Accepted Manuscript Outcome of occult uterine leiomyosarcoma after surgery for presumed uterine fibroids: A systematic review Elizabeth A. Pritts, MD William H. Parker, MD Jubilee Brown, MD David L. Olive, MD PII:
S1553-4650(14)01214-X
DOI:
10.1016/j.jmig.2014.08.781
Reference:
JMIG 2379
To appear in:
The Journal of Minimally Invasive Gynecology
Received Date: 31 July 2014 Revised Date:
15 August 2014
Accepted Date: 17 August 2014
Please cite this article as: Pritts EA, Parker WH, Brown J, Olive DL, Outcome of occult uterine leiomyosarcoma after surgery for presumed uterine fibroids: A systematic review, The Journal of Minimally Invasive Gynecology (2014), doi: 10.1016/j.jmig.2014.08.781. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Outcome of occult uterine leiomyosarcoma after
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surgery for presumed uterine fibroids:
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A systematic review
Elizabeth A. Pritts, MD, William H. Parker, MD, Jubilee Brown, MD, David L. Olive, MD.
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The authors have no commercial, proprietary, or financial interest in the product or
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companies described in this article.
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Corresponding Author:
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Elizabeth A. Pritts, MD, Wisconsin Fertility Institute, 3146 Deming Way, Middleton,
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Wisconsin
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Email: [email protected]
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Fax: 608-829-0748
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From the Wisconsin Fertility Institute, Middleton, Wisconsin (Pritts and Olive); University of Texas
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MD Anderson Cancer Center, Houston, Texas (Brown); Department of Obstetrics and Gynecology,
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UCLA School of Medicine and Medical Center, Santa Monica, California (Parker).
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Precis
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Evidence for adverse outcomes following morcellation of occult leiomysarcomas is sparse
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and biased, and drawing firm conclusions is premature at this time.
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Abstract
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There is concern that morcellation of occult leiomyosarcoma during surgery for presumed
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fibroids may significantly worsen the patient’s outcome. We reviewed the existing medical
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literature to better understand if such a risk was demonstrable, and if so what the
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magnitude of that risk might be. We identified 4864 papers initially, of which 60 were
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evaluated in full. Seventeen were found to have outcomes information and included in this
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review. Six studies addressed the question of whether morcellation of occult
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leiomyosarcomas resulted in inferior outcomes compared to en bloc uterine (and tumor)
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removal. In these 6 studies, results suggest en bloc removal may result in improved
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survival and less recurrence, but data are highly biased and of poor quality. There is no
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reliable evidence that morcellation (power or otherwise) significantly results in tumor
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upstaging. Finally, there is no evidence from these 17 studies that power morcellation
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differs in any way from any other types of morcellation, or even simple myomectomy, in
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patient outcome. Whether electromechanical morcellation poses a unique danger to the
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patient with occult LMS is an open question and one clearly in need of more extensive
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investigation before conclusions are drawn and policies are created.
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Introduction
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Uterine fibroids are benign monoclonal tumors derived from uterine myometrial cells.
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They are extremely common, affecting 80% of women by age 50, the vast majority of whom
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are asymptomatic. Women who are symptomatic usually complain of heavy menstrual
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bleeding or abdominal/pelvic discomfort due to the bulk of the tumors. Fibroids are a
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significant burden to women; women with symptomatic fibroids have lower scores on
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quality-of-life assessments than women with hypertension, heart disease, chronic lung
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disease or arthritis. (1) The economic burden of fibroids is estimated to be 4-9 billion
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dollars yearly in the United States alone (2).
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Traditionally, treatment options for fibroids have included hysterectomy and myomectomy
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through either large abdominal incisions or the vagina. However, when large tissue
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masses are removed through relatively small incisions, the tissue must be cut into smaller
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segments to facilitate removal (morcellation).
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Minimally invasive procedures can now be applied to fibroid surgery, affording women
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many treatment options previously unavailable and often allowing them to return home
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the same day. Non-surgical procedures include uterine artery embolization, and high-
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intensity focused ultrasound, whereas surgical procedures include radio frequency
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ablation of myomas, hysteroscopic and laparoscopic myomectomy with uterine
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preservation, and vaginal or laparoscopic hysterectomy for women who do not desire to
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retain their uterus. As many symptomatic fibroid laden uteri are quite large, techniques
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and instrumentation have been developed to allow the removal of the extirpated tissue
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through very small incisions. Initially, hand operated instruments that were inefficient led
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to hand-fatigue and carpal tunnel syndrome for the surgeon (3), limiting their use. Electro-
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mechanically assisted (power) morcellation was approved by the Food and Drug
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Administration in 1995 and greatly improved the capacity to morcellate, making minimally
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invasive surgical procedures more widespread and available to significantly more women.
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Uterine sarcomas, which include leiomyosarcoma, endometrial stromal sarcoma and (until
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recent reclassification) carcinosarcoma, are aggressive cancers that are very rare,
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comprising 3% of uterine malignancies (4). The accepted treatment for uterine sarcoma is
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total abdominal hysterectomy and avoidance of morcellation to remove the entire cancer
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and prevent spreading throughout the abdomen. Unfortunately, leiomyosarcoma is
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difficult to differentiate from benign fibroids and a reliable method of pre-operative
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diagnosis is not available. Infrequently, women operated upon for presumed uterine
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fibroids have been subsequently found to have uterine sarcoma after histopathologic
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examination.
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Recently the FDA issued a statement discouraging the use of electromechanical (power)
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morcellators, citing safety concerns, chief among these being the inadvertent dissemination
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of occult uterine cancer in patients undergoing hysterectomy and myomectomy for
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presumed benign leiomyomata (5). Sparse evidence was presented regarding the effect of
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morcellation upon patient outcome.
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We agree that dissemination of tumor via morcellation, with a resultant increased rate of
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recurrence and poorer survival, is a plausible hypothesis. However, we felt it was
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important to review the existing medical literature on the subject to better understand if
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such a risk was demonstrable, and if so what the magnitude of that risk might be.
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Methods
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A literature search was initially performed using the PubMed/MEDLINE database and the
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Cochrane Library. The search was performed for all manuscripts published after 1960 and
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all languages using the search terms “myoma”, “leiomyoma”, “fibroid”, “hysterectomy”,
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“myomectomy”, “neoplasm”, leiomyosarcoma”, “incidence”, “pathology”, “histopathology”,
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“morcellation”, “complication”, and “inadvertent”. All references found were evaluated for
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the inclusion and exclusion criteria listed below and their bibliographies were then hand-
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searched for other potentially relevant publications.
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One author (EAP) conducted a preliminary review; all papers deemed to meet inclusion
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and exclusion criteria were then reviewed by one other author (DLO).
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We identified 4864 papers initially, and excluded 4804 through evaluation of the title or
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abstract. Sixty papers were evaluated in full, and 16 with outcomes data were included
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(Figure 1).
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Inclusion criteria included publications involving humans that were peer-reviewed. All
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publications were required to contain original data. Papers were only included if they
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contained cases for surgery (hysterectomy or myomectomy) in which fibroid-related
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indications were the primary indication for the procedure. Those cases found solely via
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hysteroscopy were excluded. Studies that included cohorts from the same institutions
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during the same time periods were included, but noted as such.
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Criteria for Leiomyosarcoma
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If a manuscript classified a presumed fibroid as a leiomyosarcoma without any additional
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information (or ambiguous information), then the tumor was classified as such in our
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analysis. However, if a histopathologic description was provided, this was used as a means
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of classification. The criteria used for classification are those adopted by the World Health
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Organization (6). These criteria indicate that a malignant neoplasm composed of cells
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demonstrating uterine smooth muscle differentiation with coagulative tumor cell necrosis
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(not hyaline necrosis) is a leiomyosarcoma. If no such necrosis exists, then the diagnosis is
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made only if the mitotic index is ≥ 10 mitoses per 10 high-power fields and there is diffuse,
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moderate to severe cytologic atypia. The microscopic criteria required to meet each of the
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3 requirements is quite specific.
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If a pathologic description of findings was inconsistent with the stated pathologic diagnosis,
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we utilized the histopathology and reclassified the diagnosis on this basis. Studies in which
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“sarcomas” or “malignancies” were found, but were not specified as “leiomyosarcoma”
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were excluded.
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Outcomes
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We included studies that provided outcome data of any type for the patients diagnosed
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with occult leiomyosarcoma after either morcellation or en bloc removal. Such outcomes
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included the presence of residual disease, evidence of recurrence, and/or survival.
