An analysis of retroperitoneal STS that also covered LMS revealed that R1/2 resections and tumor injuries are significant independent predictors of poorer OS (13). These data can also be taken as surrogate evidence for the effects of tumor injury in the course of inadequate surgery performed on uterine sarcomas.

A negative impact on DFS and OS should always be expected whenever a uterine LMS is subjected to morcellation, though the data situation pertaining to OS remains very poor. One study on uterine sarcoma (including LMS) has shown that morcellation only results in a slight increase in the rate of pelvic recurrence without distant metastases, and without any measurable impact on OS (72). In an early study (86), outcomes were retrospectively compared between patients who underwent TAH without tumor morcellation (n = 31) and those who underwent surgery that included abdominal, vaginal or laparoscopic tumor morcellation (n = 25). The percentage of patients with abdominopelvic dissemination, as shown by peritoneal sarcomatosis or vaginal apex recurrence, was significantly greater in patients with than without tumor morcellation (86). In uni- and multivariate analysis, tumor morcellation was significantly associated with poorer DFS and OS. This has been the only study to date in which OS was also significantly shorter. Endoscopic follow-up examinations (82, 100) of LG-ESS, STUMP and LMS patients who underwent morcellation revealed intraperitoneal tumor dissemination in 64% of cases that occurred within 3mo in 43% of cases, and that had not been present at the time of primary surgery. There was no evidence for newly developed distant metastases in any of these cases (cf. Fig. 2.1.12 (A)–(C), 4.1.13 (C), (D), 4.1.14 (C)). Three of four LMS patients in whom there was peritoneal dissemination succumbed to their disease after a mean period of 24.3 mo. Given the poor overall OS with which LMS are associated (see above), it is indeed questionable that the aforementioned outcomes were directly associated with the present intraperitoneal dissemination. A recent analysis (37) compared intraperitoneal morcellation to TAH without morcellation in terms of their effects on patient’s prognosis. The study revealed a significantly shorter abdominopelvic RFI when morcellation was performed (10.9 vs. 39.6mo for TAH). The OS rate at 36mo was 64% in the morcellation cohort and 73% in the TAH cohort, but the difference was not statistically significant.

A meta-analysis (11) covering morcellated vs. non-morcellated LMS revealed an odds ratio of 3.16 for all recurrences, 4.11 for intraabdominal recurrences and 2.42 for the death rate. The cumulative relapse rate was only significantly elevated for intraabdominal disease. The authors themselves do conclude, however, that the numerous biases in the study do not allow any definitive conclusions to be drawn as to the impact on OS.

A further study (65) compared morcellation of LMS performed in the context of various different surgical (abdominal, vaginal, laparoscopic) methods to TAH without morcellation, and revealed no differences between the two groups in terms of OS. There was an (albeit statistically non-significant) increase in the rate of recurrence in the morcellation group, even though the two most important prognostic variables (tumor size and elevated MI) were less pronounced/lower in this group. Morcellation had no impact on the rate of distant metastasization.

In a recent retrospective analysis (79), morcellated LMS had better (!) 5-year RFI and 5-year OS than non-morcellated tumors (each group included abdominal, vaginal and laparoscopic operations), though the difference was not statistically significant. The statistically non-significant RFI-related findings in the morcellation arm (which in itself was relatively small) need to be regarded critically. Prognostically relevant factors (like stage of disease and patient’s age) were lower, while tumor size (esp. relevant for stage I) and MI were not devoted sufficient consideration in this group. The most important finding from this study was that the rate of distant metastasization was identical for both surgical methods. Since survival is primarily determined by the distant metastases, this finding at least lends support to the assumption that there is no impact on OS in LMS patients (which is already very short as is). No distant metastases were found in three cases in which there was (in part expansive) pelvic and intraperitoneal recurrence following morcellation of an LMS (40). By contrast, the causal connection between morcellation and a shorter RFI is further supported by the fact that, in these cases, locoregional and intraabdominal recurrences were considerably more frequent than in LMS patients who underwent adequate surgical procedures (69, 86). Nor can it be discerned from the DKSM data that morcellation or any form of tumor injury does result in increased distant metastasization. In contrast, intraperitoneal recurrences have been observed to develop repeatedly without distant metastases occurring (cf. Fig. 2.1.12 (A)–(C)).

