Cervical cancer in women under age 40: A cohort study of clinicopathological characteristics and fertility-sparing surgery outcomes

Highlights

• •Cervical cancer in women under the age of 40 underscores significant gaps in cervical cancer prevention efforts.
• •Cytology demonstrated significantly lower sensitivity in diagnosing adenocarcinoma compared to squamous carcinoma.
• •Fertility-Sparing Surgery offers a promising approach, with low cancer recurrence rate and encouraging pregnancy outcomes.

Abstract

Objectives

The clinical management of cervical cancer patients under age 40 presents unique challenges, requiring a balance between complete cancer resection and fertility preservation. This study aimed to report on the clinicopathological characteristics of a cohort of young patients, along with the oncologic and reproductive outcomes of those who underwent fertility-sparing surgery (FSS).

Methods

The pathology database at a single institution was searched for women under age 40 who were diagnosed with invasive cervical cancer between 2015 and 2022. Electronic medical charts were reviewed for demographics, tumor characteristics, clinical management, and surveillance. Statistical analysis was performed using Wilcoxon rank-sum test and chi square test.

Results

A total of 57 patients (median age: 34 years; range: 27–40 years) met the inclusion criteria. Cancer histology included squamous cell carcinoma (70 %), adenocarcinoma (28 %), and adenosquamous carcinoma (2 %). The FIGO stage was I (72 %), II (7 %), III (19 %), and IV (2 %). The sensitivity of cytology was 67 %, with notably low significantly for adenocarcinoma (38 %). HPV vaccination documentation was missing for 44 patients (77 %). Among the 16 patients with stage I cancer who underwent FSS, one experienced cancer recurrence (7 %), and four successfully achieved pregnancy.

Conclusions

Our cohort study of young cervical cancer patients highlights deficiencies in cervical cancer prevention, including limitations in cytology-based screening and inconsistent documentation of HPV vaccination. FSS offers a promising approach, with low cancer recurrence rates and encouraging pregnancy outcomes.

1. Introduction

Human papillomavirus (HPV)-associated cervical cancer has significantly decreased in the United States, primarily due to the widespread screening and vaccination programs (Buskwofie et al., Apr 2020). Nonetheless, there will be an estimated 13,360 new cases in 2025, with a median age of 50 at time of diagnosis (Siegel et al., 2025). Women under the age of 40 are often seen as having a low risk of developing cervical cancer, given that HPV carcinogenesis usually takes one to two decades (Burger et al., 2020). However, 2016–2020 SEER data reveals that 14 % of cervical cancer cases occurred in the 20–34 age group, and an additional 24 % occurred in the 35–44 age group (SEER, 2016). The clinical management of this younger patient population poses unique challenges, as it involves not only achieving complete cancer resection but also considering fertility preservation, thereby adding to the complexity of their care. (Plante, Jul 2013).

Fertility-sparing surgery (FSS), including procedures such as conization and trachelectomy, is a viable treatment option for patients of reproductive age diagnosed with early-stage cervical cancer (FIGO stage IA1-IB2) who wish to preserve their fertility for future pregnancies (Schmeler et al., Oct 2021). Certain criteria must be met, such as tumor size ≤ 2 cm, squamous or adenocarcinoma histology, negative imaging for metastatic disease, depth of invasion < 10 mm, and margins negative for malignancy or dysplasia (Schmeler et al., Oct 2021, Ramirez et al., Jan 2014). A recent systematic review indicated promising pregnancy rates (55 % and 43 % post-conization/simple trachelectomy or radical trachelectomy) as well as live birth rates (72 % and 44 %) (Kuznicki ML et al., 2021). While cancer recurrence and death rates are generally low post-FSS, they should not be disregarded, with reported rates of 4.2 % and 0.8 % respectively for conization/simple trachelectomy, and 3.9 % and 1.4 % for radical trachelectomy (Bentivegna E et al., 2016).

This retrospective cohort study provides a comprehensive analysis of our experience and outcomes in treating 57 young cervical cancer patients at our tertiary care cancer center. We reported the clinicopathological characteristics, treatment modalities utilized, and surveillance outcomes, with a particular emphasis on evaluating the oncologic and reproductive outcomes resulting from FSS procedures.