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Results and Discussion
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Seventeen publications were found that met our inclusion and exclusion criteria (7-23). They were
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categorized as to whether and how they addressed each of two principal questions: (1) When an
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occult LMS is encountered does morcellation result in an inferior outcome compared to en bloc
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uterine (and tumor) removal?, and (2) When an occult LMS is morcellated, is there a difference in
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outcome depending upon the type of morcellation utilized?
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(1) When an occult LMS is encountered, does morcellation result in an inferior
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outcome compared to en bloc uterine (and tumor) removal?
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Six publications address this issue. Each is summarized and critiqued here.
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a. George and colleagues (9) compared 39 women who underwent en bloc removal of LMS
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by total abdominal hysterectomy with 19 women undergoing morcellation. Women with 7
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myomectomies and those with the tumor removed via an extraction bag were excluded.
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The ages were 37-77 for abdominal hysterectomy and 40-68 for the morcellation group.
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Patients had either stage I, II or III LMS in the abdominal hysterectomy group, and had
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disease presumed to be confined to the uterus in the morcellation group. None of the
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patients were reported to have undergone completion (removing remaining uterine tissue
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as well as bilateral salpingo-oophorectomy) or staging surgery. Morcellation was
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performed with a “spinning blade or a scalpel”, without delineation of exact numbers; thus,
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results are relevant in regards to morcellation in general, not for any specific method of
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morcellation.
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The recurrence free survival rates were longer for the en bloc resection group (10.8 vs.
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39.6, p=.002). The morcellation cohort also had an increased risk of recurrence (HR 3.18
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(95% CI 1.5-6.8)). Overall survival rate at 36 months was 64% in the morcellation cohort
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and 73% in the abdominal hysterectomy group, a comparison that did not demonstrate a
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significant difference (p=0.20).
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While this study is the largest and most complete addressing this question, there are
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several issues limiting reliability of the data. First, the data were retrospectively collected,
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with all the inherent biases that result from gathering and examining data after the fact.
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Secondly, the publishing center was a referral center; the number of patients referred and
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the timing of referral were not provided. Moreover, we do not know the reasons for
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referral and (more importantly) which patients with similar situations were not referred,
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and their outcomes. Thus, the degree of selection bias cannot be ascertained from the
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information provided (24,25).
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b. Morice and associates (14) studied patients with uterine sarcomas in an attempt to
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determine the impact of initial surgical management. Data were examined from 157
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patients, of whom 123 had information on their surgical management available.
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Morcellation was performed in 34 cases.
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These cases included vaginal, abdominal or laparoscopic hysterectomies with morcellation
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in the operative note, myomectomies, and hysteroscopic resection of fibroids or even
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simple tumor biopsies. Ages ranged from 23-77 years. The study included all 3 types of
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sarcomas: Leiomyosarcomas, carcinosarcomas and endometrial stromal sarcomas. They
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state that 59% of the women had completion or staging surgery, and 95% of these had
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completion surgery at a median time of 2 months. Seventy percent had no disease
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progression.
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The only comparison in the manuscript in which LMS is extracted from the other tumors is
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for recurrence of disease. None of the 17 women with or the 36 women without
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morcellation had recurrence at 3 months, and 1/15 with and 5/36 without morcellation
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had recurrence at 6 months (NS).
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This study, though often quoted in the literature, does not provide much information
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regarding this query. “Most” cases were referred, and data were retrospectively
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accumulated. LMS was generally not separated from other sarcomas, and stages I-IV were
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included but not stratified in the analysis. Finally, the types of surgeries were varied in
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type, route and degree of morcellation, and no extractable data were given regarding these
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issues. The only information of value is the demonstration that in these women short-term
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recurrence risk did not differ with or without morcellation.
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c. Park and colleagues (17) compared 31 women with LMS and no morcellation to 25
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women who during their surgeries underwent morcellation: 18 with laparoscopically-
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assisted vaginal hysterectomies, 1 with vaginal hysterectomy, 5 with mini-laparotomy
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myomectomies, and 1 with laparoscopic myomectomy. All had either presumed stage I or II
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disease, with 36% of the surgeries for abdominal hysterectomy referred, and 68% of the
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patients with morcellation referred. However, only 7 patients in total had surgical
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completion or staging, and none were upstaged at that time (6 after morcellation, 1 after
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abdominal hysterectomy). Only 1 of the patients who underwent morcellation had power
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morcellation.
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In the multivariate analysis, tumor morcellation (OR 3.11; 95% CI 1.07-9.06) and higher
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stage of tumor (OR 20.34; 95% CI 1.27-325.58) were associated with poorer overall
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survival. In the univariate analysis, tumor morcellation was associated with poorer disease
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free survival (OR 2.59; 95% CI 1.03-6.50).
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Although retrospective in some respects, these data were obtained from a cancer registry
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where prospective entry of much information is likely. Although it is well analyzed, it still
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includes data from many women that were referred at an unknown time from their original
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surgery and diagnosis.
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Moreover, while a statistically significant difference was seen for survival, this may have
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been due to the exceptionally good outcomes seen in the control (en bloc resection)
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patients. The survival rate of 84% in these women are far higher than that expected from
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the oncology literature. While the cause of this difference may still be surgical technique
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rather than selection bias, the validity and applicability of these data must be approached
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with skepticism.
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d. Einstein (8) published results of 5 women that were referred for treatment of
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leiomyosarcoma to their center after power morcellation, tumor fragmentation or en bloc
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removal of the specimen by hysterectomy. Ages ranged from 35-71 years, and staging
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surgery occurred anywhere from 41-132 days after initial diagnosis. In 2 of the patients
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with power morcellation for tumor extraction, the first had no change in staging at
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completion surgery (stage I) and had no evidence of disease at 30 months. The second
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patient was upstaged at her completion surgery from stage I to III. She had no evidence of
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disease at 61 months. The patient with abdominal fragmented extraction was upstaged
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from stage I to III at completion surgery, and was alive with disease at 31 months. In the 2
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patients with abdominal hysterectomies without morcellation, 1 remained stage I at
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completion surgery and had no evidence of disease at 37 months. The second patient had
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upstaging to stage IV before her completion surgery and was alive with disease at 6
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months. It is difficult to draw any conclusions regarding this initial query from these very
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limited data.
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e. Leibsohn (10) reported upon 10 women with leiomyosarcoma. However, 3 were
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diagnosed pre-operatively and 2 failed to meet modern criteria for leiomyosarcoma.
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Of the remaining 5 patients with unsuspected leiomyosarcoma, 4 had hysterectomies, and
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1 had an abdominal myomectomy, followed by a completion hysterectomy. Of the 4
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patients with en bloc removal, 3 were deceased at 6, 8, and 12 months. They were 49, 50
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and 51 years old. The fourth patient was 45 years old, and had no evidence of disease at 55
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months. The 57 year old patient with an abdominal myomectomy as her primary surgery
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was upstaged from stage I to II at completion surgery. She was alive with disease at an
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unspecified time. Again, it is difficult to draw definite conclusions from these variable
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histories and outcomes.
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f. Perri and associates (18) compared 21 women who underwent abdominal hysterectomy
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to 16 women in which LMS was disrupted: the overall survival was better with en bloc
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uterine removal (OR 2.8; 95% CI 1.02-7.67). Ages were 39-74 years in the en bloc group
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and 30-64 years in the tumor disruption group. The women undergoing morcellation had a
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variety of techniques used, but none were via power morcellation. The study was
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retrospective, but was limited to patients with presumed stage I LMS. A subset of patients
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that had completion surgery and were upstaged were excluded from this analysis. There
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were 4 patients with abdominal myomectomy (2 recurred), 4 patients with hysteroscopic
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myomectomy (3 recurred), 4 patients with abdominal supracervical hysterectomy (2
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recurred), 2 women with laparoscopic hysterectomies (2 recurred), and 2 patients with
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abdominal hysterectomy during which the tumor with punctured with a sharp instrument
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(1 recurred).
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Question #1 Summary
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These studies provide some evidence that en bloc uterine removal when occult LMS is
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found, particularly when at an early stage, provides a lower risk of dissemination and
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recurrence, as well as improved survival (Table 1) when compared to removal with
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morcellation. However, these findings are not uniformly seen in all studies. Furthermore,
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the heterogeneity of the studies, their retrospective nature, small numbers, and
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accumulation via referral make these conclusions tenuous and difficult to establish definite
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conclusions.
