Long term outcomes of patients with leiomyosarcoma of uterine vs Long term outcomes of patients with leiomyosarcoma of uterine vs. extra-uterine origin Srikanth Divi, Medical Student, Univ. of Pittsburgh Meghan Levy, Kurt Weiss MD, Mark Goodman MD, Richard McGough MD

Background of Leiomyosarcoma (LMS) Approximately 10,000 soft tissue sarcomas are diagnosed in the US annually1 LMS composes up to 10% (1000 cases) and is the third most frequent sarcoma after pleomorphic sarcoma NOS and liposarcoma2 Classification: visceral gastrointestinal, separate from GIST uterine somatic peripheral soft tissues (cutaneous, deep soft tissue) retroperitoneal (50%) vascular bone (rare) Benign soft tissue tumors greatly outnumber sarcomas (up to 100-1 in one review). Adult STS comprise of only 1% of all adult cancers. There are over 50 different tumor entities within STS, a lot of them that are classified and separated upon histological analysis. LMS composes up to 10% of STS cases (although some studies state up to 25%) and can be classified into sites of origin. Retroperitoneal tumors are the most common, representing up to half of all LMS, while they can also be found in peripheral soft tissues, where they can be subdivided into cutaneous (good prognosis) or deep soft tissue (extension from dermis into subcuticulartissue). GIST has only recently been reliably separated from LMS, and in the past many GISTs were included in LMS diagnoses. Within non-cutaneous LMS, there are two main groups (uterine vs. extra-uterine). Uterine LMS seems to have different gene expression patterns and sensitive to certain combinations of chemotherapy (gemcitabine and docetaxel), giving credibility to the notion that this might be a different disease altogether.

Background of Leiomyosarcoma (LMS) About 2/3 of retroperitoneal LMS occur in women, median age 60 y Presenting symptoms nonspecific: abdominal mass, swelling, pain, weight loss, nausea, or vomiting Presenting size often large (mean size and weight: 16 cm, 1600g) In contrast, tumors of the extremities affect men and women equally Significantly smaller (6 cm) than retroperitoneal tumors

Background of Leiomyosarcoma (LMS) Leiomyomas not necessarily associated with malignant transformation to LMS Observation that significant number of tumors arise from small blood vessels LMS also seen in the setting of hereditary retinoblastoma (abnormal Rb1 locus)

Prognosis of patients with somatic soft tissue (SST) LMS Farshid et al., 42 patients3 (2002) 8% developed local recurrence, 45% developed mets Age > 62, size > 4cm, extensive necrosis correlated with metastasis Conclusion: majority are of vascular origin (39/42 pts), disruption of tumor w/ biopsy is significant RF Mankin et al., 66 patients4 (2004) 50% survival at 4.2 years, 62% developed mets Tumors with greater size (>500 cm3) had 82% mortality rate Conclusion: presence of mets, size of tumor, MSTS stage effect on survival outcomes Farshid et al. This study was carried out in Australia in 2002 to analyze 42 patients with LMS of the somatic soft tissues LMS from cutaneous, visceral (uterine and GI), retroperitoneal, and major vessel lms were excluded. patients included 21 females vs 21 males (range: 26 to 86 years, with mean 60 years). Mose tumors arose in the deep tissue as opposed to superficial tissues (27 vs 15), among which 39 arose from a small vein. in the follow-up period (mean: 47 months), 8% of patients developed local recurrence, and 45% developed mets. In a univariate analysis, age > 62 years, size > 4cm, and extensive necrosis all correlated with metastasis. In multivariate analysis, disruption by previous incisional biopsy or incomplete excision was the only significant risk factor for mets. Conclusion: majority of SST leiomyosarcomas are actually of vascular origin – clinical and biological ramifications. Risk of mets predicted by multivariate linear regression model that also includes age, FFCC (French Federation for Cancer Centers) grade, and disruption. In view of vascular origin, possibility that tumor disruption may facilitate or promote access to bloodstream merits further study Mankin et al. (66 patients since 1982) from Harvard. Multivariate Cox regression analysis showed that only three variables were independently significant in terms of effect on survival outcomes (1: the presence of mets, 2: size of the tumor, 3: MSTS stage).

Prognosis of patients with somatic LMS Scandinavian Sarcoma Group, 225 pts (2006)5 10 year survival rate (with localized disease): 49% Higher grade, larger tumor size, deeper location all significantly correlated with decreased survival Overall prognosis is poor even with local control (w/ or w/o radiotherapy) Abraham et al. 115 pts (2012)1 1, 5, and 10 year survival: 87%, 57%, 19% Histological grade, tumor depth, and mets significant predictors of mortality The SSG analyzed patients from 1986 to 2001 (15 year period) and included all non-visceral LMS (cutaneous, subcutaneous, deep-seated LMS of extremities, trunk wall and superficial head and neck tumors). median age of patients 70 years, median tumor size 4.0cm, median followup 5.5 years, local treatment adequate in 75% of patients who didn’t have mets at presentation 10 year survival rate for those patients that presented with localized disease was 49% in multivariate analysis, higher grade, larger tumor size, deeper location all correlated with decreased survival. Prognosis poor even with local control Abraham et al. 115 patients with somatic LMS studied over a 10 year period (1996-2005), only included patients with tumors of the soft tissues, vasculature or bone uterine, cutaneous, GI forms were excluded

Prognosis of patients with somatic LMS Radkowski et al., 65 pts – 20125 Overall 1, 2, and 5 year survival: 91%, 87%, and 68% Pts with deep lesions, grade 3 disease, and advanced stage have poorer prognosis 65 patients followed for a mean of 4.1 years, mean tumor diameter 7cm 70% of all patients had tumors deep to the fascia In all stages of disease the 1, 2, 5 year surival were 91%, 87%, and 68% mitotic rate and tumor depth were significant predictors of disease.

