Clinical management of uterine sarcomas

Review

Clinical management of uterine sarcomas Frédéric Amant, An Coosemans, Maria Debiec-Rychter, Dirk Timmerman, Ignace Vergote Lancet Oncol 2009; 10: 1188–98 Leuven Cancer Institute, Gynaecological Oncology, University Hospital Gasthuisberg, Katholieke Universiteit, Leuven, Belgium (Prof F Amant MD, A Coosemans MD, Prof D Timmerman MD, Prof I Vergote MD); Department of Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium (Prof M Debiec-Rychter PhD) Correspondence to: Prof Frédéric Amant, Leuven Cancer Institute (LKI), Gynaecological Oncology, University Hospital Gasthuisberg, Katholieke Universiteit, Herestraat 49, 3000 Leuven, Belgium [email protected]

Malignant pure mesenchymal uterine tumours encompass endometrial stromal sarcoma (ESS), uterine leiomyosarcoma, and undifferentiated sarcomas. This Review discusses pathology, preoperative diagnosis, and standard treatment of uterine leiomyosarcoma and low-grade ESS (distinct from undifferentiated uterine sarcomas), with an emphasis on targeted treatment. We show that several features on ultrasonography and MRI can raise suspicion of a uterine sarcoma; however, there are no pathognomonic features on any imaging technique. For both ESS and uterine leiomyosarcoma, hysterectomy with bilateral salpingo-oophorectomy, but without lymphadenectomy, is the standard surgical treatment for early stage disease. The clinical benefit of chemotherapy is limited, which underscores the importance of targeted therapy. ESS and uterine leiomyosarcoma are driven by different pathways, resulting in a different clinical behaviour. ESS typically is a hormone-sensitive tumour with indolent growth. Uterine leiomyosarcoma is notorious for its aggressive growth and poor outcome. Individualisation of treatment is mandatory, because randomised trials are almost non-existent. The progesterone and oestrogen receptors are clinically important targets for most primarily advanced or recurrent ESS and a subset of recurrent uterine leiomyosarcomas. Potential future targets and targeted treatments that are under investigation are presented for both entities.

Introduction Mesenchymal tumours other than uterine fibroids are uncommon because sarcomas of the uterus constitute only 3% of uterine malignancies.1 Uterine sarcomas encompass leiomyosarcoma (figure 1), carcinosarcoma, and endometrial stromal sarcoma (ESS) according to traditional classification systems. Tumour biology of carcinosarcomas points toward an epithelial origin, as shown by in-vitro data, immunohistochemical studies, and molecular comparison between the epithelial and mesenchymal component.2 The focus in this Review will be on the most common pure mesenchymal tumours: uterine leiomyosarcoma and ESS. ESS was formerly classified as low-grade ESS. Tumours previously termed high-grade ESS are currently called poorly differentiated or undifferentiated uterine sarcoma. Although there is no universal staging system for uterine sarcomas, the International Federation of Gynecology and Obstetrics (FIGO) surgical staging system for endometrial cancer is used.

No imaging modality can offer a reliable preoperative diagnosis. CT is unable to differentiate between different types of uterine pathology. However, ultrasonography and MRI are able to offer a much more detailed analysis of pathology.3 Thus, uterine sarcomas are uncommon and the preoperative diagnosis is problematic. Preoperative referrals are rare. Many women have surgery for presumed benign conditions (eg, uterine leiomyoma) and snap frozen tissues are not preserved. As a result, the collection of satisfactory tumour samples and the undertaking of prospective trials are challenging. Only a few series are reported and results from studies with level 1 evidence are non-existent. The purpose of this Review is to provide information on the pathology, preoperative diagnosis, and standard treatment of uterine leiomyosarcoma and ESS. Knowledge of tumour biology forms the basis for delineating targeted treatment modalities that are currently used, under investigation, or avoidable.

Uterine leiomyosarcoma Histopathology Most uterine leiomyosarcomas are sufficiently differentiated, at least focally, to allow recognition of their smooth-muscle nature. They are obviously malignant on microscopic examination. The diagnostic strategy should include a search for the mitotic index, presence of atypia, and coagulative tumour-cell necrosis.4 Uterine leiomyosarcomas need to be distinguished from mitotically active or atypical leiomyomas and uterine smooth-muscle neoplasms with low malignant potential. Coagulative tumour-cell necrosis is decisive and should be distinguished from hyaline and ulcerative necrosis.4

Imaging studies Figure 1: Uterine leiomyosarcoma

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Most uterine leiomyosarcomas are described as large oval-shaped tumours with inhomogeneous and bizarre www.thelancet.com/oncology Vol 10 December 2009

Review

internal echo pattern at ultrasonography. They contain mixed echogenic and poor echogenic parts surrounded by a thinned myometrium. Central necrosis is common. Findings at colour doppler ultrasonography include irregular vessel distribution within the tumour, with low impedance to flow (low resistance indices)5 and high peak systolic velocities. However, there is much overlap in colour doppler findings between uterine leiomyosarcomas and benign leiomyomata. Findings in uterine leiomyosarcomas on MRI vary and include a lobulated mass of high-signal intensity on T2-weighted images, a sharply marginated mass of low-signal intensity that closely resembles a leiomyoma, or a mass with focally infiltrative margins.6,7 Signal intensity is not a reliable indicator of malignancy.7 Detection of scattered foci of haemorrhages or necrosis can suggest the diagnosis of uterine leiomyosarcoma. These necrotic areas are seen as areas of slightly higher intensity on T1-weighted images and as heterogeneous areas on T2-weighted images.8 A consistent finding in uterine leiomyosarcomas is the absence of calcifications. Hysterectomy is advocated when imaging modalities cannot exclude a malignancy. Uterine leiomyosarcomas accumulate 18-fluorodeoxyglucose ([¹⁸F]FDG), which is detected by PET, and the combined use of PET with CT is promising, because it provides both morphological and anatomical information.9 However, PET findings should be interpreted cautiously, because low-grade and small uterine leiomyosarcomas (including small metastases) are less likely to be detected. Although several features at ultrasonography and MRI can raise suspicion of a uterine sarcoma, there are no pathognomonic features on any imaging technique.

