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An open letter to the FDA regarding the use of morcellation procedures for women having surgery for presumed uterine fibroids

In November, 2014 the FDA ruled that power morcellation was contra-indicated in “the majority of women” having surgery for uterine fibroids due to the potential risk of spreading occult uterine sarcoma.  Although problems with this ruling were immediately apparent, the passage of time has allowed for more clarity on the related medical issues.

Prevalence of Leiomyosarcoma among women having surgery for presumed uterine fibroids

The prevalence of occult leiomyosarcoma among women with fibroids is critical for every patient.  All medical procedures have potential risk and the patient’s understanding of risk is the foundation of medical decision-making.

The FDA estimated that for every 458 women having surgery for fibroids, one woman would be found to have an occult leiomyosarcoma (LMS).  We challenge this calculation.  To estimate this risk, the FDA searched medical databases using the terms “uterine cancer” AND “hysterectomy or myomectomy”.   Because “uterine cancer” was required, studies where cancer was not found or discussed were not identified.  Nine studies, all but one of which were retrospective, were analyzed including a non-peer-reviewed letter to the editor and an abstract from an unpublished study. (Leung, Rowland)    Additionally,  three “leiomyosarcoma ” cases identified by the FDA do not meet current pathologic criteria for cancer and would now be classified as benign “atypical” leiomyomas.  If atypical leiomyomas and non-peer-reviewed data are excluded, the FDA identified 8 cases of LMS among 12,402 women having surgery for presumed leiomyomas, a prevalence of 1 in 1,550 (0.064%).

Pritts et al. recently published a more rigorous meta-analysis of 133 studies and determined that the prevalence of LMS among women having surgery for presumed fibroids was 1 in 1,960, or 0.051%.   All peer-reviewed reports in which surgery was performed for presumed fibroids were analyzed, including reports where cancer was not found. Inclusion criteria required that histopathology results be explicitly provided and available for interpretation. Among the 26 randomized control trials analyzed, 1,582 women had surgery for fibroids and none were found to have LMS.   Bojahr et al., recently published a large population-based prospective registry study and reported 2 occult LMS among 8,720 women having surgery for fibroids (0.023%).    In summary, the re-analyzed FDA dataset yields a prevalence of 1 in 1,550 (0.064%), the Pritts study reports a prevalence of 1 in 1,960 (0.051%) with the RCT’s having a prevalence of 0 and the Bojahr study reported a prevalence of 2 of 8,720 (0.023%). We acknowledge that with rare events statistical analysis may be uncertain and confidence Intervals may be wide.  However, these numbers do not support the FDA’s estimated prevalence of LMS among women having surgery for presumed fibroids and those at risk for morcellation of a leiomyosarcoma.

Prognosis for women with morcellated LMS

Leiomyosarcoma, removed intact without morcellation have a poor prognosis.  Based on SEER data, the 5 year survival of Stage I and II LMS is only 61%. (Kosary)   Whether morcellation influences the prognosis of women with LMS is not known and the biology of this tumor has not been well studied.  Distant metastasis occur early in the disease process, primarily hematogenous dissemination.  Four frequently quoted published studies examine survival following power-morcellation.  Surprisingly, virtually none of the women in these studies had power-morcellation.  Furthermore, the data presented in these reports are poorly analyzed and patient numbers are very small.  Park, et. al. reported only one of the 25 morcellated cases had laparoscopic surgery with power-morcellation.   Eighteen women had a laparoscopically-assisted vaginal hysterectomy with scalpel-morcellation performed through the vagina, one had a vaginal hysterectomy with scalpel-morcellation and 5 had mini-laparotomy with scalpel-morcellation through small lower abdominal incisions.  Seventeen of the 25 patients plotted in the published survival curve were referred to the hospital after initial diagnosis or the discovery of a recurrence at another institution. Since the number of non-referred women with less aggressive disease or without recurrence is not known, it is not possible to determine differences in survival between patients with and without morcellation.    In a study by Perri et. al., none of the patients had power-morcellation.   Four women had an abdominal myomectomy, four had a hysteroscopic myomectomy with tissue confined within the uterine cavity, two had a laparoscopic hysterectomy with scalpel-morcellation, four had a supra-cervical abdominal hysterectomy with cut-through at the cervix and two had an abdominal hysterectomy with injury to the uterus with a sharp instrument.   When comparing the outcomes for women with morcellated and non-morcellated LMS, Morice et. al., found no difference in recurrence rates or over-all and disease-free survival at six months.  In the only study to compare use of power- with scalpel-morcellation in women with LMS, Oduyebo et. al. found no difference in outcomes for the 10 women with power-morcellation and five with scalpel-morcellation followed for a median of 27 months (range, 2-93).    Notably, a life table analysis of the above studies showed no difference in survival between morcellation methods. (Pritts)