2. Methods

This study was approved by the Institutional Review Board of the Icahn School of Medicine at Mount Sinai. The pathology database was searched for invasive cervical cancer cases between 2015 and 2022. Inclusion criteria were women under the age of 40 at the time of diagnosis, with any stage disease, and who had histological specimens available for review at our cancer center. Author YL reviewed all cases and confirmed the cancer diagnoses. Electronic medical charts were reviewed for age, race/ethnicity, BMI, insurance status, smoking, combined oral contraceptive use, HPV vaccination, HIV status, cervical cytology and high-risk HPV co-testing results prior to cancer diagnoses, clinical management (FSS, non-FSS surgical intervention, chemotherapy or radiation), and surveillance results (obstetric outcomes and cancer recurrence). Pathology reports were reviewed for cancer histology and grade. Stage was assigned using the 2018 revised International Federation of Gynecology and Obstetrics (FIGO) staging system for carcinoma of the cervix, which incorporates clinical assessment, pathological findings, and radiologic findings in the staging process. (Bhatla et al., Apr 2019) The Wilcoxon rank-sum test was used to compare continuous variables, while Pearson's chi-square test was utilized for comparing categorical variables. All statistical analyses were conducted using R version 4.0.2 with p value of 0.05 utilized for statistical significance.

3. Results

A total of 57 patients met inclusion criteria. The median age was 34 (range 27–40). Table 1 details cohort characteristics by FIGO stage. The cancer histological types were squamous cell carcinoma (SCC, n = 40, 70 %), adenocarcinoma (n = 16, 28 %), and adenosquamous (n = 1, 2 %). Cancer grade was specified for 48 cases, including well (n = 18), moderate (n = 22), and poorly-differentiated (n = 8). Of the 57 patients, 46 had pre-treatment imaging studies that were performed at our center including magnetic resonance imaging (MR), computed tomography (CT), positron emission tomography (PET), or a combination. Among the four trachelectomy patients, three had an MR abdomen/pelvis scan performed pre-operatively. The FIGO stage distribution in our cohort was as follows: I (n = 41, 72 %), II (n = 4, 7 %), III (n = 11, 19 %), and IV (n = 1, 2 %). Stage I cases were further classified as IA1 (n = 11), IA2 (n = 5), IB1 (n = 20), IB2 (n = 4), and IB3 (n = 1). HPV vaccination status was known for 13 patients (23 %), including those who received the full dose (n = 6), one dose (n = 4), and no vaccination (n = 3). The HPV types identified in the six fully vaccinated patients were negative (1), HPV16 (1), and non-16/18 (4). Seventeen patients (30 %) had documentation of previous or current oral contraceptive pill (OCP) use.

Table 1.

Patient characteristics by FIGO stage Data are presented as number of cases (percentage) unless otherwise indicated.

Characteristics		Case number (n = 57)	FIGO I (n = 41)	FIGO II-IV (n = 16)	P value
Age	Median (range, years)	34 (27–40)	34 (27–40)	34 (27–38)	0.972
Race/ Ethnicity	White – Non-Hispanic	17 (30 %)	16 (39 %)	1 (6 %)	0.036 *
	Black – Non-Hispanic	11 (19 %)	6 (15 %)	5 (31 %)
	Hispanic	19 (33 %)	14 (34 %)	5 (31 %)
	Asian	4 (7 %)	3 (7 %)	1 (6 %)
	Other	6 (11 %)	2 (5 %)	4 (25 %)
BMI	Median (range)	25 (17–42)	25 (18–38)	27 (18–42)	0.332
Parity	Median (range)	0 (0–5)	0 (0–4)	0 (0–5)	0.422
Living with HIV		4 (7 %)	1 (2 %)	3 (19 %)	0.03 *
Smoking History		16 (29 %)	12 (31 %)	4 (25 %)	0.669
Previous OCP Use		17 (30 %)	13 (32 %)	4 (25 %)	0.619
Insurance Status (n = 55)	Medicaid	26 (47 %)	15 (38 %)	11 (69 %)	0.041 *
	Private	29 (53 %)	24 (62 %)	5 (31 %)
HPV types (n = 43)	HPV 16/18	22 (51 %)	16 (55 %)	6 (50 %)	0.385
	Others	19 (44 %)	12 (41 %)	7 (58 %)
	Negative	2 (5 %)	2 (7 %)	0
Tumor histology	Squamous	40 (70 %)	26 (63 %)	14 (88 %)	0.196
	Adenocarcinoma	16 (28 %)	14 (34 %)	2 (12 %)
	Adenosquamous	1 (2 %)	1 (2 %)	0
Recurrence		9 (16 %)	4 (10 %)	5 (31 %)	0.056

* Indicates significance p value < 0.05.

