The significance of systemic immune-inflammation index (SII) and age in vulvar squamous cell carcinoma: a retrospective analysis of prognostic factors

2.1 Study design and patient selection

We conducted a retrospective cohort study of all vulvar cancer patients who underwent treatment at the Cancer Hospital of Shantou University Medical College between 01 January 1998 and 28 February 2021. From an initial pool of 88 patients, we excluded those with non-squamous histologies (n = 9), leaving 79 patients with VSCC for final analysis. The inclusion criteria were: (1) histologically confirmed primary VSCC; (2) initial treatment involving surgical resection; (3) absence of synchronous malignancies; (4) availability of preoperative complete blood count (CBC) results; and (5) complete clinical follow-up records.

2.2 Data collection procedures

Using standardized data extraction forms, we collected detailed information from electronic medical records and pathology reports. The collected variables included: patient demographics (age at diagnosis), tumor characteristics (maximum diameter, location, 2009 International Federation of Gynecology and Obstetrics (FIGO) stage), histopathological features (depth of stromal invasion measured from the epithelial-stromal junction, lymphovascular space invasion, differentiation status), treatment details (surgical approach, lymph node dissection extent, adjuvant therapy), and follow-up data. Preoperative laboratory values, including absolute neutrophil count (ANC), lymphocyte count, and platelet count, were recorded from CBC tests performed within 2 weeks prior to surgery. The SII was calculated using the formula: SII = (ANC × platelet count)/lymphocyte count.

2.3 Clinical management protocol

All patients underwent standardized preoperative evaluation, including complete physical examination with documentation of lesion size, distance from midline structures (clitoris, urethra, vagina, anus), and groin lymph node assessment. Radiological staging included contrast-enhanced computed tomography (CT) scans of the thorax, abdomen, and pelvis. Histopathological confirmation was obtained through punch or incisional biopsy prior to definitive surgery.

Surgical procedures were performed according to contemporary guidelines. The standard approach involved radical excision of the primary tumor with at least 2 cm macroscopic margins, extending down to the fascia lata. Intraoperative frozen section analysis was routinely performed to assess margin status, with immediate re-excision undertaken for positive margins when technically feasible without compromising urinary function or quality of life. For selected cases requiring extensive resection, reconstructive procedures using local flaps were performed by plastic surgeons.

Lymph node management followed a risk-adapted approach. Patients with stage Ia disease and clinically negative groins did not undergo inguinofemoral lymphadenectomy due to the <1% risk of nodal metastasis. For lateralized tumors (>2 cm from midline), ipsilateral inguinofemoral lymphadenectomy was performed through a separate incision. Contralateral dissection was added when ipsilateral nodes showed metastatic involvement. For a selected number of patients treated in the later years of the study period, sentinel lymph node (SLN) biopsy was performed as an alternative to full lymphadenectomy for clinically node-negative early-stage disease (tumor size <4 cm). SLNs were examined with ultrastaging protocols. Complete lymphadenectomy was performed if metastatic disease was identified in the SLN. Any grossly enlarged or suspicious nodes identified intraoperatively were resected and submitted for frozen section evaluation. Postoperative radiotherapy to the groin was recommended for patients with ≥2 positive lymph nodes or evidence of extracapsular extension. The dose of radiotherapy was determined according to the range of the primary lesion and residual lesions. For patients with microscopically detected minimal metastasis after inguinal lymphadenectomy, a total dose of 50 Gy with fractionated dose of 1.8 to 2.0 Gy each time was basically sufficient. A dose of up to 60 Gy was given to reduce tumor burden for multiple positive lymph nodes or extracapsular spread patients. If there was a large residual lesion, the radiotherapy dose was 60 to 70 Gy to control local lesions. Concurrent chemoradiation, typically for patients with positive margins or extracapsular extension, was most commonly utilized with weekly cisplatin (40 mg/m²). Palliative chemotherapy for advanced or metastatic disease was most frequently based on platinum compounds (cisplatin or carboplatin), often combined with paclitaxel.