Of note, laparoscopic-aided morcellation allows the surgeon to inspect the pelvic and abdominal cavities and irrigate and remove tissue fragments under visual control. In contrast, the surgeon cannot visually inspect the peritoneal cavity during vaginal or mini-laparotomy procedures.  Morcellation within containment bags have recently been utilized in an attempt to avoid spread of tissue.  These methods have not yet been proven effective or safe, and there is  concern that bags may make morcellation more cumbersome and less safe.

What the FDA Restrictions Mean for Women

The FDA communication states, “the FDA is warning against the use of laparoscopic -morcellators in the majority of women undergoing myomectomy or hysterectomy for treatment of fibroids.”  This statement is not consistent with current evidence.  Moreover, a severe restriction of morcellation, including vaginal and mini-laparotomy morcellation, would limit women with symptomatic leiomyomas to one option, total abdominal hysterectomy. For women with fibroids larger than a 10-week pregnancy size, which most often require either scalpel or power-morcellation in order to remove tissue, a ban on morcellation would eliminate the following procedures:

  • vaginal hysterectomy (scalpel morcellation)
  • mini-laparotomy hysterectomy (scalpel morcellation)
  • laparoscopic hysterectomy (scalpel morcellation)
  • laparoscopic supra-cervical hysterectomy (cervix cut-through)
  • open supra-cervical hysterectomy (cervix cut-through)
  • laparoscopic myomectomy (power morcellation)
  • mini-laparotomy myomectomy (scalpel morcellation)
  • hysteroscopic myomectomy (intrauterine morcellation)
  • uterine artery embolization (no specimen and will delay diagnosis)
  • high-intensity focused ultrasound (no specimen and will delay diagnosis)

If abdominal hysterectomy is recommended to women with fibroids, will women be better off?

By focusing exclusively on the risk of LMS, the FDA failed to take into account other risks associated with surgery.   Laparoscopic surgery uses small incisions, is performed as an out-patient procedure (or overnight stay), has a faster recovery (2 weeks versus 4-6 for open surgery) and is associated with lower mortality and fewer complications.  These benefits of minimally invasive surgery are now well-established in gynecologic and general surgery.  Using published best-evidence data, a recent decision analysis showed that, comparing 100,000 women having laparoscopic hysterectomy with 100,000 having open hysterectomy, the group having laparoscopic surgery  would experience 20 fewer peri-operative deaths, 150 fewer women would have a pulmonary or venous embolus and 4,800 fewer women would have a wound infection. (Seidhoff)   Importantly, women having open surgery would have 8,000 fewer quality-of-life years.  A recently published study found that  in the eight months following the FDA safety communication, utilization of laparoscopic hysterectomies decreased by 4.1% (p=0.005) and both abdominal and vaginal hysterectomies increased (1.7%, p =0.112 and 2.4%, p=0.012, respectively). (Harris)  Major surgical complications (not including blood transfusions) significantly increased from 2.2% to 2.8% (p=0.015), and the rate of hospital readmission within 30 days also increased from 3.4% to 4.2% (p=0.025).  These observations merit consideration as women weigh the pros and cons of minimally-invasive surgery with morcellation versus open surgery.  These observations merit consideration as women weigh the pros and cons of minimally invasive surgery with possible morcellation vs. open surgery.

Clinical Recommendations

Recent attention to surgical options for women with uterine leiomyomas and the risk of an occult leiomyosarcoma is a positive development in that the gynecologic community is re-examining relevant issues. We respectfully suggest that the following clinical recommendations be considered:

