Günter Köhler, Katja Evert, Marek Zygmunt and Matthias Evert

5High-grade endometrial stromal sarcoma and undifferentiated uterine sarcoma

5.1Uterine high-grade endometrial stromal sarcoma and undifferentiated uterine sarcoma

5.1.1General, epidemiology, etiology, pathogenesis, staging

HG-ESS and UUS are pure homologous uterine sarcomas. Endometrial stromal sarcomas had originally been divided into LG-ESS and HG-ESS. This differentiation was primarily based on the number of M/10 HPF. At the time, tumors with < 10M/10HPF were categorized as LG-ESS, while such with ≥ 10 M/10 HPF were termed HG-ESS. It had, however, already been known for some time that prognosis did not always correlate with mitotic count. Accordingly, the categorization of tumors into LG- and HG-ESS along the lines of MI was abandoned some years ago. Instead, stromal sarcomas were pathologico-anatomically differentiated into endometrial stromal sarcoma (ESS) and undifferentiated endometrial sarcoma (UES) on the basis of cytologic pleomorphism, the degree of nuclear atypia and the presence of TCN. These two entities also differed in terms of their immunologic and cytogenetic profiles (27), a difference that could be drawn on in cases of uncertainty when having to discern between the two. Under this classification, ESS (optionally ESS low-grade) constituted themore differentiated and prognostically more favorable tumor, while UES was comparably less differentiated and clearly the more aggressive of the two. According to the criteria of the time, tumors with an MI of ≥ 10M/10HPF could be ESS, and tumors with an MI < 10M/10HPF could be classified as UES. Differentiation between the two was thus guided by cytologic/nuclear properties and features.

Already at the time, this switch in classification had a severe impact on the validity of numerous studies and their findings, also such regarding prognosis.

The current WHO Classification of 2014 (60) has returned to the distinction into LG-ESS and HG-ESS, but now also includes UUS. Tumors previously categorized as UES now need to be divided into HG-ESS and UUS. What makes this a difficult endeavor is that even contemporary handbooks on gynecologic pathology use the terms UES and UUS interchangeably or synonymously (9). It is likely that the majority of tumors previously classified as UES will be HG-ESS under the current WHO Classification (60). To date, no randomized studies have yet been conducted with a specific focus on UUS. Retrospective studies on this type of neoplasm are rare, and even when they use the term UUS, studies generally incorporate tumors previously classified as UES, which also includes lesions that fulfill current UUS criteria, but not only. The same applies for the current NCCN Guidelines Uterine Sarcomas 2.2016 (55). Therapeutic recommendations for these two entities currently only marginally differ from each other, if at all. The recommendations made in this monograph thus always refer to both of these types of sarcoma. Specific reference is made whenever the approach might differ between the two.

HG-ESS and UUS need to be clearly differentiated from LG-ESS, pathogenetically, morphologically, clinically, prognostically and therapeutically. The data situation for HG-ESS and UUS is particularly poor in terms of research into adequate therapy. Recommendations are largely based on isolated case studies and retrospective analyses with relatively small samples that frequently cover all stages of disease. We are not aware of any valid reliable data. Interpreting the results from these studies is further exacerbated by the fact that they often investigate both UUS and LG-ESS together.

HG-ESS, UUS and LG-ESS account for a combined share of 15–20% of all uterine sarcomas. The HG-ESS/UUS and LG-ESS subcategories have a rough ratio of 1 to 2 (34, 76), while the inner ratio between HG-ESS and UUS is about 55 to 45% (34). Women with HG-ESS and UUS have a median age of between 58 and 63 years, and are thus noticeably older than LG-ESS patients (34, 40, 76, 86). Among DKSM cases, LG-ESS patients had a median age of 46 years (mean 46.7), compared to 58 years (mean 58.1) among HG-ESS patients and 60 years (mean 59.8) among patients with UUS, a difference to the former of 12 and 14 years, respectively (34). There is, therefore, also a significant age difference between HG-ESS and UUS patients.

