Morcellation of uterine leiomyomas: a plea for patient triage

Morcellation of uterine leiomyomas: a plea for patient triage

Comment with CNS metastases is 4–6 months, and only 20–40% of patients survive the first year.7 In the past few years, there has been increasing inter...

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with CNS metastases is 4–6 months, and only 20–40% of patients survive the first year.7 In the past few years, there has been increasing interest in assessment of novel therapies for the treatment of breast cancer that has metastasised to the brain, including local and systemic approaches. At present, no cytotoxic or targeted drugs have gained regulatory approval for the treatment or prevention of breast cancer brain metastases.8 Biomarker analyses are ongoing in the BEACON study; however, the most predictive one could be as simple as a brain CT suggestive of metastasis. In the era of precision medicine, it is perhaps time to design trials to compare standards of care in radiotherapy against chemotherapy or targeted treatments and to try to optimise our approach for palliation of symptoms of breast cancer brain metastases. The incidence of cognitive dysfunction in women receiving brain radiotherapy has been shown to be substantial, and one clinical advantage of chemotherapy in this population might be to avoid this very disturbing adverse event.9 In view of the improvements in systemic therapies that led to longer overall survival, we believe that development of both therapeutic and preventive approaches for brain metastases are more important now than ever before.

Emmanouil Saloustros, *Vassilis Georgoulias General Hospital of Heraklion ‘Venizelio’, Heraklion, Greece (ES); and Hellenic Oncology Research Group, 11471, Athens, Greece (ES, VG) [email protected] We declare no competing interests. 1

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Chia SK, Speers CH, D’Yachkova Y, et al. The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic breast cancer. Cancer 2007; 110: 973–79. Cardoso F, Di LA, Lohrisch C, Bernard C, Ferreira F, Piccart MJ. Second and subsequent lines of chemotherapy for metastatic breast cancer: what did we learn in the last two decades? Ann Oncol 2002; 13: 197–207. Seah DS, Luis IV, Macrae E, et al. Use and duration of chemotherapy in patients with metastatic breast cancer according to tumor subtype and line of therapy. J Natl Compr Canc Netw 2014; 12: 71–80. Awada A, Garcia AA, Chan S, et al. Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: a randomised phase 2 study. Lancet Oncol 2013; 14: 1216–25. Perez EA, Awada A, O’Shaughnessy J, et al. Etirinotecan pegol (NKTR-102) versus treatment of physician’s choice in women with advanced breast cancer previously treated with an anthracycline, a taxane, and capecitabine (BEACON): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 2015; published online Oct 16. http://dx.doi.org/10.1016/ S1470-2045(15)00332-0. Sheik-Yousouf A, Gandhi S, Dukhovny S, Verma S. A comparison of physician and patient perceptions of clinically important endpoints in the treatment of Metastatic Breast Cancer (MBC). EJC Supplements 2010; 8: 77. Pestalozzi BC, Francis P, Quinaux E, et al. Is risk of central nervous system (CNS) relapse related to adjuvant taxane treatment in node-positive breast cancer? Results of the CNS substudy in the intergroup Phase III BIG 02-98 Trial. Annal Oncol 2008; 19: 1837–41. Lin NU, Amiri-Kordestani L, Palmieri D, Liewehr DJ, Steeg PS. CNS metastases in breast cancer: old challenge, new frontiers. Clin Cancer Res 2013; 19: 6404–18. Brown P, Asher A, Ballman K, Farace E, Cerhan J, Anderson S. NCCTG N0574 (Alliance): a phase III randomized trial of whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 brain metastases. Proc Am Soc Clin Oncol 2015; 33: Abstr LBA4.

Morcellation of uterine leiomyomas: a plea for patient triage Uterine leiomyomas are the most common tumours of the genital tract; nearly 70% of white women and more than 80% of black women will have at least one by the age of 50 years. Treatment is necessary in 15–30% of these women.1 Apart from this benign lesion, the uterus can harbour malignant tumours, including endometrial cancer and tumours of mesenchymal origin, so-called sarcomas. These include a wide range of monophasic or biphasic tumours, including leiomyosarcoma, endometrial stromal sarcoma, smooth-muscle tumour of uncertain malignant potential, undifferentiated sarcoma, adenosarcoma, and some very rare tumours. Between 1970 and 2000, 419 uterine sarcomas were registered in Norway.2 Based on NOCCA and NORDCAN databases, incidence rates were about 0·3 cases per 100 000 for endometrial stromal sarcoma and about 0·4 cases per 100 000 for leiomyosarcoma.3 1454

