Risk,Risk Reduction and Management of Occult Malignancy Diagnosed after Uterine Morcellation: A Commentary

Abstract

Minimally invasive surgical techniques compared with laparotomy offer the advantages of less intraoperative blood loss, shorter hospitalization, fewer wound complications and faster return to baseline activity for both hysterectomy and myomectomy. While morcellation allows for the laparoscopic removal of large specimens, it may result in intraperitoneal dissemination of benign disease or upstaging of occult malignancy leading to compromised survival. There has been heightened scrutiny over appropriate patient selection and preoperative assessment in light of recent warnings against power morcellation issued by the US FDA. This commentary therefore summarizes the magnitude of such risks associated with uterine morcellation, current national regulatory statements and potential merits of risk-reducing approaches such as contained morcellation. The importance of patient counseling is underscored.

Keywords

carcinosarcoma disseminated leiomyomatosis endometrial stromal sarcoma laparoscopy leiomyoma leiomyosarcoma morcellation

Approximately 400,000–600,000 hysterectomies and 30,000 myomectomies are performed annually in the USA [1,2]. Uterine leiomyomata or fibroids are among the most common benign tumors to affect women, occurring in two thirds of the female population [3]. Often leading to pelvic pain and abnormal uterine bleeding, fibroids are also the most frequent indication for hysterectomy in the USA [4].

Gynecologists have increasingly adopted minimally invasive surgical approaches since the first laparoscopic hysterectomy in 1988 by Harry Reich in Pennsylvania [5]. Nearly 50% of all hysterectomies performed for benign indications are now accomplished through laparoscopy [6]. A laparoscopic approach generally offers less intraoperative blood loss, shorter hospitalization, fewer wound complications and faster return to baseline activity for both hysterectomy and myomectomy compared with laparotomy [7 –9].

Technique of specimen removal in patients with enlarged uteri can pose a unique challenge to laparoscopic surgeons, for which morcellation first arose as a solution in the early 1990s. The purpose of this commentary is to review various techniques of morcellation, the clinical complications that may arise from inadvertent morcellation of both benign histopathologies and occult malignancies, management/prognosis of patients with such complications, as well as summarize the most current agency statements that offer guidance with respect to patient selection for morcellation procedures.

Morcellation techniques

Morcellation, the fragmentation of solid tissue into smaller specimens to facilitate removal, is one method for delivery of larger specimens, but can result in dissemination of disease, including malignancy. One of the faults of the existing dialogues regarding ‘morcellation’ is a myopic focus upon intraperitoneal power morcellation and leiomyosarcoma. Often missing from discussions altogether is consideration of risk associated with transabdominal/transvaginal manual morcellation and dissemination of nonsarcomatous or even benign pathology.

Manual transabdominal & transvaginal morcellation

This can be accomplished with a scalpel:

Transabdominally through extension of port sites or creation of a minilaparotomy [10,11]; or

Transvaginally though the cuff or posterior colpotomy in the case of preservation of the cervix [12,13].

There are no specific data regarding risk of disease dissemination with these techniques, but because the morcellation occurs outside the pelvis and often via a coring technique that may leave the serosa intact, some believe it may be safer than other forms of morcellation [14].

Intracorporeal power morcellation

Electromechanical devices for intracorporeal use were developed in 1991 [15] and approved by the US FDA for gynecologic indications as early as 1995 [16]. Electromechanical power morcellators have also been applied in certain general surgery (e.g., splenectomy) and urologic (e.g., prostatectomy, nephrectomy) procedures. These devices generally utilize a spinning circular blade or radiofrequency energy at the end of a tube system through which tissue is fed using a grasper. At least 11 different morcellators (e.g., Steiner [Karl Storz, El Segundo, CA], Sawalhe [Karl Storz], GyneCare X-tract [Ethicon, Somerville, NJ], GyneCare Morcellex [Ethicon], GyneCare Morcellex-Sigma [Ethicon], RotoCut G1 [Karl Storz], VarioCarve/Morce Power Plus [Olympus, Center Valley, PA], PKS PlasmaSord [Olympus], LiNA Xcise [LiNA Medical, Norcross, GA], WISAP MorcDrive [WISAP Medical Technology, Germany], MOREsolution Tissue Morcellator [AxtroCare/BlueEndo, Lenexa, KS]) have been used for gynecologic indications, with morcellation rates of 6.2–40.4 g/min [17]. There are no data to suggest the superiority of one electromechanical power morcellator over another [18]. It is the authors’ opinion that, because of the high-speed and rotational design, electromechanical morcellation more so than manual morcellation may allow widespread dispersion of target tissues. Arkenbout and colleagues [19] found an average of 12.8 ± 9.2 (range: 1–37) macroscopic scatter pieces during morcellation of 23 uteri during laparoscopic supracervical hysterectomy using power morcellation via motor peeling technique. The number of scatter pieces increased with uterine size (6.7 ± 5.1, 15.1 ± 7.5, 22.8 ± 8.9 for uterine weights of <350 g, 350–750 g and >750 g, respectively).