2.4 Pathological assessment

All surgical specimens underwent comprehensive pathological evaluation by dedicated gynecologic pathologists. The stromal invasion depth was defined as the depth from the epithelial-stromal junction of the adjacent, most superficial dermal papilla to the deepest point of invasion. Lymph node specimens were evaluated for number of metastatic nodes, size of metastasis, and presence of extranodal extension. All cases were staged according to the 2009 FIGO classification system.

2.5 Statistical analysis

Independent t-test with Welch’s correction was employed to compare the SII levels between lymph node-negative and lymph node-positive groups. We performed receiver operating characteristic (ROC) curve analysis to determine the optimal cutoff value for SII in predicting lymph node metastasis, which was identified as 497.975. Survival outcomes were analyzed using Kaplan-Meier methods with log-rank tests for comparison. Overall survival (OS) was calculated from the date of initial diagnosis to the date of death from any cause or last follow-up. Progression-free survival (PFS) was defined as the interval from surgery to first recurrence or death. Univariate and multivariate Cox proportional hazards regression models were used to assess prognostic factors for survival outcomes. Categorical variables were compared using chi-square or Fisher’s exact tests as appropriate. All statistical tests were two-sided, with p-values < 0.05 considered statistically significant. Analyses were performed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA).

3.1 Patient characteristics

From January 1998 to February 2021, we identified 88 patients with vulvar cancer, of which 79 (89.8%) had histologically confirmed VSCC. The remaining cases (n = 9) included rare histologic subtypes, such as melanoma and Paget’s disease, which were excluded from further analysis. As detailed in Table 1, the median age at diagnosis was 62 years (range 34–88 years), with a median follow-up duration of 49 months (range 6–275 months). The cohort demonstrated favorable 5-year survival outcomes, with OS and PFS rates of 79% and 77%, respectively.

Regarding tumor characteristics, the majority of lesions were located in the labia majora (60.8%, n = 48), followed by the clitoris (19.0%, n = 15), labia minora (16.4%, n = 13), and others (3.8%, n = 3). Most patients presented with unifocal disease (69.6%, n = 55), while the remainder had multifocal involvement. Lymph node evaluation revealed a median of 12 nodes resected (range: 5–32), with 26 patients (32.9%) showing nodal metastases. Among node-positive cases, the median number of involved nodes was 3 (range: 1–16), and 4 patients (15.4%) exhibited extranodal extension.

3.2 Treatment approaches and outcomes

As summarized in Table 2, surgical management consisted of radical vulvectomy in 40.9% (n = 33) of cases and wide local excision in 59.1% (n = 46). Reconstruction was required in 29 patients (36.7%), utilizing various techniques, including local flaps and complex closures. No significant differences were noted with regard to reconstruction techniques. Lymph node assessment revealed that 69.2% of patients underwent inguinofemoral lymphadenectomy, while 13.6% had biopsy of enlarged nodes only. Two patients underwent lymphadenectomy following positive sentinel node biopsy.

Adjuvant therapy was administered to 22 patients (27.8%), consisting of radiotherapy alone (n = 13), concurrent chemoradiation (n = 7), or chemotherapy alone (n = 2). The latter group included patients who declined recommended radiotherapy.

3.3 Prognostic factor analysis

The SII level demonstrated significant associations with lymph node status. As shown in Fig. 1, the SII levels were significantly elevated in the lymph node-positive group compared with the lymph node-negative group (p = 0.036, Student’s t-test with Welch’s correction), with mean SII values 907.31 ± 929.93 and 500.39 ± 210.40, respectively.

Fig. 1.Comparison of systemic immune-inflammation index (SII) between lymph node-negative (LN (−)) and lymph node-positive (LN (+)) groups. The SII levels were significantly elevated in the LN (+) group compared with the LN (−) group (p = 0.036, Student’s t-test with Welch’s correction). Values represent the systemic immune-inflammation index scale (0–2000). LN status was defined as the presence (LN (+)) or absence (LN (−)) of lymph node metastasis. LN (−): n = 53; LN (+): n = 26.

In ROC curve analysis for predicting lymph node metastasis, SII yielded an area under the curve of 0.672. At the optimal cut-off value of 497.975, sensitivity and specificity were 0.769 (76.9%) and 0.566 (56.6%), respectively. The high SII group demonstrated numerically lower 5-year survival outcomes (OS: 72.7% vs. 86.5%; PFS: 73.8% vs. 79.8%), though these survival differences did not reach statistical significance.

