Abstract
Introduction:
Uterine carcinosarcoma without myoinvasion, limited to the endometrial lining/polyp or with no residual uterine disease at the time of hysterectomy, is extremely uncommon with unknown oncologic outcomes. Thus, this study aimed to evaluate the long-term outcomes of carcinosarcoma patients without myoinvasion.
Methodology:
Patients with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IA carcinosarcoma without myoinvasion who underwent surgery from 12/1998–1/2023 were identified from 11 centers worldwide. Patients were classified by tumor status (limited to the endometrium, limited to polyp, no residual disease in the hysterectomy specimen) and by type of adjuvant therapy (chemotherapy vs. no chemotherapy). Survival analysis follow-up was limited to the first five years after surgery.
Results:
Of 97 patients included, 28 (28.9%) had disease confined to a polyp, 55 (56.7%) to the endometrium, and 14 (14.4%) had no residual disease in the hysterectomy specimen. Patients received observation only (n=16, 16.5%), vaginal brachytherapy (VB) alone (n=14, 14.4%), external beam radiation therapy (EBRT)±VB (n=5, 5.2%), chemotherapy±VB (n=51, 52.6%), chemotherapy and EBRT±VB (n=7, 7.2%), while adjuvant therapy was unknown in 4 (4.1%) patients. Twenty-nine patients (29.9%) recurred, mostly with a distant pattern of relapse. Five-year recurrence-free survival (RFS) was 63.5% (95% CI, 53.4–75.4%) and overall survival (OS) was 72.0% (95% CI, 62.6–82.9%). Median follow-up for patients without recurrence was 56.9 months (interquartile range, 21.8–72.9). No significant differences were observed in RFS and OS based on status of the tumor (P=0.99 and P=0.43, respectively). The difference in RFS and OS was not statistically significant based on receipt of chemotherapy (P=0.08 and P=0.07, respectively).
Conclusion:
Patients with carcinosarcoma without myoinvasion have a poor prognosis with a high recurrence rate with distant pattern. The use of chemotherapy did not achieve statistical significance but may be limited by our small series.
Keywords: uterine carcinosarcoma, endometrial cancer, polyp, survival outcome
Introduction
Uterine carcinosarcoma is a rare and aggressive type of high-grade endometrial cancer 1–3. Also known as malignant mixed Mullerian tumor, carcinosarcoma is a biphasic neoplasm characterized by the presence of both carcinomatous (epithelial) and sarcomatous (stromal tissue) elements 4. Evidence from genomic analysis has suggested including this tumor among endometrial cancer due to the common origin of the stromal and epithelial components 5,6. Although carcinosarcomas represent approximately 5% of all endometrial cancers, they account for 16.4% of all deaths due to epithelial uterine malignancy. Even in the early-stage, prognosis remains poor, with a 5-year survival rate of 50% or less (5-year OS: 54.8% for stage I, 36.9% for stage II) 1,7.
Common adjuvant treatment options for uterine carcinosarcoma include chemotherapy and radiation therapy, while the combination of both (multimodality therapy) has shown the most benefit in reducing the risk of recurrence and improving survival rates at all stages 8,9. Moreover, recent evidence suggests that external beam radiation therapy (EBRT) should be included for carcinosarcoma cases with high-grade epithelial components and sarcoma dominance (>50% of sarcoma component in uterine tumor) 10. However, National Comprehensive Cancer Network (NCCN) recommendations for carcinosarcoma are not altered by the presence or absence of myoinvasion 11. The 2020 European Society of Gynaecological Oncology (ESGO)/European Society for Radiotherapy and Oncology (ESTRO)/European Society of Pathology (ESP) categorize carcinosarcoma without myoinvasion as “intermediate-risk”. Due to limited data on optimal treatment for these patients, the best management remains uncertain. Adjuvant therapy is generally considered on a case-by-case basis or not recommended12.
Carcinosarcoma without myoinvasion includes tumor without residual disease in the hysterectomy specimen or tumor that is confined to an endometrial polyp or the endometrium. The literature on this clinical scenario is limited to a few case reports 13–16, and while some studies mention non-myometrial invasive disease in their dataset, they lack specific descriptions of treatment and clinical outcomes 17–19. Oncologic outcomes of patients with carcinosarcoma without myoinvasion remain unknown, and there is no consensus on the optimal adjuvant treatment 12,20. Thus, the aim of this study was to further assess the long-term survival outcomes of patients with uterine carcinosarcoma without myoinvasion.