Risks associated with morcellation

Risks associated with morcellation of specimens range from injury to adjacent organs resulting in nearly immediate morbidity or mortality to dissemination of tissue resulting in persistent disease requiring additional treatment and potentially affecting survival. Very little has been written to discuss morcellation of entities that often become the basis for referral to a gynecologic oncologist, such as disseminated leiomyomatosis, STUMP, or even type II epithelial tumors – which are more likely to lack endometrial thickening on transvaginal ultrasound and may fail to trigger preoperative suspicion.

Immediate

Longer operative times are associated with the use of intraperitoneal electromechanical morcellation as well as a higher incidence of bowel and vessel injury when compared with other forms of morcellation [13]. Nearly all complications cited in a systemic review of cases using powered tissue removal between 1993 and 2013 conducted by Milad & Milad were attributed to surgeon inexperience [20]. There were 31 bowel injuries, 27 vascular injuries, three ureteral injuries, one bladder injury and one diaphragmatic injury, 2/3 of which were recognized intraoperatively. In at least six instances, these injuries led to patient death.

Delayed

The potential for iatrogenic dissemination of benign and malignant disease remains one of the greatest limitations to tissue morcellation. Incomplete tissue removal at the time of surgery remains central to the debate over safe use of morcellator devices. Morcellated specimens can also represent a diagnostic challenge for pathologists and may obscure the diagnosis of malignancy in as many as 20% of cases according to some reports [21].

Morcellation of conditions of benign & undetermined malignant potential: peritoneal leiomyomatosis, endometriosis, adenomyosis, leiomyoma variants, STUMP

Investigators theorize that the implantation of microscopic fragments of myometrium and endometrium within the abdominal cavity stimulates neovascularization and allows subsequent growth of the implant [22,23]. Parasitic leiomyomata and disseminated peritoneal leiomyomatosis are the most commonly reported benign complications following power morcellation, with an incidence ranging from 0.1 to 1% of cases [24,25]. Diffuse adenomyosis and endometriosis have also been reported [26,27], though causality in relationship to morcellation is difficult to establish. Patients may present with abdominopelvic pain and dyspareunia at an interval from surgery ranging from 2 to 16 years [23,25,28]. Repeat surgical excision and/or hormonal modulation may be necessary [29]. Whether these benign implants have the potential for malignant degeneration remains a topic of debate [30,31].

Uterine smooth muscle tumors and their potential for malignant behavior exist as a continuum based on histologic criteria (Figure 1) [32,33]. Approximately one leiomyoma variant (e.g., atypical, mitotically active, cellular, plexiform leiomyomas) occurs for every 100 leiomyomas [34]. Some investigators have suggested that STUMP (Smooth muscle Tumor of Undetermined Malignant Potential) may undergo malignant transformation into leiomyosarcoma [35]. In one series, 27% of patients with STUMP had recurrences and one of four patients succumbed to disease [36]. Others have found the rate of recurrence to be closer to 8–11% [37]. In another series, there were no differences between in long-term survival when stratified by surgical approach (i.e., open versus laparoscopic) or extent of surgery (i.e., hysterectomy versus myomectomy) among 41 cases of STUMP [38]. It is evident that this entity is incompletely understood at present. Accordingly, few data exist regarding the clinical repercussions of iatrogenic implants involving atypical leiomyoma or STUMP [34]. Mowers et al. published the experience at University of Michigan with reoperation after inadvertent morcellation in five patients with STUMP [39]. With a median time to surgical re-exploration of 7 weeks (range 6–16.4 weeks), all five patients had peritoneal spread of disease. Interestingly, only two had undergone intraperitoneal power morcellation; the others had undergone abdominal myomectomy with hand morcellation (n = 1), laparoscopic bivalving (n = 1) and power morcellation within a specimen bag (n = 1). All patients remained alive at the time of the report, with follow-up ranging from 2.8 to 35.1 months.

Figure 1.

