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Background
This is a very rare cancer arising predominately within the endometrium. Most of the patients present with abnormal uterine bleeding and occasionally pelvic pain. On physical examination, there is frequently uterine enlargement. Despite its rarity, this is an important diagnosis because of the very different and sinister prognosis for some of these tumors. The pathologist may be faced with a difficult task of suggesting or diagnosing this disease based upon a small sampling or curretting of the endometrium. The key differentiating point rests in separating low grade tumors from leiomyomas, a very common tumor of the uterus. These tumors that have been misdiagnosed as leiomyomas may recur many years later or even metastasize.
OUTLINE
PATHOGENESIS CHARACTERIZATION JAZFI-JJAZ1 GENE FUSION
Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, Japan.
Classification and terminology of non-low-grade endometrial sarcomas, which show significant nuclear atypia, have been controversial. Currently, these tumors seem to be classified all together into "undifferentiated endometrial sarcoma (UES)." However, it remains unclear whether these non-low-grade sarcomas are universally "undifferentiated."
We divided these sarcomas morphologically into undifferentiated endometrial sarcoma with nuclear uniformity (UES-U) and undifferentiated endometrial sarcoma with nuclear pleomorphism (UES-P), and compared their molecular genetic and immunohistochemical profiles. Eighteen low-grade endometrial stromal sarcomas (ESS-LG), 7 UES-U, and 6 UES-P were examined. All the patients with ESS-LG were still alive, either with or without disease, whereas 4 of the 5 patients with advanced stage UES-U and all 3 of the patients with advanced stage UES-P had died of the disease. JAZF1-JJAZ1 fusion transcript was detected in 6 (50%) out of 12 ESS-LG and in 1 (33%) of 3 UES-U, whereas it was not detected in any of the cases of UES-P. ESS-LG and UES-U frequently showed positive immunoreaction for estrogen receptor (ESS-LG: 94%, UES-U: 57%) and progesterone receptor (ESS-LG: 94%, UES-U: 57%), whereas all the UES-P were negative for these receptors. Nuclear beta-catenin expression was more frequently recognized in ESS-LG (47%) and UES-U (85%), compared with UES-P (33%). Moreover, nuclear accumulation of p53 and TP53 gene missense mutations were limited to 3 UES-P cases.
Our data suggest that UES-U shares some molecular genetic and immunohistochemical characteristics with ESS-LG, but UES-P considerably differs from ESS-LG.
*Department of Pathology, Massachusetts General Hospital, Boston, MA Departments of †Pathology §Human Genetics, C.H.U. Sart-Tilman, Lie`ge, Belgium ‡Department of Pathology, Memorial Sloan Kettering Cancer Center, New-York, NY.
The most common cytogenetic alteration observed in low-grade endometrial stromal tumors (EST) is the t(7;17)(p15;q21) translocation, resulting in the fusion of the JAZF1 and JJAZ1 genes. By reverse-transcription polymerase chain reaction, the translocation has been detected overall in one-third of ESTs, but only rarely in its variants.
The purpose of this study was to develop a fluorescence in situ hybridization assay for detection of this translocation using archival paraffin-embedded samples of ESTs with smooth muscle differentiation and to assess the nature of the smooth muscle component of these tumors. Representative paraffin blocks of 9 endometrial stromal nodules and 1 low-grade endometrial stromal sarcoma were collected for the study. In 1 case, the block selected also contained areas of sex cordlike differentiation. A fluorescence in situ hybridization probe set was designed to detect the t(7;17)(p15;q12) on tissue sections. Six out of 10 collected ESTs were assessable. Fusion signals were detected in 3 out of 6 cases (50%) in both the conventional endometrial stromal and the smooth muscle components of the tumors. The tumor sample with sex cordlike differentiation harbored the fusion signal in all the 3 components.
Our results support the contention that the endometrial stromal and smooth muscle components of these tumors have the same origin, either from a common precursor cell with pluripotential differentiation or from endometrial stromal cells that have undergone smooth muscle metaplasia.
Our results indicate that the detection of this chromosomal abnormality can be used to diagnose ESTs with smooth muscle differentiation when the smooth muscle component is predominant.
*Divisions of Molecular Oncology, Women's and Perinatal Pathology, and Cytogenetics, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115 daggerProgram in Molecular Diagnostics, Department of Pathology, Yale University School of Medicine, New Haven, CT 06510 double daggerDepartment of Medicine, Duke University School of Medicine, Durham, NC.