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Another method of evaluating outcomes is to assess upstaging at subsequent completion
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surgery for power or hand morcellation and en bloc removal of the tumor. This is difficult
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to assess, as few comparative data exist given the fact that en bloc resection often does not
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proceed to completion surgery. However, it is possible to coalesce the published cases
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where completion surgeries were performed, in both comparative and uncontrolled
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studies. In order to better qualify if the upstaging was due to the morcellation procedure
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itself, or just a bias of referral at recurrence, we stratified the data based upon the timing of
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the completion (or staging) surgery. We looked at those women with staging surgeries that
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were completed within 30 days (early) and those that were completed after 30 days (late).
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In cases where the time to completion surgery was not explicitly stated, we included those
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in the late staging category (Table 2). Numbers are small and data are heterogeneous,
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making it hard to discern any meaningful information. However, there does not appear to
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be a difference for upstaging between hand and power morcellation.
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(2) When an occult LMS is morcellated, is there a difference in outcome depending
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upon the type of morcellation utilized?
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The largest single study comparing morcellation types is by Oduyebo and colleagues (15),
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who examined 15 patients with occult LMS that underwent morcellation, 10 by
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electromechanical means and 5 by hand. The ages were 25-58 years. Seven of the 15
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patients had completion surgery immediately. Although a previous review by the FDA
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implies that they were uncovered at a single institution (26), 67% of these cases were
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referred from other medical centers. Most patients were presumed to have stage I disease
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at primary surgery (10/15).
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Among the 10 women undergoing power morcellation, 8 had completion surgery. Of these,
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4 remained stage I and had no evidence of disease between 20.2 and 48.7 months. One
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woman was upstaged from III-IV, and was deceased at 5.1 months. Another was found to
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be stage IV at initial surgery and was deceased at 3 months. Two were upstaged from I to
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III, with 1 surviving with evidence of disease at 8.3 months and the other deceased at 37.5
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months.
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Of the 2 patients that did not undergo completion surgery the first had recurrence and
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debulking surgery at 20 months and was deceased at 48 months. The second woman was
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stage I at initial surgery and has had neither completion surgery nor evidence of disease in
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15.3 months.
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Of the 5 patients undergoing hand morcellation, only 1 underwent completion surgery.
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That patient remained stage I and had no evidence of disease at 4.5 months. Of the
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remaining 4 patients that did not undergo completion surgery, 1 had debulking surgery at
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7 months and was alive with evidence of disease at 72 months, 1 had debulking surgery at
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18 months and was deceased at 30.4 months, and 2 were stage I at initial diagnosis and had
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no evidence of disease at 1.8 and 26 months. Thus, outcome measures such as recurrence
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and survival cannot be meaningfully compared in this study due to the limited numbers,
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heterogeneity of stages and treatment approaches. In addition, numerous factors which
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correlate with recurrence were not studied: mitotic count, presence of necrosis, tumor size,
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and gene expression profile (27).
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Since no single study directly compared types of morcellation in occult LMS for differences
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in outcome with substantial numbers of cases, we extracted all cases of occult LMS that
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were identified in the literature where the type of morcellation was specified and length of
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survival was provided as an outcome. Thirty-two such cases were found in various studies,
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small series, and case reports. Of these, 24 surgeries utilized power morcellation, with 15
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patients alive at the conclusion of follow up and 9 deceased (length of follow-up 3-61
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months). Nine women underwent morcellation by non-electromechanical methods, with 7
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surviving and 2 deaths (length of follow-up 1-72 months). Life table analysis comparing
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these 2 datasets showed no significant difference in the 2, no great surprise given the
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paucity of data (Figure 2). It is also possible that the 24 surgeries using power morcellation
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do not have unique patient data, in that three reports (9,15,21) have overlapping dates of
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inclusion from the same institutions. All three studies included women treated at Brigham
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and Women’s Hospital through the department of Obstetrics and Gynecology; two also
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included patients treated at Massachusetts General Hospital and the Dana Farber Cancer
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Institute. They included the years 2007-2012, 2005-2012, 2005-2010, and in 2 studies
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(9,15) they stated they reviewed data on “all” patients treated at their institutions. As it
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was not possible to determine if these reports duplicated patients, we included data from
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all reports.
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Question #2 summary
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Given the paucity and poor quality of existing data examining this issue, it is impossible to
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reach a meaningful conclusion regarding the relative dangers of morcellation methods
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other than to say that there is currently no evidence that any one type of morcellation
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(including electromechanical morcellation) is more worrisome than another.
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Conclusions
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Earlier we raised 2 questions in need of answers if the effect of morcellation upon the
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outcome of women with occult LMS is truly to be understood. Neither can be clearly
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answered with data currently available. The available evidence points to a worsening
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outcome when occult tumor is morcellated versus removed en bloc, but even here the data
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are far from definitive. The studies are relatively small, mostly retrospective, and all from
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referral centers with limited information regarding the referral. Furthermore, not all show
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differences in recurrence rates, dissemination, upstaging, or survival. This may be due to
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different tumor pathologic findings and biological behaviors.
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Many authors point to power morcellation, with its unique potential to disperse malignant
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tissue throughout the pelvis, as the cause of upstaging and worsening survival rates.
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However, In the 6 studies used for survival outcomes, Einstein’s group included 2 women
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with power morcellation (in the 3 reported upon), both George and Morice did not
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delineate how many were power in the 19 and 17 women studied, Perri and Leibsohn had
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no power morcellation cases in 1 and 16 patients, and Park included only 1 woman with
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power morcellation out of his 25 cases. Thus, there were only 3 confirmed cases where
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power morcellation was utilized in these 6 studies; the vast majority of cases were women
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that had vaginal morcellation of both uteri and fibroids, non-power laparoscopic and
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abdominal hand morcellation (tissue fragmentation) of uteri and fibroids, and even tumor
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puncture or biopsy during an en bloc procedure.
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Nonetheless, others have claimed in public forums that power morcellation frequently
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results in peritoneal dissemination of leiomyosarcomas, with resultant upstaging of
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disease, and ultimately decreased survival. The publication referenced for these claims is
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by Seidman and colleagues (21). Unfortunately, this study has been widely misquoted and
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the data erroneously reported (26). For example, the FDA has claimed that among 1091
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cases, there was a 64.3% rate of peritoneal dissemination of tumor following power
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morcellation. When a leiomyosarcoma was found, they state that peritoneal dissemination
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occurred in 4 of 7 (57%). Such pronouncements are highly misleading. Most occult tumors
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found in this study were in fact atypical fibroids or leiomyoma variants, not malignancies.
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Only 1 leiomyosarcoma was found at the authors’ institution, and at completion surgery
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there was no dissemination seen. This patient was reported alive at 42 months of follow-
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up.
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What leads to confusion in this manuscript is that 6 additional patients, referred from other
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institutions, were also reported. Four were referred at 1 month post-procedure, one at 13
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months, and the other at 16 months. The latter 2 were likely referred after identification of
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recurrence. Four of these 6 had dissemination, (including the 2 that were referred late) and
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three of these women died. Unfortunately, we are not provided any information on the
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number of leiomyosarcoma cases at these outlying hospitals that were not sent to the
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referral center (possibly because they did well).
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Another claim based on data from this publication is that it demonstrates that any type of
369
tumor is capable of being disseminated by power morcellation, malignant or benign. Of
370
those tumors that were found “in-house”, 4 of 12 showed evidence of dissemination.
371
Unfortunately, the authors failed to provide a comparison group of women undergoing a
372
second surgery having experienced other types of morcellation or even en bloc removal.
373
We thus have no idea if the 33% rate of dissemination at later surgery is typical or
374
enhanced for these tumor types.
375
One final point: even if peritoneal dissemination does occur with one or more of these
376
techniques, it is unclear whether this is the factor responsible for adverse outcomes.
377
Leiomyosarcomas metastasize hematogenously rather than by direct extension.
378
Dissemination of tumor throughout the peritoneum may not necessarily increase true
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tumor burden. It may be that any type of tumor penetration at the time of surgery will
380
enhance hematogenous spread of tumor cells, meaning that tumor spread may occur prior
381
to and independent of morcellation.
382
In summary, given the small numbers, variable time and rationale for referral of the
383
women, and the lack of information regarding women who had similar situations yet were
384
not referred; we are unable to draw meaningful conclusions about this information.