Methods
This multi-institutional retrospective study included 11 centers worldwide. Patients were eligible if they had a final diagnosis of uterine carcinosarcoma without invasion of the myometrium from December 1, 1998, through January 31, 2023. Cases of carcinosarcoma with no myoinvasion included: tumor confined to a polyp, limited to the endometrium, or with no residual disease in the hysterectomy specimen. The study was limited to cases surgically staged including at least hysterectomy, bilateral salpingo-oophorectomy, and nodal surgical staging. Nodal staging included pelvic and/or paraaortic lymphadenectomy (LND) and/or sentinel lymph node (SLN) biopsy. Also, patients (n=3) with unilateral retroperitoneal staging, either SLN or LND, were included. Patients with invasive synchronous neoplasms or neoadjuvant treatment were excluded. Extent of lymphovascular space invasion was defined using the World Health Organization (WHO) 21 definition or ESGO/ESTRO/ESP guidelines12, with no inter-centre consistency in the cut-off of involved vessels on at least one pathology slide. Pathology re-review was conducted by expert gynecologic pathologists at each individual institution. Patients were classified by having negative or positive (focal or substantial) lymphovascular space invasion 22. Histopathologic data, encompassing carcinoma and sarcoma components, histology types, and the sarcoma/carcinoma proportion, were classified as previously described 10. Adjuvant treatment, which was prescribed as part of standard of care and physician preferences, was defined as observation alone, vaginal brachytherapy (VB), EBRT±VB, chemotherapy±VB, and combined treatment with chemotherapy plus EBRT±VB. We assessed patients by tumor status (confined to polyp, limited to the endometrium, no residual in hysterectomy specimen) and adjuvant chemotherapy (chemotherapy vs. no chemotherapy). Patients with unknown adjuvant treatment were excluded from the analysis on the role of chemotherapy (chemotherapy yes vs. no chemotherapy). Considering the small sample size of patients undergoing chemotherapy plus EBRT±VB, we just described the outcome of these patients without performing a specific statistical analysis evaluating the role of combined therapy.
Statistical analysis
Patient and tumor characteristics were summarized as number (percentage), mean (SD), or median (interquartile range [IQR]), as appropriate. Univariate Cox proportional hazards regression models were fit to evaluate the association between baseline characteristics and recurrence/death within five years after surgery summarized as hazard ratio (HR) and 95% confidence interval (CI). The Kaplan-Meier method was used to estimate 5-year overall survival (OS) and recurrence-free survival (RFS). Time-to-event was calculated from the date of surgery to the date of death or last follow-up for OS and from the date of surgery to the date of recurrence or last relevant clinical follow-up for RFS. Recurrence sites were also retrieved and classified as: vaginal, peritoneal, hematogenous, and lymphatic (pelvic, paraaortic, other distant lymphatic – inguinal, mediastinal, supraclavicular). We also compared outcomes by tumor location (endometrium vs polyp vs no residual disease) and by adjuvant chemotherapy (chemotherapy vs. no chemotherapy). All calculated P values were two-sided, and P<0.05 was considered statistically significant. Statistical analyses were performed using the SAS 9.4 software package (SAS Institute, Inc., Cary, NC). Additional details regarding data collection are available in the appendix. In accordance with the journal’s guidelines, we will provide our data for independent analysis by a team selected by the Editorial Team for the purposes of additional data analysis or for the reproducibility of this study in other centers if such is requested.
Results
Study cohort
Of 103 women with uterine carcinosarcoma and no myoinvasion, 97 patients met the inclusion criteria (Figure S1). Fourteen (14.4%) patients had no residual disease in the hysterectomy specimen, 28 (28.9%) tumor confined to polyp, and 55 (56.7%) tumor limited to endometrium. Demographic and clinical characteristics are summarized in Table 1. Lymphovascular space invasion was negative in 80 cases (82.5%), positive (focal or substantial) in 10 (10.3%) patients, and unknown in 7 (7.2%).
Table 1.