Nonrandom cytogenetic abnormalities of chromosomes 6, 7, and 17 have been reported within low-grade endometrial stromal sarcomas (LGESSs), and among these abnormalities, the t(7;17)(p15;q21) is the most common aberration described. Previously we had shown that this translocation joins 2 genes, JAZF1 and JJAZ1, located on chromosomes 7 and 17, respectively.
To determine the frequency of the t(7;17), we analyzed 4 stromal nodules and 24 LGESS by both reverse transcriptase-polymerase chain reaction and fluorescence in situ hybridization (FISH). In addition, we examined 4 cases of highly cellular leiomyoma, a benign morphologic mimic of LGESS.
Overall, evidence for the JAZF1-JJAZ1 fusion was found in 60% of endometrial stromal neoplasms analyzed (8/16 ESS and 4/4 stromal nodules). One LGESS demonstrated only rearrangement of 7p15 by FISH analysis and karyotypic analysis of this case showed t(6;7)(p21;p15). The fusion was not detected in any highly cellular leiomyomas.
Our data suggest that the JAZF1-JJAZ1 fusion is a frequent, although nonuniform, feature of endometrial stromal neoplasia, irrespective of benign versus malignant classification and smooth muscle differentiation. In addition, the detection of the fusion by reverse transcriptase-polymerase chain reaction or FISH for JJAZ1 at 7p15 may be diagnostically useful.Molecular Detection of JAZF1-JJAZ1 Gene Fusion in Endometrial Stromal Neoplasms with Classic and Variant Histology: Evidence for Genetic Heterogeneity
Huang, Hsuan-Ying MD; Ladanyi, Marc MD; Soslow, Robert A MD
From the Department of Pathology Memorial Sloan-Kettering Cancer Center, New York, NY. Dr. Huang's current affiliation is Department of Pathology, Chang Gung Memorial Hospital, Kaoshiung Medical Center, Taiwan.
The American Journal of Surgical Pathology : Volume 28(2) February 2004 pp 224-232 Abstract quote Endometrial stromal tumors (ESTs), including low-grade endometrial stromal sarcomas (LGESSs) and endometrial stromal nodules (ESNs) of classic histology, exhibit characteristic morphologic features and contain the nonrandom t(7;17)(p15; q21), which results in the fusion of two novel genes, JAZF1 and JJAZ1 . ESTs may pose diagnostic challenges when they involve extrauterine sites, present as metastases, or display variant histologic appearances. The aim of this study was to evaluate the frequency of the JAZF1-JJAZ1 gene fusion among primary uterine, metastatic, and primary extrauterine ESTs of various histologic types and its role as a possible diagnostic adjunct.
Using a nonnested reverse transcriptase-polymerase chain reaction approach, we assayed for JAZF1-JJAZ1 gene fusion transcripts in 10 cases with available fresh-frozen tissue. These included five primary uterine (two classic, one mixed smooth muscle, and one epithelioid LGESS; one classic ESN), four metastatic (two fibromyxoid, one classic, and one epithelioid LGESS), and one extrauterine (classic LGESS) tumor. The same primer set and assay conditions were used on five additional paraffin-embedded cases with adequate RNA, including three primary uterine (one fibromyxoid and one mixed smooth muscle LGESS; 1 mixed smooth muscle ESN) and two intraabdominal recurrent (two mixed smooth muscle LGESSs) ESTs. Two cellular leiomyomas and one ESS cell line (ESS-1) without the t(7;17) at the cytogenetic level were run in parallel as controls. JAZF1-JJAZ1 gene fusion transcripts were detected in five (33%) of 15 ESTs, including three of eight primary uterine, one of four metastatic, one of one extrauterine, and none of two recurrent cases. Most ESTs of classic histology showed evidence of JAZF1-JJAZ1 fusion (4 of 5 cases), whereas only one mixed smooth muscle ESN of 10 variant cases was positive. Positivity for JAZF1-JJAZ1 fusion transcripts was found in four of 10 fresh-frozen samples and in one of five paraffin-embedded ESTs. The control specimens were all negative.
In conclusion, our data suggest that ESTs are genetically heterogeneous, with the prevalence of the JAZF1-JJAZ1 fusion being highest among ESTs of classic histology. Hence, the diagnostic utility of a JAZF1-JJAZ1 fusion transcript assay in ESTs may be limited to the classic histologic subset.
