Clinical case
A 59-year-old nulliparous woman with history of multiple uterine fibroids status post myomectomy for abnormal uterine bleeding 20 years prior and recent total abdominal hysterectomy and salpingo-oophorectomy for recurrent, intermittent postmenopausal bleeding presented for management of pathological diagnosis of leiomyosarcoma. Workup prior to hysterectomy had included endometrial biopsies (EMBs) which were benign and serial pelvic ultrasounds over 18 months demonstrating a stable 5.4 cm uterine fibroid. MRI prior to surgery demonstrated a dominant 5.4 cm myometrial mass concerning for a degenerating leiomyoma vs leiomyosarcoma ( Fig. 9.1 ). Pathology from her surgery was notable for a 5 cm uterine leiomyosarcoma limited to the myometrium with necrosis, marked cytologic atypia and 14 mitoses/10 high-powered fields. Computed tomography (CT) of the chest, abdomen and pelvis demonstrated multiple 1 to 2 mm indeterminate pulmonary nodules. How would you manage this patient?
Epidemiology
While uterine sarcomas are a rare form of uterine malignancy, making up only 3% to 9% of all uterine cancers, they represent a heterogeneous group of uterine tumors. Uterine leiomyosarcoma is the most common, accounting for approximately 70% of uterine sarcomas. The remaining 30% of uterine sarcomas include other histologies such as endometrial stromal sarcoma, adenosarcoma, and perivascular endothelial cell tumor (PEComa) (see Chapter 10 ).
The median age of diagnosis for uterine leiomyosarcoma is in the mid-50s, and most patients do not have any clear predisposing risk factors. Black women have a two-fold higher risk of uterine leiomyosarcoma than white women, and there have been some reported associations with obesity and diabetes. Hereditary syndromes such as hereditary retinoblastoma have a reported risk of approximately 13% for developing any soft-tissue sarcoma, including uterine leiomyosarcoma, while those with Li–Fraumeni syndrome, a defect in p53, also have a higher risk with one study reporting 7% to 8% of women with Li–Fraumeni syndrome developing leiomyosarcoma. Pelvic radiation exposure has also been reported to increase the risk of developing a uterine sarcoma, as has hormone exposure. In large registry studies, the percentage of women with uterine corpus cancers postpelvic irradiation was 0.08% to 2.4%; of those malignancies, uterine sarcomas made up 18% to 43%. Time interval for postirradiation sarcomas between first and second neoplasm was 132 months (14–396).
Tamoxifen use for greater than 5 years demonstrated significant increase in risk of uterine leiomyosarcoma, while shorter exposure had no association. In one study, the relative risk associated with 5 years of tamoxifen use for all uterine malignancy was 4.1 (1.7–9.5). In National Surgical Adjuvant Breast and Bowel Project (NSABP), secondary malignancies were characterized by organ site and histology specifically; they reported a risk of uterine sarcoma to be 17 per 1000 women years. This compares to a risk of uterine adenocarcinoma reported at 2.2 and 0.71 per 1000 women years for those exposed and unexposed to Tamoxifen respectively. The prognosis of women with uterine sarcoma who had taken tamoxifen was no different than women without exposure to tamoxifen, once stage and histology were controlled for.
Pathology
Leiomyosarcomas (LMS) of the uterus are overall rare but make up the majority of uterine sarcomas. The diagnosis of leiomyosarcoma is based on demonstrating smooth muscle differentiation and criteria for malignancy.
Gross description
While leiomyomas are grossly white and whorled on cut surface, LMS are often hemorrhagic with necrosis and soft with a “fish flesh” texture. However, this is not always the case, and some may have a firm-to-hard consistency that is predominantly white in color and mimics the appearance of a benign leiomyoma. Tumor size is often greater than 5 cm in greatest dimension, even in early-stage disease.
Microscopic description
Overall, the tumor is hypercellular, with a fascicular pattern of growth of elongated, spindled cells, with tumor cells typically easily recognized as with smooth muscle differentiation ( Fig. 9.2 A and B ). The tumors can have spindled, epithelioid, or myxoid features. Other findings such as multinucleated tumor cells, osteoclast-like giant cells, xanthomatous change, and rhabdoid-like cells with inclusion bodies can be seen. While many LMS invade into the surrounding myometrium, some may have a well-circumscribed margin. Lymphovascular invasion can be seen in 10% to 20% of tumors.