The differentiation of benign and malignant lesions requires expert pathologists. It is therefore not surprising that imaging frequently fails to identify malignant mesenchymal uterine tumours.4,5 CT scans inform little about uterine details and have generally been used to identify extrauterine extension in the pelvis and metastatic disease. On MRI, the appearance of leiomyosarcoma is variable and pathognomic features of malignancy are lacking, especially for small tumours.5 Morcellation is part of the endoscopic armamentarium and is designed to remove large leiomyomas, thus avoiding laparotomy and its associated longer recovery period and possible complications. However, morcellation and spilling of malignant cells changes the natural spread pattern and increases the risk of transperitoneal www.thelancet.com/oncology Vol 16 November 2015

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dissemination and recurrent cancer. The US Food and Drug Administration calculated that the risk of morcellating an unsuspected uterine sarcoma is one in 352 and the risk of morcellating an unsuspected uterine leiomyosarcoma is one in 498.6 The FDA subsequently recommended that laparoscopic power morcellators should no longer be used for hysterectomy or myomectomy in most women with uterine leiomyomas. However, clinicians need to strike a balance between denying all women the benefits of an endoscopic approach versus the risk that some women will die as a consequence of morcellation of a malignancy. At our clinics, we use a vaginal ultrasonography as a triage instrument to identify patients who preferably should not undergo a morcellation. Some ultrasound features are indicative of a sarcoma while others are for leiomyomas. A sarcoma is generally solitary, large, and oval shaped with heterogeneous echogenicity. There might be irregular anechoic areas due to necrosis or haemorrhage. On colour Doppler imaging, a sarcoma is more often highly vascularised (score 3–4) with prominent irregular intralesional vascularity more often than leiomyomas. The vessels are of unequal size and exhibit irregular branching. Because of their rapid growth, most sarcomas are large at diagnosis. Myometrial lesions with a large diameter (eg, exceeding 8 cm) should be managed with circumspection.7 A leiomyoma is typically a round lesion. The echogenicity of a leiomyoma is highly variable, ranging from uniform hypoechogenic or hyperechogenic to lesions of mixed echogenicity, often with echogenic areas or calcifications. Calcifications can cause prominent shadowing. If the calcifications lie scattered in the leiomyoma, it gives rise to socalled fan shaped shadows. In case of peripheral calcification, so-called edge shadows are seen. If the leiomyoma is almost entirely calcified, it causes very strong shadowing behind the lesion. The vascularity is mainly peripheral (circular flow), although some leiomyomas have irregular or prominent internal vessels. It has to be stressed that these ultrasonographic features are based on case series and expert opinion and not on prospective observational studies.8 In clinical practice, good judgement is based on reassuring or non-reassuring ultrasonographic features (panel). Prospective, multicentre data collection with www.thelancet.com/oncology Vol 16 November 2015

Panel: Reassuring and non-reassuring (ultrasonographic) features of uterine tumours Benign features Round lesion Several lesions Wide range of small and large lesions Absence of central necrosis Regular outline Absence or limited growth (over a 3 month interval) Low blood flow Calcifications with shadowing Suspicious features Oval lesion One lesion Large lesion Central necrosis Irregular or lobulated outline Fast growth (over 3 months interval) High blood flow Absence of calcification and absence of shadowing Atypical growth (postmenopausal, post-embolisation, and under gonadotropin-releasing hormone analogues) Ovarian fibroma

standardised terms and definitions9 could improve our ability to differentiate between benign and malignant myometrial lesions. Assessment of tumour biology could also help to triage patients. Leiomyomas are hormone sensitive and regress in the postmenopausal period. Sarcomas tend to be rapidly growing tumours. Serial ultrasound examinations at an interval of about 3 months have been suggested in case of uncertainty about the malignant character of a myometrial lesion.8 Although a rapid increase in size should raise the suspicion of malignancy, some leiomyomas also grow rapidly. The absence of substantial growth could be considered to be reassuring. Additionally, presumed leiomyomas that insufficiently respond to gonadotrofin releasing hormone analogues10 or uterine artery embolisation are more likely to have a malignant behaviour. Solid ovarian tumours preoperatively diagnosed as ovarian fibromas with a large diameter also have a higher risk to be malignant. In conclusion, we believe that the patient should be informed about the risks of morcellation, their preoperative ultrasonography findings and tumour biology, and the available alternatives, rather than morcellation being entirely discouraged. 1455

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Frédéric Amant*, Thierry Van den Bosch, Ignace Vergote, Dirk Timmerman Department of Obstetrics and Gynaecology, University Hospitals KU Leuven, 3000 Leuven, Belgium (FA, TV, IV, DT); Center for Gynecologic Oncology Amsterdam, Antoni van Leeuwenhoek–The Netherlands Cancer Institute, Amsterdam, The Netherlands (FA); and Department of Obstetrics and Gynecology, Tienen Regional Hospital, Tienen, Belgium (TV) [email protected]

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We declare no competing interests. 1 2

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Bulun SE. Uterine fibroids. N Engl J Med 2013; 369: 1344–55. Abeler VM, Royne O, Thoresen S, Danielsen HE, Nesland JM, Kristensen GB. Uterine sarcomas in Norway. A histopathological and prognostic survey of a total population from 1970 to 2000 including 419 patients. Histopathology 2009; 54: 355–64. Koivisto-Korander R, Martinsen JI, Weiderpass E, Leminen A, Pukkala E. Incidence of uterine leiomyosarcoma and endometrial stromal sarcoma in Nordic countries: results from NORDCAN and NOCCA databases. Maturitas 2012; 72: 56–60.

