Clinical and Histopathological Predictors of Recurrence in Uterine Smooth Muscle Tumor of Uncertain Malignant Potential (STUMP): A Multicenter Retrospective Cohort Study of Tertiary Centers

A total of 103 patients were initially considered. Sixteen patients with no histological confirmation at pathological review (n =12, 7 reclassified as a variant of leiomyoma, 5 as LMS) or with follow-up shorter than 6 months (n = 4) were excluded. Finally, 87 patients with a confirmed diagnosis of STUMP were included in the study (Table 1).

The mean age at diagnosis was 46 (standard deviation (SD) 10, range 19–82) years, the most frequent ethnicity was Caucasian (83 of 87, 95% of patients), and the mean follow-up was 67 (SD ± 65, range 6–256) months.

The mean BMI was 25 (SD 4, range 19–40, 20 missing data), 51 of 79 patients (65%, 8 missing data) had previous pregnancies, 11 of 74 were smokers (15%, 13 missing data), and 65 of 85 (76%, 2 missing data) were symptomatic at the time of diagnosis.

Detailed data regarding the surgical procedures were collected. Most patients underwent hysterectomy (59 of 87, 68% of patients), while a laparoscopic approach was performed in only 12 of 87 (14%) patients.

In 28 of 87 (32%) cases, the tumor was morcellated or fragmented intraoperatively. In 12 of 28 (43%) patients who initially underwent a myomectomy, a hysterectomy was performed after the histological diagnosis of STUMP.

All STUMPs were confined to the uterine body at the time of first surgery, with a mean largest dimension of 73 (SD 44, range 5–230) mm.

STUMP histopathological features were comprehensively analyzed. Moderate or severe cytological atypia was observed in 28 of 87 (68%) cases and diffuse cytological atypia in 27 of 87 (33%). Necrosis was observed in 34 of 87 (39%) cases: in 24 (71%) samples, the findings were consistent with ischemic necrosis, and in 10 (29%) with coagulative necrosis. High cellularity was observed in about half of the STUMPs (42 of 87, 48% of cases), and apoptotic figures in 26 of 87 (30%) cases. Other histopathological features (epithelioid or myxoid patterns, degenerative features, and the presence of atypical mitosis and/or vascular intrusions) were rarely present. The mean value of mitoses/10 HPFs was 6 (SD 7, range 1–43) and cases with a mitotic count/10 HPFs ≥ 6 and > 10 were 35 (40%) and 13 (15%), respectively.

The mean Ki-67 value (10 missing data) was 16% (SD 15%, range 1–80%), while a Ki-67 value > 20% was observed in 15 of 77 (20%) cases. Mean ER- and PR-positive cells were 72% (21 missing data, SD ± 20, range 5–100%) and 83% (21 missing data, SD 18%, range 0–100%), respectively. ER expression < 72% was observed in 32 of 66 (48%) cases, and PR expression < 83% in 19 of 66 (29%) STUMPs. Finally, p53 and p16 were found to be expressed in 16 of 57 (30 missing data, 28%) and 19 of 47 (40 missing data, 40%) cases.

Associated leiomyomas and/or adenomyosis were reported in 46 of 86 (1 missing data, 54%) and 11 of 86 (1 missing data, 13%) of the surgical specimens, respectively.

Overall, 18 (20.7%) cases recurred: 11 as LMS (12%) and 7 as STUMP (7.8%). The mean time to recurrence was 79 (SD 55, range 10–174) months. Of the 18 STUMPs that recurred, 5 (5.7%) patients died because of this disease [disease-specific survival (DSS): 94.3%].

No significant differences were observed between patients with and without disease recurrence in terms of age, number of previous pregnancies, BMI, type of symptoms, menopausal, and smoking status.

The following histopathological and immunohistochemical features showed a significantly different distribution according to recurrence: (a) presence of epithelioid features (p = 0.009), (b) higher mitotic count/10 HPFs (p = 0.01), (c) mitotic count ≥ 6/10 HPFs (mean value of mitotic count in the whole series) (p = 0.042) and > 10 per 10 HPFs (p = 0.004), (d) Ki-67 value > 20% (p = 0.04), (e) lower PR expression (p = 0.048), (f) PR expression < 83% (mean value of PR expression in the whole series) (p =0.036), and (g) diffuse p16 expression (p = 0.01).

Distribution of all clinical and histopathological characteristics according to recurrence is presented in Table 2.

Logistic regression univariate analysis showed an association between multiple variables and recurrence (Table 3). Multivariate logistic regression showed that STUMP morcellation/fragmentation (OR 6.17, 95% CI 1.707–22.32, p = 0.006), mitotic count > 10/10 HPFs (OR 4.78, 95% CI 1.05–21.7, p = 0.043), and epithelioid features (OR 4.26, 95% CI 1.028–17.63, p = 0.046) were independent predictors of recurrence.