385
Our group looked at the issue from an analysis of the data culled from the papers in this
386
systematic review. There were only 27 women with staging information after morcellation
387
(all methods); of these, 11 were upstaged (Table 2). Of these, only 5 were upstaged at
388
immediate completion surgery; the remainder had late staging surgery, likely due to
389
established recurrence.
390
Even these data may overstate the risk. The concept of upstaging is based upon the
391
presumption that occult leiomyosarcomas are stage I at the initial surgery. However, given
392
the presumed benign nature of the pathology at the time of that surgery, it is unlikely that
393
anything more than a cursory inspection of the abdomen was performed. In fact, many
394
patients were young healthy women who underwent abbreviated preoperative evaluation.
395
This may have led to an underestimation of the initial stage in any number of these women.
396
It is of course a plausible hypothesis that power morcellation, or for that matter any type of
397
morcellation, might disseminate tissue throughout the peritoneum. However,
398
dissemination can occur with virtually any type of surgical intervention. In three of the
399
studies reviewed, there were six cases of LMS found after abdominal myomectomy,
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resulting in three recurrences and two deaths (10, 18,19). Furthermore, disseminated
401
leiomyomatosis, once thought to be a result of intraperitoneal spread via surgery, is now
402
believed to arise de novo. The same may hold true for apparent dissemination of
403
leiomyosarcoma: in a dozen women, this disorder has been associated with sarcomatous
404
degeneration even in the absence of uterine fibroids (28).
405
However, given the concern surrounding dissemination, a proposed solution is the use of
406
containment bags. Current containment bags come with a myriad of their own problems.
407
The morcellation itself occurs blindly without the ability to visualize the blade during the
408
morcellation and extraction. This may result in inadvertent injury. There are, however,
409
morcellation bags in development that utilize pneumoperitoneum and are inflated to
410
expand within the entire pelvis. Utilizing this product may eliminate the associated risks
411
stated above. If indeed morcellation is the issue, and not just disruption of tumor with
412
subsequent vascular seeding, then such containment bags may provide an excellent
413
solution to the problem.
414
Before reaching unsubstantiated cause and effect conclusions for an instrument or surgical
415
technique, it is important to logically dissect each of the issues related to the presumed
416
adverse outcome. Before concluding that power morcellation should be restricted or
417
banned, the following facts should be scientifically demonstrated: (1) Morcellation of LMS
418
results in significantly poorer survival than en bloc removal of the tumor, and (2) Power
419
morcellation produces more intraperitoneal tissue dissemination with more frequent
420
upstaging and poorer survival than other conservative surgical methods for fibroids.
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Unfortunately, there is insufficient information to demonstrate either of these
422
preconditions, much less both of them.
423
Whether electromechanical morcellation poses a unique danger to the patient with occult
424
LMS, or all types of morcellation and tumor injury (including the traditional laparotomic
425
myomectomy) provide similar risks is an open question and one clearly in need of more
426
extensive investigation before conclusions are drawn and policies are created.
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References
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1) Rowe MK, Kanouse D, Mittman BS, et al. Quality of life among women undergoing hysterectomies. Obstet Gynecol 1999;93:915-21.
441
2) Cardozo ER, Clark AD, Banks NK, Henne MB, Stegmann BJ, Segars JH. The estimated
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annual cost of uterine leiomyomata in the United States. Am J Obstet Gynecol. 2012
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Mar;206(3):211.e1-9.
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3) Park A, Lee G, Seagull H, et al. Patients benefit while surgeons suffer: An impending epidemic. J Am Coll Surg 2010;210(3):306-13.
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4) D’Angelo E, Prat J. Uterine sarcomas: A review. Gynecol Oncol 2010;116:131-9.
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5) http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm393576.htm.
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6) WHO Classification of tumors. In: Tavassoli FA, Devilee P, editors. Pathology and genetics of tumors of the breast and female genital organs. Lyon: IARC Press; 2003.
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7) Anupama R, Ahmad SZ, Kuriakose S, et al. Disseminated peritoneal leiomyosarcomas
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2011;18:386-9.
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8) Einstein MH, Barakat RR, Chi DS, et al. Management of uterine malignancy found
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incidentally after supracervical hysterectomy or uterine morcellation for presumed
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benign disease. Int J Gynecol Cancer 2008;18:1065-70.
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9) George S, Barysauskas C, Serrano C, et al. Retrospective cohort study evaluating the impact of intraperitoneal morcellation of outcomes of localized uterine
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leiomyosarcoma. Cancer 2014;00:1-5.
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10)Leibsohn S, d’Ablaing G, Mishell D, et al. Leiomyosarcoma in a series of
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hysterectomies performed for presumed uterine leiomyomas. Am J Obstet Gynecol
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11)Leung F, Terzibachian JJ, Gay C, et al. Hysterectomies performed for presumed
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laparotomic surgical routes? Gynecol Obstet Fertil 2009;37:109-11.
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12)Mettler L, Alzarez-Rodas E, Semm K. Hormonal treatment and pelviscopic
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13)Milman D, Zalel Y, Biran H, et al. Unsuspected uterine leiomyosarcoma discovered
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during treatment with a gonadotropin-releasing hormone analogue: A case report
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14)Morice P, Rodriguez A, Rey A, et al. Prognostic value of initial surgical procedure for patients with uterine sarcoma: Analysis of 123 patients. Eur J Gynaecol Oncol
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15)Oduyebo T, Rauh-Hain AJ, Meserve EE, et al. The value of re-exploration in patients with inadvertently morcellated uterine sarcoma. Gynecol Oncol 2014;132:360-5.
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16)Ota T, Huang KG, Sicam RVG, et al. Unusual trocar site metastasis in a uterine
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17)Park JY, Park SK, Kim DY, et al. The impact of tumor morcellation during surgery on
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the prognosis of patients with apparently early uterine leiomyosarcoma. Gynecol
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Oncol 2011;122:255-9.
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18)Perri T, Korach J, Sadetzki S, et al. Uterine leiomyosarcoma: Does the primary
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19)Van Dinh T, Woodruff JD. Leiomyosarcoma of the uterus. Am J Obstet Gynecol 1982;144:817-23.
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20)Rekha W, Amita M, Sudeep G, et al. Unexpected complication of uterine myoma morcellation. Aust NZ J of Obstet and Gynaecol 2005;45:248-58.
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21)Seidman MA, Oduyebo T, Muto M, et al. Peritoneal dissemination complicating
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morcellation of uterine mesenchymal neoplasms. PLoS ONE 2012;7(11):1-8.
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22)Sinha R, Hegde A, Mahajan C, et al. Laparoscopic myomectomy: Do size, number, and location of the myomas form limiting factors for laparoscopic myomectomy? J
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23)Theben J, Schellong ARM, Altgassen C, et al. Unexpected malignancies after
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laparoscopic-assisted supracervical hysterectomies (LASH): An analysis of 1,584
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LASH cases. Arch Gynecol Obstet 2013;287:455-62.
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24)Malkasian, GD, Annegers JF. Subsequent primary malignancies after endometrial carcinoma and ovarian carcinoma. Cancer. 2003;55(10):614-8. 25)Mariani A, Cha SS, Bergstralh MS, et al. Referral and ascertainment bias in patients
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26)http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterial
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vices/UCM404148.pdf.i
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27)Lee YF, John M, Falconer A, et al. A gene expression signature associated with
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metastatic outcome in human leiomyosarcomas. Cancer Res 2004;64:7201-4.
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28)Biscaglia M, Galliani C, Pizzolitto S, et al. Leiomyomatosis Peritonealis Disseminata:
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Report of 3 cases with extensive review of the literature. Adv Anat Pathol
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2014;21:201-15.