HG-ESS and LG-ESS both derive from the endometrial stroma(8, 38, 58). This commonality notwithstanding, they are nonetheless pathogenetically independent of one another. A fusion of the YWHAE and NUTM2 genes (YWHAE-FAM22), a result of chromosomal translocation of t(10;17) (q22;p13), can be found in HG-ESS. In LG-ESS, by contrast, JAZF1-SUZ12 is the most characteristic gene fusion (Tab. 5.1.1) (cf. Chapter 4) (19, 41, 42). The fact that HG-ESS and LG-ESS exhibit differing fusion genes suggests that an HG-ESS does not usually develop from an LG-ESS (74). But there this is a first report of aYWHAE-NUTM2A/B ESS that was confined to the endometrium and which exhibits entirely LG morphology (3). On the other hand, not all HG-ESS show YWHAE-NUTM2-gene fusion and not all LG-ESS exhibit LG-ESS related gene fusions (50). The principal difference between HG-ESS and UUS lies in the fact that the cytological criteria of the former resemble endometrial stroma to any degree (74). These cytological criteria as well as the fusion genes found in LG-ESS and HG-ESS are absent in UUS (19, 38, 41). UUS and LMS occasionally show focal expression of cyclin D1, though said expression is usually weak when present (42). In contrast, UUS exhibit complex chromosomal aberrations, with gains on 2q, 4q, 6q, 7p, 9q, and 20q, and losses/deletions on 3q, 10p, 14q (21). UUS generally exhibits no specific type of differentiation, and its histogenesis remains unclear (60). UUS thus constitutes an independent type of neoplasm. There have been accounts of cases in which HG-ESS and UUS have developed from or alongside an LG-ESS (16, 28, 38, 60). Significant associations between HG-ESS/UUS and tamoxifen therapy are considerably rarer than is the case for LG-ESS, LMS and CS (22, 75).

HG-ESS/UUS constitute the most common sarcomatous components in homologous CS (cf. Chapter 7, Vol. 2) and homologous AS (cf. Chapter 6, Vol. 2) with SO. HG-ESS/UUS are occasionally also classified as monophasic CS in which the epithelial component is not (or no longer) discernible. This could be supported by the fact that, like CS, these types of neoplasms sometimes exhibit positive immunoreactivity to ERBB-2, while ERBB-2 is not overexpressed in LG-ESS, LMS and AS (4).

New FIGO staging and UICC TNM classification for LMS and stromal sarcomas (cf. Tab. 2.1.1) have applied since 2009.More detail pertaining to the problems resulting from said change in staging and classification are presented in the chapter on LG-ESS.

High-grade endometrial stromal sarcomas and undifferentiated uterine sarcomas predominantly arise in postmenopausal women. These two entities had previously been comprised under the term “undifferentiated endometrial stromal sarcoma”. Nowadays, the majority of tumors falling under the aforementioned nomenclature are classified as high-grade endometrial stromal sarcoma. High-grade endometrial stromal sarcomas derive from the endometrial stroma. High- and low-grade endometrial stromal sarcomas have independent pathogeneses and are to be regarded as two separate tumor types. In particular, they differ substantially in terms of their expression of different fusion genes. The pathogenesis and histogenesis of undifferentiated uterine sarcomas remain unclear. Undifferentiated uterine sarcomas only exceptionally develop from an endometrial stromal sarcoma. High-grade endometrial stromal sarcoma and undifferentiated uterine sarcomas, too, must be regarded as independent types of neoplasms. The same staging criteria apply to both of these tumors as also apply to low-grade endometrial stromal sarcomas and leiomyosarcomas.