In summary, it is possible that morcellation only increases the risk of intraabdominal recurrence, but not (at least in the short term) the risk of potentially lifethreatening pulmonary and hepatic metastases. Since patients with LMS already have a very poor prognosis, and death is usually a result of distant metastasization, it cannot be reliably claimed that morcellation actually shortens survival.

Another study (85) on LG-ESS compared outcomes of patients who underwent TAH or LAVH with morcellation to TAH or LAVH without morcellation. The results revealed that 5-year DFS and abdominal-pelvic DFS were significantly poorer in the morcellation arm (with a majority of endoscopic procedures). Interestingly, no intraperitoneal recurrences were observed in 7 cases in which incidentally detected LG-ESS were subjected to TLH with morcellation (which was necessary in order to be able to extract the uterus) (117). Within the data provided by a DKSM working group, among 3 cases of LG-ESS that were morcellated, 1 recurred once, another recurred 3 times, and the third developed 4 consecutive recurrences, all within up to 5 years. Despite the relatively long interval, there were no cases of distant metastasization or deaths (58).

Resection margins that are not definitively disease-free are equally associated with an elevated risk of recurrence (113). A disease-free margin of < 1mm is deemed an independent risk factor for STS that is significantly associated with elevated recurrence risk and poorer OS (13). Since uterine sarcomas have no capsule, or have a pseudo-capsule that in fact consists largely of compressed tumor tissue, it is almost inevitable that TE will leave R1 and RX situations. In one study, for LMS, tumor injury and/or positive surgical margins had a hazard ratio of 5.6 for developing local recurrence, while an impact on OS and the rate of distant metastasization could not be confirmed (113). In another study, among LG-ESS patients who underwent TE, not one remained recurrence-free within 5 years, while there were no differences in terms of OS (6). Intraperitoneal masses (sometimes very large) have been observed to develop within 2wk to 3mo of performing endoscopic TE or morcellation with and without SLH on LMS and LG-ESS (19, 27, 58, 90). In a recent publication, a significant lowering of RFI compared to THE (8.2 vs. 46.6 mo) among all uterine sarcomas was observed (48). For these reasons, performing TE on uterine sarcomas needs to be deemed prognostically critical and regarded as inadequate surgical treatment (28, 31).

SLH and SAH are generally associated with the risk of leaving intravascular ormyometrial invasion/infiltration routes in the uterine stump. Even if the surgical report describes an R0 resection, from a clinical perspective, it must nonetheless be assumed that such operations will leave RX situations. This is further exacerbated by the fact that SLH is virtually always combined with morcellation. Early tumor recurrences are known to occur within 3mo following such procedures (3). The situation is apparently similar in cases in which the uterus is injured with a sharp instrument (90). Accordingly, clamping with sharp instruments must be categorically avoided whenever sarcoma is even suspected. According to a retrospective study, any form of tumor injury resulted in a 2.8-fold increase in mortality and significantly shorter RFS and OS (p = 0.03 resp. 0.04), though it needs to be mentioned that the study was based on a relatively small sample, there were numerous biases, and the important prognostic factor “tumor size” was not taken into consideration (90). In the DKSM materials database, LMS subjected to inadequate surgery (any form of tumor or uterus injury) had a recurrence rate of 28.3%, compared to 27.7% in cases in which adequate procedures were opted for. However, it is important to consider that the women who underwent adequate modes of surgery (n = 101) had an average age of 55 years and a mean tumor diameter of 9 cm, and thus a poorer primary prognosis than the women subjected to inadequate operations (age 47 years, tumor diameter 6.5 cm) (58). According to DKSM data, the median time period from surgery to first recurrence was 17mo among LMS patients subjected to adequate operations, and 7mo for women who underwent inadequate surgery (58). Among LG-ESS patients corresponding median time period for adequate surgery was 29.6mo (13 of 92 patients) and for inadequate surgery 7mo (14 of 67 patients) with a relapse rate of 14.1% and 21%, respectively (58).