A wide spectrum of uterine smooth muscle tumors may mimic uterine leiomyoma in the preoperative setting. Histologically, these differ by presence of necrosis, extent of atypia and mitotic activity. Recurrence rates for each entity in the unmorcellated setting are provided parenthetically. Insufficient data exist to prognosticate recurrence in instances of morcellation. hpf: High power field; STUMP: Smooth muscle Tumor of Undetermined Malignant Potential.

Morcellation of malignant conditions: carcinoma, leiomyosarcoma, endometrial stromal sarcoma, carcinosarcoma

In the USA, there are approximately 40,000 new diagnoses of uterine cancer per year. Carcinomas represent the majority of cases. Endometrial cancers can be broadly conceptualized as type I and type II disease. Type I cancers tend to be grade 1/2 endometrioid endometrial cancers, and are associated with unopposed estrogen with retention of estrogen receptor (ER)/progestin receptor (PR) status and indolent behavior; deleterious mutations in k-Ras, PTEN or mismatch repair mechanisms predominate. Type II cancers, including grade 3 endometrioid, clear cell and serous histologies, develop in the absence of estrogen excess and carry a worse prognosis; aneuploidy, mutations in p53 and HER2/Neu overexpression are common [40]. Staging for type I cancers routinely consists of total hysterectomy, bilateral salpingo-oophorectomy and pelvic/periaortic lymphadenectomy, though in certain populations there may be a role for ovarian preservation [41] as well as omission of lymphadenectomy [42]. Staging for type II cancers includes total hysterectomy, bilateral salpingo-oophorectomy, pelvic/periaortic lymphadenectomy and infracolic omentectomy. The FIGO (Federation Internationale de Gynecologie et Obstetrique) staging criteria for carcinomas were revised in 2009 (Table 1). Endometrial cancers usually present with abnormal or postmenopausal vaginal bleeding that facilitates preoperative diagnosis, though cases of incidental morcellation of endometrioid carcinomas during robotic urogynecologic procedures has been reported at a frequency of 4% [43]. Patients with Lynch syndrome (germline mutations in MLH1, MSH2, MSH6, PMS2) may have a 15–60% lifetime risk of developing uterine cancer, compared with a baseline population risk of 2.5%, with a mean onset between 48 and 62 years [44].

Table 1.

FIGO staging: endmetrial carcinoma and carcinosarcoma.

Stage	Definition	5-year survival
		Endometrioid†,‡	Carcinosarcoma§
Stage I:		98%	59%
– A	<50% myometrial invasion
– B	≥50% myometrial invasion
Stage II	Invasion of cervical stroma	86%	59%
Stage III:		67%	22%
– A	Tumor invades serosa or adnexae
– B	Tumor invades vagina or parametrium
– C1	Positive pelvic nodes
– C2	Positive periaortic nodes
Stage IV:		37%	9%
– A	Bladder or rectal involvement
– B	Distant metastases

Dissemination of disease otherwise confined to the uterus (e.g., stage I) to the abdomen (e.g., stage III-sarcoma; stage IV-carcinoma) that may occur as a result of morcellation can lead to severely compromised survival. Conceivably the morcellation of a stage I disease that leads to abdominal implants could result in decreases in 5-year overall survival (upstaging).

†

Overall survival is provided except for endometrioid where relative survival rate is listed.

‡

Data taken from [44].

Data taken from [113].

Uterine sarcomas constitute only 6% of uterine cancers, or 2400 cases annually. Among 6815 women across 39 studies of sarcoma in women undergoing myomectomy published 1950–1993, only 0.26% had uterine sarcoma [45]. Risk factors include postmenopausal status, use of tamoxifen >5 years and a history of pelvic radiation [33]. Both uterine fibroids and leiomyosarcoma are more prevalent in black women. Women with hereditary leiomyomatosis and renal cell carcinoma syndrome are also at increased risk in the premenopausal period [46]. The incidence of leiomyosarcoma peaks between 40 and 50 years, whereas incidence of carcinosarcoma continues to rise after menopause. In contrast to epithelial carcinomas, often no measure exists in the preoperative setting to definitively exclude uterine malignancies that arise from mesenchyme [18,47,48]. Interval uterine growth of greater than 6 weeks gestational size over 1 year has historically and arbitrarily been proposed as a concerning clinical sign for sarcoma [49], however, in retrospective reviews the incidence of sarcoma in women who meet this criterion remains quite low. Among 580 patients across 26 studies of sarcoma in women undergoing hysterectomy published 1962–1993, only 2.6% had a history of rapid uterine enlargement [45].