5.1.2Macroscopic and microscopic features

Gross examination of HG-ESS/UUS often reveals polypoid fleshy masses in the cavity of the uterus that are yellowish, yellowish-gray, or grayish-white in color, and which are characterized by hemorrhages and necroses as well as extensive myometrial invasion in some cases. Decomposed necrotic masses can constitute up to 90% of the tumor (Fig. 5.1.1 (A)). HG-ESS/UUS generally exhibit rapid growth, quickly fill the entire uterine cavity, and are associated with a rapid increase in the size of the uterus. Rapid tumor growth causes the cervix to distend relatively early on, and tumor masses become visible in the vagina. The edge of the outer cervical os and sometimes the cervical canal can be easily discernible on palpation, which suggests that the tumor has developed and grown from the cavum uteri (Fig. 5.1.1 (A), (B), 5.1.7(A)). Direct cervical involvement or growth into the cervix is not uncommon (Fig. 5.1.9 (A)–(F), 5.1.11 (A)). The borders of the uterus are often exceeded within a very short period of time (Fig. 5.1.1 (C)). Due to their rapid growth rate, HG-ESS already have mean and median diameters of 8.0 and 7.5 cm, respectively, at the time of initial diagnosis (min: 1.7 cm; max: 15 cm) (34). The fact that UUS are generally larger at the time of initial diagnosis strongly underlines their higher degree of malignancy compared to HG-ESS. UUS have mean and median sizes of 12.2 and 11 cm (min: 2.6 cm; max: 24 cm), respectively (Tab. 5.1.2) (34). The low-grade component of HG-ESS (see below) can sometimes be easy to discern on gross observation, and bears resemblance to the macroscopic features found in LG-ESS (74).

Fig. 5.1.1: Macroscopic appearance of undifferentiated uterine sarcoma. (A) almost 90% of this tumor in a 78-year-old patient consists of necrosis, the vast pressure resulting from the tumor’s growth has caused the cervix to expand; (B) the uterine cavity of a 77-year-old patient is filled by a 13 cm× 10 cm large tumor that is partly necrotic and that has prolapsed from the cervix in a polypoid fashion; additionally, metastases were found on the peritoneum of the urinary bladder and in the left adnex; (C), (D) perforation of the wall of the uterus as a result of the pressure generated by the tumor’s rapid growth, as depicted in this case of a 68-year-old woman, is a common finding, (D) the uterus from (C) has been opened in the area of the fundus. Like in (A), (B), it is noticeable that the undifferentiated uterine sarcoma has predominantly developed intercavitarily and is characterized by a high degree of pleomorphism. Uninvolved endometrium is marked with arrows.

Tumor decomposition and/or necrosis can result in pyometra (Fig. 5.1.11 (A)). HG-ESS and UUS are highly pleomorphic and thus can already be clearly discerned from the more knotty, nodular, and uniform LG-ESS on the basis of gross macroscopic appearance. Furthermore, while the former are predominantly intracaval, the latter are usually intramurally localized. Macroscopically discerning HG-ESS and UUS from polymorphous LMS, CS or G3-EC is barely possible.

HG-ESS essentially represents a group of tumors that has previously been classified as “UES with nuclear uniformity” (monomorphic UES) (38). UES with nuclear uniformity has also been classified as a hybrid tumor (58) and occasionally referred to as ESS high-grade (93). Within HG-ESS or monomorphic UUS, there is a coexistence of areas of low-grade structures with close resemblance to LG-ESS on the one hand, and (usually predominating) high-grade areas on the other. The low-grade component is characterized by uniform low-grade spindle cells with visible cytological connections to the endometrial stroma, and finger- or worm-like (permeative) myometrial invasions. The high-grade areas, in contrast, exhibit higher degrees of nuclear atypia, ample TCN, a usually clearly elevatedMI (> 10 M/10 HPF), LVI, and destructive myometrial invasions. The high-grade component typically exhibits nests of round cells that are separated from each other by a capillary network. The round cells can occasionally exhibit a rhabdoid character and a pseudoglandular appearance (35, 38, 58, 60) (Fig. 5.1.2 (A)–(C)).