Current treatment Adnexal or lymphatic spread is only present in about 3% of early stage uterine leiomyosarcomas.10,11 Lymph-node involvement is more frequent in advanced-stage disease. In a series of 1396 patients, adnexectomy and lymphadenectomy failed to be independent prognostic factors for survival.12 However, the ovaries are frequently removed because of age, the small chance of ovarian metastasis, and the potential for a low-grade hormonesensitive uterine leiomyosarcoma. A simple hysterectomy with oophorectomy, but without lymphadenectomy, is therefore standard treatment for early stage uterine leiomyosarcomas (figure 2). In premenopausal women, a simple hysterectomy (without oophorectomy) can be considered.13 There is no proven benefit for any adjuvant treatment with only two randomised trials having explored the benefit of adjuvant treatment.14,15 The value of adjuvant doxorubicin was already investigated 20 years ago. 156 women with resected stage I–II sarcoma and various histologies (ie, uterine leiomyosarcomas, carcinosarcoma, and ESS) were randomly assigned to doxorubicin with non-random use of adjuvant pelvic www.thelancet.com/oncology Vol 10 December 2009

radiation, and overall survival was similar for the doxorubicin and control groups.14 This single randomised trial on adjuvant chemotherapy included only 48 patients with uterine leiomyosarcomas. Recurrences occurred in 11 of 25 (44%) patients in the doxorubicin group and in 14 of 23 (61%) patients in the control group. Although this study is considered negative, the findings are, in fact, inconclusive.14 Reed and colleagues15 randomly assigned 103 patients with leiomyosarcomas to either observation or pelvic radiation (51 Gy in 28 fractions over 5 weeks). There was no benefit for patients with uterine leiomyosarcomas who received adjuvant radiotherapy.15

See Online for webappendix

Early stage endometrial stromal sarcoma

Early stage uterine leiomyosarcoma

Hysterectomy with oophorectomy*

Hysterectomy with oophorectomy

Recurrence Recurrence <6 months

Recurrence >6 months†

Chemotherapy

• Consider targeted therapy • Consider resection of metastatic disease

Cytoreductive surgery, including organ resection and metastasectomy

Targeted treatment

Secondary cytoreductive surgery

Targeted treatment

Chemotherapy

Figure 2: Treatment strategy for early stage endometrial stromal sarcoma (ESS) and uterine leiomyosarcoma *Retention of the ovaries can be considered in young women with small ESS. †Refers to a small and highly selected group of patients.

Drug

Schedule

Response

Response rate, N (%)

Omura (1983)1*

Doxorubicin

60 mg/m² every 3 weeks

NR

7/28 (25)

Sutton (1992)2*

Ifosfamide

1·5 mg/m² for 5 days

6 PR

6/35 (17)

Sutton (1999)3*

Paclitaxel

175 mg/m² every 3 weeks

3 CR

3/33 (9)

Gallup (2003)4*

Paclitaxel

175 mg/m² every 3 weeks

4 CR

4/48 (8)

Look (2004)18

Gemcitabine

1000 mg/m² every 3 weeks on days 1–8–15

1 CR, 8 PR

9/42 (21)

Anderson (2005)5*

Temozolomide

50–75 mg/m² daily for 6 out of 8 weeks

1 CR

1/13 (8)

Sutton (2005)6*

Liposomal doxorubicin

1 CR, 4 PR

5/35 (14)

Amant (2009)19

ET-743

50 mg/m² every 4 weeks

1·5 mg/m² every 3 weeks 5 PR

5/11 (45)

Hensley (2002; single Gemcitabine; institution)16 docetaxel

900 mg/m², days 1 and 8; 100 mg/m², day 8

3 CR, 15 PR 18/34 (53)

Gemcitabine; docetaxel

900 mg/m², days 1 and 8; 100 mg/m², day 8

3 CR, 10 PR

Hensley (2008; collaborative study)17

13/48 (27)

N=number of patients. PR=partial remission. CR=complete remission. NR=not reported. *See webappendix for these references.

Table 1: Single agent and combination chemotherapy activity in uterine leiomyosarcomas

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Nielsen (2002)27

N

Reference tissue

Discriminating genes

Gene function

11

Synovial sarcoma, liposarcoma, GIST, MFH, MPNST

Calponin-positive: Actin (ACTG2), myosin (MYH11, MYLK), leiomodin (MOD1), myosin phosphatase (MYPT12) Calponin-negative: MIG, SCYA5, LOXL1, MME, COL7A1, PLOD, CD11b, CD68

Genes involved in muscle structure and function

CDKN2A, diaphanous 3, doublecortin, calpanin 6,

Cell cycle regulation

Skubitz (2003)30

7

Myometrium

Lee (2003)29

9

Synovial Interleukin 17B, proteolipid 1 sarcoma, MFH

Lee (2004)23

Quade (2004)7* Baird (2005)8*

37 Other sarcoma

9

BMP2, PDAP1, CDC27, CDK2AP1 IFNAR2, RIT1, GPSM1, GRB7, MAPKAPK2, PAK2 BCL2A1 GMPS

Myometrium, uterine leiomyomas

Cytokine synthesis, cellular and collagen metabolism, macrophage antigens

Immune response Cell growth and cell cycle control Signal transduction Apoptosis Nucleotide metabolism

