Vulvar squamous cell carcinoma is the most common histological subtype of vulvar cancer and predominantly strikes older, postmenopausal women. Its prognosis hinges to a remarkable degree on one factor: whether cancer cells have reached the inguinofemoral lymph nodes. Five-year survival rates fall from 80 to 90 percent in early-stage disease to just 20 to 40 percent once nodal involvement is present. Yet determining nodal status preoperatively remains difficult, and the surgical answer—inguinofemoral lymphadenectomy—carries a heavy price, including wound breakdown, infection, and chronic lower-limb lymphedema that can rob elderly women of mobility and independence. Sentinel lymph node procedures were introduced to reduce this burden, but they are not suitable for every patient, leaving a persistent need for simple, reliable biomarkers that can flag high-risk disease before the operating room.

The biological logic behind the new study rests on a growing recognition that cancer-related inflammation is a hallmark of tumor progression. Neutrophils, monocytes, and platelets circulating in the blood promote tumor growth, angiogenesis, invasion, and immune evasion, while lymphocytes mediate antitumor surveillance. The systemic immune-inflammation index integrates platelet, neutrophil, and lymphocyte counts into a single number reflecting the interplay of inflammation, thrombosis, and immune competence. The systemic inflammation response index swaps platelets for monocytes, combining neutrophil, monocyte, and lymphocyte counts to capture monocyte-driven tumor-associated inflammation. Both can be computed from any standard blood count, making them among the most accessible candidate biomarkers in oncology.

Age is central to the story, not merely as a demographic variable but as a biological process. Aging-associated hematopoietic remodeling skews blood production toward myeloid cells, raising neutrophil and monocyte output while lymphoid output falls. In parallel, older adults experience inflammaging—chronic, sterile, low-grade inflammation driven by senescent cells and accumulated cellular damage—alongside immunosenescence, the progressive deterioration of adaptive immune surveillance. Because SII and SIRI are built directly from the cell compartments most affected by these changes, an elevated score in an elderly patient may reflect both tumor-driven inflammation and the aging of the immune system itself, potentially creating a more immunosuppressive, tumor-permissive environment.

To test whether these indices carry clinical information in vulvar cancer, the team conducted a retrospective single-center cohort study, identifying 168 patients and applying strict exclusion criteria—autoimmune disorders, immunosuppressive therapy, active infection, prior malignancy, and non-squamous histology among them—to arrive at a final cohort of 92 women. The mean age at diagnosis was 72.18 years, hypertension was the most common comorbidity, and lymph node metastasis was present in 52.2 percent of evaluable cases, while lymphovascular space invasion (LVSI) appeared in 17.4 percent. Preoperative blood counts, taken within one month of surgery and before any treatment, were used to calculate both indices.

The results were striking in pattern, if moderate in strength. Both indices were significantly higher in patients with lymph node metastasis and LVSI, and both correlated positively with the largest tumor diameter—SII with a Spearman rho of 0.215 and SIRI with 0.248—though neither correlated with the depth of stromal invasion or with p16 or p53 status. Receiver operating characteristic analysis yielded an area under the curve of 0.653 for SII and 0.670 for SIRI in predicting nodal metastasis, and a nearly identical 0.732 versus 0.733 for LVSI. A formal paired DeLong comparison found no statistically significant difference between the two indices for either endpoint, meaning neither marker outperformed the other in discrimination.

The most compelling result emerged from multivariable logistic regression. After adjustment for age, tumor size, tumor grade, and lymphovascular space invasion, an elevated SIRI—defined by a Youden-derived cutoff of 1.55—remained independently associated with lymph node metastasis, with an adjusted odds ratio of 4.30 and a 95 percent confidence interval of 1.51 to 12.27. Elevated SII, by contrast, lost statistical significance after full adjustment. For LVSI prediction, both indices achieved their best discrimination of the study, with AUCs of 0.73, high negative predictive values of 0.94 and 0.95, but low positive predictive values of roughly 0.30—a profile that could prove useful for ruling out lymphovascular invasion, though the authors caution that these thresholds are exploratory and cohort-specific.

Why might the monocyte-containing index hold an edge? The researchers propose a plausible, if unproven, mechanism rooted in tumor immunology. Tumors secrete CCL2 and CSF1, chemical signals that recruit circulating monocytes into the tumor microenvironment, where they differentiate into M2-like tumor-associated macrophages and myeloid-derived suppressor cells. These populations suppress T-cell immunity and secrete VEGF-C, promoting peritumoral lymphangiogenesis—the growth of new lymphatic vessels that cancer cells can exploit to enter the circulation. Platelets, which feature in SII but not SIRI, act mainly on tumor cells that have already entered the bloodstream. This pathway would explain why both indices discriminated best for LVSI, the entry step of the metastatic cascade, and why the monocyte-sensitive SIRI retained its independent association with nodal spread. The authors stress, however, that tumor-infiltrating myeloid cells were not directly measured, leaving the mechanism hypothetical.