LVI of HG-ESS have discohesive cell clusters and thus clearly lack the features described for LG-ESS (70). This also serves to explain why HG-ESS are metastasized more frequently, while dissemination is slower in LG-ESS, i.e. is more rapid when the latter is punctured or otherwise injured (for details see Chapters 4 and 6). The coexistence of differing cytological criteria is also associated with variations in CD10, ER, and PGR expressions within the tumor (38, 58, 60, 74). Diffuse and strong CD10, ER, and PGR expression can be found in the low-grade component in particular. It is thus by all means appropriate to conduct HR testing at least in HG-ESS with a view to potential HT. By contrast, the high-grade component is characterized by ER, PGR, and CD10 negativity (74). These findings correlate with diffuse and strong cyclin D1 positivity.

Fig. 5.1.2: High-grade endometrial stromal sarcoma – histology. (A) pleomorphic high-grade area with a low-grade component that is typical for this type of tumor. (B), (C) the same tumor has a heterologous component in the form of rhabdomyosarcoma, with clear expression of desmin as shown in (C).

Cyclin D1 is regarded as a marker for the fusion gene YWHAE-FAM22 (40, 41) that is only found in the high-grade component of HG-ESS (Tab. 5.1.1).While this fusion gene may not be traceable in some cases, it nonetheless remains an important characteristic of HG-ESS that does not occur in LG-ESS or UUS, though it can be focally and weakly expressed in UUS and LMS on rare occasions (42). But there this is a first report of a YWHAE-NUTM2A/B ESS that was confined to the endometrium and which exhibits entirely LG morphology (3). On the other hand, not all LG-ESS exhibit LG-ESS related gene fusions (50). Diffuse expression of cyclin D1 has also been described in cases of undifferentiated endometrial carcinoma (77), but also in clear cell sarcoma of the kidney (6).

Table 5.1.1 contrasts the features and characteristics of JAZF1/JJAZ1 and YWHAE/ FAM22A/B translocations in endometrial stromal sarcomas.

The fusion genes JAZF1 and JJAZ1 are occasionally traceable in HG-ESS (38, 40, 41, 74). Ten percent of cells express p53. Some HG-ESS express CD117, the antigen or protein of the proto-oncogene c-Kit. In one corresponding study, 5 of 11 tumors showed a positive reaction to KIT (71). Such tumors are generally eligible for treatment with the c-Kit inhibitor and TKI imatinib (71). A further recent study revealed no mutations of the

Tab. 5.1.1: Comparison between JAZF1/JJAZ1 and YWHAE/FAM22A/B translocation in low- and highgrade endometrial stromal sarcomas (20).

	JAZF1/JJAZ1	YWHAE/FAM22A/B
Translocation	t(7;17) (p15;q21)	t(10;17) (q22;p13)
Endometrial stromal sarcoma	low-grade	high-grade
Growth characteristics
Myometrial infiltration	frequent	frequent
Vascular invasion	frequent	frequent
Biphasic (round and spindle cells)	rare	frequent
Stromal vascularization	prominent arterioles surrounded by tumor cells	thin-walled capillary network
Cytologic features
Shape of nuclei	round to spindled	round, arranged in nests
Size of nuclei	small (≈ 2–4 × nuclei of lymphocytes)	large (≈ 4–6 × nuclei of lymphocytes)
Membrane of nuclei	smooth contour	irregular contours
Nuclear polymorphism	homogeneous nuclei	irregular nuclei
Mitotic activity	usually < 5M/10 HPF	> 10M/10 HPF
Tumor cell necrosis	occasionally	frequent
Receptors (ER, PR, CD10)	usually positive	negative (in the high-grade section)
Cyclin D1	negative	positive
5-year survival rate	ca. 85%	< 50%

KIT, PDGFRA and EGFR genes in LG-ESS and HG-ESS/UUS. In another analysis (73), overexpression of KIT, PDGFRA and EGFR was observed in only 2 (3%), 23 (35.4%) and 7 (10.8%) cases, respectively, while EGFR gene amplifications were not encountered. Overall, the simultaneous presence of positive, negative or heterogeneous ER, PGR, CD10, and cyclin D1 expression, and of the YWHAE-FAM22 and JAZF1 and JJAZ1 fusion genes, shows that both HG-ESS and LG-ESS derive from the endometrial stroma. The observation that an HG-ESS is reminiscent of or bears resemblance to the endometrial stroma in any way is a decisive diagnostic factor that clearly delineates such neoplasms from UUS (74). More recently, three different categories of HG-ESS have been defined on the basis of IHC and genetic characteristics. However, they do not differ clinically or in terms of prognosis (74).