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George/2014
# of patients
Recurrence
Recurrence/DiseaseFree Survival
Overall Survival
Abdominopelvic Recurrence
39 En bloc 19 Morcellation (power and hand)
Morcellation: HR 3.18
En bloc vs Morcellation: 10.8 vs 39.6 months
En bloc: HR 1.85
En bloc vs Morcellation: 20% vs 85.7%
(95% CI: 1.5-6.8*)
(p=0.003*)
Perri/2009
En bloc vs Morcellation: 14% vs 7% (NS)
31 En bloc 25 Morcellation (power and hand)
En bloc: OR 2.59 (95% CI: 1.03-6.50*)
21 En bloc 16 Morcellation (power and hand/ tumor injury)
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En bloc: OR 3.11 (95% CI: 1.07-8.93*)
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Park/2011
36 En bloc 17 Morcellation (power and hand/ tumor injury)
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Morice/2003
(95% CI: 0.7-4.7 NS)
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(p=0.001*)
En bloc vs Morcellation: 12.9% vs 44% (p=0.032*)
En bloc: OR 2.8 (95% CI: 1.02-7.67*)
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Table 1. Survival Outcomes: En bloc versus Morcellation (key)
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•* = statistically significant •NS = not significant •HR=Hazard Ratio •OR= Odds Ratio •vs = versus •CI=Confidence Interval
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Power
2
Late /unknown 1
#
1
Leibsohn/1990
1
Leung/2009
1
Mettler/1994
1
Milman/1998
7
2
1
Seidman/2012
7
2
2
Sinha/2008
2
Theben/2013
1
1
1
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Table 2: Upstaging at early or late/unknown times
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Early
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Early
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En bloc
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Table 2: Upstaging at early or late/unknown times
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•Power Morcellation –Early staging: 4/19 (21%) –All staging: 8/19 (42%) •Hand Morcellation –Early staging: 1/6 (17%) –All staging: 2/6 (33%)
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•En bloc Removal –Early staging: 0/2 (0%) –All staging 1/2 (50%)
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Figure 1. Meta-analysis outcomes Over 4000 articles were reviewed resulting in 17 papers with outcome data.
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Figure 2. Power versus Hand Morcellation Life table analysis of survival of patients with leiomyosarcoma following power and hand morcellation. X-axis = months. Y-axis = proportion surviving.
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References: 7, 8, 11, 15, 16, 20-23
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http://www.AAGL.org/jmig-22-2-JMIG-D-14-00388
S1553-4650(14)01214-X
DOI:
10.1016/j.jmig.2014.08.781
Reference:
JMIG 2379
To appear in:
The Journal of Minimally Invasive Gynecology
Received Date: 31 July 2014 Revised Date:
15 August 2014
Accepted Date: 17 August 2014
Please cite this article as: Pritts EA, Parker WH, Brown J, Olive DL, Outcome of occult uterine leiomyosarcoma after surgery for presumed uterine fibroids: A systematic review, The Journal of Minimally Invasive Gynecology (2014), doi: 10.1016/j.jmig.2014.08.781. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Pritts
Outcome of occult uterine leiomyosarcoma after
2
surgery for presumed uterine fibroids:
3
A systematic review
Elizabeth A. Pritts, MD, William H. Parker, MD, Jubilee Brown, MD, David L. Olive, MD.
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The authors have no commercial, proprietary, or financial interest in the product or
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companies described in this article.
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Corresponding Author:
11
Elizabeth A. Pritts, MD, Wisconsin Fertility Institute, 3146 Deming Way, Middleton,
12
Wisconsin
13
Email: [email protected]
14
Fax: 608-829-0748
15
From the Wisconsin Fertility Institute, Middleton, Wisconsin (Pritts and Olive); University of Texas
16
MD Anderson Cancer Center, Houston, Texas (Brown); Department of Obstetrics and Gynecology,
17
UCLA School of Medicine and Medical Center, Santa Monica, California (Parker).
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18
Precis
19
Evidence for adverse outcomes following morcellation of occult leiomysarcomas is sparse
21
and biased, and drawing firm conclusions is premature at this time.
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Abstract
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There is concern that morcellation of occult leiomyosarcoma during surgery for presumed
25
fibroids may significantly worsen the patient’s outcome. We reviewed the existing medical
26
literature to better understand if such a risk was demonstrable, and if so what the
27
magnitude of that risk might be. We identified 4864 papers initially, of which 60 were
28
evaluated in full. Seventeen were found to have outcomes information and included in this
29
review. Six studies addressed the question of whether morcellation of occult
30
leiomyosarcomas resulted in inferior outcomes compared to en bloc uterine (and tumor)
31
removal. In these 6 studies, results suggest en bloc removal may result in improved
32
survival and less recurrence, but data are highly biased and of poor quality. There is no
33
reliable evidence that morcellation (power or otherwise) significantly results in tumor
34
upstaging. Finally, there is no evidence from these 17 studies that power morcellation
35
differs in any way from any other types of morcellation, or even simple myomectomy, in
36
patient outcome. Whether electromechanical morcellation poses a unique danger to the
37
patient with occult LMS is an open question and one clearly in need of more extensive
38
investigation before conclusions are drawn and policies are created.
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Introduction
39
40
Uterine fibroids are benign monoclonal tumors derived from uterine myometrial cells.
42
They are extremely common, affecting 80% of women by age 50, the vast majority of whom
43
are asymptomatic. Women who are symptomatic usually complain of heavy menstrual
44
bleeding or abdominal/pelvic discomfort due to the bulk of the tumors. Fibroids are a
45
significant burden to women; women with symptomatic fibroids have lower scores on
46
quality-of-life assessments than women with hypertension, heart disease, chronic lung
47
disease or arthritis. (1) The economic burden of fibroids is estimated to be 4-9 billion
48
dollars yearly in the United States alone (2).
49
Traditionally, treatment options for fibroids have included hysterectomy and myomectomy
50
through either large abdominal incisions or the vagina. However, when large tissue
51
masses are removed through relatively small incisions, the tissue must be cut into smaller
52
segments to facilitate removal (morcellation).
53
Minimally invasive procedures can now be applied to fibroid surgery, affording women
54
many treatment options previously unavailable and often allowing them to return home
55
the same day. Non-surgical procedures include uterine artery embolization, and high-
56
intensity focused ultrasound, whereas surgical procedures include radio frequency
57
ablation of myomas, hysteroscopic and laparoscopic myomectomy with uterine
58
preservation, and vaginal or laparoscopic hysterectomy for women who do not desire to
59
retain their uterus. As many symptomatic fibroid laden uteri are quite large, techniques
60
and instrumentation have been developed to allow the removal of the extirpated tissue
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through very small incisions. Initially, hand operated instruments that were inefficient led
62
to hand-fatigue and carpal tunnel syndrome for the surgeon (3), limiting their use. Electro-
63
mechanically assisted (power) morcellation was approved by the Food and Drug
64
Administration in 1995 and greatly improved the capacity to morcellate, making minimally
65
invasive surgical procedures more widespread and available to significantly more women.
66
Uterine sarcomas, which include leiomyosarcoma, endometrial stromal sarcoma and (until
67
recent reclassification) carcinosarcoma, are aggressive cancers that are very rare,
68
comprising 3% of uterine malignancies (4). The accepted treatment for uterine sarcoma is
69
total abdominal hysterectomy and avoidance of morcellation to remove the entire cancer
70
and prevent spreading throughout the abdomen. Unfortunately, leiomyosarcoma is
71
difficult to differentiate from benign fibroids and a reliable method of pre-operative
72
diagnosis is not available. Infrequently, women operated upon for presumed uterine
73
fibroids have been subsequently found to have uterine sarcoma after histopathologic
74
examination.
75
Recently the FDA issued a statement discouraging the use of electromechanical (power)
76
morcellators, citing safety concerns, chief among these being the inadvertent dissemination
77
of occult uterine cancer in patients undergoing hysterectomy and myomectomy for
78
presumed benign leiomyomata (5). Sparse evidence was presented regarding the effect of
79
morcellation upon patient outcome.
80
We agree that dissemination of tumor via morcellation, with a resultant increased rate of
81
recurrence and poorer survival, is a plausible hypothesis. However, we felt it was
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important to review the existing medical literature on the subject to better understand if
83
such a risk was demonstrable, and if so what the magnitude of that risk might be.
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Methods
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A literature search was initially performed using the PubMed/MEDLINE database and the
88
Cochrane Library. The search was performed for all manuscripts published after 1960 and
89
all languages using the search terms “myoma”, “leiomyoma”, “fibroid”, “hysterectomy”,
90
“myomectomy”, “neoplasm”, leiomyosarcoma”, “incidence”, “pathology”, “histopathology”,
91
“morcellation”, “complication”, and “inadvertent”. All references found were evaluated for
92
the inclusion and exclusion criteria listed below and their bibliographies were then hand-
93
searched for other potentially relevant publications.
94
One author (EAP) conducted a preliminary review; all papers deemed to meet inclusion
95
and exclusion criteria were then reviewed by one other author (DLO).