Clinicopathologic characteristics of patients, pathology report, and adjuvant therapy
| Characteristic | N=97 |
|---|---|
| Age at surgery (years), mean (SD) | 65.9 (8.8) |
| BMI (kg/m2), mean (SD) | 31.4 (7.9) |
| Race | |
| Asian | 3 (3.1) |
| Black or African American | 11 (11.3) |
| White | 79 (81.4) |
| Other | 2 (2.1) |
| Unknown/chose not to disclose | 2 (2.1) |
| SLN removed | |
| None removed | 47 (48.5) |
| Bilateral | 46 (47.4) |
| Unilateral | 4 (4.1) |
| Number of SLNs removed: RIGHT, median (IQR) | 1 (1, 3) |
| Number of SLNs removed: LEFT, median (IQR) | 1 (1, 3) |
| Pelvic LND performed | 50 (51.5) |
| Pelvic LND type | |
| None | 47 (48.5) |
| Bilateral | 50 (51.5) |
| Number of pelvic nodes removed during LND: RIGHT, median (IQR) | 8 (5, 11) |
| Number of pelvic nodes removed during LND: LEFT, median (IQR) | 8 (5, 10) |
| Paraaortic LND performed | 42 (43.3) |
| Number of paraaortic nodes removed during LND, median (IQR) | 5 (3, 9) |
| Omental biopsy/Omentectomy | 65 (67.0) |
| Tumor status | |
| No residual in the uterine specimen | 14 (14.4) |
| Confined to polyp | 28 (28.9) |
| Limited to endometrium | 55 (56.7) |
| LVSI | |
| Negative | 80 (82.5) |
| Positive (focal or substantial) | 10 (10.3) |
| Unknown | 7 (7.2) |
| Peritoneal cytology | |
| Negative | 66 (68.0.) |
| Positive | 12 (12.4) |
| Not done | 17 (17.5) |
| Unknown | 2 (2.1) |
| Adjuvant therapy | |
| None | 16 (16.5) |
| VB only | 14 (14.4) |
| EBRT ± VB | 5 (5.2) |
| Chemotherapy ± VB | 51 (52.6) |
| Chemotherapy and EBRT ± VB | 7 (7.2) |
| Unknown | 4 (4.1) |
Abbreviations: BMI, body mass index; EBRT, external beam radiation therapy; IQR, interquartile range; LVSI, lymphovascular space invasion; SD, standard deviation; SLN, sentinel lymph node; LND, lymphadenectomy; VB, vaginal brachytherapy.
Results reported as N (%) unless otherwise noted.
Data on combined-histologic pattern (carcinoma/sarcoma) was available in 32 patients and the distribution was as follows: 14 high-grade/homologous, 14 high-grade/heterologous, 1 low-grade/homologous, 3 low-grade/heterologous (Table S1). The proportion of sarcoma and carcinoma was available in only 10 patients: 2 with sarcoma dominance, 5 without sarcoma dominance, and the remaining 3 had equal both components.
Forty-three (44.3%) patients underwent lymph node staging through SLN biopsy only, 50 (51.5%) had pelvic full LND (with or without SLN biopsy and/or paraaortic LND), and four (4.1%) had SLN biopsy and paraaortic LND. Surgical staging included omental biopsy or omentectomy in 65 cases (67.0%) and peritoneal washing in 78 patients (80.4%), of which 12/78 (15.4%) were positive for malignant cells. Fifty-one (52.6%) patients received adjuvant chemotherapy±VB, while 7 (7.2%) patients received combined treatment including chemotherapy plus EBRT±VB. The remaining 35 patients (36.1%) without postoperative chemotherapy received observation only (n=16, 16.5%), VB alone (n=14, 14.4%), or EBRT±VB (n=5, 5.2%). Four (4.1%) patients had unknown information on adjuvant treatment (Table 2).
Table 2.
