Clinical case
A 51-year-old patient presents with abnormal uterine bleeding and a 6 cm intrauterine, polypoid mass on pelvic ultrasound imaging ( Fig. 10.1 ). Office endometrial biopsy (EMB) was suggestive of uterine adenosarcoma. She was taken to the operating room for a TLH, BSO, and pelvic sentinel lymph node assessment. Final pathology revealed a stage IA uterine adenosarcoma with sarcomatous overgrowth and presence of lymphovascular space invasion. Do you offer this patient any adjuvant therapy and if so what?
Epidemiology
Uterine sarcomas are rare entities, representing only 1% of all gynecologic malignancies, and 3% of all uterine cancers. Uterine sarcomas are comprised of different subtypes, the most common being uterine leiomyosarcoma (25%–60% cases), endometrial stromal sarcoma (10%–20% cases), high-grade undifferentiated sarcoma (HG-US) (3%–5% cases), and uterine adenosarcoma (5%–9% cases). The mortality rate associated with uterine sarcomas is much higher than their endometrial cancer counterparts, which has been mostly driven by high-risk uterine leiomyosarcoma. Five-year overall survival rates have been reported between 25% and 80%, depending on sarcoma histologic subtype and stage. There have been no significant differences in incidences of these rare uterine sarcomas by ethnicity. Given the limited numbers of patients that incur this diagnosis annually, challenges exist in preoperative diagnosis, workup, and treatment of these rare tumors. Universal adoption of adjuvant treatment strategies following surgical management has also been limited given lack of prospective clinical trials in these tumors. Thus, majority of treatment recommendations have been based on review of available data and consensus agreements. In this chapter, we will focus specifically on the rare uterine sarcoma subtypes of adenosarcoma, endometrial stromal sarcoma, and smooth muscle tumors of uncertain malignant potential (STUMP).
Etiology/risk factors
The majority of uterine adenosarcoma diagnoses arise from the uterus, and median age ranges from 41 to 66 years. A large SEER database study reported that 52% of patients were between the age of 40 and 65 years, 39% were older than 65 years, and 10% of patients were younger than 40 years. Müllerian adenosarcomas can also arise from other gynecologic tissues including the ovaries, cervix, vagina, fallopian tubes, and peritoneum. The association between endometriosis and extrauterine adenosarcoma cases has been described; however, a direct causal link has not been established. In a large case series of 1000 patients with biopsy-proven endometriosis, the incidence of cancer was 5.5%, with majority of tumors being carcinoma (endometrioid or clear cell) and minority adenosarcoma. Additional risk factors for uterine adenosarcoma identified have included treatment with selective estrogen receptor modulator (SERM) medications such as tamoxifen. However, despite endometrial changes that can occur with SERMs, the relative risk of developing uterine cancer has been shown to be 2.5, of which majority are uterine carcinomas and not adenosarcoma. Other potential risk factors for uterine adenosarcoma have included previous pelvic radiation or prolonged exposure to estrogen.
Endometrial stromal sarcomas make up only approximately 0.2% of all uterine malignancies. Notably, ESS are often diagnosed slightly earlier than their higher grade leiomyosarcoma counterparts, usually occurring in women aged 40–55 years old. Additionally, analysis of the National Cancer Database (NCDB) reported that women with ESS often have smaller tumors than those with high-grade sarcomas of the uterus.
STUMP tumors are typically diagnosed in women suspected to have benign uterine leiomyoma on preoperative evaluation. The median age at diagnosis is 41–48 years, with a range of 20–75 years. There are not clearly defined risk factors for the development of uterine STUMP tumors, and they have not been associated with history of pelvic radiation such as with other uterine sarcomas.
Pathology
Adenosarcoma
Adenosarcomas are, as the name implies, a biphasic tumor, with a benign epithelial component and malignant stromal component. An uncommon tumor, adenosarcoma has been seen in a broad age range with as low as 10 years of age and with incidence highest in perimenopausal and postmenopausal women.