96
We identified 4864 papers initially, and excluded 4804 through evaluation of the title or
97
abstract. Sixty papers were evaluated in full, and 16 with outcomes data were included
98
(Figure 1).
99
Inclusion criteria included publications involving humans that were peer-reviewed. All
100
publications were required to contain original data. Papers were only included if they
101
contained cases for surgery (hysterectomy or myomectomy) in which fibroid-related
102
indications were the primary indication for the procedure. Those cases found solely via
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hysteroscopy were excluded. Studies that included cohorts from the same institutions
104
during the same time periods were included, but noted as such.
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Criteria for Leiomyosarcoma
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If a manuscript classified a presumed fibroid as a leiomyosarcoma without any additional
109
information (or ambiguous information), then the tumor was classified as such in our
110
analysis. However, if a histopathologic description was provided, this was used as a means
111
of classification. The criteria used for classification are those adopted by the World Health
112
Organization (6). These criteria indicate that a malignant neoplasm composed of cells
113
demonstrating uterine smooth muscle differentiation with coagulative tumor cell necrosis
114
(not hyaline necrosis) is a leiomyosarcoma. If no such necrosis exists, then the diagnosis is
115
made only if the mitotic index is ≥ 10 mitoses per 10 high-power fields and there is diffuse,
116
moderate to severe cytologic atypia. The microscopic criteria required to meet each of the
117
3 requirements is quite specific.
118
If a pathologic description of findings was inconsistent with the stated pathologic diagnosis,
119
we utilized the histopathology and reclassified the diagnosis on this basis. Studies in which
120
“sarcomas” or “malignancies” were found, but were not specified as “leiomyosarcoma”
121
were excluded.
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Outcomes
125
We included studies that provided outcome data of any type for the patients diagnosed
126
with occult leiomyosarcoma after either morcellation or en bloc removal. Such outcomes
127
included the presence of residual disease, evidence of recurrence, and/or survival.
128
Results and Discussion
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Seventeen publications were found that met our inclusion and exclusion criteria (7-23). They were
132
categorized as to whether and how they addressed each of two principal questions: (1) When an
133
occult LMS is encountered does morcellation result in an inferior outcome compared to en bloc
134
uterine (and tumor) removal?, and (2) When an occult LMS is morcellated, is there a difference in
135
outcome depending upon the type of morcellation utilized?
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(1) When an occult LMS is encountered, does morcellation result in an inferior
138
outcome compared to en bloc uterine (and tumor) removal?
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Six publications address this issue. Each is summarized and critiqued here.
141
a. George and colleagues (9) compared 39 women who underwent en bloc removal of LMS
142
by total abdominal hysterectomy with 19 women undergoing morcellation. Women with 7
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myomectomies and those with the tumor removed via an extraction bag were excluded.
144
The ages were 37-77 for abdominal hysterectomy and 40-68 for the morcellation group.
145
Patients had either stage I, II or III LMS in the abdominal hysterectomy group, and had
146
disease presumed to be confined to the uterus in the morcellation group. None of the
147
patients were reported to have undergone completion (removing remaining uterine tissue
148
as well as bilateral salpingo-oophorectomy) or staging surgery. Morcellation was
149
performed with a “spinning blade or a scalpel”, without delineation of exact numbers; thus,
150
results are relevant in regards to morcellation in general, not for any specific method of
151
morcellation.
152
The recurrence free survival rates were longer for the en bloc resection group (10.8 vs.
153
39.6, p=.002). The morcellation cohort also had an increased risk of recurrence (HR 3.18
154
(95% CI 1.5-6.8)). Overall survival rate at 36 months was 64% in the morcellation cohort
155
and 73% in the abdominal hysterectomy group, a comparison that did not demonstrate a
156
significant difference (p=0.20).
157
While this study is the largest and most complete addressing this question, there are
158
several issues limiting reliability of the data. First, the data were retrospectively collected,
159
with all the inherent biases that result from gathering and examining data after the fact.
160
Secondly, the publishing center was a referral center; the number of patients referred and
161
the timing of referral were not provided. Moreover, we do not know the reasons for
162
referral and (more importantly) which patients with similar situations were not referred,
163
and their outcomes. Thus, the degree of selection bias cannot be ascertained from the
164
information provided (24,25).
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b. Morice and associates (14) studied patients with uterine sarcomas in an attempt to
166
determine the impact of initial surgical management. Data were examined from 157
167
patients, of whom 123 had information on their surgical management available.
168
Morcellation was performed in 34 cases.
169
These cases included vaginal, abdominal or laparoscopic hysterectomies with morcellation
170
in the operative note, myomectomies, and hysteroscopic resection of fibroids or even
171
simple tumor biopsies. Ages ranged from 23-77 years. The study included all 3 types of
172
sarcomas: Leiomyosarcomas, carcinosarcomas and endometrial stromal sarcomas. They
173
state that 59% of the women had completion or staging surgery, and 95% of these had
174
completion surgery at a median time of 2 months. Seventy percent had no disease
175
progression.
176
The only comparison in the manuscript in which LMS is extracted from the other tumors is
177
for recurrence of disease. None of the 17 women with or the 36 women without
178
morcellation had recurrence at 3 months, and 1/15 with and 5/36 without morcellation
179
had recurrence at 6 months (NS).
180
This study, though often quoted in the literature, does not provide much information
181
regarding this query. “Most” cases were referred, and data were retrospectively
182
accumulated. LMS was generally not separated from other sarcomas, and stages I-IV were
183
included but not stratified in the analysis. Finally, the types of surgeries were varied in
184
type, route and degree of morcellation, and no extractable data were given regarding these
185
issues. The only information of value is the demonstration that in these women short-term
186
recurrence risk did not differ with or without morcellation.
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c. Park and colleagues (17) compared 31 women with LMS and no morcellation to 25
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women who during their surgeries underwent morcellation: 18 with laparoscopically-
189
assisted vaginal hysterectomies, 1 with vaginal hysterectomy, 5 with mini-laparotomy
190
myomectomies, and 1 with laparoscopic myomectomy. All had either presumed stage I or II
191
disease, with 36% of the surgeries for abdominal hysterectomy referred, and 68% of the
192
patients with morcellation referred. However, only 7 patients in total had surgical
193
completion or staging, and none were upstaged at that time (6 after morcellation, 1 after
194
abdominal hysterectomy). Only 1 of the patients who underwent morcellation had power
195
morcellation.
196
In the multivariate analysis, tumor morcellation (OR 3.11; 95% CI 1.07-9.06) and higher
197
stage of tumor (OR 20.34; 95% CI 1.27-325.58) were associated with poorer overall
198
survival. In the univariate analysis, tumor morcellation was associated with poorer disease
199
free survival (OR 2.59; 95% CI 1.03-6.50).
200
Although retrospective in some respects, these data were obtained from a cancer registry
201
where prospective entry of much information is likely. Although it is well analyzed, it still
202
includes data from many women that were referred at an unknown time from their original
203
surgery and diagnosis.
204
Moreover, while a statistically significant difference was seen for survival, this may have
205
been due to the exceptionally good outcomes seen in the control (en bloc resection)
206
patients. The survival rate of 84% in these women are far higher than that expected from
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the oncology literature. While the cause of this difference may still be surgical technique
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rather than selection bias, the validity and applicability of these data must be approached
209
with skepticism.
210
d. Einstein (8) published results of 5 women that were referred for treatment of
211
leiomyosarcoma to their center after power morcellation, tumor fragmentation or en bloc
212
removal of the specimen by hysterectomy. Ages ranged from 35-71 years, and staging
213
surgery occurred anywhere from 41-132 days after initial diagnosis. In 2 of the patients
214
with power morcellation for tumor extraction, the first had no change in staging at
215
completion surgery (stage I) and had no evidence of disease at 30 months. The second
216
patient was upstaged at her completion surgery from stage I to III. She had no evidence of
217
disease at 61 months. The patient with abdominal fragmented extraction was upstaged
218
from stage I to III at completion surgery, and was alive with disease at 31 months. In the 2
219
patients with abdominal hysterectomies without morcellation, 1 remained stage I at
220
completion surgery and had no evidence of disease at 37 months. The second patient had
221
upstaging to stage IV before her completion surgery and was alive with disease at 6
222
months. It is difficult to draw any conclusions regarding this initial query from these very
223
limited data.
