Liquid Biopsy Catches Cancer Cells Slipping Into Blood During Cervical Cancer Surgery

Every year, surgeons around the world operate on thousands of women with early-stage cervical cancer, removing tumors that imaging and pathology have declared small, localized, and highly curable. Yet in roughly one in ten of these patients, the disease returns months or years later, sometimes in distant organs that the original tumor never touched. The question that has haunted gynecologic oncology for decades is deceptively simple: where do those recurring cells come from? A new preliminary study from France suggests that part of the answer may be visible in the bloodstream, in real time, while the operation itself is underway.

Researchers at Montpellier University Hospital and Nimes University Hospital conducted a bicentric prospective pilot study, published in BMC Cancer, to test whether circulating tumor cells, or CTCs, could be detected in the peripheral blood of patients during laparoscopic surgery for early-stage cervical carcinoma. The trial, registered on ClinicalTrials.gov as NCT04770090, enrolled eleven patients with histologically confirmed FIGO stage IA1 to IB2 disease, the earliest and most favorable spectrum of cervical cancer. The study was approved by the Ethics Committee IDF11 in Saint-Germain-en-Laye and conducted in accordance with the Declaration of Helsinki, with written informed consent obtained from every participant before inclusion.

The technical centerpiece of the investigation was the CellSearch system, the most clinically validated platform for CTC enumeration in the world. CellSearch exploits a defining biological property of epithelial tumor cells: they express EpCAM, an epithelial cell adhesion molecule, along with cytokeratins, structural proteins of the epithelial cytoskeleton, while lacking CD45, the marker that identifies white blood cells. Blood is drawn into specialized tubes, processed through immunomagnetic enrichment that captures EpCAM-positive cells, and then stained with fluorescent antibodies against cytokeratin and CD45 alongside a nuclear dye. Under automated digital microscopy, a cell is counted as a CTC only if it is nucleated, cytokeratin-positive, CD45-negative, and morphologically consistent with an epithelial tumor cell. This stringent definition is what makes CellSearch the reference standard, capable of finding a single tumor cell among billions of blood cells.

What set this study apart from most liquid biopsy research was its timing protocol. The investigators collected blood at three precisely defined perioperative moments: preoperatively, before any surgical manipulation, designated T0; immediately after creation of the pneumoperitoneum, the carbon dioxide gas inflation of the abdomen required for laparoscopy, designated T1; and just before colpotomy, the surgical opening of the vagina that allows removal of the specimen, designated T2. This three-point sampling design allowed the team to track intraoperative CTC dynamics, asking not merely whether tumor cells circulate in these patients, but whether the surgical process itself changes their numbers.

The results were striking in their pattern. CTCs were detected in three of the eleven patients, a detection rate of 27.3 percent, with a 95 percent confidence interval ranging from 7.3 to 60.7 percent. Crucially, in all three cases the cells appeared only during the operation, never in the preoperative sample. One patient had two CTCs detected at T1, right after pneumoperitoneum creation, while two patients had CTCs detected at T2, before colpotomy, with counts of fifty and two cells respectively. Among the CTC-positive patients, two had epidermoid carcinoma and one had adenocarcinoma, and their disease spanned stages IA1, IA2, and IB1, showing that perioperative cell shedding was not confined to one histological type or one stage within the early spectrum.

The finding that CTCs emerged only intraoperatively, and never preoperatively, carries significant technical and biological weight. It suggests that in these early-stage patients, the baseline burden of circulating tumor cells is so low that even a highly sensitive platform like CellSearch cannot find them before surgery begins. The appearance of cells during the operation raises the possibility that surgical steps, from gas insufflation of the abdomen to manipulation of the tumor-bearing uterus, may dislodge tumor cells into the venous circulation. This echoes a long-standing debate in gynecologic oncology about the potential of minimally invasive surgery to influence tumor cell dissemination, a debate that intensified after major trials questioned the oncological safety of laparoscopy in cervical cancer. The current study does not resolve that controversy, but it provides a direct measurement tool for investigating it at the cellular level.

Histopathological examination of the hysterectomy specimens added another layer of complexity. Residual tumor was found in six of the eleven patients, or 54.5 percent, including one of the CTC-positive patients. After a median follow-up of thirty-four months, one recurrence occurred in the cohort, a rate of 9.1 percent, consistent with the expected recurrence rate for early-stage disease. Notably, the recurrence happened in a patient without perioperative CTC detection, a counterintuitive observation that underscores the preliminary nature of the findings and the danger of drawing prognostic conclusions from such a small sample.

The authors are explicit about the limits of their data. With only eleven patients and a single clinical event, no conclusions can be drawn about the prognostic or therapeutic value of perioperative CTC detection. The wide confidence interval around the detection rate reflects the statistical reality of pilot studies, and the single recurrence in a CTC-negative patient cannot be interpreted as evidence that CTCs are uninformative. What the study does establish is feasibility: the perioperative detection of CTCs in peripheral blood during surgery for early-stage cervical cancer is technically achievable, and the intraoperative dynamics of these cells can be measured with a standardized, reproducible protocol.

The broader significance lies in what this feasibility opens. Liquid biopsy, the analysis of tumor-derived material in blood, has transformed oncology in cancers such as breast, prostate, and colorectal carcinoma, where CTC counts guide prognosis and, in some settings, treatment decisions. Cervical cancer has lagged behind, partly because early-stage disease sheds so few cells that detection platforms struggle to find a signal. By demonstrating that CTCs can be captured during the surgical window itself, the Montpellier and Nimes team has created a methodological foundation for larger prospective cohorts that could ask whether intraoperative cell shedding predicts recurrence, whether it correlates with surgical technique, and whether it could one day inform decisions about adjuvant therapy or follow-up intensity.

For now, the message to patients and clinicians is one of cautious promise. Early-stage cervical cancer remains highly curable, and the vast majority of patients who undergo surgery are cured. This study does not change practice, and its authors emphasize that validation in larger cohorts is essential before any clinical use. But it does change what is measurable. For the first time in this disease, the operating room itself has become a laboratory for observing cancer cells in transit, and the bloodstream has become a window into the earliest moments of a process that may, in a small minority of patients, lead to recurrence. That shift, from retrospective pathology to real-time cellular observation, is the kind of technical advance that quietly reshapes how a disease is understood, and it begins with eleven patients, three blood draws each, and the detection of a handful of cells that no one could see before.

Subject of Research: Cervical cancer

Article Title: Circulating tumor cells detection by liquid biopsy during early-stage cervical cancer surgery: a preliminary feasibility study

Article References: Jeanmart, A., Duraes, M., Francini, S., Rathat, G., Crantelle, L., Duroyon, M. M., Macioce, V., Mollevi, C., Ferrer, C., Cayrefourcq, L., & Alix-Panabires, C. (2026). Circulating tumor cells detection by liquid biopsy during early-stage cervical cancer surgery: a preliminary feasibility study. BMC Cancer. https://doi.org/10.1186/s12885-026-17152-2

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17152-2

Keywords: cervical cancer, liquid biopsy, circulating tumor cells, laparoscopy, surgical oncology, CellSearch, cancer recurrence, gynecology, Circulating, tumor, cells, detection