The spectrum of smooth muscle neoplasms can range from benign to uncertain malignant potential to malignant. Due to this wide spectrum, diagnostic criteria are applied to smooth muscle neoplasms to arrive at a correct diagnosis and associated prognosis. The histologic features for criteria include nuclear/cytologic atypia, mitotic index and coagulative tumor cell necrosis ( Table 9.1 ). Once a smooth muscle neoplasm reaches any combination of 2 of the following 3, the diagnosis can be made of a leiomyosarcoma: coagulative tumor cell necrosis, mitotic index ≥ 10/10 HPF, and diffuse moderate to severe atypia. It should be noted that these criteria are only for conventional LMS. Different criteria are applied to variants such as epithelioid leiomyosarcoma and myxoid leiomyosarcoma, which are discussed later. If the neoplasm has atypical features but does not meet 2 of the 3 criteria for leiomyosarcoma, the neoplasm may be categorized as a smooth muscle tumors of unknown malignant potential (STUMP), the criteria of which are covered further in a later chapter.
| Criteria | Two of 3 criteria needed for conventional leiomyosarcoma |
|---|---|
| Diffuse Atypia | Moderate to Severe |
| Mitotic activity | ≥ 10 mitoses/10 HPF |
| Coagulative tumor cell necrosis | Present |
The correct diagnosis can only be reached if the criteria are appropriately defined and applied. For example, the presence of any necrosis does not suffice for the check box of “necrosis present”, but specifically coagulative tumor cell necrosis is needed. Coagulative tumor cell necrosis is an abrupt transition between normal and necrotic tissue, with the necrotic cells having the appearance of “ghost” cells of dying but recognizable cells ( Fig. 9.3 ). This contrasts with hyaline or infarct type necrosis, which shows areas of necrosis surrounded by a rim of hyalinization separating necrosis from normal tissue.
Variants
Epithelioid
Epithelioid LMS are smooth-muscle tumors that show a predominant epithelioid-type histology, with the epithelioid cells having an oval or polygonal appearance with abundant eosinophilic to clear cytoplasm. Typical spindled-cells of a conventional leiomyosarcoma may be seen but should be a minor element. Most show coagulative tumor cell necrosis and moderate to severe nuclear atypia. However, in contrast to conventional LMS, the mitotic activity may be as low as 3 mitoses per 10 HPFs.
Myxoid
Myxoid LMS are usually described grossly as gelatinous, mucoid, or myxoid, being an early indicator of the histologic appearance. These variants typically are diffusely hypercellular or with variable cellularity of hyper/hypocellular areas. Myxoid stroma commonly comprises most of the tumor volume, while the neoplastic cells are arranged in bundles and fascicles. Criteria for diagnosis differ for this variant from conventional leiomyosarcoma as even as low as 2 mitosis per 10 HPF should be considered as worrisome for malignancy.
Immunohistochemistry
As LMS are of smooth muscle differentiation, smooth muscle markers such as desmin and h-caldesmon will be positive. In some cases, when the tumor is very high grade, several markers may be needed to establish smooth muscle differentiation, and if all are negative, a diagnosis of high-grade sarcoma, NOS, may be appropriate. LMS of the gynecologic tract are usually positive for estrogen receptor (ER) and progesterone receptor (PR). In challenging cases, p16 and p53 stains may be employed as they can be overexpressed in LMS; however, the stains are not always helpful.
Differential diagnosis
When the tumor shows definitive smooth muscle differentiation, the differential may include the spectrum of smooth muscle neoplasms, including leiomyoma, mitotically active leiomyoma, atypical leiomyoma, and STUMP. In these cases, close histologic evaluation is necessary to determine if criteria of atypia, mitotic activity and necrosis are met to make a definitive diagnosis. If atypical features are seen but a definitive diagnosis cannot be made, consideration should be made for submission of additional sections as features of malignancy may be patchy or only focally seen.
Endometrial stromal sarcomas may mimic leiomyosarcoma but they are characterized by shorter spindle cells, spiral arteriole-like vessels and diffuse CD10 positivity, with the caveat being that this marker is not specific and may be expressed in LMS.
Rhabdomyosarcoma as a pure sarcoma is uncommon in the uterus, and while usually pleomorphic, occasional tumors have a prominent spindled cell component. These tumors can show eosinophilic cytoplasm with cross-striations, the latter being typical of skeletal muscle differentiation. Rhabdomyosarcomas, which can be confirmed by immunohistochemical stains such as myogenin or myo-D1; these markers are negative in LMS.