Cellular metabolism, cell CYP1A2, IFI30, LYZ, NNMT, PPPICA, TYMS, PTPNSI, RUNXI, HLXB9, MCM2 structure, signal transduction and transcriptional regulation PBX1 MYLK, CCN1, SLMAP, IL4R, WDR1, RAB23

Cellular metabolism, signal transduction and transcriptional regulation

Meza-Zepeda 12 GIST (2006)28

AURKB, SREBF1, MFAP4, FLJ10847

Signal transduction, transcriptional regulation and cell adhesion and interaction

Matsumara (2006)49

Acrogranin

Glycoprotein with growth regulatory activity and potent mitogenic effects

17 Other sarcoma

2

Normal uterine smooth muscle

N=number of patients. ACTG2=gamma-2-actin. MYH11=myosin heavy chain 11. MYLK=myosin light-chain kinase. MOD1=modifier 1 protein. GIST=gastrointestinal stromal tumour. MFH=malignant fibrous histiocytosis. MPNST=malignant peripheral nerve sheet tumour. MIG=mitogen-inducible gene. SCYA5=small-inducible cytokine A5. LOXL1=lysyl oxidase homologue 1. MME=matrix metalloproteinase. COL7A1=collagen alpha-1(VII) chain precursor. PLOD=procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 precursor. CD11b=CD11 antigen-like family member B. CD68=macrosialin precursor (Gp110). CDKN2A=cyclin-dependent kinase inhibitor 2A. BMP2=bone morphogenetic protein 2. PDAP1=PDGFA-associated protein 1. CDC27=cell division cycle protein 27 homologue. CDK2AP1=cyclindependent kinase 2-associated protein 1. IFNAR2=interferon alpha/beta receptor 2. RIT1=Ras-like protein expressed in many tissues. GPSM1=G-protein-signalling modulator 1. GRB7=growth factor receptor-bound protein 7. MAPKAPK2=MAP kinase-activated protein kinase 2. PAK2=p21-activated kinase 2. BCL2A1=Bcl-2-related protein A1. GMPS=GMP synthetase. CYP1A2=cytochrome P450 1A2. IFI30= gamma-interferon-inducible protein IP-30). LYZ=lysozyme C precursor. NNMT=nicotinamide N-methyltransferase. TYMS=thymidylate synthase. RUNX1=runtrelated transcription factor 1. HLXB9=motor neuron and pancreas homeobox protein 1. MCM2=minichromosome maintenance protein 2 homologue. PBX1=pre-B-cell leukaemia transcription factor 1. MYLK=myosin light chain kinase. CCN1=calmodulin-dependent calcineurin A subunit alpha isoform. SLMAP= sarcolemmal membraneassociated protein. IL4R=interleukin-4 receptor alpha chain precursor. WDR1=WD repeat-containing protein 1. RAB23=Ras-related protein Rab-23. AURKB=Aurora-related kinase 2. SREBF1=sterol regulatory element-binding protein 1. MFAP4=microfibril-associated glycoprotein 4 precursor. FLJ10847=inducible cAMP early repressor. *See webappendix for these references.

Table 2: Expression profiling data from uterine leiomyosarcomas

In advanced-stage or recurrent disease, treatment is palliative only.13 Quality of life should be considered at every stage. Uterine leiomyosarcoma with transperitoneal spread is more difficult to resect than ovarian cancer. This difficulty is mainly explained by a more infiltrative growth. As a result, cytoreductive surgery without residual tumour is less likely to be achieved. Systemic treatment is the best option when the aim is to extend life. Single-agent treatment has the least toxic effects and is favoured. Responses to single-agent and combination chemotherapy are summarised in table 1; combinations that are too toxic or showed less activity 1190

are not included. Doxorubicin still shows the best balance between activity and toxic effects and is a first-line option with a 25% response. Gemcitabine is active in combination with docetaxel,16,17,20 but also has activity as a single-agent drug.18 A prospective randomised phase 2 study has shown that gemcitabine plus docetaxel is better than gemcitabine alone for soft-tissue sarcoma in terms of response, progressionfree survival, and overall survival.21 However, responses were low (12 of 73 [16%] in the combination group and four of 49 [8%] in the gemcitabine-alone group) and more toxic effects were noted in the combination group. Most patients received previous cytotoxic therapy in this series. In a series of chemotherapy-naive patients with uterine leiomyosarcomas, gemcitabine plus docetaxel after resection yielded a median 2-year progression-free survival (PFS) of 39 months.22 This combination warrants further investigation in uterine leiomyosarcoma. ET-743 is a promising drug, but its reported activity refers to a pooled analysis with low numbers.23 Uterine leiomyosarcomas showing a disease-free interval of 6 months or more require a different approach.24 A disease-free interval is an indicator of tumour biology and these uterine leiomyosarcomas might have a less aggressive growth pattern. This subset of tumours is more likely to express hormonal receptors that allow targeted treatment. Hormonal treatment or surgery can, therefore, be considered first instead of chemotherapy. Resection of a solitary metastasis might improve the outcome.24 Because most uterine leiomyosarcomas portend an aggressive growth, resection of isolated metastases will benefit only a highly selected group.