Gross description
The tumor typically is exophytic and polypoid, filling the uterine cavity and may project through the uterine cervix. On exam, the lesion may be confused with benign endocervical or endometrial polyps. Tumor size has been reported to range from 1 to 17 cm, with an average size of 5 cm. On cut surface, the tumor can show variable cystic and solid components, with papillary projections into cystic spaces that may be appreciated on gross examination. If there is sarcomatous overgrowth, the tumor may have areas of a more “fleshy” appearance, as is described in other sarcomas.
Microscopic description
On low power examination the tumor may resemble a phyllodes tumor of the breast, with leaf like architecture caused by intraglandular projections ( Fig. 10.2 ). The epithelium is bland, simple Müllerian-type epithelium, usually endometrioid, in the forms of glands or cysts, with no significant architectural complexity or cytologic atypia. Metaplastic changes in the epithelium can be seen, including tubal, squamous or mucinous features. The stromal component is malignant and typically is a low-grade spindle cell sarcoma, with no specific differentiation. The stroma will show hypercellular areas around glands, known as periglandular stromal condensation or periglandular cuffing. Mitotic activity was previously required for the diagnosis at a rate of at least 2 per 10 HPF, but as mitotic activity can be very focal or difficult to identify a diagnosis of adenosarcoma can be made when other classical architectural patterns are present. High-grade stromal component defined as severe nuclear pleomorphism identifiable at low-power magnification can be seen in a subset of cases, without meeting criteria for sarcomatous overgrowth. Regardless, the presence of a high-grade component should be noted, as it may be associated with more aggressive behavior. Heterologous components may also be seen, notably rhabdomyoblastic differentiation ( Fig. 10.3 ), but chondrosarcoma, liposarcoma and sex cord-stromal differentiation have also reported.
“Adenosarcoma with sarcomatous overgrowth” is a diagnosis rendered when more than 25% of the tumor shows pure sarcoma without admixed glandular component. The type or grade of sarcoma is not specific to this diagnosis, though typically (approximately 70%) are high grade. This should be reported, as they are associated with extrauterine disease at presentation along with high rates of recurrence and mortality.
Differential diagnosis
Lesions with both epithelial and mesenchymal components dominate the differential, ranging from benign to malignant. Endometrial polyps, adenomyomas, and adenofibromas all have epithelial and mesenchymal components that are histologically benign. As originally described, adenofibroma has similar architectural features to an adenosarcoma, though the stroma is usually hypocellular and fibrotic, and mitoses should be absent. However, the diagnosis of adenofibroma has been removed from the 2020 WHO Classification of Female Genital Tumors as they are either considered to be low-grade adenosarcomas, or polyps with unusual phyllodes architecture or stromal cellularity. When a tumor has an “adenofibroma-like” appearance examination of the entire lesion to identify more typical features of adenosarcoma is warranted.
Carcinosarcoma is another biphasic neoplasm that should be considered. In a subset of cases, carcinosarcoma can have phyllodes like architecture mimicking adenosarcoma. Adequate sampling of the lesion is required to exclude the presence of any malignant epithelium.
Lastly the diagnosis of SMARCA4-deficient undifferentiated sarcoma should be considered in the differential diagnosis. These tumors may have a leaf-like polypoid architecture which can mimic adenosarcoma but is composed essentially of an undifferentiated tumor with prominent rhabdoid morphology. These tumors show loss of SMARCA4 by immunohistochemistry (IHC) and have a very aggressive clinical course.
Molecular findings
Testing of adenosarcomas has shown somatic gene alterations only in the sarcoma component, further supporting these lesions as being primarily a mesenchymal neoplasm. Mutations noted have included FGFR2, KMT2C, and DICER1, while amplifications in MDM2/CDK4/HMGA2 and TERT have been identified along with fusions in NCOA2/3. Adenosarcomas with sarcomatous overgrowth have been reported to have ATRX mutations, MYBL1 amplification, higher number of copy number mutations, and more common global chromosomal instability and chromothripsis. And lastly, TP53 alterations are more common in high-grade adenosarcoma in contrast to low-grade adenosarcomas.