The sarcomatous component of a carcinosarcoma may resemble a leiomyosarcoma, especially in cases of a predominant sarcomatous component. Sampling the tumor extensively may be necessary to identify a minor carcinomatous component.
Molecular findings
Uterine LMS have been shown to have mutations in RB1, TP53 and PTEN, while whole-exome sequencing has also shown frequent alterations in TP53, RB1, ATRXZ, and MED12. MED12 has been shown to be more specific to uterine LMS and those with a favorable prognosis, while TP53 and ATRX mutations have been correlated with poor prognosis.
Diagnosis and workup
Differential diagnosis
The differential diagnosis for uterine mass includes both benign and malignant tumors, with the most common etiology being benign uterine leiomyoma. In terms of malignancy, possibilities including malignancy of endometrial origin or sarcoma, of which leiomyosarcoma is the most common.
Signs and symptoms
It is clinically challenging to distinguish uterine leiomyosarcoma from its benign counterpart, uterine leiomyoma. Both can present with vaginal bleeding, increasing abdominal girth or bloating, pelvic pain and pressure, and/or palpable uterine mass. In a review of these symptoms, approximately half of women with uterine leiomyosarcoma reported abnormal uterine bleeding, a much lower percentage than women with other uterine/endometrial malignancies. Half had increasing girth or a palpable mass.
Physical exam findings
In a postmenopausal patients a growing uterine mass or a newly symptomatic uterine fibroid are highly concerning for malignancy. For premenopausal women, neither rapid growth of uterine mass nor overall tumor size is necessarily indicative of increased risk of sarcoma.
Rapid growth of a uterine mass, generally defined as increasing by ≥ 6-week gestational size within 1 year, has been classically cited as an important delineator between leiomyoma and leiomyosarcoma. However, a literature review of 26 studies reported that only 2.6% of uterine sarcomas had a history of rapid uterine enlargement. One large study of over 1000 women undergoing hysterectomy or myomectomy for presumed uterine leiomyoma also did not support rapid growth of uterine mass as predictive of leiomyosarcoma. In this study, the incidence of sarcoma was low in all patients, with an incidence of 1 in 371 (0.27%) in those with rapid growth and 2 in 961 (0.15%) in those without rapid growth. Additionally, prospective studies of fibroids evaluated with MRI regularly every 3 months for 1 year demonstrated that rapid growth, defined as an increase of > 30% over a 3-month period, occurred in 36.6% of tumors.
Data on large uterine size as a predictive factor are more limited, but have also shown no clear association with uterine leiomyosarcoma. A study of women undergoing myomectomy for large uterine size, defined as > 16 weeks in size, reported on 91 women and did not describe a single leiomyosarcoma on final pathology. Therefore, the vast majority of premenopausal women with either rapid enlargement or enlarged uterine mass size do not have a leiomyosarcoma.
Tumor markers
There are no routinely used tumor markers to detect or predict uterine leiomyosarcoma. There have been small retrospective studies that indicate that uterine leiomyosarcoma may have a higher level of lactate dehydrogenase (LDH) than uterine leiomyoma; one study of 45 LMS and 180 controls demonstrated an OR for malignancy of 6.5 (95% CI, 2.6–15.8) with an LDH > 193. Another retrospective study of 2254 women with uterine masses, 43 of which were diagnosed with uterine sarcoma, combined use of LDH isoenzyme subtypes (LDH1, LDH3) predicted sarcoma with 100% sensitivity and 99% specificity, though this has not been replicated in other populations. The use of LDH has subsequently been incorporated into some preoperative prediction modeling with variable success.
Imaging
Workup of a uterine mass often begins with the use of transvaginal ultrasound ( Table 9.2 ). Uterine LMS are described as containing mixed echogenicity, commonly with central necrosis. The use of color Doppler may include irregular vessel distribution with low resistance indices. However, these findings are not unique to leiomyosarcoma and can be found in benign leiomyoma as well. Therefore, concerning features should prompt the use of magnetic resonance imaging (MRI) or CT scan for operative planning. However, these methods have also not been shown to reliably distinguish between uterine leiomyosarcoma and leiomyoma.