Leiomyosarcoma represents 30% of all uterine sarcomas [50]. Endometrial stromal sarcoma accounts for 15% of uterine sarcomas [51], and up to 30% of women have extrauterine disease at time of presentation [52]. Most cases of leiomyosarcoma are diagnosed postoperatively, regardless of route of tissue extraction [53]. Among women undergoing hysterectomy, Parker and colleagues reported an incidence over a 4-year period of 0.27% (1/351) among women with access to routine medical care [45]. In a study by Leibsohn and colleagues of an urban population with scant to no prior gynecologic care, the rate was 0.49% [46]. These estimates appear consistent with a number of more recent reports [53 –56], though one meta-analysis using 130 papers including 28,000 women undergoing surgery for presumed fibroids suggests that the rate may actually be as low as 1:7450 [57].

Leiomyosarcoma and endometrial stromal sarcomas are staged distinctly from endometrial carcinoma (Table 2). For leiomyosarcoma, no role exists for lymph-adenectomy in the absence of gross extrauterine disease; positive nodes occur in only 3% of such instances [58]. Radiation therapy is of arguable benefit [33] and administration of chemotherapy for completely resected early stage disease varies by institution [59]. Endometrial stromal sarcomas are best addressed with hormonal antagonism, though benefit for adjuvant treatment in early stage disease has not been proven [60].

Table 2.

FIGO staging: leiomyosarcoma and endometrial stromal sarcoma.

Stage	Definition	5-year survival
		Leiomyosarcoma†	Endometrial stromal sarcoma‡
Stage I:	Disease confined to the uterus	76%	90%
– A	Tumor ≤5 cm
– B	Tumor >5 cm
Stage II:		60%	40%§
– A	Adnexal involvement
– B	Involvement of other pelvic tissues
Stage III:		45%	64%
– A	Abdominal involvement one site
– B	Abdominal involvement >one site
– C	Metastases to pelvic and/or periaortic lymph nodes
Stage IV:		29%	37%
– A	Bladder or rectal involvement
– B	Distant metastases

†

Data taken from [112].

‡

Data taken from [44].

Likely inaccurate due to low numbers.

Among the mixed mullerian tumors, carcinosarcomas (malignant epithelial and stromal components) represent 40–50% of all sarcomas and are staged according to guidelines for type II disease; adenosarcomas (benign epithelial and malignant stromal component) represent a minority of cases.

Five-year overall survival for endometrial carcinoma, leiomyosarcoma, carcinosarcoma and endometrial stromal sarcoma are provided in Tables 1 & 2. Upstaging of disease that would have otherwise been confined to the uterus (e.g., stage I) to the abdomen (e.g., stage III) that may occur as a result of morcellation can lead to severely compromised survival.

Measures to minimize risks associated with morcelation

A complete preoperative evaluation must be performed for risk stratification. The American Association of Gynecologic Laparoscopists (AAGL) has proposed standardized preoperative assessment protocols including transvaginal ultrasound, endometrial biopsy and Papanicolaou testing. Intraoperatively, alternative surgical methods have been explored to help reduce risk of tissue dissemination. Some authorities have recommended restriction of morcellation to premenopausal women. In one insurance database, among 232,882 women who underwent a minimally invasive approach to hysterectomy, the rate of uterine cancers was 27 per 10,000 morcellations and the risk ratio of malignant disease was 4.97, 19.37, 21.36 and 35.97 for women ages 50–54, 55–59,60–64, ≥65 years, respectively [61].

Preoperative imaging ultrasound

Pelvic ultrasound is often a starting point in gynecologic workup and can aid in diagnosis of malignancy, though detection is imperfect and no stringent diagnostic criteria for malignancy exist. While endometrial hyperplasia often accompanies type I endometrial carcinomas, a thin endometrial stripe may not exclude type II endometrial cancers [62]. Furthermore, malignant processes may be quite heterogeneous in appearance. In a descriptive study of 10 cases of endometrial stromal sarcoma, Kim and coauthors described four distinct patterns: a polypoid mass with nodular myometrial extension, an intramural mass with an ill-defined margin and echogenicity, an ill-defined large central cavity mass, or diffuse myometrial thickening [63]. Adenomyosis may also mimic endometrial stromal sarcoma if diffuse within the myometrium.

The addition of Doppler ultrasound may improve discrimination of malignant processes. Kurjak et al. documented Doppler ultrasound patterns one day prior to hysterectomy in 2,010 women [64]. There were 1850 leiomyomatous uteri, 150 normal uteri and 10 leiomyosarcomas on final pathology. All instances of uterine sarcoma were associated with abnormal tumoral blood vessels as manifested by lower resistive index (RI; p < 0.001). An RI cutoff of 0.40 provided sensitivity of 90.91%, specificity of 99.82%, positive predictive value of 71.43% and negative predictive value of 99.96%. In contrast, however, other authors have shown no ability of ultrasound to distinguish leiomyosarcoma from leiomyoma, though mean RI among carcinosarcomas was lower than that of leiomyomas (0.41 ± 0.06 vs 0.59 ± 0.01; p < 0.001) [65].