Endometrial stromal sarcoma
Endometrial stromal sarcomas are uncommon tumors, which are broadly classified as either low-grade endometrial stromal sarcoma (LG-ESS) or high-grade endometrial stromal sarcoma (HG-ESS). This entity has evolved over the last several decades from a histologic and molecular standpoint, and now also includes a relatively recent inclusion of HG-ESS with BCOR fusion.
Gross description
Typically LG-ESS is superficial and involves the endometrium, grossly seen as a soft, tan to yellow polyp or mass and may show gross necrosis or hemorrhage. As LG-ESS has myometrial invasion by definition, it may show a grossly identifiable infiltrative pattern of growth, with irregular, tan-yellow cords or nodules of tumor extending into the myometrium. Extension into myometrial or parametrial veins may occur and are seen as “worm-like” plugs of tumor. LG-ESS may also grow as well-demarcated, well-circumscribed nodules within the myometrial wall, without definitive gross evidence of invasion. Conversely, it can also have such diffuse invasion of the myometrium that the myometrium is diffusely thickened, without a well-defined tumor seen.
HG-ESS typically forms a polypoid, intracavitary mass and is usually poorly circumscribed. However, there is significant overlap between the gross appearance of LG-ESS and HG-ESS, without definitive features to grossly distinguish the two tumors.
Microscopic description
In LG-ESS, the tumor cells are uniform with scant cytoplasm that resemble the cells of proliferative-phase endometrial stroma, with an arborizing vascular pattern of spiral arterioles and occasionally ropey collagen ( Fig. 10.4 ). Nearly 50% of tumors have mitotic index between 1 and 9 mitoses per 10 HPF, with a range from rare or no mitoses identified to up to over 30. Of note, the mitotic count is neither used for the diagnosis nor grading of these tumors. In tumors that appear well-circumscribed, careful sampling of the tumor/myometrial interface is important to identify focal invasion. While endometrial stromal nodules and LG-ESS show similar histology, distinction should be made on the presence of invasion. If the neoplasm shows finger like projections measuring > 3 mm in extent from the main mass or > 3 in number, then a diagnosis of LG-ESS should be made. Up to 25% of cases exhibit foci of sex cord-like differentiation, resembling uterine tumors with ovarian sex cord-like tumors (UTROSCT) ( Fig. 10.5 ). The two entities are distinguished by the percentage of sex cord-like features being focal in LG-ESS vs greater than 50% in UTROSCT.
HG-ESS usually shows a two cell population, with a mixture of round and spindled cell areas, though tumors with pure components of either can occur. The round cell component is usually highly cellular and arranged in vague nests, with large nuclei (4–6 times the size of background lymphocytes) and scanty to moderate eosinophilic cytoplasm. High mitotic rate (> 10 mitoses per 10 HPF, with up to 77 per 10 HPF reported) and tumor necrosis is invariably present. In comparison, the spindle cell component is arranged in loose or intersecting fascicles, with ovoid to oblong nuclei with an overall bland, monomorphic cytologic appearance. In comparison to the round cell component, the spindle cell component shows lower mitotic activity (typically 3 or less mitoses per 10 HPF).
HG-ESS with BCOR fusion typically show striking, extensive myxoid stroma, with uniform tumor cells arranged in haphazard fascicles. The cells are predominantly spindled, with spindled or oval to round intermediate sized nuclei.
Immunohistochemistry
Typically LG-ESS is diffusely positive for CD10, though the marker it not entirely specific and can be positive in mimics such as cellular leiomyoma. Smooth muscle markers, such as desmin, may also be positive in LG-ESS, especially those with smooth muscle differentiation; therefore, a panel of CD10 and specific smooth muscle markers such as SMMS-1, calponin, and h-caldesmon should be considered. IHC stains for ER and PR are typically diffuse and strong.