| Diagnostic workup |
|---|
| Physical exam Basic laboratory testing including CBC and LDH Imaging—could include pelvic ultrasound, CT, and/or MRI Consider endometrial sampling |
For CT or PET/CT, leiomyosarcoma have been shown to generally have higher FDG uptake while leiomyoma tend to have mild FDG uptake; however, this varies by individual tumor. MRI is considered the more useful modality given its improved discrimination for soft tissue. One retrospective study of 19 leiomyosarcoma compared with 22 atypical leiomyoma reported that four qualitative MRI features were most strongly associated leiomyosarcoma: nodular borders, hemorrhage, T2 dark areas (lack of uptake), and central unenhanced areas consistent with central necrosis. The sensitivity and specificity were greatest when a lesion had 3 or greater of these features. Other studies similarly report that a mass with infiltrative margins has been shown to be more likely to be a leiomyosarcoma, and notably, a consistent finding of leiomyosarcoma is a lack of calcifications.
When comparing MRI techniques, diagnostic accuracy increases with the use of contrast-enhanced MRI compared with diffusion-weighted imaging (sensitivity 0.94, specificity 0.96). This study also reported that use of diffusion coefficient may provide increased diagnostic precision. A prospective study including 10 patients with leiomyosarcoma and 130 with degenerating fibroids investigated the role of Gd-DTPA contrast enhanced dynamic MRI in combination with serum LDH and reported a 100% specificity and positive predictive value with the use of LDH and dynamic MRI, though this study was limited in sample size and difficult to generalize to a broader patient population. Based on this data, there is no current recommendation for routine MRI prior to surgery for presumed uterine fibroids but concerning clinical or ultrasound findings warrant MRI imaging.
Diagnostic testing
Unfortunately, there are no definitive preoperative diagnostic tests that reliably distinguish uterine leiomyosarcoma from benign leiomyoma. Studies of preoperative endometrial sampling, by dilation and curettage (D&C) or EMB, have reported sensitivity of 30% to 60%. While this is a much lower sensitivity than in other endometrial malignancies, sampling may still detect a significant subset of cases and should be considered preoperatively. In practice, women presenting with abnormal uterine bleeding, such as intermenstrual bleeding or menorrhagia, warrant endometrial sampling for pathologic evaluation. The American College of Obstetrics and Gynecology recommends sampling performed in all patients with AUB older than 45 years, or in those younger than 45 years with history of unexposed estrogens, failed medical management, or persistence of their AUB. Thus these criteria should be applied to bleeding in the setting of a uterine mass, though the presence of a uterine mass alone may not warrant sampling.
Staging system
The AJCC staging system for leiomyosarcoma is included in a general staging system for soft-tissue sarcomas in the trunk and extremity ( Table 9.3 ). There is a separate AJCC staging system for sarcomas of the bone. The AJCC staging system is difficult to apply to leiomyosarcoma. Therefore FIGO adopted the TNM system specifically for leiomyosarcoma and endometrial stromal sarcoma ( Table 9.4 ). The latter is more commonly used among gynecologic oncologists.
| AJCC 8th edition | |
|---|---|
| T1 | Tumor ≤ 5 cm in greatest dimension |
| T2 | Tumor > 5 cm and ≤ 10 cm in greatest dimension |
| T3 | Tumor > 10 cm and ≤ 15 cm in greatest dimension |
| T4 | Tumor > 15 cm in greatest dimension |
| N0 | No regional lymph node metastasis or unknown lymph node status |
| N1 | Regional lymph node metastasis |
| M0 | No distant metastasis |
| M1 | Distant metastasis |
| Stage groups | |
| Stage IA | T1; N0; M0; G1 |
| Stage IB | T2, T3, T4; N0; M0; G1 |
| Stage II | T1; N0; M0; G2/3 |
| Stage IIIA | T2; N0; M0; G2/3 |
| Stage IIIB | T3, T4; N0; M0; G2/3 |
| Stage IV | Any T; N1; M0; any G Any T; any N; M1; any G |
| Stage | Definition | |
|---|---|---|
| Leiomyosarcomas and endometrial stromal sarcomas | ||
| I | Tumor limited to uterus | |
| IA | Less than 5 cm | |
| IB | More than 5 cm | |
| II | Tumor extends beyond the uterus, within the pelvis | |
| IIA | Adnexal involvement | |
| IIB | Involvement of other pelvic tissues | |
| III | Tumor invades abdominal tissues (not just protruding into the abdomen). | |
| IIIA | One site | |
| IIIB | More than one site | |
| IIIC | Metastasis to pelvic and/or paraaortic lymph nodes | |
| IV | IVA | Tumor invades bladder and/or rectum |
| IVB | Distant metastasis | |
Prognostic factors
While approximately 60% of women present with uterine confined disease, recurrence rates remain high. As such current staging systems, including FIGO and AJCC, are limited in their ability to predict patient prognosis. This is likely due to the fact that other prognostic features, including age, grade, and menopausal status are not included in staging. For example, a SEER national database study reported a four-fold higher incidence in women older than 50 years old (RR 6.4 vs 1.5 per 100,000). In a study from the French Federation of Cancer Centers Sarcoma Group of 1240 patients with sarcoma of various subtypes, histologic grade was associated with prognosis in the 148 included patients with uterine leiomyosarcoma. Additionally, mitotic score and vascular invasion have both been associated with metastasis free interval.