  • The risk of LMS is higher in older post-menopausal women and greater caution should be exercised prior to recommending morcellation procedures for these women.
  • Preoperative consideration of LMS is important and women age 35 or older with irregular uterine bleeding and presumed fibroids should have an endometrial biopsy, which occasionally may detect LMS prior to surgery.  Women should have  normal results of cervical cancer screening.
  • Ultrasound or MRI findings of a large irregular vascular mass, often with irregular anechoic (cystic) areas reflecting necrosis, may cause suspicion of LMS.
  • Women wishing minimally-invasive procedures with morcellation, including scalpel-morcellation via the vagina or mini-laparotomy, or power-morcellation using laparoscopic guidance, should understand the potential risk of decreased survival should LMS be present.  Open procedures should be offered to all women who are considering minimally -invasive procedures for “fibroids”.
  • Following morcellation, careful inspection for tissue fragments should be undertaken and copious irrigation of the pelvic and abdominal cavities should be performed to minimize the risk of retained tissue.
  • Further investigations of a means to identify LMS pre-operatively should be supported.  Likewise, investigation into the biology of LMS should be funded to better understand the propensity of tissue fragments or cells to implant and grow.    With that knowledge, minimally- invasive procedures could be avoided for women with LMS and women choosing minimally-invasive surgery could be re-assured that they do not have LMS.

Respecting women who suffer from leiomyosarcoma, we conclude that the FDA directive was based on a misleading analysis.   Consequently, more accurate estimates regarding the prevalence of LMS among women having surgery for fibroids should be issued. Women have a right to self-determination.   Modification of the FDA’s current restrictive guidance regarding power-morcellation would empower each woman to consider the pertinent issues and have the freedom to undertake shared decision-making with her surgeon in order to select the procedure which is most appropriate for her.

William Parker, MD
Clinical Professor
UCLA School of Medicine
Director, Minimally Invasive Gynecologic Surgery
Santa Monica-UCLA Medical Center

Jonathan S Berek, MD, MMS
Laurie Kraus Lacob Professor
Director, Stanford Women’s Cancer Center
Director, Stanford Health Care Communication Program
Chair, Department of Obstetrics and Gynecology
Stanford University School of Medicine

Elizabeth Pritts, MD
Wisconsin Fertility Institute
Middleton, WI

David Olive, MD
Wisconsin Fertility Institute
Middleton, WI

Andrew M. Kaunitz, MD
University of Florida Research Foundation Professor
Associate Chair, Department of Obstetrics and Gynecology
University of Florida College of Medicine–Jacksonville

Eva Chalas, MD, FACOG, FACS
Chief, Division of Gynecologic Oncology
Director of Clinical Cancer Services
Vice-Chair, Department of Obstetrics and Gynecology
Winthrop-University Hospital

Daniel Clarke-Pearson, MD
Professor and Chair
Clinical Research, Gynecologic Oncology Program
UNC-Chapel Hill

Barbara Goff, MD
Professor of Obstetrics and Gynecology
Director, Division of Gynecologic Oncology
University of Washington
Seattle, WA

Robert Bristow, MD
Professor and Chair
Department of Obstetrics and Gynecology
UC Irvine School of Medicine

Hugh S. Taylor, M.D.
Anita O’Keeffe Young Professor and Chair Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine
Chief of Obstetrics and Gynecology
Yale-New Haven Hospital

Robin Farias-Eisner, MD
Chief of Gynecology and Gynecologic Oncology
Department of Obstetrics and Gynecology
David Geffen School of Medicine at UCLA

Amanda Nickles Fader, MD
Director of the Kelly Gynecologic Oncology Service
Director, F.J. Montz Fellowship in Gynecologic Oncology
Johns Hopkins Medicine

G Larry Maxwell, MD, FACOG, COL(ret) U.S. Army
Chairman, Department of Obstetrics and Gynecology, Inova Fairfax Hospital
Co-P.I., DOD Gynecologic Cancer Translational Research Center of Excellence
Professor, Virginia Commonwealth School of Medicine
Executive Director, Globe-athon to End Women’s Cancer

Scott C Goodwin, MD
Hasso Brothers Professor and Chairman, Radiological Sciences
University of California, Irvine

Susan Love, MD
Dr. Susan Love Research Foundation

William E Gibbons, MD
Professor
Director, Division of Reproductive Medicine
Director, Fellowship Training
Department of Obstetrics and Gynecology
Baylor College of Medicine
Chief, Reproductive Medicine the Pavilion For Women at Texas Children’s Hospital
Houston, Texas

Leland J. Foshag, M.D., FACS
Surgical Oncology, Melanoma and Sarcoma
John Wayne Cancer Institute
Santa Monica, California

Phyllis C. Leppert, MD, PhD
Emerita Professor of Obstetrics and Gynecology
Duke University School of Medicine
President, The Campion Fund, Phyllis and Mark Leppert Foundation for Fertility Research

Judy Norsigian
Co-founder, Our Bodies, Ourselves
Boston, Mass

Charles W. Nager, MD
Professor and Chairman
Department of Reproductive Medicine
UC San Diego Health System

