Endometrial Sarcomas

Cheng-Han Lee MD

The molecular alterations of uterine mesenchymal tumors have attracted more attention in recent decades because of the findings of recurrent genetic aberrations in a subset of these tumors. Although some of these genetic alterations show overlap between epithelial and mesenchymal malignancies in the uterus, there are some aberrations that are unique to uterine sarcomas. As a group, uterine sarcomas account for approximately 2% of all uterine malignancies if epithelial tumors with sarcomatous differentiation (carcinosarcomas/malignant müllerian mixed tumors and adenosarcomas) are excluded. Uterine sarcomas can be broadly classified into three major groups based on their line of cellular differentiation: endometrial stromal sarcomas (ESSs), uterine leiomyosarcomas (ULMSs), and undifferentiated endometrial/uterine sarcomas (UESs) (Table 9-1). Although a number of other sarcoma types that occur more frequently in extrauterine locations have been reported to occur in the uterus, embryonal rhabdomyosarcoma (RMS) forms the bulk of this remaining miscellaneous group of uterine sarcomas. This classification scheme also reflects our current understanding of the molecular biology of these tumors. With the exception of RMS, which tends to develop in younger age patients, the other uterine sarcomas typically occur in middle to older age women. This chapter will review briefly the molecular biology of the more common uterine sarcomas and the implication in disease classification, pathologic diagnosis, and therapy.

ENDOMETRIAL STROMAL SARCOMA

ESS is a histologically low-grade sarcoma that exhibits a histology and immunophenotype akin to that of endometrial stromal cells.¹ Even though some cases can display foci of convincing smooth muscle differentiation by histology and immunohistochemistry, most cases of ESS typically have admixed areas that demonstrate more classic histology and immunophenotype.² Although the risk of metastases is low, ESS is associated with a significant risk of local recurrence. Over time, a subset of ESS can progress, displaying a higher grade histology and eventually dedifferentiating to an apparently undifferentiated sarcoma while still possessing the same genetic aberration typical of usual low-grade ESS.³

Molecular Genetics and Biology

The published karyotypes on ESS are variable, but the majority exhibit a relatively simple karyotype.⁴^,⁵^,⁶^,⁷^,⁸ and ⁹ Even though cases with more complex karyotype have been reported, it is likely that some of these tumors previously classified as ESS would now be reclassified

under UES. Overall, rearrangements of chromosome 6p21, 7p15, and 17q21 are frequent in ESS.⁷^,⁸ By cytogenetic, polymerase chain reaction, and/or fluorescence in situ hybridization (FISH) analysis (Fig. 9-1), approximately half of ESSs carry a characteristic t(7;17)(p15;q21), resulting in gene fusion between JAZF1 and SUZ12.¹⁰ The same t(7;17) and gene fusion is also present in all endometrial stromal nodules examined to date.¹⁰^,¹¹ Normal unrearranged SUZ12 allele is also expressed in endometrial stromal nodules not expressed in ESS with t(7;17).¹² Additionally, a small subset of cases lacking t(7;17) show 6p21 rearrangement, most often in the form of der(7)t(6;7)(p21;p22)⁵^,¹⁰ with the rearrangement of 6p21 leading to the fusion of PHF1 with partner genes such as JAZF1 or EPC1.⁵^,¹³ One case of ESS with t(X;17) involving rearrangement of SUZ12 was recently described.⁹ SUZ12 and PHF1 are both members of Polycomb group proteins, which participate in transcriptional silencing through chromatin remodeling, a mechanism that is crucial in cellular development.¹⁴ In ESS, the gene fusion likely results in the formation of functionally aberrant Polycomb complexes. Furthermore, although both endometrial stromal nodules and ESS carry t(7;17),
only ESS exhibits concurrent silencing of the unrearranged SUZ12 allele and would result in the complete abrogation of normal SUZ12 protein function. Although the precise oncogenic mechanism has not been elucidated, it would appear that abnormal transcriptional repression is central to oncogenesis of ESS. Even though abnormal expressions of Polycomb genes are commonly seen in other malignancies,¹⁴ genetic fusion/rearrangement of these Polycomb group members as demonstrated by cytogenetic and/or FISH analysis using, for example, the JAZF1 break-apart probe set (Fig. 9-1) has only been described for endometrial stromal nodules, ESS, and a subset of UES (suspected dedifferentiated ESS) to date. Therefore, this series of genetic aberrations represents a highly specific molecular diagnostic feature for the family of endometrial stromal tumors, even in cases with smooth muscle differentiation.²^,¹¹^,¹⁵^,¹⁶ However, the sensitivity of such molecular testing is inadequate because 40% to 50% of ESSs can lack these changes. There is currently also no diagnostic immunomarker that can be used to reliably distinguish ESS from other uterine sarcomas like ULMS. Further characterization of the full molecular/genetic spectrum of this disease perhaps using a next-generation sequencing approach is needed to improve the sensitivity of these diagnostic molecular tests.

Table 9-1 Classification of Uterine Sarcomas

	Genetic Aberrations	Genes of Interest	Frequency	Specificity
Uterine leiomyosarcomas (ULMSs)	Complex karyotype; frequent random structural and numerical aberrations and frequent imbalances in 1, loss in 14q and 22q, gains in 8, 17, X	Frequent TP53 mutation	Majority	No tumor-specific recurrent aberrations
Endometrial stromal sarcoma (ESS)	t(7;17)(p15;q21)	JAZF1-JJAZ1	-50%	Specific for ESN and ESS*
	t(6;7)(p21;p15)	JAZF1-PHF1	-5%	Specific for ESS^*
	Other types of 6p21 rearrangement: t(6;10;10)(p21;q22;p11), t(3;6)(q29;p21.1)	PHF1 rearrangement; partner gene EPC1 in 10p11	<5%	Unknown
	Other undefined translocation: t(10;17)(q22;p13), t(X;17)(p11;q23)	Genes unknown	-5%	Unknown
Undifferentiated endometrial/uterine sarcoma (UES)	Complex karyotype; multiple numerical and structural aberrations	Frequent TP53 mutation	Majority	No tumor-specific recurrent aberrations^*
Embryonal rhabdomyosarcoma (ERMS)	Frequent allelic loss in 11p15; some show complex karyotype		Majority	No tumor-specific recurrent aberrations
^One case of UES with uniform nuclear feature was reported to express JAZF1-JJAZ1* fusion gene transcript. ESN, endometrial stromal nodule.

FIGURE 9-1: A case of endometrial stromal sarcoma positive for JAZF1 rearrangement, as demonstrated by the break-apart fluorescence in situ hybridization assay (red signal: centromeric JAZF1 probe; green signal: telomeric JAZF1 probe).

Potential Biologically Oriented Therapies

A notable feature of ESS is its expression of estrogen receptor (ER) and progesterone receptor (PR).³^,

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