Uterine LMS Uterine LMS is rare, it accounts for only 1% of all uterine cancers6, however it represents up to 1/3 of all uterine sarcomas 30-35% of patients have evidence of extra-uterine disease at the time of presentation 5 year survival for metastatic disease is less than 40% with current therapies Median age: 50 years, about 10 years older than the median age of presentation for leiomyoma7 Frequency of incidental LMS detected in women at various ages having surgery for presumed leiomyoma: 31-40 y: 0.2% 41-50 y: 0.9% 51-60 y: 1.4% 61-81 y: 1.7% Uterine LMS believed to be a separate disease entity from peripheral soft tissue LMS (along with GI LMS behaving differently…)

Motivation for study Does extra-uterine LMS have the same prognosis as uterine LMS? Some patients with extra-uterine LMS had hysterectomies in the past Difference in outcomes between those with and those without hysterectomies? Two distinct disease entities (uterine LMS and extra-uterine LMS) may actually overlap, with patients presenting decades later with recurrences of uterine LMS. At our institution we have treated several patients with LMS in the peripheral soft tissues. It turns out that some of these patients have prior history of uterine LMS (that became metastatic to the extremities). This brought up the question, do patients with uterine disease do better or worse compared to LMS that arises outside the uterus. Additionally, out of the patients that had non-uterine LMS, we wondered how many of these patients had prior hysterectomies? Is it possible that patients with non-uterine LMS actually just had later manifestations of a uterine LMS (that was undiagnosed previously and was removed with the hysterecomy). Is there a difference in outcomes between patients with non-uterine LMS who had a hysterectomy before vs. those that didn’t?

Hypothesis Patients with uterine LMS have decreased survival compared to extra-uterine LMS Of patients with extra-uterine LMS, those with prior hysterectomies have decreased survival

Methods Searched using MARS (Medical Archive Record System) in UPMC system from 1982-present Surgical pathology reports with designated search terms Retrieved lists were filtered for correct diagnoses Diagnosis of extra-uterine LMS 513 cases of extra-uterine LMS Included tumors from: GI, cutaneous, peripheral soft tissue, retroperitoneal, vascular, etc. Diagnosis of uterine LMS 127 patients

Methods Patient characteristics identified: age at diagnosis tumor characteristics (size, # mitoses, % necrosis, grade, FIGO stage) metastases Survival data collected from: UPMC patient charts (inpatient and outpatient visits) National and municipal registries Censored survival data used to construct Kaplan Meier curves

Results Uterine LMS Extra-uterine LMS Sample Size 127 513   Uterine LMS Extra-uterine LMS Sample Size 127 513 Median Survival 4.97 4.28 5 yr 49.4% 46.7% 10 yr 31.5% 27.3% 15 yr 24.5% 20.0% 25 yr 18.4% 11.8% Hazard Ratio: 1.042 [0.815, 1.333] Logrank Test: χ2= 0.1074, p = 0.7431

Results

Results – analysis of patients with Extra-uterine LMS Of the 513 patients with extra-uterine LMS: 269 were females 177 with no documentation of hysterectomies 75 found to have hysterectomies prior to dx of LMS 17 had hysterectomies after dx of LMS 75/269 = 27.9% of females with hysterectomies prior to dx of LMS Differences in survival?

Results – analysis of patients with Extra-uterine LMS Median Survival Time Median Estimate Std. Error 95% Confidence Interval Lower Bound Upper Bound No hyst. 4.250 .713 2.852 5.648 Prior Hyst. 6.420 1.091 4.281 8.559 Overall 5.060 .696 3.696 6.424 Overall Comparisons   Chi-Square df Sig. Log Rank (Mantel-Cox) 3.029 1 .082

Discussion Uterine vs. extra-uterine LMS has similar long term outcomes, not statistically significant Median survival: 4.97 y vs. 4.28 y HR 1.042, p = 0.74 Among extra-uterine LMS, those with prior hysterectomies had a longer survival time, not statistically significant Median: 6.42 y vs. 4.25 y p = 0.084

Limitations Population heterogeneity Does not stratify for commonly used clinical parameters: Margin status XRT Chemotherapy Other treatments

Conclusion Retrospective review of 640 cases of LMS Uterine Extra-uterine No difference in long term survival outcomes Future directions: Evaluate contribution of clinical parameters Outcomes of patients with somatic soft tissue LMS

References Abraham et al. Outcomes and prognostic factors for a consecutive case series of 115 patients with somatic leiomyosarcoma. J Bone Joint Surg Am. 2012 Apr 18; 94(8): 736-44 O’Sullivan et al. Radiological imaging features of non-uterine leiomyosarcoma. Br J Radiol. 2008 Jan; 81(961): 73-81 Farshid et al. Leiomyosarcoma of Somatic Soft Tissues. Am J Surg Pathol. 2002. 26(1): 14–24. Mankin et al. Leiomyosarcoma of Somatic Soft Tissues. Clin Orthop Relat Res. 2004 Apr ; (421): 225-31 Radkowski et al. Leiomyosarcoma of the somatic soft tissues. J Surg Orthop Adv. 2012. 21(2): 96-101 Leitao et al. Surgical cytoreduction in patients with metastatic uterine leiomyosarcoma at the time of initial diagnosis. Gynecol Oncol. 2012 May. 125(2): 409-413

Acknowledgments Meghan Levy Alma Heyl – Clinical Research Coordinator Kurt Weiss, MD and Mark Goodman, MD Richard McGough, MD – Project Mentor

Thank you