HG-ESS is typically negative or only weakly positive for IHC stains CD10, ER and PR, while cyclin D1 shows strong, diffuse positivity (in > 70% of cases), best exhibited in the round cell component.
HG-ESS with BCOR fusion shows diffuse staining with CD10 approximately 80% of cases and a similar proportion of cases with exhibiting cyclin-D1 expression. ER and PR staining is variable.
Molecular findings
LG-ESS harbor recurrent chromosomal translocations, the most common of which, occurring in approximately 50% of cases, is the t(7;17)(p15;q21) translocation, producing the JAZF1-SUZ12 gene fusion. Other reported translocations include PHF1-JAZF1 t(6;7)(p21;p15), EPC1-PHF1 t(6;10;10)(p21;q22;p11.2) and MEAF6-PHF1 t(1;6)(p34;p21).
Usual type HG-ESS will typically harbor the translocation t(10;17)(q22;p13), producing the YWHAE-NUTM2A/ B (previously known as FAM22 ) gene fusion. The newly described BCOR HG-ESS is characterized by t(X;22)(p11;q13), resulting in a fusion of ZC3H7B and BCOR.
Differential diagnosis
The most important differential for classic LG-ESS is an endometrial stromal nodule. Tumors should be well sampled along the tumor-myometrial junction to fully evaluate for the presence of invasion. Areas of smooth muscle metaplasia should not be confused with background myometrium, potentially over calling invasion in an endometrial stromal nodule. The presence of vascular invasion further supports a diagnosis on ESS over a stromal nodule. LG-ESS with significant smooth muscle differentiation may mimic leiomyosarcoma, just as extensive sex cord-like features may mimic UTROSCT. Intravascular leiomyomatosis in which the smooth muscle tumor is cellular can mimic LG-ESS and immunostains for smooth muscle markers may facilitate the correct diagnosis.
The main differential for HG-ESS is an undifferentiated endometrial/uterine sarcoma (UUS), which is characterized by markedly pleomorphic cells with prominent nucleoli in diffuse sheets with no resemblance to proliferative-phase endometrium. The marked cytologic atypia present in UUS is not typically seen in HG-ESS which has more uniform round cell morphology. Furthermore, UUS is typically positive for CD10 and has diffuse cyclin D1 expression, while negative for ER and PR. The differential staining for CD10 further support a diagnosis of UUS over HG-ESS; though expression can be variable and a UUS is essentially a diagnosis of exclusion.
In HG-ESS with BCOR the differential focuses on tumors with myxoid change, and includes entities such as myxoid leiomyosarcoma, inflammatory myofibroblastic tumors (IMT), and LG-ESS with fibromyxoid changes. IHC staining with smooth muscle markers and ALK can help distinguish from myxoid leiomyosarcoma and IMT, respectively, while a panel of CD10, ER, PR, and cyclin-D1 may distinguish from LG-ESS.
Smooth muscle tumors of uncertain malignant potential
STUMP represent a subcategory of uterine smooth muscle tumors that cannot be diagnosed unequivocally as benign or malignant. Patients range in age from 25 to 75 years of age, with a mean of approximately 44 years of age, distinguishing these patients in age by approximately 10 years before most leiomyosarcomas are diagnosed. While patients diagnosed with uterine STUMPs can be cured by hysterectomy, recurrence or metastasis can occur.
Gross description
The gross appearance of STUMPs is usually similar to a typical leiomyoma. Some tumors may have areas of hemorrhage, necrosis or degenerative type changes. Reported size ranges from 2.5 to 12.2 cm, with a mean of 7.2 cm. The tumors are typically located intramurally but can also be seen submucosal and subserosal.