HISTOLOGICAL TYPES CHARACTERIZATION ENDOMETRIAL STROMAL NODULE Well circumscribed tumoral proliferation of uniform cells resembling stromal cells of normal proliferative phase endometrium
Non-infiltrative, expansile borderMay have fingerlike projections into the adjacent myometrium, but not exceeding 3 mm
No blood vessel invasion
Minimal cytologic atypia mitotic activity is usually low
Endometrial stromal nodules and endometrial stromal tumors with limited infiltration: a clinicopathologic study of 50 cases.Dionigi A, Oliva E, Clement PB, Young RH.
James Homer Wright Pathology Laboratories of the Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Am J Surg Pathol 2002 May;26(5):567-81 Abstract quote Experience with endometrial stromal nodules (ESNs) is limited, and no series has been published since the frequent misdiagnosis of highly cellular leiomyomas as ESNs was highlighted. Additionally, although the entirely well-circumscribed margin of most ESNs readily allows a separation from endometrial stromal sarcomas with their typical permeative invasion, some tumors have greater irregularity of their margin than allowable for an ESN following the guidelines of Tavassoli and Norris, but without the typical, and usually extensive, infiltration of endometrial stromal sarcomas. These have been diagnosed by us descriptively as endometrial stromal tumors with limited infiltration.
Three cases of this type and 47 ESNs that occurred in patients from 31 to 86 years (mean 53 years) were analyzed. The tumors were typically fleshy and at least in part yellow and ranged from 1.2 to 22 cm (mean 7.1 cm). Seven tumors had one to six focal margin irregularities; in four tumors these did not extend >3 mm beyond the main border of the tumor and were up to three in number. The other three (endometrial stromal tumors with limited infiltration) had four to six irregularities extending up to 9 mm beyond the main border of the tumor. Most neoplasms were densely cellular, but nine were hypocellular with areas that were fibrous, hyalinized, myxoid, edematous, or combinations thereof. The tumor cells almost always had scant cytoplasm, but in one tumor many cells had abundant eosinophilic cytoplasm. There was minimal cytologic atypia. Forty-four tumors had mitotic rates of up to 5 per 10 high power fields, but six had higher rates. Typical arterioles, some of which had hyalinized walls in nine cases, were numerous in all 50 tumors but were conspicuous on low-power examination in only 22. Larger, sometimes thick-walled vessels were seen in 37 tumors but were much less conspicuous than in highly cellular leiomyomas and were often present near the margin of the tumor. The cleft-like spaces of highly cellular leiomyomas were not a feature of these tumors. Twenty-three tumors showed variable degrees of smooth muscle differentiation and sex cord-like differentiation occurred in 12. Cysts were present in 17 tumors and infarct-type necrosis in 34, the latter sometimes causing initial concern for a malignant neoplasm. Follow-up information, available for 32 patients, including five patients whose tumor had some margin irregularity, ranged up to 214 months (mean 43.5 months). All patients were alive with no recurrence.
Follow-up information was unfortunately not available for the two tumors with the greatest degree of infiltration.
The major conclusions of our study are as follows: ESNs are characteristically soft and yellow; thorough sampling of their margin is mandatory; smooth muscle metaplasia is common and irregular interdigitation of stromal neoplasia with metaplastic smooth muscle may erroneously suggest myometrial infiltration; although typically densely cellular about 20% of ESNs are hypocellular and often fibrous; cellular neoplasms are often punctuated by hyaline plaques; sex cord-like differentiation, broad zones of necrosis and rarely epithelioid cells may complicate the microscopic appearance; typical arterioles are an important microscopic finding but are not always striking, particularly on low-power evaluation; the tumors may have a component of large blood vessels more typical of highly cellular leiomyomas, but they are not as conspicuous as in the latter and the clefts that are frequent in highly cellular leiomyomas are not a feature of ESNs.
ENDOMETRIAL STROMAL SARCOMA Older terminology divided tumors into low grade and high grade based upon the mitotic counts
Current designation is to classify low grade tumors if there is the characteristic morphology of endometrial stroma and tounge-like growth
High grade tumors arise within the endometrium but lack endometrial stromal differentiation
Low grade tumors Identical to stromal nodule but with an infiltrative border between tumor and myometrium
Older designation had tumors with >10 mitotic figures/10 hpf designated as high grade, regardless of the cytologic findings. Current classification ignores the mitotic count and diagnoses high grade tumors if there is marked cytologic atypia
High grade tumors Invasive tumor with at least moderate nuclear pleomorphism and hyperchromasia and cells having a faint resemblance to endometrial stromal cells
Small vascular channels permeate the tumor
May have significant cytologic atypiaUndifferentiated endometrial sarcoma Term reserved for tumors which are pure sarcomas arising within the endometrium but showing no evidence of endometrial stromal differentiation IMPORTANT HISTOLOGIC VARIANTS
- Unusual Morphologic Features of Endometrial Stromal Tumors: A Report of 2 Cases.