Tumour biology Uterine leiomyosarcomas show multiple and often varied gene alterations and very complex karyotypes, which impair the identification of crucial initiation lesions.25 By use of microarray-based comparative genomic hybridisation (CGHarray), frequent loss of chromosome 10 and 13q was noted in extrauterine and uterine leiomyosarcoma, with minimal recurrent regions in 10q21.3 (75%) and 13q14.2-q14.3 (75%), the regions where tumour-suppressor genes PTEN and RB1 reside.26,27 Recurrent regions of amplifications (ie, 1q21, 5p14-pter, 8q, 12q13-15, 13q31, 17p11, 19p13, and 20q13) were identified.25 Many uterine leiomyosarcomas have been characterised by transcriptional profiling. It is difficult to compare the uterine leiomyosarcoma-associated transcriptomes reported in various published studies (table 2). In one study, expression profiling of uterine and extrauterine leiomyosarcomas was compared, but no differences were noted,28 suggesting that malignant smooth-muscle tumours share their tumour signature, and possibly their pathogenetic mechanisms, regardless of origin. Lee and www.thelancet.com/oncology Vol 10 December 2009

Review

colleagues23,29 assessed the possible relation between gene-expression profiles and metastatic behaviour in leiomyosarcomas. This study led to the identification of two distinct subgroups, one of which showed a more metastatic gene-expression profile and predicted a poorer prognosis than the other. Recent expression profiling by use of cDNA microarrays has shown highly-expressed candidate genes in the amplified chromosome 17p13.1-p11.2 region, among which the seroninethreonine protein kinase, AURKB, might be a possible target for therapy.30 Data on the immunohistochemical analysis of expression markers in uterine leiomyosarcomas are summarised in table 3. Most uterine leiomyosarcomas express the platelet-derived growth factor receptor-alfa (PDGFR-α), Wilms’ tumour gene 1 (WT1), aromatase, and gonadotropin-releasing hormone receptor (GnRH-R). Expression profiles of oestrogen and progesterone receptor show wide variation. Although KIT expression has been documented, immunohistochemical findings alone are insufficient for identifying targets for treatment. Androgen receptor positivity has been detected in ten of 25 (40%) of uterine leiomyosarcomas.31 Two studies32,34 have been done on PDGFR-β, but report conflicting findings. Uterine leiomyosarcomas almost always have absence of epidermal growth factor receptor (EGFR) and epidermal growth factor receptor 2 (ERBB2) expression.39

Targeted treatment Targeted treatment with proven benefit Targets of the oestrogen and progesterone receptor have been successful for treating patients with uterine leiomyosarcomas with indolent growth. Case reports show responses to medroxyprogesterone, aromatase inhibitors, and mifepristone (table 4). Aromatase inhibitors block the conversion of androgens to oestrogens in peripheral-fat tissue. The antiprogestational activity of mifepristone results from a competitive interaction with progesterone at the progesterone receptor. Ideally, the receptor status is determined in the recurrent tumour.40 The findings from a running clinical phase 2 trial (NCT00414076), comparing the use of letrozole versus expectative management in uterine leiomyosarcomas are eagerly awaited (table 5).

to be frequently mutated in sporadic cancers and cancer-related hereditary syndromes. Monoallelic loss of PTEN contributes to tumour growth in the context of other somatic mutations, and PTEN protein concentrations correlate with disease severity, suggesting that PTEN is functionally haploinsufficient.42 Mice carrying homozygous deletion of Pten alleles develope widespread smooth-muscle-cell hyperplasia and abdominal leiomyosarcomas.41 In this model, constitutive mTOR activation was restricted to the leiomyosarcoma, showing the requirement for additional molecular events in addition to Pten loss for tumourigenesis. A marked induction of insulin receptor substrate-2 (IRS2) and phosphorylated AKT together with a concomitant upregulation of downstream effectors were also noted. IGF and IGF-receptor overexpression are frequently noted in leiomyosarcoma in humans,25,43,44 possibly adding to the upregulation of the PI3K-AKT-mTOR pathway. Importantly, the PTEN status has been shown to be crucial for the outcome of recently developed clinical therapies targeted at receptor tyrosine kinases (RTK).45 Clinically applicable approaches to counteract the effects of PTEN loss include PI3K, AKT, and mTOR inhibitions. Combining RTK-targeted therapies with therapies aimed at counteracting the effects of PTEN loss, or combinations Uterine leiomyosarcoma

PDGFR-β

7–100% (19)

KIT

0–100% (150) *

EGFR

4% (25)33

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87% (8)32 0–100% (16)32,34

32,34

0–100% (53)10–13*, 15*,16*,23*,32,36

9–16 ,32,34,35,52

··

Oestrogen receptor

18–87% (105)9*,17–19*,31

40–100% (34)19*,22*,37,38

Progesterone receptor

18–80% (104)9*,17–19*,31

60–100% (33)19*,22*,37,38

Aromatase

59% (22) *

0–83% (28)19*,23*

19

100% (2) *

76% (29)24*

Androgen receptor

40% (25)31

36% (14)38

WT1

76% (38)51

47–93% (39)25*,26*,51

GnRH receptor

20

0% (10)39

ERBB2

0% (21)39

Data are a summary of all studies done and are presented as the range of positivity, %, and the total number of studied samples (N). PDGFR=platelet derived growth factor. EGFR=epidermal growth factor receptor. GnRH=gonadotrophin releasing hormone. WT1=Wilms’ tumour gene 1. *See webappendix for these references.