As shown in Table 1, FIGO II-IV disease was associated with non-white race/ethnicity, HIV positivity and public insurance status (p < 0.05). Table 2 compares cohort characteristics by surgical management (FSS vs. non-FSS) and shows that receipt of FSS was associated with prior OCP use and private insurance (p < 0.05).

Table 2.

Patient characteristics by management.

Characteristics		Case number (n = 57)	Fertility −Sparing (n = 16)	Non-Fertility Sparing (n = 41)	P Value
Age	Median (Range)	34 (27–40)	32 (28–40)	35 (27–40)	0.067
Race/Ethnicity	White – Non-Hispanic	17 (30 %)	8 (50 %)	9 (22 %)	0.147
	Black – Non-Hispanic	11 (19 %)	1 (6 %)	10 (24 %)
	Hispanic	19 (33 %)	4 (25 %)	15 (37 %)
	Asian	4 (7 %)	2 (13 %)	2 (5 %)
	Other	6 (11 %)	1 (6 %)	5 (12 %)
BMI	Median (Range)	25 (17–42)	24 (18.6–35.6)	26 (17.7–42.0)	0.528
Parity	Median (Range)	0 (0–5)	0 (0–2)	0 (0–5)	0.252
Living with HIV		4 (7 %)	0	4 (10 %)	0.195
Smoking History		16 (29 %)	2 (14 %)	14 (34 %)	0.158
Previous OCP Use		17 (30 %)	8 (50 %)	9 (22 %)	0.038 *
Insurance Status (n = 55)	Medicaid	26 (47 %)	2 (13 %)	24 (60 %)	0.002 *
	Private	29 (53 %)	13 (87 %)	16 (40 %)
HPV types (n = 43)	HPV16/18	22 (51 %)	8 (62 %)	14 (50 %)	0.743
	Others	19 (44 %)	5 (38 %)	14 (50 %)
	Negative	2 (5 %)	1 (8 %)	1 (4 %)

* Indicates significance p value < 0.05.

Cervical cytology result prior to cancer diagnosis was available for 41 patients (median time: 3 months, range: 0–24 months): NILM (n = 6, 15 %), ASCUS (n = 3, 7 %), LSIL (n = 4, 10 %), ASC-H (n = 7, 17 %), AGUS (n = 2, 5 %), HSIL (n = 18, 44 %) and malignancy (n = 1, 2 %). When we consider cytological diagnosis of ASC-H, AGUS, HSIL and malignancy as high-grade category, the sensitivity of cytology in detecting cervical cancer was 67 %. False negative rate of cytology was 33 %. Cytology showed significantly lower sensitivity for diagnosing adenocarcinoma in comparison with squamous carcinoma (38 % versus 80 %).

High-risk HPV (HR-HPV) testing prior to cancer diagnosis was positive for HPV 16/18 (n = 22, 51 %), positive for non-16/18 high-risk types (n = 19, 44 %) and negative for HR-HPV (n = 2, 5 %). The sensitivity of HPV testing was 95 %, and it was similar for both adenocarcinoma and squamous carcinoma (92 % and 97 %, respectively).

A total of 37 patients underwent cytology and HPV cotesting. The cotesting results were as follow: 4 NILM/HPV16/18, 2 NILM/others, 3 ASCUS/HPV16/18, 1 LSIL/HPV16/18, 2 LSIL/others, 1 AGUS/HPV16, 1 AGUS/negative HPV, 5 ASC-H/HPV16, 2 ASC-H/others, 8 HSIL/HPV16/18, 7 HSIL/others, and 1 malignant/others.

Following the cancer diagnosis, 16 patients (28 %) underwent FSS procedures, including conization/LEEP (n = 12) and trachelectomy (3 radical, 1 simple). Among them, 6 underwent sentinel lymph node biopsy, and 3 underwent complete pelvic lymphadenectomy. All patients had stage I disease, including 7 with stage IA1, 2 with stage IA2, and 7 with stage IB1. The remaining 41 patients (72 %) underwent non-FSS management, including simple hysterectomy (n = 2), radical hysterectomy (n = 22), and chemoradiation/radiation (n = 17). In our cohort, 20 patients underwent non-FSS definitive surgical management with ovarian retention, none of whom experienced a cancer recurrence. As shown in Table 3, there were statistically significant differences between the FSS group and non-FSS group regarding cancer histology and number of FIGO stage I cases.

Table 3.

Cancer characteristics by management.