Magnetic resonance imaging

Recently, MRI has emerged as a superior tool for the discrimination of uterine leiomyoma from leiomyosarcoma. Findings suggestive of sarcoma include central areas of intermediate to high T2-weighted low attenuation indicative of necrosis or hemorrhage, irregular margins, lack of calcifications and tissue heterogeneity. Carcinosarcomas may appear as large solid masses encompassing the endometrial cavity, also often accompanied by central necrosis. Unfortunately, various subtypes (e.g., typical, calcified, cystic, myxoid, red/coagulative necrotic, cellular) of leiomyomata may share features of leiomyosarcoma, especially when degenerating [66]. The reported accuracy, sensitivity, specificity, positive predictive value and negative predictive value for MRI in the detection of leiomyosarcoma range from 69 to 97%, 56 to 100%, 88 to 100%, 67 to 100%, 80 to 100% [67 –70]. Contrast administration or diffusion weighting techniques may add diagnostic value to MRI. Administration of the paramagnetic contrast agent gadolinium produces increases T1-weighted signal intensity in instances of greater delivery due to enhanced vascularity. Diffusion-weighted MRI sequences can provide unique information about tissue cellularity; diffusion is inversely correlated to tissue cellularity and intravascular water molecules have greater diffusion because of blood flow than those in extracellular and intracellular spaces [71]. Apparent diffusion coefficients have been shown to discriminate leiomyosarcomas (lower) from leiomyomas (higher) [72,73]. Thomassin-Naggara and colleagues reported successful discrimination of pathology among 47/51 (92%) patients (including 19 sarcomas, 6 tumors of uncertain malignant potential and 26 benign pathologies) using a multivariate model incorporating diffusion weighted signal intensity, mean apparent diffusion coefficient and T2 signal intensity [74].

Some have advocated for the use of serum lactate dehydrogenase (LDH) isozymes to improve performance of MRI to distinguish leiomyosarcoma from degenerating leiomyoma. Serum LDH is often elevated in leiomyosarcomas [75] secondary to coagulative-type tumor cell necrosis and may be a marker of aggressive behavior reflecting tumor growth exceeding vascular supply [76]. In some reports, elevated serum LDH was documented in 43–66% of leiomyosarcoma [75,76]. In a study of 140 patients including 10 leiomyosarcomas and 130 degenerating leiomyomas, all 10 (100%) leiomyosarcomas and 32 (25%) degenerating leiomyomas exhibited elevated LDH [77]. Interestingly, all 10 leiomyosarcomas exhibited enhancement at 60 s following gadolinium infusion, compared with only 4/32 degenerating leiomyomas. The specificity/positive predictive value/negative predictive values of MRI, gadolinium-enhanced MRI and gadolinium-enhanced MRI with LDH were, therefore, 93.1%/52.6%/100%, 93.8%/83.3%/100% and 100%/100%/100%, respectively.

Preoperative endometrial biopsy & cervical cytology

For women at risk of delivery of a nonintact specimen, tissue sampling is an important step in the preoperative evaluation. All patients with abnormal uterine bleeding should undergo endometrial sampling to identify cancerous or precancerous lesions. Multiple studies have established the sensitivity of endometrial pipelle biopsy in detection of endometrial carcinoma in symptomatic women (95–97.5% for endometrioid, 86.5% for non-endometrioid histologies) [78,79]. Endometrial biopsy in women without abnormal uterine bleeding, however, remains an imperfect screening test. A case series released in 2011 examined the efficacy of performing endometrial biopsy (with or without pelvic ultrasound) preoperatively for asymptomatic women undergoing hysterectomy with pelvic floor repair. The authors postoperatively diagnosed four endometrial adenocarcinomas and one leiomyosarcoma; two of the cases of adenocarcinoma and the case of leiomyosarcoma underwent endometrial tissue sampling prior to surgery that failed to make the diagnosis [80]. McPencow and colleagues modeled cost–effectiveness of universal endometrial evaluation prior to morcellation in surgical procedures for prolapse [81]. Using an endometrial cancer prevalence of 0.6 and a 40% risk of upstaging after morcellation, the expected per-patient cost was $8800, $9023 and $9112 over 5 years for no screening, endometrial biopsy and transvaginal ultrasound, respectively. The estimated incremental cost–effectiveness ratio was $207,348 for endometrial biopsy and $298,038 for transvaginal ultrasound compared with no screening. Prevalence of endometrial cancer and the risk of endometrial cancer upstaging after morcellation had the greatest impact on the cost–effectiveness of screening.