Table 3: Immunohistochemical analysis of potential therapeutic targets in uterine leiomyosarcoma and endometrial stromal sarcoma (ESS)

Targeted treatment with potential benefit The insulin growth-factor (IGF) receptor-AKT-mTOR axis is important in muscle physiology. The PI3K-AKT pathway is also a common point of convergence in signal-transduction networks affected in sarcomas. On the basis of immunohistochemical studies, Hernando and co-workers41 recently reported this growth-promoting cascade to be hyperactivated in leiomyosarcoma. This pathway is negatively regulated by PTEN, a dual-function lipid and protein phosphatase originally identified as a protein encoded by a tumour-suppressor gene, shown

60–70% (38)

PDGFR-α

ESS

32,33

N

Target

Hormone

Clinical Response response duration

Uchida (1996)27*

1

Progesterone receptor Medroxyprogesterone PR

3·75 years

Hardman (2007)28*

1

Oestrogen receptor

PR

1 year

PR

3 years

9% PR

5 months

Koivisto-Korander (2007)40 O’Cearbhaill (2009)29*

Anastrazole

1 of 3 Progesterone receptor Mifepristone 34

Oestrogen receptor

Aromatase inhibitor (74% letrozole)

N=number of patients. PR=partial remission. *See webappendix for these references.

Table 4: Successful targeted treatment in uterine leiomyosarcoma

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Target

Sarcoma

NCT00474994 Sunitinib (SU11248)

Cellular signalling by targeting multiple RTKs (PDGFRs, VEGFRs, KIT, RET, CSF-1R, FLT3)

Metastatic, locally advanced, 2 or locally recurrent non-GIST sarcoma (including all uterine sarcoma)

Completed

Furthermore, in view of the fact that WT1 is overexpressed in uterine leiomyosarcomas, undifferentiated uterine sarcomas, and ESS,51 attacking WT1 on the protein or RNA level is a potential therapeutic strategy.

NCT00414076

Aromatase enzyme

Uterine leiomyosarcoma

2

Recruiting

Targeted treatment unlikely to result in a clinical benefit

NCT00659360 AZD0530

SRC and ABL

Recurrent locally advanced, or metastatic soft-tissue sarcoma (including ESS)

2

Recruiting

NCT00753688 Pazopanib

PDGFRs, VEGFRs, and KIT

3 Metastatic soft-tissue sarcoma that has relapsed or not responded to treatment

Recruiting

Metastatic soft-tissue or bone sarcoma

Recruiting

Drug

SUCCEED trial

Letrozole vs observation

Deforolimus mTOR

Phase Status

3

RTKs=receptor tyrosine kinases. PDGFR=platelet-derived growth-factor receptor. VEGFR=vascular endothelial growth factor receptor. CSF=cerebral spinal fluid. FLT=Fms-like tyrosine kinase. GIST=gastrointestinal tumour. SRC=proto-oncogene tyrosine-protein kinase Src. ABL=Abelson murine leukaemia viral oncogene. mTOR=mammalian target of rapamycin.

Table 5: Clinical trials (active and recently completed) investigating targeted treatment for mesenchymal tumours, including uterine leiomyosarcoma and endometrial stromal sarcoma (ESS)

of these with conventional chemotherapy agents, might also have a therapeutic advantage. PI3K, AKT, and mTOR inhibitors are currently being investigated in clinical trials. Deforolimus, an mTOR inhibitor, is currently being tested in the SUCCEED phase 3 trial (table 5). Preclinical studies suggest that COX inhibitors could have a role in preventing tumour onset or progression in uterine cancers with dysregulation of the high-mobility group A 1 (HMGA1)-α–COX-2 pathway.46,47 HMGA1 encodes the HMGA1-α and HMGA1-β protein isoforms, which function as architectural chromatin-binding proteins involved in regulating gene expression. HMGA1-a binds directly to the COX-2 promoter in-vivo and upregulates expression of COX-2 in uterine tumorigenesis, in transgenic mice models and in humans. Both, HMGA1-a and COX-2 are highly overexpressed in human uterine leiomyosarcomas.46 Drugs that block COX-2 function include sulindac (a COX-1/COX-2 inhibitor) or celecoxib (a specific COX-2 inhibitor). Importantly, these drugs have less toxic effects than chemotherapeutic agents used to treat advanced-stage uterine cancers.48 On the basis of cDNA microarray analysis, acrogranin (also called pluripotent cell-derived growth factor or progranulin) has been identified as a promising target for drug development. Acrogranin, a pluripotent growth factor that mediates cell-cycle progression and cell motility, is highly expressed in uterine leiomyosarcomas. This expression is correlated with a high histological grade and poor prognosis.49 WT1, located on chromosome 11p13, has a role in several haematological and solid malignancies by an overexpression of its protein in these tumours.50 Because WT1 is highly immunogenic and restricted to tumour cells, it is an attractive target for immunotherapy. 1192

Trastuzumab is unlikely to be of clinical use because ERBB2 has not been detected in uterine leiomyosarcomas.39 Although immunohistochemical expression has been reported in uterine leiomyosarcomas, the KIT receptor is unlikely to be a target for antityrosine-kinase drug therapy using known inhibitors—eg, imatinib. The KIT receptor contributes to tumourigenesis by activating mutations. However, uterine leiomyosarcomas lack both the KIT oncogenic mutations and KIT phosphorylation, suggesting that KIT is not involved in the pathogenesis of uterine leiomyosarcoma.35,36,52,53 Similarly, uterine leiomyosarcomas do not carry activating PDGFR mutations; therefore, targeting these genes does not seem rational.33 Tamoxifen is associated with the induction of uterine leiomyosarcoma54 and invitro data support stimulation of uterine leiomyosarcoma cells by tamoxifen.55 And sorafenib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, produced one partial remission in 37 patients (3% response) with soft-tissue leiomyosarcoma.56