Univariate Cox regression analysis (Table 4) showed that surgical fragmentation/morcellation (HR 3.68, 95% CI 1.42–9.54, p = 0.007), epithelioid features (HR 3.14, 95% CI 1.17–8.40, p = 0.022), higher mitotic count (HR 1.04, 95% CI 1.005–1.084, p = 0.03), presence of > 10 mitoses/10 HPFs (HR 2.84, 95% CI 1.10–5,19, p = 0.04), higher Ki-67 proliferation index (HR 1.033, 95% CI 1.009–1.057, p = 0.006), Ki67 > 20% (HR 3.06, 95% CI 1.07–8.73, p = 0.06), PR expression < 83% (HR 4.15, 95% CI 1.47–11.7, p = 0.007), and diffuse p16 expression (HR 13.1, 95% CI 1.56–11.7, p = 0.08) were associated with shorter RFS.

All the variables found to be significant in the univariate analysis also had an impact on recurrence-free survival (RFS) as calculated by the Kaplan–Meier method (Fig. 1).

By multivariate Cox analysis, morcellation/fragmentation (HR 5.65, 95% CI 1.53–20,8, p = 0.009) and mitotic count considered as a linear variable (HR 1.073, 95% CI 1.019–1.130, p = 0.008) were confirmed to be independently associated with RFS.

Concerning clinical and surgical variables, the main finding of the present study is the association between morcellation/fragmentation and the risk of recurrence/shorter RFS. Overall, the optimal surgical approach to remove STUMP is a topic of debate given that there is no clear evidence whether surgical radicality offers a survival advantage; moreover, STUMPs can also occur during the reproductive age in patients desiring pregnancy, thus a conservative procedure must be taken into consideration.¹⁶ In our study, we found no differences in terms of recurrence rates according to surgical procedures, similar to the results reported by other authors.^2,8‐11,18 The same was not true for morcellation: recurrences were significantly more frequent after any type of morcellation (power or hand morcellation). This finding strongly supports the limited evidence available so far suggesting this association. In a small study on seven patients with a diagnosis of STUMP or endometrial stromal sarcoma who underwent power or hand morcellation during hysterectomy or myomectomy, six cases of recurrence were observed after surgical reexploration. Interestingly, a relapse was also seen in a case using a contained bag system.¹⁹ A recent study on 152 patients affected by early-stage uterine LMS also showed that any type of morcellation is related to risk of recurrence.²⁰ Furthermore, in a retrospective multicenter study on 125 patients affected by uterine sarcomas or STUMPs, women undergoing either morcellation or power morcellation experienced a three-fold increase in the risk of death in comparison with patients who had not (p = 0.02), and a trend toward an increase of risk for recurrence was specifically found in the limited series (n = 11) of women undergoing morcellation for STUMP (HR 7.7, p = 0.09).²¹ The Food and Drug Administration (FDA)²² and the American College of Obstetricians and Gynecologists (ACOG)²³ stated that morcellation should be avoided in patients over the age of 50 years, while for younger patients the possibility of a minimally invasive surgery should be carefully considered weighing the risk–benefit ratio. In this context, in-bag morcellation could reduce or nullify the risk of recurrence; however, solid evidence is lacking.²⁴

Our data support that morcellation/fragmentation should not be performed if a STUMP is suspected and, if performed, close follow-up is advised.

Histopathological classification of STUMPs represents a diagnostic gray area between leiomyomas and LMSs. To tackle this unmet diagnostic need, we evaluated the prognostic significance of several histological features potentially related to more aggressive tumor biology. The presence of epithelioid features and a higher mitotic count were found to be significant predictors of recurrence, while cellular atypia, which is included in STUMP diagnostic criteria,¹⁴ was not, similarly to other authors’ findings.^1,9‐11,25 STUMPs frequently show high cellularity; however, this finding also lacks correlation with outcomes^1,9,25 as observed in our study. The presence of necrosis is a common feature of LMS;²⁶ however, it can also be detected in STUMPs partly owing to tissue ischemia.¹⁴ Nevertheless, no relationship between necrosis and recurrence rates was conclusively demonstrated in previous studies,^1,8‐10 as well as in the present series. Similarly, the presence of apoptosis^1,8 does not appear to be correlated with the risk of relapse.

Gupta et al.⁸ suggested that atypical mitoses, epithelioid differentiation, and vascular intrusion are possible predictors of recurrence. In the present series, we found higher recurrence rates and shorter RFSs in cases with epithelioid differentiation. In line with this observation, this feature was found to be related to more aggressive biological behaviors in studies analyzing the whole USMT spectrum.^27,28 Myxoid features, another rare morphological trait that can mimic the inflammatory myofibroblastic tumor,²⁹ did not correlate with worse outcomes.