A geroscience lens sharpens the interpretation further. Vulvar squamous cell carcinoma arises in women whose immune systems have already undergone profound remodeling: myeloid skewing raises neutrophil and monocyte counts, inflammaging sustains low-grade inflammation, and immunosenescence weakens T-cell surveillance. Every one of these changes pushes both indices upward, since their myeloid terms rise while the lymphocyte term falls. Notably, chronological age was not an independent predictor of nodal metastasis in the study’s models—but the authors argue this does not undermine an aging-related interpretation, because chronological age is an imperfect proxy for biological immune aging. The team also found no association between the indices and p16 or p53 status, suggesting that systemic inflammation may capture invasive and metastatic behavior that transcends the two known molecular subtypes of the disease, HPV-associated and HPV-independent p53-aberrant tumors—an observation of practical relevance in an elderly population where HPV-independent disease predominates, though limited staining data temper this conclusion.

The study’s honest accounting of its own limits is as instructive as its positive findings. Bootstrap internal validation with 2,000 resamples revealed meaningful optimism: the optimism-corrected AUC of the SIRI-extended model, 0.638, was no better than that of the clinicopathological base model, and adding continuous SIRI to the base model improved neither model fit nor discrimination significantly. With only 8.8 events per predictor coefficient in the cutoff-based models, overfitting was a real risk, and re-estimated thresholds varied across bootstrap samples, particularly for the LVSI endpoint. The retrospective single-center design, the absence of routine C-reactive protein measurement, missing p16 and p53 stains in roughly a third to two-fifths of patients, and the lack of survival outcomes all constrain generalizability. The authors conclude that SII and SIRI are insufficient as standalone biomarkers but are inexpensive, readily available candidate adjunctive markers that deserve prospective multicenter validation—ideally integrated with molecular profiling, imaging, and geriatric assessment. For a disease whose treatment can trade survival for lifelong lymphedema, even a modest, free signal from a routine blood draw may ultimately help spare vulnerable women the surgeries they do not need.

Subject of Research: Blood count-derived inflammatory indices as biomarkers of metastatic spread in vulvar squamous cell carcinoma

Article Title: Systemic immune-inflammation and inflammation response indices as biomarkers of lymph node metastasis and lymphovascular space invasion in vulvar squamous cell carcinoma

Article References: Keszthelyi, M., Sebok, P., Kárpáti, C., Sebők, B., Lőczi, L., Ács, N., Merkely, P., Tóth, R., Vida, B., & Lintner, B. (2026). Systemic immune-inflammation and inflammation response indices as biomarkers of lymph node metastasis and lymphovascular space invasion in vulvar squamous cell carcinoma. GeroScience. https://doi.org/10.1007/s11357-026-02509-z

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02509-z

Keywords: vulvar squamous cell carcinoma, systemic immune-inflammation index, systemic inflammation response index, lymph node metastasis, lymphovascular space invasion, biomarkers, inflammaging, immunosenescence, tumor-associated macrophages, geroscience, preoperative risk stratification, gynecologic oncology

The research team, led by Na Lu, Xiaosu Liu, and Yaqin Wang of the Department of Gynecologic Oncology, together with radiotherapy specialist Xiaodong Han, assembled a cohort of 788 patients who underwent surgical treatment for cervical squamous cell carcinoma between June 2012 and March 2019. All patients had full-thickness infiltration of the cervix by tumor, and each case was reviewed in detail for pathological characteristics including tumor volume, maximum tumor diameter, pathological grade, growth pattern, gross tumor type, vaginal invasion, nerve invasion, and the presence or absence of lymphovascular space invasion, commonly abbreviated LVSI. LVSI refers to the presence of tumor cells within the vascular or lymphatic channels surrounding the tumor, a finding that pathologists detect under the microscope and that has long been suspected as a conduit for cancer spread.

To analyze survival, the investigators constructed stratified Cox proportional hazards regression models, stratifying by pathological grade to address a minor violation of the proportional hazards assumption, a statistical refinement that improves the reliability of hazard ratio estimates when the effect of a variable changes over time. For the lymph node analyses, they employed both conventional multivariable binary logistic regression and restricted cubic spline logistic regression, the latter allowing the relationship between continuous variables such as tumor volume and metastasis risk to be modeled flexibly rather than being forced into a purely linear form. The team examined three distinct metastatic outcomes: any lymph node metastasis, high-level lymph node metastasis defined as spread to nodes at or above the common iliac artery, and multiple metastatic lymph nodes, defined as three or more positive nodes.