Endometrial biopsy has low sensitivity in the diagnosis of leiomyosarcoma and depends greatly on tumor location. In one series, only 36% of endometrial biopsies detected leiomyosarcoma preoperatively; in each instance the tumor location was submucosal [82]. Slightly higher detection rates of 50% for leiomyosarcoma have been reported in other series [48]. The sensitivity for endometrial stromal sarcomas may be as low as 33% [47].

Ideally, women should also have documented cervical cytology, however, this provides limited value in the detection of postmenopausal endometrial disease, including carcinomas and especially sarcomas. Van den Bosch et al. evaluated 128 consecutive menopausal women presenting with uterine bleeding (n = 116) or endometrial cells on a previous cervical cytology smear (n = 12). Endometrial sampling led to diagnosis of carcinoma in six women, but endometrial cells were not reliably found (33%) on cervical smear. The presence of endometrial cells on ectocervical cytology showed a sensitivity of 67% and specificity of 78% for endometrial carcinoma versus 80 and 76%, respectively, for endocervical cytology. The positive predictive value for endometrial malignancy of the presence of endometrial cells on cervical cytology ranged between 13 and 17%. The presence of atypical endometrial cells on cervical smear was associated with endometrial malignancy in almost half the cases [83].

Intraoperative frozen section & irrigation techniques

Some authors have advocated performance of intraoperative frozen section of multiple biopsy specimens prior to morcellation [84]. Unfortunately, accuracy of frozen section for uterine leiomyosarcoma is particularly poor; in some series, it is as low as 11–38% [47,78]. Among the 12 patients with uterine sarcoma reported by Parker et al., only 2 had undergone intraoperative frozen section; in one instance, the correct diagnosis of carcinosarcoma was made but in the other, frozen section showed cellular leiomyoma but permanent slides revealed leiomyosarcoma [45].

In one review of 41 cases of iatrogenic parasitic myoma across 23 studies, Huang and colleagues noted that many were localized to the dependent portion of the abdomen. The authors hypothesized that simply irrigating vigorously with position changes may decrease the incidence of iatrogenic parasitic myoma [85].

Contained morcellation

Little literature exists on the use of specimen retrieval pouches in reducing the risk of tissue dissemination, though the theoretical benefit of morcellation in an endoscopic bag is quite logical [86]. Critics cite concerns for leakage due to accidental puncture by instruments required for morcellation, as a result of pulling the bag through a narrow trocar site, or secondary to frictional heat generation if a power morcellator is used [87]. Overall, the preclinical and technical performance of such bags has been encouraging. Rassweiler and colleagues found all but one of seven commercially available laparoscopic bags to be impermeable to tumor cell suspensions with digital manipulation [88]. In another study, laparoscopic bags ruptured at after application of 30–133 pounds [89]. Cohen and colleagues attempted power morcellation within a bag insufflated to 10–25 mm Hg using a stitch-sealed nylon bag and multiport approach, clear plastic bag and multiport approach, and clear plastic bag and single-port approach. Only the nylon bag resulted in leakage [90].

Successful morcellation under laparoscopic visualization using a bag exteriorized through the abdominal wall at the site of a trocar has been described. Serur and Lakhi manually morcellated of uteri weighing up to 2100 g in patients with a BMI up to 37.5 kg/m² complicated by vaginal stenosis [91]. Electromechanical transabdominal contained morcellation was found to be feasible in 73 patients with benign disease across four institutions [92]. Similarly, McKenna and colleagues outlined outcomes with the Sydney Contained In Bag Morcellation (Syd CIBM) system for five cases with uteri weighing up to 978 g [93].

Two case series have demonstrated success with use of laparoscopic bags and vaginal morcellation during endometrial cancer staging. Favero and colleagues describe a technique used in conjunction with laparoscopic hysterectomy in eight cases of known endometrial cancer, in which the uterus was bisected and morcellated vaginally within a polyurethane endoscopic pouch. The pilot study was limited, however, in that the eight patients were only followed for 3 months postoperatively, though none showed evidence of disease [94]. Montella and colleagues later published a series of 12 patients who underwent vaginal morcellation in a laparoscopic bag following total laparoscopic hysterectomy for endometrial cancer, and followed these patients for 18 months after surgery. None of these patients had experienced local or distant recurrence [95].