Microscopic description
The tumor is composed of spindled cells with eosinophilic cytoplasm and blunted elongated nuclei arranged in intersecting fascicles. The diagnosis is based on a combination of atypia, mitotic activity or uncertainty in the type of necrosis, that does not meet the threshold of a leiomyosarcoma. STUMPs can be broadly put into three categories: (1) focal/multifocal or diffuse significant cytologic atypia lacking tumor cell necrosis with a mitotic index of < 10 per 10 HPFs, (2) cytologically bland smooth muscle tumors with a mitotic index of less than 10 mitoses per 10 HPFs with the presence of coagulative tumor cell necrosis and (3) cytologically bland smooth muscle tumors with a mitotic index greater than or equal to 15 mitoses per 10 HPFS and lacking tumor cell necrosis.
Differential diagnosis
The differential diagnosis for STUMP primarily includes the spectrum of smooth muscle tumors from benign to malignant. Careful application of the criteria for atypia, mitotic activity and coagulative tumor cell necrosis can help separate tumors into leiomyoma, STUMP and leiomyosarcoma.
Variants of leiomyoma can show focal atypia or necrosis, concerning for a STUMP, but are benign. Apoplectic leiomyoma have foci of necrosis and elevated mitotic activity and can be misdiagnosed as a STUMP; however, awareness of exogenous hormonal therapy as well as recognition that the necrosis is infarct/hyaline necrosis aids in the diagnosis of apoplectic leiomyoma. Fumarate hydratase (FH)-deficient leiomyoma are also on the differential with STUMP, as FH-deficient leiomyomas may have bizarre nuclear features. The presence of staghorn-like vessels, edema, and intra-cytoplasmic globules/inclusions, along with loss of expression of FH by IHC aids in the diagnosis of an FH-deficient leiomyoma.
IMT can also be on the differential for STUMPs as they can have a combination of cytologic atypia, increased mitotic index and coagulative tumor cell necrosis with positivity for smooth muscle markers. ALK testing by IHC or fluorescent in-situ hybridization can be helpful in this scenario as IMTs are usually positive by one or the other methodology.
Molecular findings
There are no defining molecular findings for STUMP. However, recently genomic profiling has shown the ability to predict potential for aggressive behavior, dividing STUMPs into groups: those that behave more like leiomyoma and those that behave more like leiomyosarcoma, based on a genomic index cut-off of 10.
Diagnosis and workup
Differential diagnosis
Most patients diagnosed with uterine adenosarcoma, endometrial stromal sarcoma, or STUMP tumors present with abnormal uterine bleeding and a pelvic mass diagnosed by imaging. However, patients with uterine adenosarcoma and endometrial stromal sarcoma are more likely to have an endometrial or polypoid like mass, vs STUMP tumors which typically resemble smooth muscle tumors in the myometrium and closely resemble uterine leiomyomas.
Signs and symptoms
The majority of patients with rare uterine sarcoma subtypes will experience abnormal uterine bleeding in 65%–75% of cases. Other associated clinical symptoms include pelvic pain or demonstration of pelvic mass in 10%–30% of cases, and abnormal vaginal discharge in 11% of cases.
Physical exam findings
On clinical examination, patients with rare uterine sarcoma subtypes may have an enlarged uterus or palpable pelvic mass, prolapsing uterine mass visible in the vagina, endocervical polyp or cervical mass ( Table 10.1 ). Rarely, these tumors are diagnosed and detected on routine Papanicolaou smear examination.