224
e. Leibsohn (10) reported upon 10 women with leiomyosarcoma. However, 3 were
225
diagnosed pre-operatively and 2 failed to meet modern criteria for leiomyosarcoma.
226
Of the remaining 5 patients with unsuspected leiomyosarcoma, 4 had hysterectomies, and
227
1 had an abdominal myomectomy, followed by a completion hysterectomy. Of the 4
228
patients with en bloc removal, 3 were deceased at 6, 8, and 12 months. They were 49, 50
229
and 51 years old. The fourth patient was 45 years old, and had no evidence of disease at 55
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months. The 57 year old patient with an abdominal myomectomy as her primary surgery
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was upstaged from stage I to II at completion surgery. She was alive with disease at an
232
unspecified time. Again, it is difficult to draw definite conclusions from these variable
233
histories and outcomes.
234
f. Perri and associates (18) compared 21 women who underwent abdominal hysterectomy
235
to 16 women in which LMS was disrupted: the overall survival was better with en bloc
236
uterine removal (OR 2.8; 95% CI 1.02-7.67). Ages were 39-74 years in the en bloc group
237
and 30-64 years in the tumor disruption group. The women undergoing morcellation had a
238
variety of techniques used, but none were via power morcellation. The study was
239
retrospective, but was limited to patients with presumed stage I LMS. A subset of patients
240
that had completion surgery and were upstaged were excluded from this analysis. There
241
were 4 patients with abdominal myomectomy (2 recurred), 4 patients with hysteroscopic
242
myomectomy (3 recurred), 4 patients with abdominal supracervical hysterectomy (2
243
recurred), 2 women with laparoscopic hysterectomies (2 recurred), and 2 patients with
244
abdominal hysterectomy during which the tumor with punctured with a sharp instrument
245
(1 recurred).
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Question #1 Summary
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These studies provide some evidence that en bloc uterine removal when occult LMS is
250
found, particularly when at an early stage, provides a lower risk of dissemination and
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recurrence, as well as improved survival (Table 1) when compared to removal with
252
morcellation. However, these findings are not uniformly seen in all studies. Furthermore,
253
the heterogeneity of the studies, their retrospective nature, small numbers, and
254
accumulation via referral make these conclusions tenuous and difficult to establish definite
255
conclusions.
256
Another method of evaluating outcomes is to assess upstaging at subsequent completion
257
surgery for power or hand morcellation and en bloc removal of the tumor. This is difficult
258
to assess, as few comparative data exist given the fact that en bloc resection often does not
259
proceed to completion surgery. However, it is possible to coalesce the published cases
260
where completion surgeries were performed, in both comparative and uncontrolled
261
studies. In order to better qualify if the upstaging was due to the morcellation procedure
262
itself, or just a bias of referral at recurrence, we stratified the data based upon the timing of
263
the completion (or staging) surgery. We looked at those women with staging surgeries that
264
were completed within 30 days (early) and those that were completed after 30 days (late).
265
In cases where the time to completion surgery was not explicitly stated, we included those
266
in the late staging category (Table 2). Numbers are small and data are heterogeneous,
267
making it hard to discern any meaningful information. However, there does not appear to
268
be a difference for upstaging between hand and power morcellation.
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(2) When an occult LMS is morcellated, is there a difference in outcome depending
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upon the type of morcellation utilized?
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272
The largest single study comparing morcellation types is by Oduyebo and colleagues (15),
274
who examined 15 patients with occult LMS that underwent morcellation, 10 by
275
electromechanical means and 5 by hand. The ages were 25-58 years. Seven of the 15
276
patients had completion surgery immediately. Although a previous review by the FDA
277
implies that they were uncovered at a single institution (26), 67% of these cases were
278
referred from other medical centers. Most patients were presumed to have stage I disease
279
at primary surgery (10/15).
280
Among the 10 women undergoing power morcellation, 8 had completion surgery. Of these,
281
4 remained stage I and had no evidence of disease between 20.2 and 48.7 months. One
282
woman was upstaged from III-IV, and was deceased at 5.1 months. Another was found to
283
be stage IV at initial surgery and was deceased at 3 months. Two were upstaged from I to
284
III, with 1 surviving with evidence of disease at 8.3 months and the other deceased at 37.5
285
months.
286
Of the 2 patients that did not undergo completion surgery the first had recurrence and
287
debulking surgery at 20 months and was deceased at 48 months. The second woman was
288
stage I at initial surgery and has had neither completion surgery nor evidence of disease in
289
15.3 months.
290
Of the 5 patients undergoing hand morcellation, only 1 underwent completion surgery.
291
That patient remained stage I and had no evidence of disease at 4.5 months. Of the
292
remaining 4 patients that did not undergo completion surgery, 1 had debulking surgery at
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7 months and was alive with evidence of disease at 72 months, 1 had debulking surgery at
294
18 months and was deceased at 30.4 months, and 2 were stage I at initial diagnosis and had
295
no evidence of disease at 1.8 and 26 months. Thus, outcome measures such as recurrence
296
and survival cannot be meaningfully compared in this study due to the limited numbers,
297
heterogeneity of stages and treatment approaches. In addition, numerous factors which
298
correlate with recurrence were not studied: mitotic count, presence of necrosis, tumor size,
299
and gene expression profile (27).
300
Since no single study directly compared types of morcellation in occult LMS for differences
301
in outcome with substantial numbers of cases, we extracted all cases of occult LMS that
302
were identified in the literature where the type of morcellation was specified and length of
303
survival was provided as an outcome. Thirty-two such cases were found in various studies,
304
small series, and case reports. Of these, 24 surgeries utilized power morcellation, with 15
305
patients alive at the conclusion of follow up and 9 deceased (length of follow-up 3-61
306
months). Nine women underwent morcellation by non-electromechanical methods, with 7
307
surviving and 2 deaths (length of follow-up 1-72 months). Life table analysis comparing
308
these 2 datasets showed no significant difference in the 2, no great surprise given the
309
paucity of data (Figure 2). It is also possible that the 24 surgeries using power morcellation
310
do not have unique patient data, in that three reports (9,15,21) have overlapping dates of
311
inclusion from the same institutions. All three studies included women treated at Brigham
312
and Women’s Hospital through the department of Obstetrics and Gynecology; two also
313
included patients treated at Massachusetts General Hospital and the Dana Farber Cancer
314
Institute. They included the years 2007-2012, 2005-2012, 2005-2010, and in 2 studies
315
(9,15) they stated they reviewed data on “all” patients treated at their institutions. As it
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was not possible to determine if these reports duplicated patients, we included data from
317
all reports.
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Question #2 summary
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Given the paucity and poor quality of existing data examining this issue, it is impossible to
323
reach a meaningful conclusion regarding the relative dangers of morcellation methods
324
other than to say that there is currently no evidence that any one type of morcellation
325
(including electromechanical morcellation) is more worrisome than another.
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Conclusions
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Earlier we raised 2 questions in need of answers if the effect of morcellation upon the
331
outcome of women with occult LMS is truly to be understood. Neither can be clearly
332
answered with data currently available. The available evidence points to a worsening
333
outcome when occult tumor is morcellated versus removed en bloc, but even here the data
334
are far from definitive. The studies are relatively small, mostly retrospective, and all from
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referral centers with limited information regarding the referral. Furthermore, not all show
336
differences in recurrence rates, dissemination, upstaging, or survival. This may be due to
337
different tumor pathologic findings and biological behaviors.
338
Many authors point to power morcellation, with its unique potential to disperse malignant
339
tissue throughout the pelvis, as the cause of upstaging and worsening survival rates.
340
However, In the 6 studies used for survival outcomes, Einstein’s group included 2 women
341
with power morcellation (in the 3 reported upon), both George and Morice did not
342
delineate how many were power in the 19 and 17 women studied, Perri and Leibsohn had
343
no power morcellation cases in 1 and 16 patients, and Park included only 1 woman with
344
power morcellation out of his 25 cases. Thus, there were only 3 confirmed cases where
345
power morcellation was utilized in these 6 studies; the vast majority of cases were women
346
that had vaginal morcellation of both uteri and fibroids, non-power laparoscopic and
347
abdominal hand morcellation (tissue fragmentation) of uteri and fibroids, and even tumor
348
puncture or biopsy during an en bloc procedure.