Malignancy diagnosed following morcellation: subsequent management & prognosis

Mechanism of enhanced tumorigenicity in the surgical environment

Tumors have been considered by some as ‘wounds that do not heal’ [96]. Due to a resultant milieu rich in growth factors, surgical wounds tend to enhance tumorigenicity of shed tumor cells to implant [97,98]. Such mechanisms may make intraperitoneal dissemination of tumor cells by means of morcellation particularly virulent. During the inflammatory stage of wound healing, IGF-I, PDGF, TGFα/β, EGF, IL–1 and TNFα affect macrophages. This is followed by the proliferative stage, during which there is expansion of fibroblasts, vascular endothelial cells and keratinocytes, and a surge in cytokines such as IL–6 that may facilitate immune evasion of tumor cells. Repair and remodeling ensue, during which the balance of matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases modulate fibroblasts.

Role for completion staging/survey

In the majority of instances, there is benefit in surgical re-exploration following postoperative diagnosis of malignancy in order to guide adjuvant therapy and prognosis. Oduyebo and colleagues found a rate of disseminated peritoneal disease upon re-exploration to be 28% at a median of 33 days to reoperation [99]. Seidman and colleagues found that 64% (0/1 endometrial stromal sarcomas, 1/1 cellular leiomyomas, 0/1 atypical leiomyomas and 4/7 leiomyosarcomas) of cases to be associated with disseminated disease that required debulking in this setting [35]. The rate is less pronounced in other series. Among ten uterine cancers (five leiomyosarcomas, five carcinomas) diagnosed among 1115 laparoscopic hysterectomies with morcellation, all patients who underwent completion staging had negative peritoneal cytology and only one was upstaged [100].

For women who undergo supracervical hysterectomy, Einstein and colleagues advocate radiologic assessment and completion surgery to guide adjuvant therapy [101]. In their series of 17 patients, there were three instances of motorized morcellation and one instance of transvaginal morcellation. Eight patients (47%) had endometrioid histology, five had leiomyosarcoma (29%), three had low-grade endometrial stromal sarcoma (18%) and one had carcinosarcoma (6%). Two of 13 (15%) of patients who underwent completion surgery were upstaged, both of whom had morcellated leiomyosarcomas. It is unknown whether this was related to incorrect assignment at time of initial surgery or progression during the interval between initial and completion surgery. Ouyebo and colleagues similarly urge reoperation for removal of the cervix, peritoneal biopsies including the port site, omental biopsies and debulking for cases of postoperatively diagnosed uterine sarcoma [99].

Completion hysterectomy and staging is recommended in most women diagnosed with leiomyosarcoma on final pathology of a myomectomy specimen, because in up to 2/3, residual leiomyosarcoma will be found in the hysterectomy specimen even when myomectomy was performed in open fashion [102]. In select instances young women may be managed conservatively to spare fertility, with recurrence rates reported as 0–17% [103 –105], though this rate may be underestimated as some of the patients included in these studies may have represented STUMP. In other instances, conservative management has led to local recurrence despite completion of chemotherapy [106]. These recurrence rates have been formulated from patients undergoing intact myomectomy; exact risk in women who have undergone morcellation of myomectomy specimens is not known and may be presumably higher. For example, in a study of apparent early-stage occult leiomyosarcoma by Park et al., there were six cases of morcellated myomectomy specimens (five via mini-laparotomy and one laparoscopic), but no non-morcellated direct controls [107]. Overall, in this study 52% of patients in the morcellation group had recurrent disease, compared with only 23% in the unmorcellated group. In the study by Perri et al. [52], there were four open myomectomies which were at least ‘cut through’ with a knife. Only two patients had residual leiomyosarcoma on completion hysterectomy; there were two recurrences documented at the time of the report. Only 13 patients were reported in the English literature between 1950 and 2006 to have successful pregnancy following myomectomy demonstrative of leiomyosarcoma [108].

