Incidence of sarcoma unsuspected at hysterectomy

Uterine sarcomas are rare, comprising <1% of all gynecologic malignancies. This subgroup of uterine malignancies carries a poor prognosis for those affected, even in early-stage disease ( Table 1 ). In the United States, of the estimated 52,630 new cases of uterine cancer diagnosed annually, approximately 1600 will be uterine sarcomas. The major challenge with triaging patients to the appropriate surgery is differentiating uterine sarcomas from benign uterine fibroid tumors. Using various imaging techniques, endometrial sampling, obtaining a detailed patient history, and performing a thorough physical examination have been the mainstay of preoperative evaluation for patients with uterine masses. Although these techniques provide adequate evaluation for uterine epithelial cancers, each has limitations and none can exclude the possibility of nonepithelial malignancies.

There are varying reports in the literature on the incidence of unsuspected uterine sarcoma diagnosed on final pathologic evaluation after hysterectomy. Additionally, these studies are retrospective, which further limits the quality of the data. In the special report on power morcellation and occult malignancy in gynecologic surgery issued by the American Congress of Obstetrics and Gynecology (ACOG), it is estimated that 1 in 500 women will have a postoperative diagnosis of stromal sarcoma and leiomyosarcoma. As part of the safety warning issued by the US Food and Drug Administration (FDA) on power morcellation, a comprehensive literature review of studies that reported unsuspected uterine sarcomas and leiomyosarcomas in patients who underwent hysterectomy or myomectomy for presumed benign fibroid tumors was performed. Among this population, the risks of occult sarcoma and leiomyosarcoma were reported to be 1 in 352 and 1 in 458, respectively.

Quality of the data

Further review of the studies used for the FDA’s report confirms low-quality evidence from retrospective reviews. Moreover, many of the studies were done at large referral centers on high-risk patients, possibly falsely elevating the risk of uterine sarcomas in these study groups. Of the 9 studies that were included in the FDA quantitative assessment, 5 studies were conducted in the United States ( Table 2 ). All the studies were qualitative in nature, providing level 3 evidence on the risk of uterine sarcoma at the time of hysterectomy. The largest study included 1429 patients who were 36-62 years old with abnormal uterine bleeding or abdominal pain with a pelvic mass of sufficient size or character to warrant surgical exploration. In that study, they reported 7 cases of leiomyosarcoma (0.5%). Review of the study criteria shows that there was no standard preoperative evaluation among these patients who were treated between 1983 and 1988. The study was based out of a tertiary care center with a self-referred indigent population. Two additional US studies that were reviewed by the FDA report rates of uterine sarcoma of 0.18-0.23% and leiomyosarcoma of 0.08-0.09% in high-risk patients with inconsistent preoperative work-up. Notably, of the studies that were reviewed by the FDA, multiple surgical and morcellation techniques were used to treat these patients.

Variable preoperative evaluation and lack of age and risk factor stratification among these retrospective studies ultimately lend uncertain relevance to these published data. With an annual reported incidence of 0.64 per 100,000 women, the applicability is further complicated by the rarity of these malignancies. There are limited data on the prevalence of sarcoma in morcellated specimens and even fewer cases and studies on the incidence of disseminated disease in patients who underwent minimally invasive surgical techniques with the use of power morcellation. To fully evaluate the effect of power morcellation on disease-free and overall survival in these cases, prospective studies or randomized studies are necessary; however, no such study is possible due to obvious ethical conflicts. Furthermore, the rarity of these cancers requires that data be collected over a long period of time to accrue the necessary numbers to provide sufficient statistical power to detect differences in outcome. Use of epidemiologic modeling systems may be needed to better understand the impact of morcellation in these cases. Without reliable data, any recommendation on the safety of power morcellation is premature, given the known benefits of minimally invasive surgery on patient recovery and quality of life.

Quality of the data

Further review of the studies used for the FDA’s report confirms low-quality evidence from retrospective reviews. Moreover, many of the studies were done at large referral centers on high-risk patients, possibly falsely elevating the risk of uterine sarcomas in these study groups. Of the 9 studies that were included in the FDA quantitative assessment, 5 studies were conducted in the United States ( Table 2 ). All the studies were qualitative in nature, providing level 3 evidence on the risk of uterine sarcoma at the time of hysterectomy. The largest study included 1429 patients who were 36-62 years old with abnormal uterine bleeding or abdominal pain with a pelvic mass of sufficient size or character to warrant surgical exploration. In that study, they reported 7 cases of leiomyosarcoma (0.5%). Review of the study criteria shows that there was no standard preoperative evaluation among these patients who were treated between 1983 and 1988. The study was based out of a tertiary care center with a self-referred indigent population. Two additional US studies that were reviewed by the FDA report rates of uterine sarcoma of 0.18-0.23% and leiomyosarcoma of 0.08-0.09% in high-risk patients with inconsistent preoperative work-up. Notably, of the studies that were reviewed by the FDA, multiple surgical and morcellation techniques were used to treat these patients.