| Diagnostic tools | Comments |
|---|---|
| Clinical exam | |
| Abnormal uterine bleeding | 65%–75% Cases |
| Pelvic or uterine mass | 50% Cases |
| Pelvic pain or discomfort | 20% Cases |
| Abnormal vaginal discharge | 11% Cases |
| Endometrial sampling (EMB or D&C) | Sensitivity 52%–85%, Specificity 35%–67% |
| Tumor markers | |
| Serum CA-125 | Limited reliability for primary diagnosis |
| Increased sensitivity in recurrent/metastatic (67%–70%) | |
| Serum LDH | Elevated when compared to benign disease |
| Imaging | |
| Ultrasound | Large, solid lesions, nonhomogeneous, irregularity, increased vascularity |
| CT scans | Useful for initial staging, assessment for metastatic disease, surveillance |
| MRI | Higher diagnostic accuracy for evaluation of uterine masses suspicious for sarcoma |
| PET | Data on utility limited, higher FDG uptake seen in uterine sarcomas, cost considerations |
Tumor markers
There are no reliable predictive serum biomarkers for the diagnosis of rare subtypes of uterine sarcomas. CA-125 is a membrane glycoprotein associated with coelomic epithelium, including that of the female reproductive tract. It is the most commonly used tumor marker in the diagnosis and follow-up of ovarian cancer. Serum CA-125 has been studied as a biomarker in the workup of uterine and pelvic masses; however, it can be relatively nonspecific and is typically only elevated in cases of advanced stage disease. Serum CA-125 has been a poor differentiator between benign uterine leiomyoma and early-stage sarcomas in some cases, but other studies have shown significantly higher serum CA-125 levels in uterine sarcomas compared to benign myomas. Lactate dehydrogenase (LDH) is a pyridine-linked enzyme catalyzing the reduction of free pyruvate to lactate during glycolysis. Malignant cells proliferate rapidly and have an increased rate of glycolysis. Following cell damage, LDH leaks into the bloodstream. Several studies have found higher preoperative serum LDH levels in uterine sarcomas compared to benign myomas. Nagamatsu et al. reported significant differences in LDH levels between endometrial carcinomas, uterine sarcomas, and benign leiomyomas. Patients with uterine sarcoma had higher levels of LDH when compared with endometrial carcinoma ( P = 0.0018) and benign leiomyoma ( P = 0.0023). In addition, other studies have demonstrated that the combined use of serum LDH levels with different imaging modalities (PET-CT or MRI) increased the sensitivity and specificity of differentiating between malignant uterine sarcomas and benign myomas. Nagai et al. proposed a preoperative diagnosis scoring system for uterine sarcomas (PRESS) utilizing age, serum LDH levels, and endometrial cytology results. Patients at risk for sarcoma scored 4 or higher on the scoring tool. The scoring system yielded an accuracy, sensitivity, and specificity of 94%, 80%, and 98%, respectively.
Imaging tests
Most patients for workup of abnormal uterine bleeding or uterine mass will undergo imaging of the abdomen and pelvis with either ultrasound, computed tomography (CT) scan, or magnetic resonance imaging (MRI). Ultrasound has been the gold-standard first line test in workup of abnormal bleeding or uterine mass given its wide availability, low cost, and efficiency as diagnostic tool for gynecologic anatomic abnormalities. Increased vascularity utilizing Doppler has also been useful as a sonographic tool during ultrasound to detect uterine masses concerning for malignancy. Sonographic features of uterine sarcomas on ultrasound can include large, solid lesions with nonhomogeneous echostructure, irregular cystic areas, irregular margins, marked vascularization, and unstructured solid tissue in absence of shadow cones and calcifications (see Fig. 10.1 ).
MRI represents the best approach to imaging uterine masses concerning for sarcoma and defining extent of local disease, while CT imaging is preferred for staging assessment of distant metastatic disease and follow-up. Features of uterine adenosarcoma on MRI include a well-demarcated mass that is hypointense and heterogeneous on T1, multiseptated cystic appearance on T2, and low signal on diffusion weighted imaging. Masses associated with adenosarcoma can also be polypoid, arising on a stalk, or prolapsing through the endocervical canal which can be seen on MRI imaging ( Fig. 10.6 ). On MRI, leiomyosarcomas and STUMP tumors can display high T1-weighted and T2-weighted signals (due to necrosis) and grow more rapidly than their benign counterparts. Areas of increased T2 signal and restriction of diffusion on diffusion-weighted images may indicate hypercellularity or necrosis. There is no clear imaging tool to distinguish between leiomyosarcoma and STUMP tumors, as this is a pathologic diagnosis. Contrast-enhanced MRI appears to yield higher diagnostic accuracy and higher specificity compared with diffusion-weighted MRI for discriminating between leiomyosarcoma/STUMP and benign leiomyoma, with comparable high sensitivity. Contrast-enhanced MRI has been shown to be superior to diffusion-weighted MRI based on the area under the ROC (0.92 vs 0.68, P < 0.01).