Baker PM, Moch H, Oliva E.
From the *Pathology Department, Health Sciences Centre, Winnipeg, Canada; daggerInstitute of Surgical Pathology, Department Pathology, Zurich University Hospital, Zurich, Switzerland; and double daggerPathology Department, Massachusetts General Hospital, Boston, MA.
Am J Surg Pathol. 2005 Oct;29(10):1394-1398. Abstract quote
Endometrial stromal tumors with typical morphology usually do not pose diagnostic problems. However, the finding of unusual morphologic features may be misleading in the final interpretation of these tumors.
Herein, we described two endometrial stromal sarcomas discovered in hysterectomy specimens of women 31 and 75 years of age. Features typical of endometrial stromal neoplasia were present in both cases. Additionally, in 1 case, extensive fatty metaplasia as well as smooth and skeletal muscle metaplasia were found; and in the second case, focal bizarre nuclei, smooth muscle differentiation, and fibrous change were present.
The differential diagnosis in the first case included cellular intravenous leiomyomatosis/lipoleiomyomatosis with skeletal muscle differentiation; and in the second case, a cellular smooth muscle tumor with bizarre nuclei was considered.
Endometrial stromal sarcomas with unusual histologic features: a report of 24 primary and metastatic tumors emphasizing fibroblastic and smooth muscle differentiation.Yilmaz A, Rush DS, Soslow RA.
Am J Surg Pathol 2002 Sep;26(9):1142-50 Abstract quote We report the clinicopathologic features of 24 uterine primary and metastatic endometrial stromal sarcomas with fibromyxoid features (ESS-F) and smooth muscle differentiation (ESS-SM) (endometrial stromal sarcoma variants).
Two groups of tumors were retrieved from the surgical pathology files at Memorial Sloan-Kettering Cancer Center: 1) gynecologic mesenchymal neoplasms with striking smooth muscle or fibroblastic differentiation that did not meet the clinical or histologic criteria for leiomyosarcoma or other established neoplasms containing smooth muscle; and 2) metastatic lesions showing ovoid and spindle cell morphology, involving lung, originally diagnosed as low-grade leiomyosarcoma, low-grade smooth muscle neoplasm, intravenous leiomyomatosis, fibrous hamartoma, and benign metastasizing leiomyoma.
We identified 12 patients with 30 tumors; 24 were available for review. The mean age was 51 years (range 21-74 years). Follow-up >1 year was available for eight patients, with a mean time of 8.5 years. Each patient had a uterine primary and 10 experienced metastases. Mean time to recurrence was 6.8 years. Sites of metastasis included lung, retroperitoneum, right atrium/inferior vena cava, colon, and ovaries. No patient died of disease, but in many cases the follow-up period ended with the discovery of a metastasis. Four patients were originally diagnosed with endometrial stromal sarcoma, but other presenting diagnoses included benign metastasizing leiomyoma, fibroleiomyomatous tumor of lung, smooth muscle tumor of uncertain or low malignant potential, and intravascular leiomyomatosis. On review each patient had at least one tumor (primary and/or metastasis) that was determined to be an endometrial stromal sarcoma variant. Review diagnoses were as follows: endometrial stromal sarcoma (nonvariant), ESS-F, and ESS-SM. Eight of 10 primary tumors with available slides were endometrial stomal sarcoma variants (six ESS-F and two ESS-SM). When these variant features were present, they comprised between 50% and 100% of the neoplasm. The variant histology tumors exhibited prominent spiral arterioles, perivascular edema, and stromal cell condensation around blood vessels. All metastases but one were variant tumors; eight were ESS-F and five were ESS-SM. Four metastases did not resemble the uterine primary. Desmin marked smooth muscle mostly but not specifically. h-Caldesmon marked smooth muscle exclusively. Endometrial stromal cells as well as some fibroblasts and smooth muscle cells expressed CD10.
We conclude that the presence of even focal endometrial stromal differentiation in an invasive uterine mesenchymal lesion with a predominant low-grade smooth muscle, fibroblastic, and/or myxoid phenotype should permit classification as low-grade sarcoma-they should be considered endometrial stromal sarcomas.