349
Nonetheless, others have claimed in public forums that power morcellation frequently
350
results in peritoneal dissemination of leiomyosarcomas, with resultant upstaging of
351
disease, and ultimately decreased survival. The publication referenced for these claims is
352
by Seidman and colleagues (21). Unfortunately, this study has been widely misquoted and
353
the data erroneously reported (26). For example, the FDA has claimed that among 1091
354
cases, there was a 64.3% rate of peritoneal dissemination of tumor following power
355
morcellation. When a leiomyosarcoma was found, they state that peritoneal dissemination
356
occurred in 4 of 7 (57%). Such pronouncements are highly misleading. Most occult tumors
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found in this study were in fact atypical fibroids or leiomyoma variants, not malignancies.
358
Only 1 leiomyosarcoma was found at the authors’ institution, and at completion surgery
359
there was no dissemination seen. This patient was reported alive at 42 months of follow-
360
up.
361
What leads to confusion in this manuscript is that 6 additional patients, referred from other
362
institutions, were also reported. Four were referred at 1 month post-procedure, one at 13
363
months, and the other at 16 months. The latter 2 were likely referred after identification of
364
recurrence. Four of these 6 had dissemination, (including the 2 that were referred late) and
365
three of these women died. Unfortunately, we are not provided any information on the
366
number of leiomyosarcoma cases at these outlying hospitals that were not sent to the
367
referral center (possibly because they did well).
368
Another claim based on data from this publication is that it demonstrates that any type of
369
tumor is capable of being disseminated by power morcellation, malignant or benign. Of
370
those tumors that were found “in-house”, 4 of 12 showed evidence of dissemination.
371
Unfortunately, the authors failed to provide a comparison group of women undergoing a
372
second surgery having experienced other types of morcellation or even en bloc removal.
373
We thus have no idea if the 33% rate of dissemination at later surgery is typical or
374
enhanced for these tumor types.
375
One final point: even if peritoneal dissemination does occur with one or more of these
376
techniques, it is unclear whether this is the factor responsible for adverse outcomes.
377
Leiomyosarcomas metastasize hematogenously rather than by direct extension.
378
Dissemination of tumor throughout the peritoneum may not necessarily increase true
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tumor burden. It may be that any type of tumor penetration at the time of surgery will
380
enhance hematogenous spread of tumor cells, meaning that tumor spread may occur prior
381
to and independent of morcellation.
382
In summary, given the small numbers, variable time and rationale for referral of the
383
women, and the lack of information regarding women who had similar situations yet were
384
not referred; we are unable to draw meaningful conclusions about this information.
385
Our group looked at the issue from an analysis of the data culled from the papers in this
386
systematic review. There were only 27 women with staging information after morcellation
387
(all methods); of these, 11 were upstaged (Table 2). Of these, only 5 were upstaged at
388
immediate completion surgery; the remainder had late staging surgery, likely due to
389
established recurrence.
390
Even these data may overstate the risk. The concept of upstaging is based upon the
391
presumption that occult leiomyosarcomas are stage I at the initial surgery. However, given
392
the presumed benign nature of the pathology at the time of that surgery, it is unlikely that
393
anything more than a cursory inspection of the abdomen was performed. In fact, many
394
patients were young healthy women who underwent abbreviated preoperative evaluation.
395
This may have led to an underestimation of the initial stage in any number of these women.
396
It is of course a plausible hypothesis that power morcellation, or for that matter any type of
397
morcellation, might disseminate tissue throughout the peritoneum. However,
398
dissemination can occur with virtually any type of surgical intervention. In three of the
399
studies reviewed, there were six cases of LMS found after abdominal myomectomy,
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resulting in three recurrences and two deaths (10, 18,19). Furthermore, disseminated
401
leiomyomatosis, once thought to be a result of intraperitoneal spread via surgery, is now
402
believed to arise de novo. The same may hold true for apparent dissemination of
403
leiomyosarcoma: in a dozen women, this disorder has been associated with sarcomatous
404
degeneration even in the absence of uterine fibroids (28).
405
However, given the concern surrounding dissemination, a proposed solution is the use of
406
containment bags. Current containment bags come with a myriad of their own problems.
407
The morcellation itself occurs blindly without the ability to visualize the blade during the
408
morcellation and extraction. This may result in inadvertent injury. There are, however,
409
morcellation bags in development that utilize pneumoperitoneum and are inflated to
410
expand within the entire pelvis. Utilizing this product may eliminate the associated risks
411
stated above. If indeed morcellation is the issue, and not just disruption of tumor with
412
subsequent vascular seeding, then such containment bags may provide an excellent
413
solution to the problem.
414
Before reaching unsubstantiated cause and effect conclusions for an instrument or surgical
415
technique, it is important to logically dissect each of the issues related to the presumed
416
adverse outcome. Before concluding that power morcellation should be restricted or
417
banned, the following facts should be scientifically demonstrated: (1) Morcellation of LMS
418
results in significantly poorer survival than en bloc removal of the tumor, and (2) Power
419
morcellation produces more intraperitoneal tissue dissemination with more frequent
420
upstaging and poorer survival than other conservative surgical methods for fibroids.
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Unfortunately, there is insufficient information to demonstrate either of these
422
preconditions, much less both of them.
423
Whether electromechanical morcellation poses a unique danger to the patient with occult
424
LMS, or all types of morcellation and tumor injury (including the traditional laparotomic
425
myomectomy) provide similar risks is an open question and one clearly in need of more
426
extensive investigation before conclusions are drawn and policies are created.
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Information presented at the Obstetrics and Gynecology Devices Panel of the Medical Devices Advisory Committee; FDA, July 10,2014, Washington, DC.
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George/2014
# of patients
Recurrence
Recurrence/DiseaseFree Survival
Overall Survival
Abdominopelvic Recurrence
39 En bloc 19 Morcellation (power and hand)
Morcellation: HR 3.18
En bloc vs Morcellation: 10.8 vs 39.6 months
En bloc: HR 1.85
En bloc vs Morcellation: 20% vs 85.7%
(95% CI: 1.5-6.8*)
(p=0.003*)
Perri/2009
En bloc vs Morcellation: 14% vs 7% (NS)
31 En bloc 25 Morcellation (power and hand)
En bloc: OR 2.59 (95% CI: 1.03-6.50*)
21 En bloc 16 Morcellation (power and hand/ tumor injury)
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En bloc: OR 3.11 (95% CI: 1.07-8.93*)
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Park/2011
36 En bloc 17 Morcellation (power and hand/ tumor injury)
SC
Morice/2003
(95% CI: 0.7-4.7 NS)
RI PT
Author
(p=0.001*)
En bloc vs Morcellation: 12.9% vs 44% (p=0.032*)
En bloc: OR 2.8 (95% CI: 1.02-7.67*)
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Table 1. Survival Outcomes: En bloc versus Morcellation (key)
AC C
EP
TE D
M AN U
SC
RI PT
•* = statistically significant •NS = not significant •HR=Hazard Ratio •OR= Odds Ratio •vs = versus •CI=Confidence Interval
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Power
2
Late /unknown 1
#
1
Leibsohn/1990
1
Leung/2009
1
Mettler/1994
1
Milman/1998
7
2
1
Seidman/2012
7
2
2
Sinha/2008
2
Theben/2013
1
1
1
EP
1
Table 2: Upstaging at early or late/unknown times
AC C
Late/unknown
1
TE D
Oduyebo/2014
Early
#
Early
RI PT
Einstein/2008
Early
1
SC
#
En bloc
M AN U
Author
Hand
1
Late/Unknown
1
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Table 2: Upstaging at early or late/unknown times
RI PT
•Power Morcellation –Early staging: 4/19 (21%) –All staging: 8/19 (42%) •Hand Morcellation –Early staging: 1/6 (17%) –All staging: 2/6 (33%)
AC C
EP
TE D
M AN U
SC
•En bloc Removal –Early staging: 0/2 (0%) –All staging 1/2 (50%)
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AC C
EP
TE D
M AN U
SC
RI PT
Figure 1. Meta-analysis outcomes Over 4000 articles were reviewed resulting in 17 papers with outcome data.
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Figure 2. Power versus Hand Morcellation Life table analysis of survival of patients with leiomyosarcoma following power and hand morcellation. X-axis = months. Y-axis = proportion surviving.
AC C
EP
TE D
M AN U
SC
RI PT
References: 7, 8, 11, 15, 16, 20-23
AC C
EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
http://www.AAGL.org/jmig-22-2-JMIG-D-14-00388