Endometrial stromal sarcoma Histopathology Endometrial stromal neoplasms are exclusively composed of cells resembling the endometrial stroma in its proliferative phase. The stromal nodule is the benign variant; it has well circumscribed borders and is rare.57,58 ESS represents the entity with infiltrating borders and behaves like a low-grade sarcoma, with the potential for recurrence and metastasis.59 Microscopic findings that unequivocally correspond to ESS include a uniform population of endometrial stromal-type cells invading the myometrium and myometrial vessels. Historically, ESSs were subdivided into low-grade and high-grade tumours. However, high-grade tumours do not have the typical growth pattern and vascularity of low-grade tumours and show destructive myometrial invasion rather than the lymphatic permeation of a low-grade ESS. Moreover, high-grade ESSs show marked cellular pleomorphism and brisk mitotic activity.60 As a result, the term ESS is now restricted to malignancies that were formally referred to as low-grade ESS.58 Here, we discuss ESS according to this new definition. Endometrial sarcomas without recognisable evidence of a definite endometrial stromal phenotype, designated as poorly differentiated endometrial sarcomas, are almost invariably high grade,58,61,62 and termed poorly differentiated or undifferentiated uterine sarcoma. These high-grade tumours show similarity with uterine leiomyosarcomas when clinical presentation, imaging www.thelancet.com/oncology Vol 10 December 2009

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studies, treatment modalities, and prognosis are considered.

Imaging The diagnosis of ESS can be problematic, especially in younger women. In this age group, gynaecological problems are likely to be hormonal and a uterine malignancy might be overlooked.63 On ultrasonography, ESS can present as a hypoechogenic mass with irregular margins originating from the endometrium and with irregular central or circular vascularisation. A heterogeneous pattern of the endometrium with high-intensity and hypoechoic areas scattered in the myometrium has also been linked to ESS.64 On MRI, ESS typically presents as an invasive endometrial mass6 with extensive myometrial involvement, which is either sharply demarcated or diffusely infiltrative.65 On T2-weighted images, bands of low signal intensity corresponding to preserved bundles of myometrium are noted within areas of myometrial involvement. Another common MRI finding in ESS is tumour extension along the vessels or ligaments.65 In a comparative MRI study on eight cases of ESS and 21 consecutive cases of endometrial cancer, Ueda and colleagues66 concluded that ESS more frequently had irregular margins, nodular lesions at the margin, intramyometrial nodular extension, and multiple nodular mass formation compared with endometrial cancer. However, features on both ultrasonography and MRI are non-specific for the diagnosis of ESS. Hysterectomy is advocated when imaging modalities cannot exclude a malignancy.

Current treatment Preoperative imaging is mandatory, because ESS tends to spread to the lungs and peritoneum.59 Most ESSs (65–86%) will present with disease limited to the uterus (stage I–II disease).59,67 Hysterectomy is the cornerstone of treatment in early stage disease (figure 2). The peritoneal cavity should be explored simultaneously. Lymphatic involvement of ESS is well established, as evidenced by a previous pathological designation of endolymphatic stromal myosis. Although nodal involvement increases the stage, lymphadenectomy in all ESSs is unlikely to improve survival.67–69 A policy of leaving nodes behind in a small series did not result in isolated retroperitoneal recurrences that might hamper the prognosis.68 In a large population-based analysis including 831 women with all grades of ESS, nodal involvement was 6·0% in grade 1 and 8·9% in grade 2 ESS (probably similar to low-grade ESS); however, lymphadenectomy had no effect on survival.67 In another series including 384 patients with ESS, nodal involvement was detected in seven of 100 (7%) women undergoing lymphadenectomy.69 However, no survival benefit was noted for women undergoing lymphadenectomy in this large series.69 This finding www.thelancet.com/oncology Vol 10 December 2009

might be explained by the high 5-year survival of node-positive ESS (86% for node-positive cases vs 95% for node-negative cases in the Shah series).69 The smaller than expected effect of nodal metastasis is also explained by the tendency of ESS to recur transperitoneally or in the lungs.59 Thus, these data suggest that systematic lymphadenectomy for ESS is not indicated. When lymph nodes are pathologically enlarged, lymphadenectomy is considered part of a cytoreductive procedure. The controversy on this topic is at least partially fed by the inclusion of both low-grade and high-grade sarcomas in the studies.67,70 Chan and colleagues67 noted a poorer survival in patients with positive nodes compared with patients with negitive nodes. However, the high-grade sarcomas count in large for this outcome. Additionally, incidences of nodal involvement need to be interpreted with the status of other extrauterine locations. Lymph-node involvement in tumours with other gross extrauterine involvement is unlikely to be prognostic.71 Standard treatment for ESS is hysterectomy with bilateral salpingo-oophorectomy. Although surgical castration is a logical intervention for a hormone-sensitive disease, the clinical benefit remains unproven. Therefore, in young women, this policy deserves a critical analysis. Data from small37,68,72–74 and large67,69 non-randomised series suggest that leaving the ovaries in situ does not worsen the outcome. Management of menopausal symptoms can be challenging in young women. Oestrogen-replacement therapy in women with a history of ESS has been associated with a poor outcome.37 However, these data were based on five women only and need to be confirmed. In young women, we advocate a thorough discussion on the risk and benefit of surgical castration. Individualisation of the surgical approach in this group of patients is important. After providing this information, we would accept the treatment of small ESSs (<2–3 cm) in women younger than 35 years without surgical castration. Because ESS expresses both the oestrogen and progesterone receptor, adjuvant targeted hormonal treatment can be considered to reduce recurrence.37,68 Progestins or aromatase inhibitors can be considered. There are no prospective studies investigating adjuvant treatment for ESS. Even retrospective data on clinical benefit are limited. Additionally, there are no valid data on the duration of treatment and it is unknown whether the menopausal status (after oophorectomy, for example) affects any treatment-induced effect. The benefit of adjuvant medroxyprogesterone (250 mg) or megestrol (160 mg) on a daily basis over 2 years has been suggested in two small studies.37,68 Side-effects of progestins include thrombosis and weight gain (higher circulating oestrogen levels), whereas aromatase inhibitors are associated with osteoporosis and muscle or joint complaints. The history and condition of the patient can help the decision on the treatment of choice if necessary. 1193