Stratified by FIGO stage, 5-year OS rates were 97.4%, 80.0%, 55.3%, and 0% for stages I–IV, respectively (Fig. 2). Tumor size showed a non-significant trend toward worse survival when using a 4 cm cutoff (83.9% vs. 69.2%, p > 0.05). However, nodal burden strongly predicted outcomes, with patients having ≥3 positive nodes demonstrating markedly worse 5-year OS compared to those with <2 positive nodes (21.8% vs. 82.5%, p < 0.01).

Fig. 2.Kaplan-Meier survival curves for overall survival (OS) stratified by FIGO stage. Patients with advanced tumor stages (Stage III–IV) demonstrated significantly poorer OS compared with those with Stage I and Stage II disease (p < 0.0001, log-rank test). Survival probability (0.00–1.00) was analyzed over a follow-up period of 0–300 months. Symbols (“+” markers) indicate censored observations. Tumor staging was classified as Stage I (n = 45), Stage II (n = 7), Stage III (n = 24), and Stage IV (n = 3) based on standardized criteria, emphasizing the inverse correlation between advanced-stage disease and survival outcomes.

Age significantly impacted prognosis, with patients >65 years showing inferior 5-year OS (70.7% vs. 83.5%, p = 0.039). This difference was more pronounced when analyzing patients >70 years (p = 0.0026) (Fig. 3), who also exhibited higher rates of nodal involvement (p = 0.02). Notably, tumor grade, size, and depth of invasion did not significantly correlate with nodal status.

Fig. 3.Kaplan-Meier survival analysis of overall survival (OS) stratified by age groups. Patients aged >70 years (n = 18, blue line) exhibited significantly worse OS compared to those aged ≤70 years (n = 61, red line) (p = 0.0026, log-rank test). Survival probability (ranging from 0.00 to 1.00) was plotted against follow-up time (0–300 months). The analysis highlights the prognostic impact of age (cutoff: 70 years) on survival outcomes.

3.4 Multivariate survival analysis

Multivariate Cox regression identified age >70 years (hazard ratio (HR) = 2.41, 95% confidence interval (CI): 1.32–4.39) and advanced FIGO stage (HR = 3.02, 95% CI: 1.85–4.93) as independent predictors of poorer OS. Interestingly, lymph node metastasis and age >65 years did not retain independent prognostic significance in the multivariate model.

4.1 Age as a critical prognostic factor

VSCC is predominantly a disease of postmenopausal patients, and there is a large discrepancy in the morbidity rate of VSCC by decade of life. With life expectancy increasing, older women with VSCC represent a growing population. The influence of age on the prognosis of VSCC remains conflicting. In a retrospective, multicentric analysis of 300 VSCC patients, no significant difference in PFS was observed in two divided age groups (≤50 vs. >50 years) [9]. A retrospective study of 6965 patients showed that older patients (≥50 years) had an HR of 3.9 (95% CI, 3.2–4.7) for death after controlling for race, stage, grade, and surgical treatment [10]. Our data demonstrate a clear survival disadvantage for older patients, with those over 65 years showing significantly worse 5-year overall survival compared with younger patients (70.7% vs. 83.5%, p = 0.039). This disparity becomes even more pronounced when examining patients beyond 70 years of age, who exhibited a 2.4-fold increased mortality risk (HR = 2.41, 95% CI: 1.32–4.39) in our multivariate analysis. This finding is consistent with those reported in several other studies [11]. Our analysis confirms and extends previous observations regarding the significant influence of age on VSCC outcomes.