The survival analysis yielded four independent adverse prognostic factors for overall survival. Increased tumor volume carried a hazard ratio of 1.006 per unit increase, with a P value of 0.007, indicating that even modest increases in tumor bulk translate into measurable mortality risk. Positive lymphovascular space invasion nearly doubled the hazard of death, with a hazard ratio of 1.961 and a P value below 0.001, making it the strongest pathological predictor in the model. Positive vaginal invasion raised the hazard of death by approximately 75 percent, with a hazard ratio of 1.753 and a P value of 0.001. Finally, positive lymph node metastasis itself was confirmed as an independent adverse prognostic factor, carrying a hazard ratio of 2.938, meaning that patients with nodal spread faced nearly three times the risk of death compared with those without, even after accounting for other pathological features.

Perhaps the most clinically provocative finding concerns postoperative adjuvant therapy. Across the cohort, no postoperative adjuvant treatment modality significantly affected patient survival. In an era when adjuvant radiotherapy or chemoradiation is frequently recommended for patients with intermediate- or high-risk features after radical hysterectomy, this result raises difficult questions about the magnitude of benefit that adjuvant treatment confers in this specific population. The authors caution that their analysis is retrospective and that treatment decisions were not randomized, so the finding should be interpreted as hypothesis-generating rather than as a directive to withhold therapy. Nevertheless, the absence of a detectable survival benefit across the entire cohort underscores the need for carefully designed prospective studies to define which patients truly benefit from adjuvant treatment.

The restricted cubic spline analysis of tumor volume and lymph node metastasis revealed a marginally significant overall association when tumor volume was treated as a continuous variable, with a global P value of 0.053, just shy of conventional statistical significance. However, within a clinically relevant tumor volume range of 10 to 35 cubic centimeters, the analysis detected a positive linear risk trend with an odds ratio of 1.866 and a P value of 0.040. This suggests that in the intermediate range of tumor sizes, each incremental increase in volume is associated with a steadily rising probability of nodal involvement, while the relationship may be more complex or plateau outside this range. The finding highlights the value of flexible spline modeling, which can detect localized risk trends that a rigid linear model might obscure.

The conventional multivariable logistic regression analysis identified four independent risk factors for any lymph node metastasis. Positive LVSI dominated the model with an odds ratio of 4.276, indicating that patients whose tumors showed vascular or lymphatic invasion faced more than a fourfold increase in the odds of nodal spread. Pathological grade III, representing poorly differentiated tumors, carried an odds ratio of 1.706 with a P value of 0.002. Endogenous tumor growth pattern, in which the tumor grows inward from the cervical surface, doubled the odds of metastasis with an odds ratio of 2.676 and a P value of 0.008. Most strikingly, mass-type gross tumor morphology, as opposed to ulcerative type, carried an odds ratio of 6.455 with a P value of 0.016, making it the strongest single predictor of nodal metastasis in the entire model. This finding suggests that the gross architectural appearance of the tumor, something surgeons and pathologists can observe directly, carries important prognostic information beyond what is captured by microscopic grading alone.

Among the subset of patients who already had pelvic lymph node metastasis, the researchers asked a further question: which factors predict spread to high-level nodes at or above the common iliac artery, a pattern associated with more extensive disease and worse prognosis? Two factors emerged as independent predictors. A maximum tumor diameter greater than 4 centimeters carried an odds ratio of 2.290 with a P value of 0.027, while positive LVSI again proved decisive with an odds ratio of 3.889 and a P value below 0.001. In other words, among patients with nodal disease, those with large tumors or demonstrable vascular invasion were significantly more likely to have cancer extending beyond the standard pelvic nodal basin into higher-level lymphatic territory. Additionally, LVSI positivity independently increased the risk of having three or more metastatic lymph nodes, with an odds ratio of 2.195 and a P value of 0.005.

Taken together, these results position LVSI as the core pathological risk factor in cervical squamous cell carcinoma, one that comprehensively promotes overall lymph node metastasis, high-level metastasis, and multiple nodal involvement, while simultaneously serving as one of the strongest independent predictors of reduced overall survival. Tumor volume and maximum diameter also play important roles, with volume showing a marginal linear predictive effect on nodal metastasis within a defined range and diameter exceeding 4 centimeters predicting high-level spread among node-positive patients. Vaginal invasion, pathological grade, growth pattern, and gross tumor type each contribute additional predictive information. For pathologists and gynecologic oncologists, the message is that a careful, systematic assessment of these features at the time of surgical pathology evaluation can meaningfully refine risk stratification and inform decisions about the extent of lymphadenectomy and the intensity of postoperative surveillance.

The study’s strengths include its large sample size, its detailed pathological phenotyping, and its methodologically sophisticated statistical approach, including stratified Cox modeling and restricted cubic splines. Its limitations are those inherent to retrospective single-institution designs, including the possibility of unmeasured confounding and the need for external validation in independent cohorts. The findings nonetheless provide a robust evidence base that may guide future prospective studies, particularly regarding the role of adjuvant therapy and the clinical management of patients with LVSI-positive tumors, who clearly represent the highest-risk group across multiple dimensions of disease progression.