Recurrence outcomes in the overall study population and according to adjuvant treatment
| Overall | None or VB alone | EBRT ±VB | CT alone | CT+VB | CT+EBRT ±VB | Unknown | |
|---|---|---|---|---|---|---|---|
| N=97 | N=30 | N=5 | N=10 | N=41 | N=7 | N=4 | |
| Recurrence, N (%) | |||||||
| No | 68 (70%) | 19 (63%) | 3 (60%) | 5 (50%) | 30 (73%) | 7 (100%) | 4 (100%) |
| Yes | 29 (30%) | 11 (37%) | 2 (40%) | 5 (50%) | 11 (27%) | 0 (0%) | 0 (0%) |
| Pattern of recurrence, N | |||||||
| Peritoneal isolated | 15 | 5 | 2 | 3 | 5 | - | - |
| Hematogenous isolated | 3 | 2 | - | - | 1 | - | - |
| Lymphatic isolated | 6 | 2 | - | 2 | 2 | - | - |
| Vaginal isolated | 2 | 2 | - | - | - | - | - |
| Lymphatic+vaginal | 1 | - | - | - | 1 | - | - |
| Unknown | 2 | - | - | - | 2 | - | - |
Abbreviations: CT, chemotherapy, EBRT, external beam radiation therapy; VB vaginal brachytherapy.
Oncologic outcomes
Recurrence within 5 years after surgery was documented in 29 (29.9%) patients with a median time to recurrence of 14.2 months (interquartile range (IQR), 9.8–28.5 months). The median duration of follow-up for the remaining 68 patients without recurrence was 56.9 months (IQR, 21.8–72.9 months) and median 5-year RFS for all patients were 63.5% (95% CI, 53.4–75.4%) (Figure 1A). Most recurrences were distant only. The majority were peritoneal (n=15/29, 51.7%), followed by lymphatic (n=6/29, 20.7%; 3 lymphatic pelvic, 2 lymphatic paraaortic, 1 lymphatic other), hematogenous (n=3/29, 10.3%; 3 lung), and isolated vaginal (2/29, 6.9%). One patient had a combined pattern of recurrence with vaginal and lymphatic sites, while the remaining 2 patients had an unknown site of relapse.
Figure 1. Kaplan-Meier survival curves for recurrence-free survival (RFS) (A) and overall survival (OS) (B).
The initial adjuvant treatment among the 29 patients with recurrence was as follow: 16 (55.2%) chemotherapy±VB (5 chemotherapy alone, 11 chemotherapy+VB), 11 (37.9%) observation or VB alone, 2 (6.9%) EBRT±VB. The 2 patients with isolated vaginal recurrence had initial postoperative observation, while the one with combined pattern (vaginal+lymphatic) had chemotherapy+VB. Of the 6 patients with isolated lymphatic recurrence, 4 received postoperative chemotherapy±VB, and 2 had VB alone. Looking at the patients with hematogenous or peritoneal spread (18/29, 62.1%), the distribution of adjuvant chemotherapy was equal (9 patients with chemotherapy and 9 without chemotherapy) (Table 2). Among the 29 patients with recurrence, the combined histologic pattern (carcinoma/sarcoma) was known in 17 cases (4 were high-grade homologous, 5 were high-grade heterologous, 3 had only a heterologous sarcoma component identified, and 5 had only a high-grade carcinoma component identified). The proportion of sarcoma and carcinoma was available in only 2 of the 29 patients, both without sarcoma dominance.
When examining predictors for recurrence, no significant associations between patients’ characteristics were observed (Table 3). However, when looking at the 12 patients with positive cytology at the time of surgery, 6 patients (50.0%) had recurrence, all peritoneal, despite adjuvant treatment (5 had chemotherapy±VB and 1 had VB only). Overall, 22 (22.7%) deaths occurred within five years after surgery, of which 16 (72.7%) were due to the disease. Median follow-up for the remaining 75 patients was 59.1 months (IQR, 29.5–84.3 months) and median 5-year OS was 72.0% (95% CI, 62.6–82.9%) (Figure 1B). Similar to recurrence, when examining death within 5 years following surgery, no significant associations between patients’ characteristics were observed (Table 3).
Table 3.