Variable		Case number (n = 57)	Management		P Value
			FSS	Non-FSS
			(n = 16)	(n = 41)
Histology	Squamous	40 (70 %)	7 (44 %)	33 (80 %)	0.014*
	Adenocarcinoma	16 (28 %)	8 (50 %)	8 (20 %)
	Adenosquamous	1 (2 %)	1 (6 %)	0
FIGO stage	IA1	11(19 %)	7 (44 %)	4 (10 %)	0.026*
	IA2	5 (9 %)	2 (12 %)	3 (7 %)
	IB1	20 (35 %)	7 (44 %)	13 (32 %)
	IB2	4 (7 %)	0	4 (10 %)
	IB3	1 (2 %)	0	1 (2 %)
	II	4 (7 %)	0	4 (10 %)
	III	11 (19 %)	0	11 (27 %)
	IV	1 (2 %)	0	1 (2 %)
Surveillance (median 34 months, range 7–126 months)		55	15	40	–
Recurrence		9 (16 %)	1 (7 %)	8 (20 %)	0.233

* Indicates significance p value < 0.05.

FSS: fertility-sparing surgery.

In the FSS group, one patient was lost to follow-up, while 15 patients were surveilled for a median period of 34 months (range 7 to 126 months). Among them, one incidence of cancer recurrence (7 %) was detected in a 34-year-old Hispanic woman with Stage IB1 HPV-16 associated adenocarcinoma and no history of prior HPV vaccination. She underwent a radical trachelectomy and bilateral sentinel lymph node biopsy. Final pathology revealed negative lymph nodes, negative margin status, no evidence of lymphovascular space invasion (LVSI), and no parametrial involvement. She underwent surveillance and a local upper vaginal recurrence was identified 24 months after trachelectomy. She was further treated with chemoradiation followed by brachytherapy. Four patients had a successful pregnancy post FSS management (range 7–121 months, median 19 months). Two of them had live births—one full-term and one preterm. The outcomes of the other two patients are unknown, as they received care at local hospitals.

In the non-FSS group, one patient was lost to follow-up, while 40 remained under surveillance. In this group, eight patients (20 %) recurred at median 9 months (range 2–168), including local vaginal/cervical recurrence (n = 2) and distant recurrence (n = 6, brain, femur, axilla, iliac node, and inguinal node). One patient had rapid progression resulting in death.

4. Discussion

Cervical cancer exhibits a bimodal age distribution, yet cases among patients under 40 remain relatively rare in developed countries. Managing these younger patients presents unique challenges, with limited studies documenting such experiences. Here, we report on 57 cases managed at our tertiary cancer center over an eight-year period. The median age in our cohort was 34 years, with the youngest patient being 27 years old. Most cases (n = 41, 72 %) were diagnosed at stage I, making them potentially amenable to FSS treatment. Notably, 16 women were diagnosed at advanced stages, underscoring critical gaps in existing prevention strategies.

Our selection criteria for FSS aligned with established guidelines in the field, including stage I disease, a desire for future pregnancy, squamous or adenocarcinoma histology, and pathological negative lymph nodes (excluding cases of stage IA1 disease with negative LVSI). Sixteen patients met these criteria and underwent FSS at our center. Four women achieved pregnancy following either excisional procedures (n = 3) or radical trachelectomy (n = 1), however further obstetric details were only available for two patients. One patient underwent a full-term delivery via cesarean section for obstetric indication, while another underwent a pre-term delivery at 35 weeks via cesarean section for obstetric indication. Furthermore, only one patient experienced recurrence, resulting in a recurrence rate of 7 %. Our study reaffirms that FSS is a viable and appropriate option for carefully selected patients, allowing them to achieve pregnancy while maintaining effective cancer treatment.

Our analysis of various demographic factors revealed significant differences in the receipt of FSS based on insurance payor status, with the majority of patients who underwent FSS having private insurance. Prior studies have shown that insurance status plays a key role in mediating disparities in the stage of cervical cancer diagnosis across different racial and ethnic groups (Holt et al., 2023). Due to the small size of our cohort, it is challenging to assess the impact of socioeconomic status and race on the receipt of FSS. It is worth noting that Black and Hispanic patients were significantly more likely to present with advanced-stage disease and, therefore, were not candidates for FSS. Larger-scale investigations are needed to identify potential predictors of FSS receipt among patients with early-stage, low risk cervical cancer and to determine whether disparities or biases influence treatment decisions.