The fact that intraperitoneal recurrences develop so quickly after LG-ESS have been subjected to inadequate surgery is rather surprising, considering that LG-ESS are otherwise associated with such promising courses and usually recur or metastasize rather late (for details on the prognosis of LG-ESS see Chapter 4). Their relatively promising prognosis is likely a result of the fact that, in contrast to HG-ESS, UUS and LMS, LG-ESS that infiltrate the blood and lymphatic vessels remain cohesively connected with the primary tumor for a very long time. The intravascular plugs contain both tumor cells and small vessels that are enclosed by endothelial cells. The tumor cells within the tumor thrombi are thus kept apart from blood circulation. In contrast, intravascular tumor foci in HG-ESS are composed of discohesive cell clusters, lacking the features described in LG-ESS (96) (Fig. 4.1.3 (A), (B), Fig. 5.1.3 (D) and Fig. 6.2.1 (A), (B)). Along with other factors, this feature could help to explain why LG-ESS metastasize much less frequently than HG-ESS do. From a mechanistic perspective, it can thus be assumed that tumor injuries (e.g. in the course ofmorcellation) cause the intravascular tumor plugs (96), that are originally cohesively attached to the primary tumor, to detach from their base, and to subsequently mimic or masquerade as purely intraperitoneally situated, discohesive lesions.

In summary, there is no evidence to suggest that subjecting LG-ESS to inadequate surgery, the negative impact on RFI notwithstanding, impacts negatively on 5-year OS. This can be largely explained by the fact that, according to the current data situation, the rate of distant metastasization apparently does not increase, that even extensive locoregional and intraabdominal recurrences remain in situ for a long time (Fig. 6.2.1 (D)) and are amenable to surgery, and that long-lasting PFI can be achieved under HT. Regarding LMS, the data situation is too weak to be able to definitively state that inadequate surgery has a negative impact on OS, which is already rather poor from the onset. Regardless, the shortening of RFS that inadequate surgery entails for LG-ESS and LMS has a considerable impact on quality of life.

* only supracervical laparoscopic hysterectomies

** all leiomyoma operations

*** all hysterectomies

Despite the relatively low risk of roughly one sarcoma per 1,200 LM operations, from a prognostic perspective it is nonetheless vital that the proportion of sarcomas that are subjected to inadequate surgery be clearly reduced, even in light of the possibility that OS may not be affected (see above).

6.4Anamnestic and clinical criteria suggestive of uterine sarcoma in cases of supposed leiomyoma

In order to prevent that uterine sarcomas are incidentally detected in the course of or following LM surgery, anamnestic and clinical criteria, symptoms and findings need to be given meticulous and consistent consideration, especially regarding the two most common types of uterine sarcoma (LG-ESS and LMS) (34). Differentiation from LM is the most important issue in this regard, as it constitutes the most common DD and also the most common misdiagnosis for these neoplasms. Studies by the DKSM (58) have identified several factors that can be drawn on in order to discern LMS (the most common form of uterine sarcoma) from LM (Tab. 6.4.1). It remains decisive, however, that a clinical suspected diagnosis of sarcoma can only be arrived at when multiple criteria are met.