Univariate analysis for predictors of recurrence and death within 5 years following surgery
| Characteristic | N of recurrences within 5 years | Univariate HR (95% CI) |
P | N of deaths within 5 years | Univariate HR (95% CI) |
P |
|---|---|---|---|---|---|---|
| Age at surgery (years) | 29 | 1.06 (0.67, 1.70)* | 0.80 | 22 | 1.66 (0.87, 3.18)* | 0.13 |
| BMI (kg/m2) | 29 | 0.83 (0.64, 1.07)* | 0.15 | 22 | 0.75 (0.56, 1.00)* | 0.05 |
| Race | 0.87 | 0.70 | ||||
| White (N=79) | 23 | Reference | 17 | Reference | ||
| Other (N=16) | 5 | 1.12 (0.42, 2.94) | 4 | 1.20 (0.40, 3.57) | ||
| Unknown/chose not to disclose (N=2) | 1 | 1.67 (0.23, 12.38) | 1 | 2.31 (0.31, 17.42) | ||
| Surgical approach for hysterectomy | 0.52 | 0.38 | ||||
| Open (laparotomy) (N=29) | 11 | Reference | 9 | Reference | ||
| Robotic-assisted (N=47) | 14 | 0.77 (0.35, 1.71) | 12 | 0.87 (0.36, 2.09) | ||
| Laparoscopic (N=21) | 4 | 0.52 (0.17, 1.64) | 1 | 0.28 (0.05, 1.67) | ||
| SLN removed | 0.83 | 0.91 | ||||
| None removed (N=47) | 16 | Reference | 11 | Reference | ||
| Bilateral (N=46) | 12 | 0.79 (0.38, 1.68) | 10 | 1.10 (0.47, 2.61) | ||
| Unilateral (N=4) | 1 | 1.02 (0.13, 7.73) | 1 | 1.53 (0.19, 12.04) | ||
| SLN removed | 0.57 | 0.78 | ||||
| No (N=47) | 16 | Reference | 11 | Reference | ||
| Yes (N=50) | 13 | 0.81 (0.39, 1.68) | 11 | 1.13 (0.49, 2.62) | ||
| Pelvic LND performed (N=50) | 16 | 1.10 (0.53, 2.29) | 0.80 | 11 | 0.80 (0.34, 1.85) | 0.60 |
| Paraaortic LND performed (N=42) | 13 | 0.93 (0.45, 1.94) | 0.85 | 10 | 0.83 (0.36, 1.93) | 0.67 |
| Omental biopsy/Omentectomy (N=65) | 22 | 1.35 (0.58, 3.17) | 0.49 | 17 | 1.49 (0.55, 4.04) | 0.43 |
| Pelvic washing | 0.22 | 0.11 | ||||
| No (N=17) | 3 | Reference | 0 | Reference† | ||
| Yes (N=78) | 25 | 2.11 (0.64, 6.99) | 21 | 10.52 (0.60, 186.96) | ||
| Unknown (N=2) | 1 | - | 1 | - | ||
| Tumor status | 0.99 | 0.47 | ||||
| No residual in the uterine specimen (N=14) | 4 | Reference | 1 | Reference | ||
| Confined to polyp (N=28) | 8 | 1.05 (0.32, 3.48) | 7 | 3.34 (0.41, 27.14) | ||
| Limited to endometrium (N=55) | 17 | 1.06 (0.36, 3.14) | 14 | 3.55 (0.47, 26.98) | ||
| LVSI | 0.77 | 0.55 | ||||
| Negative (N=80) | 24 | Reference | 20 | Reference† | ||
| Focal and positive (substantial) (N=10) | 2 | 0.61 (0.14, 2.57) | 2 | 0.98 (0.25, 3.79) | ||
| Unknown (N=7) | 3 | 1.12 (0.34, 3.73) | 0 | 0.20 (0.01, 3.58) | ||
| Peritoneal cytology | 0.26 | 0.17 | ||||
| Negative (N=66) | 19 | Reference | 16 | Reference† | ||
| Positive (N=12) | 6 | 1.63 (0.65, 4.09) | 5 | 1.64 (0.61, 4.47) | ||
| Not done (N=17) | 3 | 0.52 (0.15, 1.77) | 0 | 0.10 (0.01, 1.90) | ||
| Unknown (N=2) | 1 | - | 1 | - | ||
| Adjuvant therapy | 0.28 | 0.14 | ||||
| None or VB only (N=30) | 11 | Reference† | 9 | Reference† | ||
| EBRT ± VB (N=5) | 2 | 1.50 (0.36, 6.22) | 2 | 2.82 (0.65, 12.28) | ||
| Chemotherapy ± VB (N=51) | 16 | 0.59 (0.27, 1.28) | 10 | 0.56 (0.22, 1.40) | ||
| Chemotherapy and EBRT ± VB (N=7) | 0 | 0.18 (0.01, 3.40) | 0 | 0.31 (0.02, 6.00) | ||
| Unknown (N=4) | 0 | - | 1 | - | ||
| Adjuvant chemotherapy | 0.09 | 0.08 | ||||
| No (N=35) | 13 | Reference | 11 | Reference | ||
| Yes (N=58) | 16 | 0.53 (0.25, 1.09) | 10 | 0.46 (0.20, 1.09) | ||
| Unknown (N=4) | 0 | - | 1 | - |
Abbreviations: BMI, body mass index; CI, confidence interval; EBRT, external beam radiation therapy; HR, hazard ratio; LND, lymphadenectomy; LVSI, lymphovascular space invasion; SLN, sentinel lymph node; VB, vaginal brachytherapy.