Despite an extensive chart review, HPV vaccine status was undocumented for 44 out of 57 our patients (77 %) living in the urban area, which is concerning. We believe that proper documentation is an essential step toward increasing HPV vaccine uptake and improving preventive care. Among the 13 patients with vaccine records, only 6 had completed the recommended doses, highlighting a significant missed opportunity to prevent this largely preventable cancer. As anticipated, HPV16 and 18 were the most prevalent types in our cohort, (51 %), followed by other high-risk types (44 %). All of these HPV types are within the protective scope of the widely used nonavalent HPV vaccine. It is worth noting that HPV vaccination eligibility has been extended up to 45 years of age, allowing a broader population to benefit from this preventive measure (Dilley et al., Feb 2020). Currently, the American College of Obstetricians and Gynecologists (ACOG) recommends shared decision-making for catch-up vaccination for women aged 27 to 45 years (College, 2020). Importantly, various barriers to HPV vaccination must be addressed, including lack of awareness, limited healthcare access, cultural stigma, and challenges in completing the multi-dose series.

Our cohort highlighted the significant limitations of cytology-based cervical cancer screening, as 14 patients (25 %) received normal or minor cytological abnormalities immediately prior to their cancer diagnosis. Furthermore, a notable number of cases (n = 16, 28 %) were diagnosed at advanced stages ranging from stage II to IV. It is indeed alarming to identify such a high number of advanced cervical cancer cases among young women participating in screening programs. The limitations of cytology are particularly evident in cases of endocervical adenocarcinoma, as our study revealed that cytology missed 62 % of adenocarcinoma cases and 20 % of squamous carcinoma cases. In contrast, HPV testing demonstrated a substantially higher sensitivity, as it detected high-risk HPV in nearly all of our cases (95 %) regardless of cancer histology, with 51 % being the most oncogenic types 16 and 18. Consistent with previous research, our findings provide strong support for the updated cervical cancer screening guidelines, which advocate for replacing cytology with HPV testing as the primary screening tool (Xue et al., 2021).

The surgical management of early-stage cervical cancer continues to evolve. While radical hysterectomy was once the standard approach, recent studies have shown that less radical surgeries, such as conization and extrafascial hysterectomy, are safe and feasible for select patients. The ConCerv Trial was the first to explore this, enrolling eligible patients with FIGO 2009 stage IA2-IB1 cervical carcinoma, squamous (any grade) or adenocarcinoma (grade 1 or 2) histology, tumor size <2 cm, no LVSI, depth of invasion <10 mm, negative imaging for metastatic disease, and negative conization margins. This study reported a 2-year recurrence rate of 3.5 %, supporting the viability of less radical surgery in appropriately chosen patients. (Schmeler et al., Oct 2021) The SHAPE trial, a phase III, randomized, noninferiority trial, found a 3-year pelvic recurrence rate of 2.17 % in the radical hysterectomy group compared to 2.52 % in the simple hysterectomy group. (Burger et al., 2020) While further research is ongoing, these findings indicate that less radical surgery may be effective without compromising oncologic outcomes. (Plante et al., 2024).

We acknowledge several limitations within our study. Our patient population is drawn from a single institution, which may limit the generalizability of our findings. Additionally, the retrospective design constrains our ability to interpret potential physician bias or determine exactly which treatment options were presented to patients. Shared decision-making is often employed in individualized clinical decisions, yet the nuances of each treatment plan cannot be fully captured through retrospective chart review. Finally, multiple paradigm shifts in cervical cancer management occurred over the course of our data collection period, including the introduction of the new FIGO staging criteria in 2018, trials demonstrating the feasibility of less radical surgery, and the LACC trial’s findings favoring an open surgical approach for cervical cancer (Bhatla et al., Apr 2019, Ramirez et al., 2018).

In conclusion, our analysis of a cohort of young cervical cancer patients highlights the deficiencies in cervical cancer prevention, including limitations in cytology-based screening, fragmented care between multiple hospital systems, treatment delays, and insufficient documentation of HPV vaccination status. Our study also reaffirms that FSS remains a viable option for appropriately selected individuals. There is a clear and urgent need to address the rising incidence of cervical cancer among young women and to strengthen prevention and screening efforts.

CRediT authorship contribution statement

Matthew Flint: Writing – original draft, Investigation, Conceptualization. Francesca Yi: Writing – original draft, Investigation. Mona Saleh: Writing – original draft, Investigation, Conceptualization. Xulei Liu: Methodology, Investigation, Data curation. Stephanie V. Blank: Writing – review & editing, Supervision. Yuxin Liu: Writing – review & editing, Writing – original draft, Supervision, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.