Endometrial Stromal Tumors (EST), 7p15 (JAZF1), 6p21.32 (PHF1), 17p13.3 (YWHAE) Rearrangement, FISH, Tissue
Supporting the diagnosis of endometrial stromal tumors when used in conjunction with an anatomic pathology consultation
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Endometrial stromal tumors (EST) arise from the uterus and include the benign endometrial stromal nodule (ESN) and infiltrative endometrial stromal sarcoma (ESS). These tumors are characterized by a translocation that fuses JAZF1 at 7p15 to JJAZ1 at 17q21 or a variant 6;7 translocation involving JAZF1 and PHF1. Published literature employing FISH and reverse transcriptase PCR (RT-PCR) suggests rearrangement of JAZF1 occurs in approximately 76% of ESN and approximately 58% of ESS. JAZF1 is not generally considered to be involved in the genetic mechanism of the high-grade undifferentiated endometrial sarcoma (UES), although rarely some cases of UES are positive for JAZF1, which may reflect the presence of an ESS component.
For PHF1 disruption, a study of 94 EST demonstrated the following:
-PHF1/JAZF1 fusion in 4 primary ESS
-PHF1/EPC1 fusion in 2 primary ESS and 1 extrauterine ESS
-PHF1 rearrangement without a known partner in 6 primary or metastatic ESS and 1 extrauterine ESS
JAZF1/JJAZ1, PHF1/JAZF1 and PHF1/EPC1 fusions were mutually exclusive in individual patients.(4) No rearrangement of PHF1 was found in ESN, UES, or non-EST tumors in the differential diagnosis. These results indicate that PHF1 can rearrange with both known and unknown partners in addition to JAZF1 and is potentially specific for ESS.
In high-grade ESS, a recurrent t(10;17)(q22;p13) resulting in fusion of YWHAE (also called 14-3-3epsilon at 17p13.3 with either FAM22A or FAM22B was identified. In contrast, JAZF1 rearrangements are typically observed in low-grade ESS. JAZF1 and YWHAE rearrangements are mutually exclusive and have distinct gene expression profiles. YWHAE rearrangement is potentially specific for high-grade ESS as no YWHAE disruption has been reported in other uterine or nonuterine mesenchymal tumors.
The clinical utility of identifying JAZF1 rearrangement is mainly to address the differential diagnostic dilemma that occurs when ESS are present as metastatic lesions or exhibit variant morphology. In JAZF1-negative EST cases, reflex genetic analysis to identify PHF1 or YWHAE rearrangement increases the diagnostic sensitivity for EST. In addition, confirmation of YWHAE rearrangement may have prognostic implications as YWHAE defines a distinct, clinically more aggressive and histologically higher grade subgroup of ESS compared to those with JAZF1 rearrangements.
A neoplastic clone is detected when the percent of cells with an abnormality exceeds the normal cutoff for any given probe.
Detection of an abnormal clone likely indicates a diagnosis of an endometrial stromal tumor of various subtypes.
The absence of an abnormal clone does not rule out the presence of a neoplastic disorder.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
This test is not approved by the FDA and is best used as an adjunct to existing clinical and pathologic information.
Fixatives other than formalin (eg, Prefer, Bouin's) may not be successful for FISH assays. Although FISH testing will not be rejected due to nonformalin fixation, results may be compromised.
Paraffin-embedded tissues that have been decalcified are generally unsuccessful for FISH analysis. The pathologist reviewing the hematoxylin and eosin-stained slide may find it necessary to cancel testing.
FISH analysis was performed on 101 formalin-fixed, paraffin-embedded tissue specimens including 26 normal controls; 37 endometrial stromal tumors (EST) (8 endometrial stromal nodule: ESN, 20 primary or metastatic endometrial stromal sarcoma: ESS, and 9 primary or metastatic undifferentiated endometrial sarcoma: UES); and 38 histologic mimics of EST including cellular leiomyoma. The normal controls were used to generate a normal cutoff for this assay. No rearrangements of JAZF1 were identified in the 26 normal controls or 37 of the histologic mimics. A single histologic mimic was positive with a complex pattern and is being further explored. Rearrangement of JAZF1 was identified in 17 of 37 (46%) EST specimens (3 ESN, 13 ESS, and 1 UES).
PHF1 and YWHAE:
FISH analysis was performed on 91 formalin-fixed, paraffin-embedded tissue specimens including 26 normal controls, 20 EST (5 ESN, 7 primary or metastatic ESS, and 8 primary or metastatic UES), and 35 histologic mimics of EST in a blinded manner using standard sample processing techniques and FISH methodology. Also included were 6 known JAZF1-positive cases and 4 clinical cases that were negative for JAZF1 rearrangement. The normal controls were used to generate a normal cutoff for this assay. No rearrangements of PHF1 or YWHAE were identified in the 26 normal controls or 35 of the histologic mimics. One primary UES failed to hybridize and yielded no results for either probe. Rearrangement of PHF1 was identified in 1 of 19 (5%) EST specimens (primary ESS) and in 1 of 6 (17%) of known JAZF1-positive cases (metastatic ESS). Rearrangement of YWHAE was identified in 2 of 19 (11%) EST specimens (primary ESS and metastatic UES).
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
1. Koontz J, Soreng AL, Nucci M, et al: Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors. Proc Natl Acad Sci USA 2001;98(11):6348-6353
2. Nucci R, Harburger D, Koontz J, et al: Molecular analysis of the JAZF1-JJAZ1 gene fusion by RT-PCR and fluorescence in situ hybridization in endometrial stromal neoplasms. Am J Surg Pathol 2007;31(1):65-70
3. Huang HY, Ladanyi M, Soslow RA: Molecular detection of JAZF1-JJAZ1 gene fusion in endometrial stromal neoplasms with classic and variant histology-evidence for genetic heterogeneity. Am J Surg Pathol 2004;28(2):224-232
4. Chiang S, Ali R, Melnyk N, et al: Frequency of known gene rearrangements in endometrial stromal tumors. Am J Surg Pathol 2011;35(9):1364-1372
5. Lee CH, Marino-Enriquez A, Ou W, et al: The clinicopathologic features of YWHAE-FAM22 endometrial stromal sarcomas: A histologically high-grade and clinically aggressive tumor. Am J Surg Pathol 2012;36(5):641-653