Variable preoperative evaluation and lack of age and risk factor stratification among these retrospective studies ultimately lend uncertain relevance to these published data. With an annual reported incidence of 0.64 per 100,000 women, the applicability is further complicated by the rarity of these malignancies. There are limited data on the prevalence of sarcoma in morcellated specimens and even fewer cases and studies on the incidence of disseminated disease in patients who underwent minimally invasive surgical techniques with the use of power morcellation. To fully evaluate the effect of power morcellation on disease-free and overall survival in these cases, prospective studies or randomized studies are necessary; however, no such study is possible due to obvious ethical conflicts. Furthermore, the rarity of these cancers requires that data be collected over a long period of time to accrue the necessary numbers to provide sufficient statistical power to detect differences in outcome. Use of epidemiologic modeling systems may be needed to better understand the impact of morcellation in these cases. Without reliable data, any recommendation on the safety of power morcellation is premature, given the known benefits of minimally invasive surgery on patient recovery and quality of life.

Accuracy of clinical and radiographic predictors of malignancy

Historically, clinicians have been challenged by the difficult task of identifying sarcomas before surgery. The accuracy of clinical and radiographic predictors of malignancy varies widely depending on the type of uterine cancer, endometrial vs mesenchymal. The diagnosis of endometrial cancer is made reliably based on histologic and radiologic evaluation. Endometrial biopsy has high sensitivity for a diagnosis of endometrial carcinoma ; however, very few studies have reported its sensitivity in diagnosis of mesenchymal tumors and are limited to small single-institution reports. Because of the distribution of sarcomas within the myometrium, the reported sensitivities of 33-67% are not surprising.

No clear clinical features have distinguished benign uterine neoplasms reliably from malignant growths. Rapidly enlarging uterine size traditionally has been taught as a characteristic of malignant tumors ; however, this has not been supported in the contemporary literature. Parker et al reported on a cohort of 1332 women who underwent hysterectomy or myomectomy; 371 women had rapid tumor growth as their surgical indication, with only 1 case of leiomyosarcoma among this group. A literature review of 26 studies found that a history of rapid uterine enlargement was documented in only 15 of 580 patients (2.6%) with uterine sarcoma. In a more recent review, Leung et al reported only 2 cases of leiomyosarcoma among 155 patients (1.3%) with a “rapidly growing uterus” at the time of hysterectomy. Furthermore, rapid tumor growth of up to 138% of fibroid tumor volume has been demonstrated by benign leiomyomata.

Black race has been associated with a 2-fold increased risk of carcinosarcoma and leiomyosarcoma ; however, black women have a 2- to 3-fold increased baseline risk of uterine leiomyomas. Increasing age and postmenopausal status are also nonspecific risk factors for uterine sarcomas. Because fibroid tumors are hormone responsive, any growing uterine mass in a postmenopausal patient should be treated as malignancy until proved otherwise. Tamoxifen use for >5 years has also been associated with an increased risk for uterine sarcoma. No genetic mutations or polymorphisms have been connected to uterine sarcomas; however, childhood retinoblastoma and hereditary leiomyomatosis and renal cell carcinoma syndrome have been associated with sarcomas of the uterus.

Imaging modalities have emerged as crucial methods in the evaluation, surveillance, and surgical planning of many gynecologic malignancies and neoplasms. Radiologic studies, however, have limited utility in the diagnosis of uterine malignancy. Imaging cannot reliably differentiate malignant from benign causes, and the low sensitivity and specificity of radiologic studies has made triage of uterine masses to the appropriate surgical procedure difficult. Table 3 provides a summary of the utility of imaging modalities in the diagnosis of uterine sarcomas and their respective measurements of interest. All the studies are based on limited case series.

Table 3

Utility of imaging modalities in the diagnosis of uterine sarcomas

Variable	Year published	n	Cases of sarcoma, n	Measurement of interest	Sensitivity, %	Specificity, %	Level of evidence
Ultrasound scan
Hata et al	1997	46	5	Intratumoral PSV 41.0 cm/sec	80	97	3
Szabo et al	2002	129	12	Intratumoral RI <0.5	67	87	3
Exacoustos et al	2007	257	8	Increased central and peripheral vascularity	100	86	3
Magnetic resonance imaging
Schwartz et al	1998	45	4	Ill-defined margins	100	100	3
Tanaka et al	2004	24	12	High signal intensity of T2 and T1WI	73	100	3
Sato et al	2014	81	5	Signal intensity on diffusion weighted imaging + ADC	100	99	3
Positron emission tomography/computerized tomography
Nagamatsu et al	2009	53	10	SUV >3.0	100	73	3
Yamane et al	2012	15	3	SUV >4.32	100	63	3

ADC , apparent diffusion coefficient; PSV , peak systolic velocity; RI , resistance index; SUV , standardized uptake value.

Liu. Critical assessment of morcellation. Am J Obstet Gynecol 2015 .

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