In general, the possibility of sarcoma must always be considered whenever a patient aged > 50 years is suspected to have LM (see also Tab. 6.1.1). 66.1% ofLMSpatients are aged ≥ 50 years,while 80.4% of HG-ESS patients, 84% of UUS patients and 60.8% of AS patients meet this criterion (58). In contrast, only 25% of women with LG-ESS are aged ≥ 50 (median 46). Among 3,920 LM, only 16% of women were aged ≥ 50 years. The difference to the different types of sarcoma is statistically significant to a strong degree (58). In one study, 9 of 10,119 HE performed for benign gynecologic indications were incidentally revealed to have been performed on sarcomas (5 LMS, 2 LG-ESS, 2 AS) (53). Not one patient was postmenopausal, and only 2 patients were aged ≥ 50. The youngest patient was 25 years old. Thus, while a patient’s age of ≥ 50 years is by all means well suited for distinguishing uterine sarcomas from LM, this criterion alone is not enough to be able to reliably reduce the risk of occult sarcoma.

Virtually all uterine sarcomas exhibit suspicious or conspicuous characteristics and features in sonography (Tab. 6.4.2). However, for various reasons, the sonographic findings are only interpreted as being suggestive of sarcoma, even when they are suspicious, in 50.3% of LMS patients and 32% of LG-ESS patients. Sonography and Doppler sonography should be deemed suspicious if they exhibit criteria listed in Tab. 6.4.2. Details pertaining to the sonographic characteristics of the individual sarcoma types are presented at length in the corresponding subsections on imaging in the respective Chapters 1, 2, 4, 5 and Vol. 2, Chapter 6. However, after reevaluation sonography shows suspicious properties and features for LM in 15.9% and for LMS in 88.4% of cases (58). Besides patient’s age, sonographic findings and features are of pivotal importance when seeking to differentiate uterine sarcomas from LM.

Tab. 6.4.1: Anamnestic and clinical criteria suitable for discerning between leiomyoma and leiomyosarcoma; p-value all criteria < 0.01 except prior medication-based therapy (compiled by Dennis, Lehr, Köller, Krichbaum, Riechmann, Trojnarska, Lehnhoff) (58).

* excludes menorrhagia and prolonged menstrual bleeding

** refers to 193 cases

*** esp. STUMP, cellular leiomyoma and mitotically active leiomyoma

Tab. 6.4.2: Sonographic and Doppler sonographic characteristics of uterine sarcomas, particularly leiomyosarcoma.

Assumed LM are suspicious of in fact being uterine sarcoma when patients present with AUB in the form of intermenstrual bleeding (73, 111) or postmenopausal bleeding (Tab. 6.4.1). Postmenopausal bleeding occurs in 42.2% (79) resp. 45% (58) of postmenopausal LMS patients, while this applies to only 21.9% of postmenopausal LM (58). In one study, among women found to have occult sarcoma during or following HE performed for assumed benign conditions, said surgery was performed as a primary indication for abnormal bleeding in 77.8% of cases (53).

According to DKSM data, 50% of LMS (n = 224) and 40.2% of LM (n = 3,920) arise as solitary tumors, i.e. without coincidence with (other) LM (58). LMS and LG-ESS per se only very rarely occur in multiples in the wall of the uterus. The trait “solitary tumor” without the presence of secondary LM does not suffice on its own to differentiate uterine sarcomas from LM. While a recent report suggests that 100% of LMS arise solitarily, the findings were based on only 8 cases (32).However, 38.0% of LMS are solitary tumors and have a size of ≥ 8 cm, while only 9.1% of ordinary LM meet both of these criteria (58). The combined occurrence of the features “solitary tumor” and “tumor size ≥ 8 cm” thus supports a diagnosis of LMS.