To incorporate these known prognostic features, a nomogram was created and subsequently validated at Memorial Sloan Kettering and can be accessed online. This nomogram was designed based on clinical predictors and included age at diagnosis, tumor size, histologic grade, uterine cervical involvement, extrauterine spread, distant metastases, and mitotic index. The concordance probability of this nomogram was found to be superior to either FIGO or AJCC prognostic prediction.
Treatment of primary disease
Surgical resection of uterine leiomyosarcoma is the mainstay of primary treatment. For women with early stage, uterine confined disease a total abdominal hysterectomy with intact removal is recommended. The removal of bilateral fallopian tubes and/or ovaries at time of hysterectomy is often performed but does not seem to impact survival. A Surveillance, Epidemiology and End Results (SEER) database study (1988–2003) demonstrated that approximately 60% of surgeries for uterine leiomyosarcoma were performed with oophorectomy. Among women < 50 years old with stage I or II disease, 29.6% of women had ovarian preservation; these women had similar survival to those who underwent oophorectomy (5-year disease-specific survival rate of 83.2% vs 83.2%; P = 0.445). In a similar study using the National Cancer Database (NCDB), 89% of women underwent oophorectomy at time of hysterectomy and, as expected, women without oophorectomy were younger (median age 46 years vs 55 years). Among women with early leiomyosarcoma, again there was again no difference in survival with oophorectomy compared to ovarian preservation. Therefore, in a premenopausal women, it is reasonable to discuss ovarian preservation.
Routine lymphadenectomy is not recommended as uterine leiomyosarcoma has a greater propensity for hematogenous spread, with rates of lymph node metastases < 5%. Lymph node beds should be carefully assessed and any clinically enlarged or concerning lymph nodes removed. For those with intra-abdominal metastatic disease, cytoreduction to no gross residual may have improved outcomes.
At time of surgery, another consideration is that of frozen section. In a population of 1429 hysterectomies performed in the presence of symptomatic uterine mass with presumed benign disease, histologic diagnosis of uterine leiomyosarcoma was made in 7 women (0.49%). Frozen section only detected suspicion for malignancy in 3 of these 7 (42.8%). Similarly, in a retrospective study of 21 LMS, frozen section revealed the diagnosis in only 1 of the 9 cases in which frozen section was performed. Therefore, frozen section has a significant chance of false negative result and thus only definitive diagnosis of leiomyosarcoma on frozen section should impact surgical approach.
Many uterine leiomyosarcoma diagnoses are discovered on pathologic evaluation following hysterectomy. To allow for minimally invasive approach, the use of power morcellation, or the use of instruments to fragment uterine specimen to allow for laparoscopic removal, increased in popularity in the early 2000s. However, this presents a risk of disruption of occult uterine leiomyosarcoma; due to this risk, the FDA issued a “black box” warning discouraging the use of power morcellation. However, there was criticism of the lack of comprehensive review of the literature and debate regarding the reported risk (1 in 352 for any uterine malignancy and 1 in 498 for uterine leiomyosarcoma). Further studies report a much lower incidence of occult leiomyosarcoma at closer to 1 to 7 in 1000,000 women undergoing hysterectomy for presumed benign fibroids. Therefore, there has been a spectrum of response to the FDA’s black box warning, with some hospitals/departments banning the use of electromechanical morcellation, others recommend a more nuanced approach to counseling and patient selection for whom morcellation may be offered. There have been some studies investigating the potential use of contained tissue extraction, such as in-bag or scalpel-based morcellation, but the optimal method to eliminate morcellation related risk requires further study.