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For ESS with mainly transperitoneal spread, cytoreductive surgery is advocated because of the low-grade nature of the disease and the efficacy of hormone-receptor-targeted treatment.63,70 Organ resection (ie, splenectomy or partial bowel resection) can be considered, especially if this contributes to an absence of the residual tumour.63,70 The decision to resect distant metastasis (frequently lung parenchyma) should be taken on an individual basis. Adjuvant hormonal treatment is advocated until progression. ESS has an indolent growth with a tendency for late recurrence. Recurrences are common, even in early stage disease. Relapse occurs in 36–56% of early stage disease.59,75 The median time to recurrence has been shown to be 65 months and 9 months for stages 1 and 3–4, respectively.59 The indolent growth makes aggressive

N

Targeted treatment

Duration of response Type of response (months)

3

MPA

0 50 9

Progestins Pink (2006)22*

PD CR SD

Pellillo (1968)30*

1

MPA

24

CR

Baggish (1972)31*

1

MPA

30

CR CR

Krumholz (1973)32*

1

MPA

22

Schmid (1974)33*

1

17-α HPC

12

CR

Jacobsen (1975)34*

1

MPA

36

CR

Hart (1977)35*

1

MPA

12

CR

Lehrner (1979)36*

1

Meg+chemotherapy

12

CR

Brons (1980)37*

2

MPA

9 12

CR PR

Gloor (1982)38*

1

MPA

33

PR

O’Brien (1985)39*

1

MPA

30

PR PR

Tsukamoto (1985)40*

1

17-α HPC, MPA

24

Keen (1989)41*

1

MPA

90

PR

Scribner (1998)42*

1

Meg

20

CR

Chu (2003)37

8

Meg (N=4) and progestins NOS (N=4)

18–180

CR (N=4) SD (N=3) NOS (N=1)

Pink (2006)22*

5

Letrozole

37 9 10 3 0

PR PR PR PR PD

Maluf (2001)43*

1

Letrozole

Spano (2003)44*

2

Aminoglutethimide

Leunen (2004)45*

1 1

Aromatase inhibitors

9

PR

168 84

CR CR

Letrozole

36

PR

Triptorelin

12

PR

GnRH analogue Burke (2004)46*

*See webappendix for these references. N=number of patients. MPA=medroxyprogesterone. PD=progressive disease. CR=complete remission. SD=stable disease. HPC=hydroxyprogesterone caproate. Meg=megestrolacetate. PR=partial remission. NOS=not otherwise specified. GnRH=gonadotropin releasing hormone.

Table 6: Overview of progesterone and oestrogen-receptor targeted treatment in endometrial stromal sarcoma

1194

and repeated surgery valuable. Secondary and tertiary cytoreductive procedures with or without resection of distant metastases (eg, lung parenchyma or cardiac) should be considered.63,70,76,77 Intervals between the surgeries can be extended by targeting the hormone receptors (figure 2).75 When the hormonal armamentarium is exhausted, in the absence of hormonal receptors or when progression into a high-grade malignancy occurs, ifosfamide and doxorubicin seem to be active cytotoxic drugs.76,78,79

Tumour biology Up to now, three different and seemingly disease-specific fusion transcripts have been identified in ESS. About half of these tumours have been shown to contain a specific recurrent chromosomal translocation, the t(7;17)(p15;q21), resulting in the fusion of two zinc-finger genes, JAZF1 (Juxtaposed with Another Zinc Finger) and SUZ12 (also named JJAZ1).80 This translocation has been identified in each case of stromal nodule analysed,81 which raises the possibility that malignant ESS can develop from stromal proliferations that are initially benign. Micci and colleagues82 showed that the PHF1 gene in 6p21 was recombined with two different partners, with the JAZF1 gene in two ESS showing a 6p;7p rearrangement and with the EPC1 gene in 10p11 in one tumour that had a 6;10;10 translocation. The mechanism by which altered JJAZ1 presumably contributes to the neoplastic phenotype in stromal nodules and ESS is not known, nor is it understood what distinguishes the malignant behaviour of ESS from the benign behaviour of stromal nodules. Interestingly, JAZF1, PHF1, and EPC1 are members of the polycomb group (PcG) of genes, which encode proteins that act in multimeric complexes to methylate histones, leading to chromatin remodelling, regional compaction of the chromatin, and suppression of transcription from genes associated with these regions. A genetic pathway for progression of a benign precursor to a sarcoma, involving increased cell survival associated with acquisition of a PcG rearrangement, followed by accelerated cellular proliferation on allelic exclusion of the unrearranged copy of that gene, has been proposed.79 The findings of immunohistochemical analyses in ESS are summarised in table 3. Expression profiles frequently contain the oestrogen and progesterone receptors, PDGFR-α, aromatase, GnRH-R, and WT1. CD117 (KIT) was positive in only 11% of investigated ESS (6 of 53). The two studies on PDGFR-β show opposite findings.32,34

Targeted treatment Targeted treatments with proven benefit The PR is the most important target for hormonal treatment. Experience is mainly available with progestins (ie, medroxyprogesterone, megestrol, and hydroxyprogesterone; table 6). At least 25 cases of ESS www.thelancet.com/oncology Vol 10 December 2009

Review

have been reported in 16 studies, with a response of 76% (19 of 25). Aromatase inhibitors reduce oestrogen concentrations by inhibiting oestrogen synthesis in both tumour tissue and peripheral sites, and, as a consequence, they inhibit the proliferation of the tumour. An overview of clinical data on aromatase inhibitors is presented in table 6. Letrozole was most frequently used and a response was induced in eight of nine patients (88%) given an aromatase inhibitor. Injection of GnRH analogues resulted in partial remission in a single case.