LMS (n = 224) have median and mean diameters of 9 resp. 9.7 cm. A more detailed breakdown reveals that 87.9% are ≥ 5 cm, 60.2% are ≥ 8 cm, and 41.1% are ≥ 10 cm in their largest dimension (58). According to DKSM data, the figures for LM are 54.6%, 16.6% and 7.0%, respectively (58). A tumor size of ≥ 5 cm, and ≥ 8 cm in particular, can therefore be drawn on as a criterion for differentiating LMS from LM. However, it is sensible to set the cut-off value for further, more extensive diagnostic procedures at 8 cm. While setting the cut-off value at 5 cm would increase the sensitivity of risk criteria for LG-ESS and AS (median tumor diameters of 5.5 resp. 4.5 cm), doing so would also unnecessarily encompass more than 50% of LM within the risk profile. However, the accuracy in discriminating between sarcomas (especially LMS) and LM can be significantly improved if “tumor size ≥ 5 cm” is combined with the criterion “suspicious sonography” or “age ≥ 50 years” or “conspicuous/rapid growth”. The differences between LM and LMS for these combinations are highly statistically significant in univariate analysis (Tab. 6.4.1). For AS, the fact that their median diameter (4.5 cm) is below the 5 cmcut-off value, is largely compensated for by the fact that patients are generally older, often present with AUB, and frequently return suspicious sonographic findings.

The true significance of rapid or conspicuous uterine growth for properly diagnosing LMS has long been, and remains, a highly debated issue, not least because there are multiple definitions of it in the literature. According to one source, a tumor exhibits rapid growth if it doubles in size within 6mo (16), while in another study (7), a tumor is classified as growing rapidly if its volume increases by 30% or more within 1 year. In a third source, a volume increase of 20% within 6mo is defined as rapid growth (89), while a fourth publication defines rapid growth as growth equivalent to 6 weeks’ gestation within 1 year (87). For practical reasons, a tumor should be considered as exhibiting rapid or conspicuous growth if the attending medical physician clinically or sonographically describes either this condition or otherwise conspicuous progression in size.

Of the LMS covered in a recent publication, 21.9% exhibited rapid growth (79). In the DKSM materials, conspicuous/rapid uterine or tumor growth was reported in 42.6% of LMS cases (58). Two DKSM working groups covering a total of 3,920 otherwise regular LM retrospectively revealed rapid growth in 16.9% of cases (58). In an immediately subsequent prospective analysis on 193 LM conducted by the same working group, the share was 12.4%. The p-value between the LMS analysis and the two myoma analyses was strongly significant in the χ2 test (58). Another source found rapid growth in 31% of LM (26), while in a further prospective analysis (7), 26.7% of LM increased in volume by 30% within 1 year. These differences are likely a result of differences in the definitions used. Judging by the DKSM data (58) that were evaluated along identical criteria for both LMS and LM, conspicuous or rapid growth alone can apparently be sufficient for differentiating uterine sarcoma from LM.

LM with an initial diameter of ≥ 5 cm are said to only rarely exhibit growth spurts, and when they do, they are only minor (7, 26).One prospective study (89) revealed that 34% of LM of any diameter and 15% of LM with diameters of ≥ 5 cm exhibited rapid growth (> 20% in 6 mo). In the DKSM case database (58), 13.4% of LM and 41.5% of LMS had a diameter of ≥ 5 cm and exhibited conspicuously rapid growth.

Rapid growth was only recognizable in 2% of LM in patients aged 45 and older (89). According to DKSM calculations, the respective shares among LM and LMS were 9.4% and 35.7% (58). Taken together, the data (7, 58, 89) suggest that LMS should be considered a serious possibility when there is conspicuous growth, especially in combination with an initial tumor diameter of > 5 cm and a patient’s age of ≥ 45 years. Only 0.1% of LM in patients aged ≤ 25 years are observed to grow rapidly or at a suspicious pace (58). This combination of criteria is 40 times more common among patients with STUMP (including CLM and mitotically active LM), but nonetheless still rather rare (3.4% of cases). In a recent DKSM case (58), a 9 cm large, sonographically suspicious, rapidly growing “LM” in a 24-year-old symptomatic patient was found to actually be an extremely rare uterine melanoma (Fig. 6.4.1).

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