Few data are currently available on utility of F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) as a diagnostic tool for uterine sarcomas. Ho et al. evaluated utility of PET imaging in a small cohort of patients with rapidly growing uterine masses suspicious for malignancy on ultrasound or MRI. The maximum FDG uptake for leiomyosarcoma and STUMP were higher (SUV max 3.7–11.8, median 11.3) versus benign leiomyomas (SUV max 2.0–9.4; median 3.5, P = 0.003), and the metabolic tumor/necrosis ratio was higher in leiomyosarcoma/STUMP compared to benign myomas ( P < 0.001). All leiomyosarcoma/STUMP tumors had a typical pattern of FDG-uptake with a specific hollow ball sign, reflecting a sharp transition between necrotic and viable, well-preserved cells. This sign was absent in benign leiomyomas.
Diagnostic tests
Most patients with rare uterine sarcomas present with abnormal uterine bleeding (65%–75%), pelvic or uterine mass (50%), pelvic pain or pressure (20%), or abnormal vaginal discharge (11%). While typical epithelial endometrial cancers can be detected with > 90 to 95% sensitivity by office EMB or dilation and curettage (D&C), there are no preoperative diagnostic tests that have been consistently utilized to diagnose uterine sarcomas. In a group of 72 women with a diagnosis of uterine sarcoma, preoperative endometrial sampling suggested an invasive tumor in 86% (62/72) and predicted the correct histologic diagnosis in 64% (46/72). The rate of detection of invasive cancer by preoperative sampling was not significantly different among sarcomas and epithelial tumors (86% vs 84%, P = 0.76) and did not differ by sampling method (EMB vs. D&C, P = 0.84). A similar, yet smaller study of 68 patients who underwent preoperative endometrial sampling with diagnosis of uterine leiomyosarcoma, showed that 52% of preoperative biopsies showed either uterine leiomyosarcoma or atypical spindle cell proliferation, and 36% confirmed uterine leiomyosarcoma specifically. Thus, it is strongly recommended to perform endometrial sampling when a uterine sarcoma diagnosis is suspected.
Endometrial sampling combined with imaging (MRI preferred) and tumor marker assessment (serum CA-125 and LDH) can increase the detection of suspected early-stage uterine sarcoma preoperatively. However, some uterine sarcomas will be diagnosed at advanced stages by CT, MRI, or PET imaging and thus, endometrial sampling or interventional radiology guided biopsy of a metastatic lesion can also be utilized for diagnostic purposes.
Staging
Staging for uterine sarcomas follows the International Federation of Gynecology and Obstetrics (FIGO) staging 2009 criteria ( Table 10.2 ). Endometrial stromal sarcomas following the same staging guidelines as uterine leiomyosarcoma given that they are pure mesenchymal in origin. Endometrial stromal sarcomas comprise 0.2% of all uterine malignancies and 10%–20% of uterine sarcomas. Endometrial stromal sarcoma is stratified by low-grade (LG-ESS) and high-grade (HG-ESS) based on pathologic criteria. LG-ESS has been characterized by expression of estrogen receptor (ER) in 70% and progesterone receptor (PR) in 90% of cases. CD10 and Ki-67 is expressed in < 5% of cells. Most LGESS is diagnosed at an early-stage with 65%–85% of cases confined to the uterus. Patients with LG-ESS typically have an indolent course with reported 5-year overall survival rates range from 80% to 100%. However, 40%–50% will recur with possibility of remote recurrences. HG-ESS is characterized by more destructive growth and necrosis, with only 50% histologically low-grade cells. High-grade cells express cyclin D1, BCOR, ER, PR, and CD10, while low-grade cells are positive for CD10, ER and PR. The majority of patients diagnosed with HG-ESS are diagnosed at advanced stages (70%), with 5-year survival rates between 30% and 35%. There is also a subset of rare uterine sarcomas classified as HG-US. These are poorly differentiated sarcomas that do not resemble proliferative-phase endometrial stroma. HG-US is characterized by TP53 mutation, variable CD10 expression, and ER and PR expression is negative. Most patients are diagnosed at advanced stage disease (stage III 10%–13%; stage IV 52%–57%), and only 20%–25% 5-year survival rate.