Several pathophysiological and clinical factors likely contribute to this age-related survival gap. First, our findings reveal that elderly patients (>70 years) presented with significantly higher rates of lymph node metastasis (p = 0.02), suggesting more advanced disease at diagnosis. This observation aligns with previous reports documenting higher rates of nodal involvement, and thus more advanced tumor stages in older VSCC patients [11]. Second, treatment modifications necessitated by age-related comorbidities and functional status limitations may impact outcomes, as evidenced by Surveillance, Epidemiology, and End Results Program database analyses showing reduced use of radical surgery in elderly populations [12]. Older patients were at a higher risk of suboptimal treatment [13]. Elderly women more often received complete vulvectomy instead of radical wide excision or partial vulvectomy [11]. Third, the complex interplay of biological aging processes, immunosenescence, and comorbid conditions creates a microenvironment that may foster more aggressive tumor behavior while simultaneously limiting treatment tolerance. Multiple comorbidities may put the elderly patients at an increased risk of recurrence and mortality [14]. The treatment strategy in elderly VSCC patients should focus not only on the cancer itself, but also on the age and the various comorbidities that affect survival [12]. Therefore, continued efforts are crucial to optimize cancer care for elderly patients, taking into account their unique vulnerabilities and ensuring they receive adequate and appropriate treatment.

4.2 Clinical implications of SII findings

SII quantifies the interplay of three hematological components—neutrophils, platelets, and lymphocytes—that collectively mirror systemic inflammatory burden and immunocompetence. Each component exerts varied and substantial tumor-promoting effects through mechanistically divergent pathways [15]. Neutrophils contribute to tumor development by synthesizing and releasing cytokines, thereby promoting angiogenesis and immunosuppression [16, 17]. Platelets have been identified to be a major source of proangiogenic factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) [15]. Tumor-infiltrating lymphocytes exhibit anticancer properties; lymphocytopenia reflects compromised immune surveillance, characterized by reduced cluster of differentiation (CD)8+ cytotoxic T-cell and natural killer (NK) cell activity—a hallmark of advanced malignancies [18].

The SII has been demonstrated to be effective in reflecting the inflammatory status and is an independent prognostic factor of OS in cervical cancer [19], colorectal cancer [20], and several other cancer types [21, 22]. A meta-analysis performed by Ji et al. [23] confirmed that patients with high level SII were at a significantly high risk of lymph node metastasis compared with those with low level SII in gynecological and breast cancers. The study of Huang et al. [19] supported that SII had a significant correlation with tumor size but had no correlation with other clinicopathological factors, including lymph node metastasis. SII was correlated with tumor differentiation, tumor size, and TNM stage in colorectal cancer [20].

The current study provides the first evidence supporting the clinical utility of SII in VSCC management. Contrary to the findings of Huang et al. [19] in cervical cancer, who reported no association between SII and lymph node metastasis, our analysis revealed a significant association between elevated SII (optimal cut-off value of 497.975) and lymph node metastasis (43.2% vs. 20.0%, p = 0.036), which remained statistically significant after adjusting for key clinicopathological variables, consistent with observations in other cancer types [21, 24, 25].

Clinically, utilizing SII metrics to categorize patients according to their likelihood of lymph node metastasis assists clinicians in selecting optimal surgical scope and tailored therapeutic strategies. Individuals identified with elevated risks of aggressive malignancies or metastatic spread may benefit from comprehensive surgical approaches to address potential disease dissemination. Despite limitations such as a lack of treatment standardization, SII’s advantages—low cost, routine CBC availability, and quick calculation—make it feasible for resource-limited settings.

4.3 Study limitations and future directions

While our findings provide valuable insights, several limitations must be acknowledged. The retrospective design inherently limits data completeness and introduces potential selection biases. The relatively small sample size, though understandable given VSCC’s rarity, may have constrained our ability to detect more subtle associations, particularly regarding survival outcomes. Additionally, the use of the 2009 FIGO staging system, while appropriate for our study period, may limit direct comparison with more contemporary cohorts.

Future research directions should include: (1) Prospective validation of our SII cutoff (≥500) in larger, multicenter cohorts; (2) Investigation of the relationship between systemic inflammation (as reflected by SII), serum tumor markers such as squamous cell carcinoma antigen (SCC-Ag), and the local tumor immune microenvironment through immunohistochemical analysis to elucidate the underlying biological mechanisms driving metastasis and prognosis; (3) Development of integrated prognostic models incorporating SII, age, and other clinicopathological factors; (4) Evaluation of geriatric assessment tools to better guide treatment decisions in elderly patients.