Importantly, specimen fragmentation has been shown to lead to a higher rate of abdominopelvic dissemination. In one study of 56 patients, the rate of dissemination was 44% vs 12.9%, with poorer overall survival on multivariable analysis. The risk of recurrence has been estimated to be up to a four-fold increase for those women whose tumors were fragmented. Notably, literature indicates that approximately 15 to 30% of patients with uterine leiomyosarcoma will be upstaged after reexploration if morcellation was performed. Therefore, the management of morcellated leiomyosarcoma remains in debate, though at a minimum patients with history of such a procedure require close radiographic follow up for peritoneal recurrence.
Morcellation is associated not only with high recurrence risk, but with potentially different patterns of recurrence. In one study of 152 patients with stage I leiomyosarcoma, the risk of recurrence was increased (67.2% vs 86.3%) in morcellated specimens. Among patients with intact removal of specimen, the majority (69.4%) recurred at hematogenous sites only with only 18.1% having peritoneal only recurrence. Conversely, patients with morcellated tumors were more likely to recur in the peritoneum with 62.3% recurrences in peritoneum and 28.9% in hematogenous sites.
Adjuvant therapy in early-stage disease
Adjuvant systemic therapy for uterine sarcoma remains a controversial topic as there are no completed prospective, randomized trials evaluating adjuvant therapy in this group of women. Many treatment recommendations are made based on two factors: (1) a high risk of recurrence and (2) therapy that has been shown to be effective in the recurrent or metastatic setting. Incorporating the two of the most effective regimens in the metastatic setting, Sarcoma Alliance for Research through Collaboration (SARC) 005 treated women with early-stage uterine leiomyosarcoma with 4 cycles of adjuvant gemcitabine and docetaxel, followed by 4 cycles of doxorubicin if they remained disease free. The median time to recurrence was 27.4 months, with 57% of patients disease free at 3 years. These data were felt to be promising based on historical controls, and the regimen was subsequently incorporated in a large phase III study that randomized patients to treatment vs observation. Unfortunately, the trial failed to accrue and was ultimately closed. Only 38 of the targeted 218 patients enrolled, 20 of whom were assigned to chemotherapy while 18 assigned to observation. There were 8 recurrences in each arm, and the mean recurrence-free survival (RFS) was estimated at 18.1 months in the chemotherapy arm vs 14.6 months in the observation arm. Mean overall survival time was estimated at 34.3 and 46.4 months in the chemotherapy and observation arms respectively, though both of these survival outcomes are not considered statistically meaningful given small sample size. While it remains an accurate statement that no randomized trial has demonstrated a survival benefit with patients with uterine leiomyosarcoma, the difficulty in accruing to a well-designed adjuvant study appears to reflect discomfort among treating providers with randomization of high-risk patients to observation, rather than definitive evidence of lack of efficacy. Meanwhile, a recently presented retrospective study has suggested that treatment with anthracycline-based adjuvant therapy was associated with improvement in DFS (but not OS) over patients treated with gemcitabine and docetaxel in a recent retrospective 111 patient experience.
Turning briefly to the literature for adjuvant therapy of other sarcoma subtypes, adjuvant, or neoadjuvant therapy with an anthracycline and ifosfamide-based regimens has been shown to decrease risk of recurrence in both subtype specific and more heterogeneous patient populations as long as the treated population is at high risk for recurrence. While definition high risk can vary, the Sarculator, a validated nomogram for retroperitoneal and extremity sarcoma has shown some success in identifying a high-risk population that may benefit from adjuvant therapy. Consequently, present soft-tissue sarcoma guidelines do recommend consideration of adjuvant systemic therapy for intraabdominal sarcomas at high risk of metastatic disease, and the Sarculator nomogram provides a method for risk stratifying. In uterine LMS, the Memorial Sloan Kettering nomogram provides a method of risk stratification but has not been validated as a tool for selecting patients for adjuvant therapy. Informed by the experience in sarcomas at other sites, our approach is to have a discussion regarding the pros and cons adjuvant systemic doxorubicin-based therapy to patients with at least stage IB disease, with the important caveat that prevention of recurrence and overall survival has not been definitively demonstrated in this population.