Timothy Johnson, MD
Chair, Department of Obstetrics and Gynecology, University of Michigan
Arthur F. Thurnau Professor, Professor of Women’s Studies, and Research Professor in the Center for Human Growth and Development

David S. Guzick, MD, PhD
Senior Vice President, Health Affairs
President, UF Health
University of Florida

Sawsan As-Sanie, MD MPH
Assistant Professor
Director, Minimally Invasive Gynecologic Surgery and Fellowship
Director, Endometriosis Center
University of Michigan

Richard J. Paulson, MD
Alia Tutor Chair in Reproductive Medicine
Professor and Vice-Chair
Department of Obstetrics and Gynecology
Chief, Division of Reproductive Endocrinology and Infertility
Keck School of Medicine
University of Southern California

Professor Cindy Farquhar
Department of Obstetrics and Gynaecology and National Women’s Health
University of Auckland, NZ

Linda Bradley, MD
Vice Chair of Obstetrics, Gynecology and Women’s Health Institute
Director of The Fibroid and Menstrual Disorders Center
Cleveland Clinic
Dept of Obstetrics and Gynecology

Stacey A. Scheib, MD
Assistant Professor
Director of the Hopkins Multidisciplinary Fibroid Center
Director of Minimally Invasive Gynecologic Surgery
Johns Hopkins Hospital

Anton J. Bilchik, MD, PhD, FACS
Professor of Surgery
Chief of Medicine at John Wayne Cancer Institute
Santa Monica, California

Laurel W. Rice, MD
Chair of the Department of Obstetrics and Gynecology
Professor, Division of Gynecology Oncology
University of Wisconsin-Madison School of Medicine and Public Health

Carla Dionne
Founder, National Uterine Fibroid Foundation

Alison Jacoby, MD
Director, UCSF Comprehensive Fibroid Center
Interim Chief, Division of Gynecology
University of California, San Francisco

Charles Ascher-Walsh, MD
Director of Gynecology, Urogynecology, MIS
Mt. Sinai School of Medicine
New York, NY

Sarah J. Kilpatrick, MD, PhD
Chair, Department of Obstetrics and Gynecology
Associate Dean, Faculty Development
Helping Hand of Los Angeles Chair in Obstetrics and Gynecology
Cedars-Sinai Medical Center
Los Angeles, California

David Adamson, MD
Clinical Professor, Stanford University School of Medicine
Past President of the American Society for Reproductive Medicine

Matthew Siedhoff, MD MSCR
University of North Carolina at Chapel Hill
Obstetrics & Gynecology
Minimally Invasive Gynecologic Surgery, Director

Robert Israel, M.D
Professor, Department of OB/GYN
Chair, Quality Improvement
Director, Women’s Health Clinics and Referrals, LAC+USC Medical Center

Marie Fidela Paraiso, MD
Head, Female Pelvic Medicine & Reconstructive Surgery
Cleveland Clinic
Cleveland, OH

Michael M. Frumovitz, M. D., M.P.H., FACOG, FACS
Fellowship Program Director
Department of Gynecologic Oncology and Reproductive Medicine
The University of Texas MD Anderson Cancer Center

John R Lurain, MD
Marcia Stenn Professor of Gynecologic Oncology
Program director for the fellowship in gynecologic oncology
Northwestern University Feinberg School of Medicine

Ayman Al-Hendy  MD PhD FRCSC FACOG CCRP
GRU Director of Interdisciplinary Translational Research
MCG Assistant Dean for Global Translational Research
Professor and Director
Division of Translational Research
Department of Obstetrics and Gynecology
Medical College of Georgia
Georgia Regents University

Guy I. Benrubi, M.D.
Senior Associate Dean for Faculty Affairs,
Robert J. Thompson Professor and Chair,
Department of Obstetrics and Gynecology
University of Florida College of Medicine – Jacksonville

Steven S. Raman, MD
Professor of Radiology, Urology, and Surgery
Co-director of the Fibroid Treatment Program
David Geffen School of Medicine at UCLA

Rosanne M Kho MD
Associate Professor
Head, Section of Urogynecology and FPMRS
Co-Director, MIGS Fellowship Program
Columbia University Medical Center
New York, NY

Ted L. Anderson, M.D., Ph.D.
Betty and Lonnie S. Burnett Professor and Chair, Obstetrics and Gynecology
Division Director, Gynecology
Vanderbilt University School of Medicine

Kevin Reynolds, MD, FACS, FACOG
The George W. Morley Professor and Chief
Division of Gynecologic Oncology
University of Michigan
Ann Arbor Michigan

John DeLancey, MD
Norman F. Miller Professor of Obstetrics & Gynecology
University of Michigan Health System

All institutional affiliations are for identification purposes only

No signee has declared a conflict of interest


References

Bojahr B, De Wilde R, Tchartchian G.  Malignancy rate of 10,731 uteri morcellated during laparoscopic supracervical hysterectomy (LASH). Arch Gynecol Obstet 2015;292:665-672.