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Amant F, Coosemans A, Debiec-Rychter , Timmerman D, Vergote I. Clinical management of uterine sarcomas. Lancet Oncol 2009; 10: 1188–98. Shah SH, Jagannathan JP, Krajewski K, O’Regan KN, George S, Ramaiya NH. Uterine sarcomas: then and now. AJR Am J Roentgenol 2012; 199: 213–23. US Food and Drug Administration. FDA discourages use of laparoscopic power morcellation for removal of uterus or uterine fibroids, April 17, 2014. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm393689.htm (accessed Jan 1, 2015). Exacoustos C, Romanini ME, Amadio A, et al. Can gray-scale and color Doppler sonography differentiate between uterine leiomyosarcoma and leiomyoma? J Clin Ultrasound 2007; 35: 449–57. Brölmann H, Tanos V, Grimbizis G, et al, for the European Society of Gynaecological Endoscopy (ESGE) steering committee on fibroid morcellation. Options on fibroid morcellation: a literature review. Gynecol Surg 2015; 12: 3–15. Van den Bosch T, Dueholm M, Leone FP, et al. Terms and definitions for describing myometrial pathology using ultrasonography. Ultrasound Obstet Gynecol 2015; 46: 284–98. Dover RW, Ferrier AJ, Torode HW. Sarcomas and the conservative management of uterine fibroids: a cause for concern? Aust N Z J Obstet Gynaecol 2000; 40: 308–12.

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On Oct 5, 2015, we launch the first 45 disease-specific pages of a major new online initiative involving all Lancet journals that will bring together an overview Seminar and relevant Reviews, Clinical Series, Commissions, research, Case Reports, and Clinical Pictures. Over the next 18 months or so when The Lancet Clinic is complete, there will be online pages for 135 diseases, which we have identified by a combination of global burden of disease data and clinical practice needs. We hope that The Lancet Clinic will help practising doctors make better informed decisions that ultimately lead to better lives of people worldwide, and help others who want to educate or update themselves keep abreast of the evolving evidence base. Importantly, these pages will be updated at regular intervals. The authors of newly commissioned Seminars have agreed to provide regular summaries of important new evidence for 4 years. Individual clinical editors will pull together newly published material from across the Lancet journals and post links to these on the page regularly. In addition, we are continuing our regular editorial policies of commissioning more specialised Clinical Reviews and Series across The Lancet Group to provide a more focused and in-depth assessment for key diseases. And beyond providing knowledge and information, we want to encourage academic and practising clinicians to use this knowledge for advocacy and change. In 2014, The Lancet published the first Clinical Commission on liver disease in the UK and in February, 2015, we launched our first Clinical Campaign based on this

Commission. A Cancer Campaign as a joint effort between The Lancet and The Lancet Oncology followed in April. Clinical Campaigns aim to effect change based on data, knowledge, and expert interpretation in partnership with others. Further Clinical Commissions on asthma, hypertension, dementia, tuberculosis, traumatic brain injury, psychotherapy, chronic obstructive pulmonary disease, and others are underway across all Lancet journals. With these Clinical Commissions and Campaigns, we hope to extend our goal to publish the best science for better lives to being an active partner in using this science for actual change. Commissions and Campaigns will be part of the disease pages to encourage engagement and actions. The Lancet Clinic invites you to be part of this endeavour. *Sabine Kleinert, Richard Horton, Elena Becker-Barroso, Niall Boyce, David Collingridge, Justine Davies, Emma Grainger, Peter Hayward, John McConnell, Zoë Mullan, Lan-Lan Smith The Lancet, London EC2Y 5AS, UK (SK, RH); The Lancet Neurology, London, UK (EB-B); The Lancet Psychiatry, London, UK (NB); The Lancet Oncology, London, UK (DC); The Lancet Diabetes & Endocrinology, London, UK (JD); The Lancet Respiratory Medicine, London, UK (EG); The Lancet HIV, London, UK (PH); The Lancet Infectious Diseases, London, UK (JM); The Lancet Global Health, London, UK (ZM); and The Lancet Haematology, London, UK (L-LS) [email protected] Copyright © Kleinert et al. Open Access article distributed under the terms of CC BY.

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