Posted August 30, 2010

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A 48-year-old woman presented with abnormal vaginal bleeding. Following endometrial curettage, a total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed. The 510 gram uterus contained a 14.5 x 12.0 x 9.5 cm polypoid tumor with a smooth tan surface in the endometrial cavity. On sectioning, multiple tumor nodules were noted throughout the myometrium, extending to within 2 mm of the serosal surface.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2007, Case 13 and is an endometrial stromal sarcoma, low grade.

Criteria for Diagnosis and Comments: Sections show a cellular neoplasm infiltrating myometrium in an irregular fashion. The tumor cells are monotonous with indistinct cell borders and uniform round to oval nuclei containing fine granular chromatin. Blood vessels are conspicuous, many of them exhibiting morphology reminiscent of spiral arterioles with tumor cells surrounding them in concentric whorls. Mitotic activity is variable but is typically less than 5 per 10 high power fields. Some sections additionally show foci of tumor in lymphovascular spaces. These morphologic features are diagnostic of endometrial stromal sarcoma, low grade (ESS-LG).

Endometrial stroma sarcoma is a rare mesenchymal neoplasm, comprising only 0.2% of all female genital tract malignancies. Only 5% of malignancies in the uterine corpus are non-epithelial and of these, ESS comprises less than 10%. This tumor is clinically distinctive, occurring in a younger age group than most gynecologic malignancies, with age at presentation ranging from 42 to 53 years; in some series >50% of the patients were pre-menopausal. The most common clinical presentations of this tumor are abnormal vaginal bleeding, progressive heavy menorrhagia during normal cycles, and pelvic pain. Patients with this tumor typically lack the usual risk factors for endometrial carcinoma.

Low grade endometrial stromal sarcoma forms a polypoid intracavitary mass in most cases. However, its most distinctive feature is extensive myometrial permeation, which may be in the form of diffuse infiltration, producing myometrial thickening, a solitary tumor mass, or, most commonly, multiple irregular tumor nodules and cords throughout the myometrium, as in this case. Tumor growth within vascular and lymphatic spaces is characteristic and extrauterine extension in this form is present in up to 1/3 of patients. The polypoid portion of the tumor may exhibit necrosis, hemorrhage and/or cystic degeneration; however, in contrast to the rough or papillary appearance of polypoid sarcomatoid carcinomas, the surface of the polypoid ESS-LG is typically smooth.

The microscopic appearance of ESS-LG can vary considerably, leading to diagnostic difficulty. In addition to the characteristic features above, plaques of hyalinized fibrosis, including foci with a starburst appearance, myxoid change, foam cells, smooth muscle differentiation, and fibroblast-like spindle cells may be observed. Gaping thin-walled vascular channels are not a characteristic feature but may in some instances be very prominent and exhibit a staghorn pattern leading to confusion with hemangiopericytoma and solitary fibrous tumor. Epithelial differentiation may be observed in up to 25% of low-grade ESS and may take the form of benign endometrial glands, reported in 11-40% of all low-grade ESS, nests of clear cells, or cords and tubules reminiscent of ovarian sex cord-stromal tumors. Mitoses are typically <3 per 10 high power fields; however, otherwise typical tumors with greater than 10 mitoses /10 HPF have been reported. In most studies increased mitotic activity has not predicted a more aggressive clinical course.

The immunohistochemical profile of ESS has been widely studied. Characteristically, the tumor cells express vimentin and smooth muscle markers, including smooth muscle actin, muscle specific actin, and calponin. Tumors may show limited or no expression of desmin or h-caldesmon. CD10 is characteristically expressed in these tumors and virtually all strongly express progesterone receptor. Estrogen receptor is more variably and inconsistently expressed. Foci of epithelial differentiation are typically keratin positive but lack immunoreactivity for epithelial membrane antigen. Tumors with sex cord-like areas may exhibit immunopositivity for alpha-inhibin, calretinin and/or CD99. Interestingly, these sex cord-like foci are also typically positive for actin and desmin as well as keratin, suggesting a complex polyphenotype.

The most problematic differential diagnosis is between ESS-LG and smooth muscle neoplasms, particularly cellular leiomyoma and low grade leiomyosarcoma. In cases of ESS with prominent vascular invasion and/or extrauterine extension, intravenous leiomyomatosis also enters the differential. The smooth muscle tumors consistently show the characteristic “cigar-shaped” nuclei and express smooth muscle markers. Although a significant number of these tumors express CD10, the intensity and extent of staining is typically considerably less than that of ESS; therefore, a panel of CD10, h-caldesmon, and desmin has been found to unambiguously resolve most difficult lesions. Notably, there are endometrial stromal sarcomas that contain foci of true smooth muscle differentiation; when these foci exceed 30%, the lesion is designated a mixed endometrial stromal and smooth muscle tumor.

ESS-LG must be distinguished from endometrial stromal nodule on the benign side and high grade uterine sarcomas. The stromal nodule, unlike ESS-LG, has a circumscribed, non-infiltrative border with, at most, 2-3 mm tongues of extension into surrounding myometrium. Traditionally, ESS was divided into low and high grade categories. High grade ESS was defined as a lesion retaining characteristic features of endometrial stroma, including the vascular pattern and the characteristic endometrial pattern of reticulin staining, also seen in ESS-LG, in which reticular fibers encircle individual and small groups of cells. In contrast to ESS-LG, the nuclei of high grade ESS were larger with vesicular and clumped chromatin and the high grade lesions had high mitotic rates, usually exceeding 10-20 per 10 high power fields. However, because mitotic counts lack prognostic significance, most authorities no longer divide ESS into low and high grade categories and prefer to place lesions with high grade nuclei into the undifferentiated uterine sarcoma category. The latter tumors typically more closely resemble the sarcomatous component of a carcinosarcoma (or malignant mixed mullerian tumor, which must be rigorously excluded) and are not difficult to distinguish from a typical low grade ESS.

Adenosarcoma is also typically a large polypoid endometrial lesion and, when stroma predominant, may be confused with an ESS containing benign glands; however, endometrial stromal sarcomas uniformly lack the characteristic periglandular stromal cell cuffing seen in adenosarcoma. By definition, ESS showing focal differentiation into sex cord-like elements is distinguished from the uterine tumor resembling ovarian sex cord tumors by degree; however, the criteria for this distinction and the histogenetic spectrum of this neoplasm are still actively debated.

Low grade ESS is an indolent malignancy. The most important predictor of outcome is stage at diagnosis with stage 1 tumors conferring an excellent long-term survival, ranging from 67 to 100%. The 5-year survival for more advanced stages is 40-50%. The natural history is predominantly that of local recurrence, typically in the pelvis, with involvement of vagina, ureters, urinary bladder, omentum, and/or bowel; however, as many as 10% may metastasize to the lung and rarely, the latter may be the presenting feature. ESS-LG is slowly progressive and time to death in lethal cases may exceed 10 years. The treatment is predominantly surgical, although radiotherapy has been used in some cases with success. Treatment with progestational agents or aromatase inhibitors is effective in most tumors; conventional chemotherapy is not effective in most advanced cases.