Kosary CL. SEER survival monograph: Cancer survival among adults: U.S. SEER program, 1988-2001, patient and tumor characteristics. In: Ries LAG, Young JL, Keel GE,

Eisner MP, Lin DY, Horner MD, eds. Cancer of the corpus uteri. Bethesda, MD: National Cancer Institute, SEER Program, NIH; 2007:123-32.

Harris JA, Swenson CW, Uppal S, Kamdar N, Mahnert N, As-Sanie S, Morgan DM. Practice Patterns and Postoperative Complications Before and After Food and Drug Administration Safety Communication on Power Morcellation. Am J Obstet Gynecol (2015), doi:10.1016/j.ajog.2015.08.047.

Leung F, Terzibachian J. Re: “The impact of tumor morcellation during surgery on the prognosis of patients with apparently early uterine leiomyosarcoma [letter]. Gynecol Oncol 2012;124:172-3

Lieng M, Berner E, Busund B. Risk of morcellation of uterine leiomyosarcomas in laparoscopic supracervical hysterectomy and laparoscopic myomectomy, a retrospective trial including 4791 women. J Minim Invasive Gynecol. 2015;22:410-4

Morice P, Rodriguez A, Rey A, Pautier P, Atallah D, Genestie C, Pomel C, Lhommé C, Haie-Meder C, Duvillard P, Castaigne D. Prognostic value of initial surgical procedure for patients with uterine sarcoma: analysis of 123 patients. Eur J Gynaecol Oncol. 2003;24:237-40.

Oduyebo T, Rauh-Hain AJ, Meserve EE, Seidman MA, Hinchcliff E, George S, Quade B, Nucci MR, Del Carmen MG, Muto MG. The value of re-exploration in patients with inadvertently morcellated uterine sarcoma. Gynecol Oncol. 2014;132:360-5.

Park JY, Park SK, Kim DY, Kim JH, Kim YM, Kim YT, Nam JH. The impact of tumor morcellation during surgery on the prognosis of patients with apparently early uterine leiomyosarcoma. Gynecol Oncol. 2011;122:255-9.

Perri T, Korach J, Sadetzki S, Oberman B, Fridman E, Ben-Baruch G. Uterine leiomyosarcoma: does the primary surgical procedure matter? Int J Gynecol Cancer. 2009;19:257-60

Pritts E, Vanness D, Berek  J, Parker W, Feinberg R, Feinberg J, Olive D. The prevalence of occult leiomyosarcoma at surgery for presumed uterine fibroids: a meta-analysis. Gynecol Surg. accessed on-line 5/30/15 at: http://link.springer.com/article/10.1007/s10397-015-0894-4

Pritts E, Parker W, Brown J, Olive D. Outcome of occult uterine leiomyosarcoma after surgery for presumed uterine fibroids: a systematic review. J Minim Invasive Gynecol. 2015;22:26-33

Rowland M, Lesnock J, Edwards R, Richard S, Zorn K, Sukumvanich P, et al. Occult uterine cancer in patients undergoing laparoscopic hysterectomy with morcellation (abstract) Gynecol Oncol 2012;127:S29

Siedhoff MT, Wheeler SB, Rutstein SE, Geller EJ, Doll KM, Wu JM, Clarke-Pearson DL. Laparoscopic hysterectomy with morcellation vs abdominal hysterectomy for presumed fibroid tumors in premenopausal women: a decision analysis.  J Obstet Gynecol. 2015;212:591.e1-8

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Fibroid Doctor William H. Parker

Dr. William H. Parker is a board-certified Fellow in the American College of Obstetricians and Gynecologists. Dr. Parker is an internationally recognized expert in fibroid surgery and research. Based in Los Angeles, California, he is considered one of the best fibroid surgeons for abdominal and laparoscopic myomectomy in the United States and abroad. He has been chosen for Best Doctors in America and Top Doctors every year beginning in the late 90's.

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