Radiation therapy is commonly used in other uterine cancers. In contrast, sarcomas are generally less radio-responsive, and hematogenous dissemination to distant sites plays a larger role in treatment failure. Retrospective reports of radiation therapy in uterine leiomyosarcoma suggested an improvement in local control. To prospectively examine these findings, EORTC 55874 examined pelvic radiation and surgery vs surgery alone in patients with stage I and II uterine sarcomas (leiomyosarcoma, carcinosarcoma, and endometrial stromal sarcoma). Over 13 years, 224 patients were accrued, with 103 of these having uterine leiomyosarcoma. In the entire study cohort, there was an improvement in local RFS; however, this was not observed in the uterine leiomyosarcoma cohort. A survival benefit was not seen in any of the subgroups. As such, routine application of radiation has not been recommended for early-stage uterine leiomyosarcoma. For more advanced stages, or in specific clinical scenarios that increase risk of local recurrence (intraoperative bisection or morcellation of tumor, invasion of adjacent structures), radiation may be considered on a case by case basis.
Surveillance for recurrence
There is no current standard follow up for patients after the primary treatment of uterine leiomyosarcoma. Due to the high risk of early recurrence and propensity for both intraperitoneal and hematogenous dissemination, we recommend restaging with CT of the chest, abdomen, and pelvis every 3 months for the first two years after surgery, every 4 months for the subsequent two years, every 6 months for the following year, and consideration of annual imaging thereafter.
Survival and patterns of failure
Despite its overall rarity, uterine leiomyosarcoma makes up a large portion of deaths from uterine cancer as a result of its aggressive nature, with high risk of recurrence and overall poor prognosis. Even in the setting of uterine confined disease, recurrence rates are reported to be 50% to 70% following hysterectomy. The 5 year survival in early-stage (I–II) disease is 60% to 76%, while late-stage (III–IV) disease is only 29% to 45%. The most common site of first recurrence is the lung (40%–70%), followed by pelvic or peritoneal recurrences (14%–40%), followed by bone (30%) and liver (27%). However, the pattern of recurrence may be impacted by the use of morcellation and/or adjuvant therapy as mentioned above.
Treatment of advanced or recurrent disease
In advanced or recurrent disease, surgical management can be considered if disease is felt to be resectable with a goal of no gross residual. A retrospective study of 96 women with advanced leiomyosarcoma demonstrated a complete gross resection (CGR) was achieved in 49% of women, with improved median PFS (14.2 vs 6.8 months) for women in whom CGR was achieved. In multivariate analysis adjusting for disease distribution and use of adjuvant chemotherapy, the presence of no residual disease was independently associated with PFS. Given the often rapid recurrence after surgery, we do not offer surgical therapy to the majority of recurrent patients. Our approach is first to treat with systemic therapy and in a selected, chemoresponsive population with minimal sites of disease and limited morbidity associated with resection, consider surgery after multidisciplinary discussion.
Excluding specific, uncommon situations where local therapies are indicated, palliative chemotherapy is the primary treatment modality for recurrent and metastatic disease ( Table 9.5 ). Since its approval in the early 1970s, doxorubicin-based therapies have been a cornerstone of treatment for patients with soft-tissue sarcoma. From early in its development, a dose response curve was observed in patients with soft-tissue sarcoma, with higher doses of doxorubicin resulting in higher response rates. Consequently, most modern regimens incorporate doxorubicin at a dose of 75 mg/m 2 , which is a higher dose than in used in other malignancies. For patients with metastatic and relatively asymptomatic disease, single-agent doxorubicin is an acceptable standard of care regimen. Doxorubicin-based combinations have also been studied in an effort to increase response rate and ultimately, overall survival. Historically, these have included combinations to include ifosfamide, dacarbazine, cyclophosphamide, and/or vincristine, with clear increase in response rate over single-agent doxorubicin but no statistically significant improvement in overall survival. For patients with symptomatic disease, combination therapy is more likely to improve disease burden and overall symptoms from the cancer. Doxorubicin-based therapies are generally recommended as first line, supported by data from the GeDDiS trial which demonstrated similar efficacy of gemcitabine and docetaxel vs single-agent doxorubicin in the first-line, with the latter being better tolerated. The median PFS was 23.3 vs 23.7 weeks for those receiving doxorubicin vs gemcitabine/docetaxel, and PFS at 24 weeks did not differ between the groups (46.3% vs 46.4%, respectively). Median overall survival was also similar, at 76.3 weeks in the doxorubicin group and 67.3 weeks in the gemcitabine/docetaxel group.