Transformation of an LG-ESS into an HG-ESS is also occasionally observed (15).

UUS largely correspond to the type of neoplasm previously referred to as “pleomorphic UES” (pleomorphic variant of UES) (4). Recent studies suggest that pleomorphic UES andUUS can in fact be equated to each other (74).UUS exhibit such extensive dedifferentiation that it can often no longer be discerned that (or whether) they originated from the endometrial stroma or the myometrium. Some UUS, however, contain clearly delimited areas of LG-ESS, and could in fact constitute dedifferentiated stromal sarcomas in such cases. The cells of UUS are characterized by clear aneuploidy, marked cellular and nuclear pleomorphism including prominent nucleoli and bizarre multinucleous giant cells, and no specific type of differentiation. Expansive foci of coagulative necrosis and high rates of (often atypical)mitoses are typical characteristics of UUS (38, 60, 96). The MI usually clearly exceeds 10M/10HPF, but can be lower in some cases (Fig. 5.1.3 (A)–(C)). Though predominantly spindle celled, epithelioid and heterologous differentiations can also be observed.

Destructive myometrial infiltration is already visible on gross observation and usually occurs at multiple localizations simultaneously. Furthermore, early and extensive discohesive LVI and VI are observed in 47 and 48% of cases, respectively (Fig. 5.1.3 (D)) (34). Both are responsible for the relatively early occurrence of recurrences and metastasis and serve to clearly differentiate these entities from LG-ESS, in which VI is cohesive (cf. Chapter 4 and Fig. 4.1.3 (A), (B)). UUS/pleomorphic UES exhibit no (or occasionally weak) HR and CD10 expression (1, 11, 24, 27, 38, 60, 86). CD10 is usually also positive when cyclin D1 expression is diffuse (42). Desmin, SMA, or cytokeratins have also been traced in UUS in some cases (1, 38, 86). P53 expression is positive in 57% of UUS (27). The fusion genes typically encountered in LG and HG-ESS are not traceable in UUS (38). Ultimately, IHC analyses of UUS are very unreliable, as these dedifferentiated tumors have already lost their reactivity to numerous antigens (93). Taken together, the evidence underlines that, unlike LG-ESS and HG-ESS, and bar a few exceptional cases, UUS do not derive from the endometrial stroma. The latter is therefore called undifferentiated uterine and not undifferentiated endometrial sarcoma.

Fig. 5.1.3: Undifferentiated uterine sarcoma – histology. (A) the visibly high grade of cellular atypia is an important feature, (B) shows the high number of mitoses and apoptoses (lower and upper arrow); (C) tumor cell necroses account for roughly 50% of the total surface; (D) early vascular invasion is clearly recognizable and constitutes a pivotal factor promotive of rapid metastasization.

The most evident commonality between UUS and HG-ESS is the fact that both are highly aggressive neoplasms and contain ample TCN.

All endometrial sarcomas express EGFR (51), while UUS express EGFR, PDGFR-α and PDGFR-β (26).

The UICC no longer envisages a grading for uterine sarcomas (92).

In terms of their macroscopic features, high-grade endometrial stromal sarcomas and undifferentiated uterine sarcomas present as polypoid, fleshy, often decomposing tumors with ample necroses and hemorrhages. They are usually localized in the myometrium and endometrium and often fill the entire uterine cavity. Undifferentiated uterine sarcomas are usually already considerably larger than high-grade endometrial stromal sarcomas at the time of primary diagnosis.