CLEAR CELL CYSTIC
- Multicystic endometrial stromal sarcoma.
Perez-Montiel D, Salmeron AA, Domnguez Malagon H.
Ann Diagn Pathol. 2004 Aug;8(4):213-8. Abstract quote
Endometrial stromal sarcoma usually has the gross appearance of a single nodule, multiple masses, or a poorly demarcated lesion with occasional cystic degeneration; however, a multilocular form has not been described in the literature.
We report the case of a 25-year-old woman with a cystic multilocular lesion with thin septae measuring 8 cm, discovered by a pelvic ultrasonography. Grossly, it was a multicystic mass located in uterine fundus that was attached to myometrium and showed infiltrating borders.
We propose that cystic endometrial stromal sarcoma should be included in the differential diagnosis of cystic uterine tumors.ENDOMETRIOID GLANDS FIBROUS GIANT CELLS
- An endometrial stromal tumor with osteoclast-like giant cells.
Fadare O, McCalip B, Mariappan MR, Hileeto D, Parkash V.
Department of Pathology, EP 2-631, Yale University School of Medicine, 20 York St, New Haven, CT 06504, USA.
Ann Diagn Pathol. 2005 Jun;9(3):160-5. Abstract quote
Endometrial stromal tumors (ESTs) of the uterine corpus have a striking propensity to display diverse morphological variations, including sex cord-like, smooth muscle, or skeletal muscle differentiation; fibrous change; myxoid change; or bland endometrioid-type glands. They may also contain rhabdoid, foam, clear, or epithelioid/granular cells among others. Recently, we have encountered an EST showing smooth muscle differentiation and osteoclast-like giant cells that were predominantly concentrated in the areas showing smooth muscle differentiation.
Osteoclastlike giant cells have not been previously reported in EST to our knowledge; thus, this finding expands the morphological spectrum of these tumors. In addition, although the level of infiltration at the peripheries of the tumor exceeded that allowable under the Tavassoli and Norris criteria for stromal nodules, it did not reach the classic permeative infiltration generally associated with endometrial stromal sarcomas.
Historical, prognostic, and diagnostic aspects of margins in EST, especially in those borderline cases such as ours, are also discussed.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES Uterine hemangiopericytoma Hormone receptor analysis negative Leiomyoma Complicated by the fact that stromal tumors may show smooth muscle differentiation
Irregularly distributed and thick walled blood vessels with spindled cells and oval nuclei with moderate amounts of cytoplasm
PROGNOSIS AND TREATMENT CHARACTERIZATION 5 Year Survival 100% As many as 45% of patients die within 2 years Metastasis 50% develop recurrences, usually limited to the pelvis 50% with recurrences or metatasis
- Endometrial stromal tumor with limited infiltration and probable extrauterine metastasis: report of a case.
Kim KR, Jun SY, Park IA, Ro JY, Nam JH.
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Korea.
Ann Diagn Pathol. 2005 Feb;9(1):57-60. Abstract quote
Endometrial stromal nodule (ESN) is a tumor composed of cells closely resembling those of the endometrial stroma with minimal cytologic atypia. The most important criterion for the differential diagnosis from the endometrial stromal sarcoma (ESS) is a well-defined noninfiltrative expansile border. However, the definition of the ESN also includes a tumor with the presence of focal irregularities or fingerlike projections of the margin into the adjacent myometrium, none of which exceeds 2 to 3 mm. In some cases, however, it is difficult to differentiate marginal irregularities of ESN from "true invasion" of ESS.
We described a case of extrauterine ESS that was associated with small intramyometrial stromal lesions with limited infiltration. The intramyometrial lesion could be definitionally categorized as ESNs. However, peritumoral fibroblastic band and inflammatory stromal reactions, irregular fingerlike projections, and multiple concurrent extrauterine ESS strongly suggested that these were small primary focus of ESS mimicking ESN.
We propose that the patient with endometrial stromal tumor with limited infiltration should be more carefully followed than the usual ESN for possible metastasis and that a hysterectomy with meticulous histological examination of the specimen be performed before a diagnosis of primary extrauterine ESS is made, even in a case showing a grossly or radiologically normal uterus.Treatment Surgical, usually with total abdominal hysterectomy with bilateral salpingo-oophorectomy Low grade tumors may benefit with adjunct therapy with progestational agents Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008
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