Results per 10-year increase in age and per 5-kg/m2 increase in body mass index.
Firth’s bias correction applied due to zero cell issue.
Survival by tumor status and adjuvant treatment
Among 29 patients with recurrence, 4 had tumors with no residual disease in the hysterectomy specimen (4/14, 28.6%), 8 confined to polyp (8/28, 28.6%), and 17 limited to endometrium (17/55, 30.9%). Of note, even in the group with no residual disease, all the recurrences were distant (3 peritoneal and 1 hematogenous). Five-year RFS was 66.1% (95% CI, 43.3–100%), 62.8% (95% CI, 45.0–87.8%), and 63.3% (95% CI, 50.4–79.4%) in the no residual disease group, confined to polyp, and limited to endometrium, respectively (P=0.99, Figure 2A.). Five-year OS was 90.9% (95% CI, 75.4–100%), 70.5% (95% CI, 54.1–91.8%), and 68.7% (95% CI, 56.0–84.2%) in the no residual disease group, confined to polyp, and limited to endometrium, respectively (P=0.43, Figure 2B).
Figure 2. Kaplan–Meier curves by tumor status and adjuvant chemotherapy.
(A) Recurrence-free survival by tumor status (B) Overall survival by tumor status (C) Recurrence-free survival by adjuvant chemotherapy (D) Overall survival by adjuvant chemotherapy
Looking at the different regimen of adjuvant therapy we compared the outcome of patients who received adjuvant chemotherapy (n=58) versus patients who did not receive adjuvant chemotherapy (n=35), after excluding the four patients with unknown adjuvant therapy. Sixteen (27.6%) patients of the chemotherapy group experienced a recurrence while 13 (37.1%) patients in the no chemotherapy group recurred. Five-year RFS was 67.6% (95% CI, 55.3–82.5%) in those who received adjuvant chemotherapy and 51.7% (95% CI, 35.1–76.0%) in those who did not receive adjuvant chemotherapy (P=0.08, Figure 2C). Similarly, 5-year OS was higher in those who received adjuvant chemotherapy compared to those who did not receive adjuvant chemotherapy, 78.1% (95% CI, 66.8–91.5%) vs 61.0% (95% CI, 45.0–82.5%), respectively (P=0.07, Figure 2D). Looking at the seven patients who received combined therapy (chemotherapy plus EBRT±VB), there were no recurrences or deaths during a median of follow-up of 27.7 (min 6.1-max 108.4) months (Table S2).
Discussion
Summary of main results
Our study showed that there were no significant differences in oncologic outcomes among patients with tumor limited to the endometrium, limited to a polyp, or with no residual disease in the hysterectomy specimen. The noted differences in oncologic outcomes using chemotherapy did not meet statistical significance. However, our sample size may have been too small to detect such significance.
Results in the Context of Published Literature
This is a large cohort of surgically staged uterine carcinosarcoma without myoinvasion in which the oncological outcomes have been evaluated. The present study also encompasses data from 97 patients across 11 centers. Given the rarity of this clinical scenario, previous reports on this patient subset were limited.