Besides low-grade cellular components usually with positive hormone receptors, CD10 positivity and permeative invasions, high-grade endometrial stromal sarcomas predominantly also contain high-grade sections with ample atypia, tumor cell necroses, a mitotic index of more than 10 M/10 HPF and destructive myometrial invasion. Undifferentiated uterine sarcomas are characterized by extensive dedifferentiation with marked cellular and nuclear pleomorphism, usually with ample mitoses and tumor cell necroses as well as extensive destructive invasion into their surroundings. Undifferentiated uterine sarcomas are usually negative for CD10 and hormone receptors. Undifferentiated uterine sarcomas do not appear to have any particular type of differentiation.

5.1.3Clinical presentation, diagnostics, screening

Postmenopausal bleeding is the pivotal symptom of HG-ESS/USS. Premenopausal women usually present with AUB or irregular vaginal bleeding. Rapid tumor growth results in marked, usually irregular enlargement of the uterus, and is usually associated with lower abdominal pains and uresiesthesis. Accordingly, HG-ESS and UUS already have median diameters of 7.5 resp. 11.0 cm at the time of primary diagnosis (34). Postmenopausal uterine growth should generally arouse suspicion of sarcoma. HG-ESS/USS have a predominantly soft consistency. The rapid growth of such tumors can cause tumor masses to protrude from the cervix at a very early stage. Contact bleeding can therefore arise, and the extension or dilatation of the cervix can result in labor-like pains. Putrid, fetid discharge is also not uncommon in patients with large decomposing tumors. Symptoms and findings can be largely identical to those associated with LMS, CS and AS with SO, making differentiation from and between these different neoplasms on the basis of clinical findings alone very difficult. The uterus can be either mobile or entirely immobile, depending on the size of the tumor and its degree of dissemination/ spread into its surroundings.

Distant metastatic disease occurs very early. It is thus not seldom the case that HG-ESS/UUS are primarily discovered upon detection of their metastases.

Diagnostic procedures largely correspond to those followed for LMS or LG-ESS (see also Chapters 2 and 4). Since up to 90% of the tumor can consist of necrotic tissue, it can occur that performing multiple curettages still fails to yield any actual tumor tissue, especially in UUS. Diagnosis should be verified via THE in cases in which abrasions performed on tumors that have been clinically observed to be decomposing (HSC, macroscopic assessment of the curettage specimen) repeatedly only yield necrotic tissue. HG-ESS/UUS or malignancies are correctly diagnosed as such on the basis of curettage specimen analysis alone in only 35–65% of cases, and findings are deemed unambiguous in up to 35% of cases (34, 86).

As metastatic spread to the abdominal cavity and the lungs is already present in up to 52% of cases at the time of primary diagnosis (86), the pelvis, the abdomen, and the thorax should be subjected to imaging-based staging using CT or MRI after receipt of the histological diagnosis. There is currently no scientific justification for performing PET-CT in the context of primary diagnostics (67).

Analogous to the other types of uterine sarcoma, no particular form of screening is performed in cases of HG-ESS/UUS. There are no known precursors for either of these tumor types that would allow an early suspicion of the presence of such tumors or of the potential for such tumors to develop out of them. At best, preventive medical examinations for cervical carcinoma might reveal the presence of tumor cells that are not in line with a diagnosis of cervical carcinoma, i.e. that are suggestive of another neoplasm. The presence of malignant mesenchymal cells in cytological smear tests is virtually always strongly suggestive of sarcoma, though the exact type of sarcoma is usually not discernible. One publication does report that smear testing returned positive cytology in 8 of 11 cases of HG-ESS/UUS (47). Because exposure to tamoxifenmight be pathogenetically associated with LG-ESS/UUS, gratuitous use should be made of TVS for such patients.

Abnormal uterine bleeding and lower abdominal pains are the central symptoms of high-grade endometrial stromal sarcoma and undifferentiated uterine sarcoma. The uterus is usually clearly and irregularly enlarged, and the rapid growth of the tumor often causes it to protrude from the cervix. Sonography, hysteroscopy and curettage are the most important diagnostic methods. Imagingbased staging should be performed when the diagnosis is clear. Screening is not routinely performed.

Only gold members can continue reading. Log In or Register to continue