| (1) Leiomyosarcomas and endometrial stromal sarcomas a | ||
| 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 | |
| (2) Adenosarcomas | ||
| I | Tumor limited to uterus | |
| IA | Tumor limited to endometrium/endocervix with no myometrial invasion | |
| IB | Less than or equal to half myometrial invasion | |
| IC | More than half myometrial invasion | |
| II | Tumor extends beyond the uterus, within the pelvis | |
| IIA | Adnexal involvement | |
| IIB | Tumor extends to extrauterine pelvic tissue | |
| 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 | |
a Simultaneous endometrial stromal sarcomas of the uterine corpus and ovary/pelvis in association with ovarian/pelvic endometriosis should be classified as independent primary tumors.
Uterine adenosarcoma comprises 5%–10% of all uterine sarcomas and are characterized as mixed lesions with malignant mesenchymal and benign glandular epithelial components. In most adenosarcomas, the mesenchymal component is low-grade, resembling endometrial stromal sarcoma; however, up to 10%–25% of cases have heterologous sarcoma elements. Adenosarcoma with greater than 25% of the tumor comprised of pure high-grade sarcoma without a glandular component are designated as adenosarcoma with sarcomatous overgrowth, found in 8%–54% of cases. The FIGO staging for uterine adenosarcoma is separate from other uterine sarcomas and is also shown in Table 10.2 . The majority of patients are diagnosed as stage I in 73%–82% of cases. The 5-year overall survival for stage I patients is 63%–86%, while overall survival is less in stage III (0%–48%) and stage IV (15%) disease. The presence of sarcomatous overgrowth is a significant prognostic factor. Recurrence rates in stage I uterine adenosarcoma without sarcomatous overgrowth range from 20% to 30% compared to stage I cases with sarcomatous overgrowth between 45% and 75%.
STUMP tumors are defined as neoplasms with pathological features that preclude an equivocal diagnosis of leiomyosarcoma, but do not fulfill criteria for benign leiomyoma or its variants. The histological parameters proposed by the WHO 2014 classification refer to tumor cell necrosis, moderate-to-severe atypia, and mitotic count per 10 HPF for diagnosis of STUMP ( Table 10.3 ). Given the borderline malignant nature of STUMP tumors, there is currently no official staging system for these tumors. Even though classified as slow growing tumors, they can occasionally relapse as either a recurrent STUMP or leiomyosarcoma. Recurrence rates range from 0% to 36%, with median time to recurrence of 51 months (15 months to 9 years). Recurrent disease may involve different sites, either local in the abdomen or pelvis, or distant metastases. Five-year overall survival in patients with STUMP is 92%–100%.
| Tumor cell necrosis | Moderate to severe atypia | a Mitoses/mm 2 (mitoses/10 HPF) | Frequency of recurrence |
|---|---|---|---|
| Absent | Focal/multifocal | <4 (<10) | 17% (6 of 35 cases) |
| Absent | Diffuse | <4 (<10) | 12% (10 of 81 cases) |
| Present | None (or mild atypia) | <4 (<10) | 28% (5 of 18 cases) |
| Absent | None | >6.3 (>15) | 0% (0 of 48 cases) |
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