilocyte-positive cases also showed a longer time to regression from LSIL to negative for intraepithelial lesions or malignancy. These findings suggest that koilocytosis mainly reflects productive HPV infection and has limited utility for predicting CIN2+ in HPV-based screening triage. Excluding koilocytosis-driven low-grade cytological changes from triage positivity criteria may improve specificity and positive predictive value, supporting higher triage thresholds.

Neuroendocrine differentiation in tumors of the female genital tract is an uncommon but diagnostically consequential finding. Its interpretation is challenging because neuroendocrine marker expression does not necessarily define a neuroendocrine neoplasm. Focal or aberrant staining for synaptophysin, chromogranin A, CD56 or INSM1 may occur in otherwise conventional gynecologic carcinomas, whereas true poorly differentiated neuroendocrine carcinomas represent aggressive tumors with distinct prognostic and therapeutic implications. This narrative review examines neuroendocrine differentiation across the cervix, endometrium, ovary, vagina and vulva from an integrated clinicopathologic perspective. We emphasize that neuroendocrine differentiation should be approached as a diagnostic and biological spectrum, ranging from incidental immunophenotypic expression to carcinoma with neuroendocrine differentiation, mixed neuroendocrine/non-neuroendocrine tumors, well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Morphology remains the diagnostic anchor, while immunohistochemistry, molecular context and clinicoradiologic correlation refine classification and help exclude mimics or metastatic disease. Site-specific interpretation is essential: cervical neuroendocrine carcinoma is commonly HPV-associated and clinically aggressive; endometrial tumors require integration with p53, mismatch repair, POLE and SWI/SNF-related contexts; ovarian lesions demand distinction between primary well-differentiated neuroendocrine tumors, poorly differentiated carcinomas and metastases; and vaginal or vulvar tumors require careful exclusion of adjacent extension, cutaneous mimics and extragenital primaries. We propose a practical diagnostic framework that separates incidental marker expression from clinically meaningful neuroendocrine differentiation and links this distinction to reporting, prognosis and treatment. The central diagnostic question is not whether neuroendocrine markers are expressed but whether their expression defines a morphologically, biologically and clinically meaningful tumor category.

In the 1980s human papilloma virus (HPV) was identified as the cause of nearly all squamous cell cervical cancers (SCC), and the primary site of HPV infection at the cervix was long believed to be the basal cells of mature squamous epithelium. Considerable evidence now points to subcolumnar reserve cells (RC) nested in the endocervical epithelium as an alternative HPV target. Proof of the RC concept are i) HPV E6/E7 mRNA transcripts in histologically bland appearing p16 overexpressing thin HSIL, ii) similar genomic alterations in RC thin HSIL and invasive cervical SCC, and iii) HPV E6/E7 mRNA in endocervical RC adjacent to the preneoplastic regions. Even to date both the IARC and IPVS focus almost exclusively on HPV-associated cervical carcinogenesis originating in mature squamous cervical epithelium. The concept of dual carcinogenesis with distinct target cells for HPV at the cervix better explains most of the observations related to the natural history of cervical SCC. Further experimental substantiation of the RC as target cells for HPV and cell of origin of squamous (pre)cancer and the regulation of E6/7 expression in HPV infected proliferating RC and active metaplasia in the development of HSIL is needed. Furthermore, prospective in vivo studies of p16-positive thin HSIL lesions are necessary to document the risk of progression, but may be difficult to conduct for ethical reasons.

SMARCA4-deficient undifferentiated cervical tumor is highly malignant and responds poorly to conventional treatments, leading to a very poor prognosis. We report a case involving a primary cervical lesion measuring 9.8 cm, managed using a strategy of "PRaG5.0" combined with chemotherapy followed by sequential chemoimmunotherapy. This regimen employs short-course stereotactic body radiotherapy (SBRT, 24Gy/3Fx) as the radiotherapy component, combined with cadonilimab (a PD-1/CTLA-4 bispecific antibody), GM-CSF and thymosin α1 to form the PRaG5.0, alongside chemotherapy with nab-paclitaxel. Following the initial PRaG5.0 with chemotherapy, the patient's symptoms were markedly relieved, and CT images showed the primary lesion had shrunk to 7.2×6.0 cm. Subsequent consolidation with chemoimmunotherapy further reduced the tumor to 3.7×2.9 cm, and the treatment was well-tolerated. The patient's progression-free survival (PFS) now exceeds 12 months. This case indicates that for massive, refractory cervical tumors, PRaG5.0 combined with chemotherapy followed by sequential chemoimmunotherapy may offer an effective approach for controlling disease and extending survival.

Angiolipoleiomyomas (ALLMs) are benign mesenchymal tumours composed of vascular, muscular and adipocytic components. Very few cases have been described in the female reproductive tract. We present a case of concurrent ALLMs in the cervix associated with another apparently independent ALLM in the pararectal region. The lesions were incidentally detected on imaging and were surgically resected. Histopathology showed well-circumscribed, non-encapsulated tumours with no atypia or mitotic activity. Immunohistochemistry was positive for smooth muscle markers and negative for melanocytic and stromal markers, supporting a diagnosis of ALLM. The patient recovered well postoperatively with no recurrence at 26 months of follow-up. This case adds to the limited literature on ALLM and highlights two previously unreported features: pseudoinfiltrative margins and prominent nerve bundles. Demonstrating that such features may occur in ALLM despite its benign behaviour is important to avoid misdiagnosis and unnecessary aggressive management.

The increasing prevalence of cervical cancer in younger women highlights the need for personalized fertility-preserving treatment strategies. Current fertility preservation approaches for early-stage cervical cancer primarily involve cervical conization and radical trachelectomy. However, removing part or all of the cervix can negatively impact reproductive outcomes. These procedures increase the risk of preterm birth and miscarriage, and sometimes require additional surgery due to positive margins. Combined chemotherapy and immune checkpoint inhibitor (ICI) therapy has demonstrated promising efficacy and tolerability in treating locally advanced cervical cancer. However, its role as a non-surgical, fertility-sparing treatment for stage IB1 disease remains unclear.

Collection of samples plays a pivotal role in detection of precancerous lesion. Hence, comparative study was done on 95 women to assess the performance of self-collected vaginal samples versus physician-collected cervical samples for HPV detection. HPV positivity was similar between self (14.7%) and physician-collected samples (15.8%), with comparable genotype distributions. Physician sampling detected more cervical intraepithelial neoplasia (CIN) lesions and showed higher sensitivity, whereas self-sampling demonstrated better specificity and similar overall accuracy. There was significant difference between both the parameters. Thus, physician-collected cervical sample is better than self-collected vaginal samples.