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Other rare uterine sarcomas: Adenosarcoma, endometrial stromal sarcoma, STUMP
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.
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