Güngördük et al. 23 reported 13 cases of carcinosarcoma with disease confined to the endometrium within the overall study population. Without adjuvant therapy, these patients experienced a 23% (3/13) recurrence rate (vaginal, nodal, peritoneal), with 5-year disease-free and overall survival rates of 69.3% and 71.4%, respectively. In contrast, in our subgroup of patients with tumor confined to the endometrium only four had postoperative observation alone, and we had 17 recurrences (17/55, 30.9%) with 5-year RFS and OS rates of 63.3% and 68.7%, respectively. Our results are consistent with the earlier report, with a minimal discrepancy that could be attributable to the previous study’s small sample size.
International Federation of Gynecology and Obstetrics (FIGO) 2023 24 staging system, grouped carcinosarcoma together with other aggressive histological types, such as high-grade endometroid, serous, clear cell, undifferentiated, mixed, mesonephric-like, and gastrointestinal mucinous type carcinomas. Patients with aggressive histological types limited to a polyp or confined to endometrium are all staged as FIGO 2023 IC. While supported by evidence on uterine serous endometrial carcinoma without myoinvasion25,26, the FIGO 2023 IC stage may overgeneralize other aggressive histotypes due to a lack of specific supporting evidence. According to the ESGO/ESTRO/ESP prognostic risk classification all type of non-endometrioid carcinomas without myoinvasion have been grouped together in the “intermediate-risk” category 12. However, our findings of a high rate of recurrence, high rate of death due to disease in patients with non-myoinvasive carcinosarcoma challenge the current classification of carcinosarcoma alongside other type II high-risk endometrial cancers. Moreover, ESGO/ESTRO/ESP guidelines propose the same approach either to carcinosarcoma or to serous endometrial cancer when confined to a polyp or without myoinvasion. Although adjuvant therapy is generally not recommended in these cases, they conclude that the decision whether to proceed with adjuvant treatment or observation should be considered following multidisciplinary discussion 12.
Previous evidence on endometrial cancers without myoinvasion has been limited to serous carcinomas, which demonstrate an excellent prognosis, even with postoperative observation 27–30. These findings suggest that expectant management could be a treatment option for serous endometrial cancer confined to polyps or endometrium. However, a recent analysis of 1709 patients with serous carcinoma confined to the endometrium using the US National Cancer Database (NCDB) showed a potential survival benefit from adjuvant chemotherapy, with or without vaginal brachytherapy, although cause of death and cancer-specific progression-free survival were not available 31. Conversely, a subset analysis of 181 stage I uterine carcinosarcoma patients with endometrium involvement only, using the NCDB, showed that the use of adjuvant therapy, either chemotherapy, radiotherapy or combined therapy, did not have any OS benefit compared to no-adjuvant treatment. Of note, these findings may be limited by the lack of data on surgeon specialty or chemotherapy and radiation type32. However, in comparison to patients with serous endometrial cancer confined to polyps or endometrium, our carcinosarcoma population demonstrated significantly worse rates of relapse (29.9%), RFS, and OS with 72.7% (16/22) of the deaths due to disease. Ultimately, it seems reasonable to state that the outcome and management for patients with serous carcinoma cannot be generalized to patients with carcinosarcoma. In this context, NCCN guidelines, in contrast to ESGO/ESTRO/ESP, recommend treatment based on histotype. Specifically, chemotherapy plus VB±EBRT is indicated for all patients with stage IA carcinosarcoma, regardless of myoinvasion.
Moreover, the role of positive peritoneal cytology in carcinosarcoma patients warrants further investigation. Although not a predictive factor for recurrence or survival in our series, 12 patients had positive peritoneal cytology, with 6 experiencing a peritoneal recurrence. Despite its association with an increased risk of all-cause mortality in stage I carcinosarcoma (hazard ratio [HR] 1.84)33, malignant peritoneal cytology is not a component of cancer staging24. NCCN guidelines, however, indicate that it drives adjuvant therapy in non-invasive serous or clear cell carcinoma11, but its clinical relevance remains uncertain in non-invasive carcinosarcoma patients.
Strengths and Weaknesses
The strengths of our study include the multi-institutional design encompassing, to our knowledge, the largest cohort of patients with carcinosarcoma FIGO 2009 IA without myoinvasion. Moreover, we performed additional analysis stratifying the study-population by adjuvant chemotherapy. Additionally, all but 3 patients underwent bilateral surgical lymph node assessment, which minimized the inclusion of occult stage IIIC disease. Of note, none of the 3 patients who underwent unilateral SLN experienced lymphatic recurrence.