Proliferation activity and mitotic count represent well-recognized prognostic markers of most soft tissue tumors;³⁰ however, their significance in STUMPs is another controversial issue. In two previous studies, the mitotic count did not result as a significant prognostic parameter,^9,11 while Ip et al.¹ observed a trend toward lower mitotic counts in nonrecurring cases. Huo et al.¹⁰ proposed a cutoff of > 10 mitoses per 10 HPFs as a risk factor for recurrence, a finding confirmed by our study on multivariate analysis (although no association with RFS was observed). Finally, it should be noted that, in USMTs, the mitotic count has to be considered together with other histopathological features to correctly distinguish STUMPs from mitotically active leiomyomas and LMSs.¹⁴

Ki-67 expression is routinely evaluated in many neoplasms as a measure of proliferation activity, and in some cases, such as human epidermal growth factor receptor 2 (HER2)-negative luminal breast cancers, it can be used to identify which patients shall be treated with adjuvant chemotherapy.^31‐33 However, the usefulness of Ki-67 for USMTs is controversial. O’Neill et al.¹⁷ compared Ki-67 expression between 22 LMS and 41 other USMTs: 19 of 22 LMS showed a Ki-67 proliferation index > 20%, while all other USMTs had a Ki-67 proliferation index < 20%; however, the sample size of STUMPs in this study was remarkably low (only 4 cases). Mayerhofer et al.³⁴ compared Ki-67 rates of 25 leiomyomas, 22 STUMPs, and 20 LMS: no STUMP showed an elevated Ki-67 expression; however, no recurrence was reported among these cases. Although methodological differences are present between the different studies (e.g., antibody used and counting method), available data suggest a higher expression of Ki-67 in LMS as expected; however, STUMPs are poorly represented and Ki-67 usefulness to predict their recurrence has been poorly explored so far. A recent meta-analysis³⁵ suggested that Ki-67 is not useful to predict STUMPs recurrence; however, only 5 monocentric cohorts were analyzed in this study with a total sample size of 107 STUMPs and 15 recurrences only.^1,4,10,12,25 Moreover, the authors provided data regarding a single Ki-67 cutoff value (10%), while our results suggest that a cutoff value of 20% is related to both recurrence and shorter RFS at univariate analysis.

The impact of hormone receptors (ER and PR) has been extensively studied in breast cancer and in different gynecological tumors, observing an association between their higher expression and better prognosis.^12,36,37 In the present study, we detected, through univariate analysis, an association between lower expression of PR and a higher risk of relapse. Interestingly, a lower expression of PR is associated with worse prognosis in stage I LMS.³⁸

Finally, we studied the potential role of p16 and p53 expressions. Alterations of these oncosuppressor proteins have been documented in STUMPs and LMSs.³⁹ Some authors also suggested a predictive role, in terms of disease recurrence, of both p16 and p53 immunohistochemical expression,^1,10 a finding confirmed by a recent systematic review and meta-analysis of literature.³⁹ Nevertheless, the experience with these markers is still limited, and their evaluation is not recommended in clinical practice.¹⁶ We also found a potential relationship between diffuse p16 expression and risk of recurrence.

More recently, approaches based on molecular profiling have been proposed to improve STUMP stratification into benign and malignant lesions. Croce et al.⁴⁰ analyzed the genomic profile of a series of different USMTs (24 STUMPs, 10 LMSs, and 10 leiomyomas) by array comparative genomic hybridization to evaluate the prognostic significance of genomic alterations (i.e., genomic index). These authors found that a specific genomic index threshold (index = 10) divides the STUMP category into two groups of neoplasms with different outcomes: a group comparable with leiomyomas and another similar to LMS, but with more indolent behavior. The same authors⁴¹ suggest that USMTs classified as stage I molecular LMS with 13q loss including RB1 and 17p gain including MYOCD gain are characterized by a worse prognosis. In another study,⁴² an array CGH analysis was performed on 23 USMTs (14 STUMPs, 5 LMSs, 3 leiomyomas, and 1 undifferentiated sarcoma), suggesting that the PRKDC and PUM2 genes may have a prognostic role.

However, the number of STUMPs analyzed within these studies is relatively low,^40‐42 thus these findings should be validated/standardized on larger case series, and it should be noted that, to date, these approaches are not considered as diagnostic criteria according to the most recent diagnostic WHO classification.¹⁴

In this study, we reported a RFS and a DSS for STUMPs of 79.3% and 94.3%, respectively. A recent review⁴³ reported a lower recurrence rate range (8.7–11%), similar to those reported by Gadducci et al.¹⁶ These values are lower compared with our study, but Gupta et al.⁸ reported a significantly higher recurrence rate (36.4%) in a series of 22 STUMPs, suggesting that some variations are present among neoplasms presently classified as STUMPs according to current diagnostic criteria. With our results, we propose new histopathological parameters that could be useful for discriminating high-risk from low-risk STUMPs; however, they remain a clearly distinct entity compared with LMS since the latter show significantly higher recurrence rates (45–75%)⁴⁴ and poor 5-year survival rates (25–75%)⁴⁴ compared with STUMPs (92–100%).¹⁶

The main limitations of this study are related to its retrospective nature, and to the potential differences in terms of patients’ management due to the lack of guidelines. Nevertheless, this study is, to the best of the authors’ knowledge, the largest multicenter series investigating STUMPs recurrence, and all samples and data were obtained and reviewed within tertiary referral centers with expert pathologists and clinicians.