Targets with potential benefit There was no response to mifepristone in one case of ESS, although larger series are needed.83 Fulvestrant is a new interesting ER antagonist that has not yet been tested. Further studies of JAZF1/JJAZ1, JAZF1/PHF1, and EPC1/PHF1 and their downstream effects are necessary to provide clues that might help to eventually generate drugs that counteract the protein-level effect(s) of these cancer-specific fusion genes. Similar to uterine leiomyosarcoma, WT1 overexpression in ESS51 is a potential target for immunotherapy.

Targeted treatment unlikely to result in a clinical benefit In ESS, ERBB2 expression is absent,39 and no oncogenic mutations have been shown in PDGFR-α32 making it an unattractive target. Tamoxifen has a weak oestrogenic effect on endometrial glands and the endometrial stroma and its use is linked to ESS induction. Tamoxifen and oestrogen-replacement therapy are, therefore, contraindicated in women with a history of ESS.37

Other uterine sarcomas Undifferentiated sarcoma Undifferentiated uterine sarcoma is a poorly defined group. These tumours do not show evidence of gene-specific fusions, suggesting that they arise by a different pathogenetic mechanism compared with ESS. Immunohistochemical data are also sparse, including only a few cases per article published. On the basis of these data, it seems that undifferentiated sarcomas are positive for PDGFR-α,34 androgen receptor,38 and WT1.51 Of note, one of four samples were positive for ERBB2.39

Gastrointestinal stromal tumours Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract. Rare cases are identified outside the gastrointestinal tract and are collectively known as extragastrointestinal stromal tumours (EGISTs). EGISTs that present as gynaecological masses are rare, but might be more common than is currently recognised.84–86 Misdiagnosis can lead to inappropriate therapy, because conventional chemotherapy and radiotherapy are not effective in the www.thelancet.com/oncology Vol 10 December 2009

treatment of GISTs. Thus, it is imperative to consider EGISTs in the differential diagnosis of mesenchymal neoplasms in the uterine, fallopian tubes, or vulvovaginal or rectovaginal septum. Primary activating mutations in the KIT or PDGFRA genes, which result in constitutive activation of receptor tyrosine-kinase activity, are early oncogenic events in most adult GISTs. However, a subset of tumours (10–15%), show wild-type KIT and PDGFRA genotype. Immunohistochemical staining for KIT (CD117) has become integral to the diagnosis of GISTs, nearly 95% of which are positive for this marker. Establishing the diagnosis of KIT-negative GIST remains a challenge and is best handled by a reference pathologist with expertise in this area. The use of mutational analysis of the kinase genes KIT and PDGFRA is the standard of care in such cases. Imatinib provides targeted therapy for GIST by inhibiting the KIT and PDGFR-α tyrosine kinases. Clinical benefit is achieved in about 85% of patients with unresectable or metastatic disease, with a median PFS of 20 to 24 months.87 Importantly, the tumour KIT/PDGFRA kinase genotype has predictive significance with regard to the response to imatinib therapy; the presence of a KIT juxtamembrane mutation being the single best predictor of response to imatinib.88 Therefore, mutational analysis before imatinib treatment for unresectable or metastatic disease is strongly recommended.

Adenosarcoma Uterine adenosarcomas have a benign epithelial component, whereas the stromal component is typically a low-grade sarcoma. In 56% of cases, the sarcomatous component is ESS-like and in an additional 9% of cases a mixture of ESS-like cells and fibrosarcoma are present.89 In one study, the sarcomatous component of uterine adenosarcoma without sarcomatous overgrowth expressed the oestrogen or progesterone in 18 of 20 (90%) patients.90 In view of the similarity in tumour biology, treatment options are similar to ESS. Uterine adenosarcoma with sarcomatous overgrowth is an aggressive entity that is unlikely to be hormone sensitive.

Conclusion Uterine sarcomas are uncommon and preoperative diagnosis is frequently unknown. As a result, centralisation, large series, and randomised trials are problematic. Hysterectomy is the cornerstone of treatment for early stage uterine leiomyosarcoma and ESS. There is no proven benefit from any adjuvant treatment (ie, radiotherapy, chemotherapy, or hormonal targeted) for both entities. Hormone receptors are the most important targets for primarily advanced or recurrent ESS, as for a subset of recurrent uterine leiomyosarcomas. Progestins and aromatase inhibitors show the highest clinical activity. The efficacy of 1195

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14

Search strategy and selection criteria Information for this Review was obtained by a Search of Medline and references from relevant articles using the search terms: “sarcoma”, “endometrial stromal”, “leiomyosarcoma”, “uterine”, “ultrasonography”, “hormonal”, “magnetic resonance imaging”, “computed tomography”, “neoplasm”, “genetics”, “imaging”, “surgery”, “chemotherapy”, “molecular signature”, and “targeted therapy”. The search strategy was not limited by date and no language restrictions were applied.

15

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17

18

mifepristone and fulvestrant deserves further study in uterine leiomyosarcoma and ESS. The efficacy of new targeted drugs for uterine sarcomas is still being explored. For uterine leiomyosarcoma, clinically applicable approaches to counteract the effects of PTEN loss include PI3K, AKT, and mTOR inhibitors. Centralisation and intergroup studies are the only appropriate answer to the current paucity of evidence. Contributors FA designed the concept. All authors were involved in the literature search, writing, and final approval of the manuscript. Conflicts of interest The authors declared no conflicts of interest.

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