Study limitations are its retrospective nature, the relatively small sample size and the lack of centralized pathology review. Additionally, the study lacks detailed pathological data on carcinosarcoma characteristics, such as sarcoma dominance and type, and their role in the prognosis was not assessed. Moreover, we recognize the lack of molecular data as a limitation of our current study, although its clinical implications in carcinosarcoma histology need further research1. Given the multi-institutional nature of the study, a common protocol for surgical (i.e. SLN algorithm) and adjuvant treatment is lacking, while variability in treatment choice is inevitable. The relatively small sample size within each no myometrial invasion subcategory precludes definitive conclusions regarding prognostic differences. Finally, the statistical non-significance with the use of adjuvant chemotherapy may have been biased by our small sample size.
Implications for Practice and Future Research
Our study provides data on the prognosis of very early-stage carcinosarcoma patients highlighting its aggressive behavior. Based on our results, carcinosarcoma without myoinvasion warrants distinct categorization from other “aggressive” endometrial cancers. Our sample size may have been too small to provide a definitive conclusion regarding the benefit of postoperative chemotherapy. Further prospective data, including larger sample size and molecular characterization, may refine treatment recommendations for this rare carcinosarcoma subset. Moreover, while recent evidence34 emphasizes molecular classification for identifying aggressive p53abn endometrial cancer without myoinvasion suitable for adjuvant treatment, histology’s significance may remain. Given that most (60–90%) carcinosarcomas are p53abn1,5, further stratification of this subset warrants future research, and identifying further actionable mutations and pathways will likely drive targeted therapy innovation.
Conclusions
In the present study, we observed that carcinosarcoma patients FIGO 2009 stage IA with without myoinvasion have a high risk of recurrence with a tendency towards distant spread. The prognosis for this patient subset remains unfavorable. Given poor outcomes, consideration of adjuvant therapy is warranted. However, the inherent limitations of a small sample size and a retrospective study design suggest that high-level data supporting this recommendation are currently insufficient. Future studies are needed to clarify these findings.
Supplementary Material
WHAT IS ALREADY KNOWN ON THIS TOPIC:
Carcinosarcoma without myoinvasion is exceedingly rare, and its oncologic outcomes are largely unknown because of limited evidence.
The 2020 ESGO-ESTRO-ESP endometrial cancer guidelines categorize carcinosarcoma without myoinvasion as “intermediate risk” and adjuvant therapy is generally not recommended or considered on a case-by-case basis. However, the optimal management of patients with FIGO 2009 stage IA carcinosarcoma without myoinvasion has never been studied.
WHAT THIS STUDY ADDS:
FIGO 2009 stage IA carcinosarcoma patients with no residual tumor or residual tumor with no myoinvasion at the time of hysterectomy have a relatively high recurrence risk with a predilection for distant spread.
While the differences in oncologic outcomes of patients who received adjuvant chemotherapy compared to those who did not receive adjuvant chemotherapy did not meet statistical significance, these findings may be limited by the small sample size, calling for further exploration of optimal treatment options.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY:
This study highlights the aggressive behavior of carcinosarcoma without myoinvasion, potentially reclassifying these patients as a “high-risk”. Given poor outcomes, consideration of adjuvant therapy is warranted. However potentially due to small sample size and retrospective nature, high level data supporting this recommendation is lacking. Further investigation is needed
Acknowledgments
The authors would like to thank Dr. Ernst Lengyel for his valuable contribution and support to the present study.
Funding
Dr. Leitao is supported in part by NIH/NCI Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center.
Footnotes
The manuscript was presented as a poster presentation at the 24th European Congress on Gynecological Oncology (ESGO), SEP28–OCT 1, 2023 ISTANBUL, TÜRKIYE
Given their role as Editorial Board Member, Giuseppe Cucinella, Dimitrios Nasioudis ,Glauco Baiocchi, Andrea Mariani, and Mario Leitao, Jr. had no involvement in the peer-review of this article and have no access to information regarding its peer review.
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