Prognosis among patients with incidental morcellation of unsuspected malignancy

Many prognostic variables, such as margin status, tumor size, and extent of invasion, become impossible to interpret from morcellated pathologic specimens [109]. Morcellation of unsuspected malignancy generally portends poorer prognosis, though the available data may suffer from severe reporting bias [110]. Among the data from North America, Seidman and colleagues reported the rate of unexpected leiomyosarcoma, atypical leiomyoma, endometrial stromal sarcoma, or STUMP in to be 1.2% among 1091 morcellated specimens [34], though inferior survival outcomes were noted only in instances of disseminated leiomyosarcoma. Mean survival among cases of disseminated leiomyosarcoma was 24.3 months, whereas all cases of leiomyosarcoma without dissemination remained alive at 29.7 months. In a similar report of 13 leiomyosarcomas and 6 STUMPs, of which 25% were hand and 75% electromechanically morcellated, recurrences were exclusively pelvic – higher than expected for a disease that traditionally spreads hematogenously to lungs or liver [99]. George and colleagues in a retrospective cohort of 19 patients who underwent intraperitoneal morcellation of leiomyosarcoma, found not only a higher abdomino-pelvic recurrence rate (85 vs 20%, p = 0.001) but a decrease in recurrence-free survival (10.8 vs 39.6 months, p = 0.002) compared with 39 patients who underwent total abdominal hysterectomy [111]. Notably, good outcomes were achieved in the study by Rowland et al., in which all patients with leiomyosarcoma received gemcitabine and taxotere, one patient with IIIC mixed endometrial cancer received carboplatin/paclitaxel, and the remainder of women who had stage I carcinomas were dispositioned to observation; no recurrences were identified within a median follow-up of 17 months [100].

Studies performed outside of North America demonstrate similar trends. Park and colleagues reported on the Korean experience with 56 consecutive patients with stage I/II uterine leiomyosarcoma diagnosed between 1989–2010, 25 of whom underwent morcellation [107]. In multivariate analyses, a history of morcellation was significantly associated with poorer overall survival (OR: 3.11; 95% CI: 1.07–9.06; p = 0.038). The rate of peritoneal sarcomatosis or vaginal apex recurrence in patients who underwent morcellation exceeded that of patients who did not undergo morcellation (44 vs 13%, p = 0.032). Receipt of adjuvant therapy, ovarian preservation, performance of lymph node dissection, grade, mitotic count, tumor size, body mass index, menopausal status, parity, age (dichotomous) were not found to be factors predictive of disease-free or overall survival. The same group also found that among 27 women who did and 23 women who did not undergo morcellation of endometrial stromal sarcoma, morcellation was significantly associated with poorer disease-free survival (OR: 4.03; 95% CI: 1.06–15.30; p = 0.04). In contrast to leiomyosarcoma, many patients with endometrial stromal sarcomas can be successfully salvaged by chemotherapy or surgery, so this did not translate into compromised overall survival [112]. In a study of all consecutive patients with presumed stage I leiomyosarcoma treated from 1969–2006 at a single institution in Israel, patients who underwent total abdominal hysterectomy (n = 21) experienced a survival advantage (HR 2.8, 95% confidence interval 1.02–7.67) compared with those with tumor spillage (n = 16; i.e., via open or hysteroscopic myomectomy, laparoscopic morcellation, subtotal hysterectomy, or total abdominal hysterectomy with injury to the uterus by a sharp instrument) [53]. There were no statistically significant differences between the groups by age (median 48 years vs 52 years), menopausal status (33 vs 37%), nulliparity (14 vs 13%), or receipt of adjuvant chemotherapy, radiotherapy, or both (33 vs 50%). In a French study, a higher rate of recurrence at 3 months (8.8 vs 3.7%) was demonstrated in women with uterine sarcoma who underwent a form of morcellation (n = 28) at the time of surgery for uterine sarcoma compared with those who did not (n = 95) [113]. This did not reach statistical significance (p = 0.25), and disease-free and overall survival rates were similar in both groups.

No outcomes data exist specifically for patients with leiomyosarcoma who have undergone vaginal morcellation, however, these may prove favorable compared with intraperitoneal approaches given that morcellation through this technique occurs outside the pelvis and, in the case of coring, leaves the outer uterine serosa intact [55]. Some authors also prefer vaginal morcellation as the vaginal vault is routinely included in the radiation field when this therapy is indicated in an adjuvant setting [114].

Port site metastases

Port-site metastases represent an additional concern consequent to laparoscopic management of occult or known uterine malignancies, and have been reported even in the absence of morcellation. Port site metastasis of a leiomyosarcoma diagnosed postoperatively has been described after laparoscopic-assisted vaginal hysterectomy [115], and after laparoscopic biopsy for retroperitoneal sarcoma [116]. The rate of port site metastasis in the LAP2 study by the Gynecologic Oncology Group that compared endometrial cancer staging by laparotomy versus traditional laparoscopy was only 4 in 1696 patients (0.24%) [117]. In robotic staging procedures, this rate is approximately 1.1–1.4% [118,119]. Rates following morcellation have not been established. Risk appears to be greatly enhanced by the presence of ascites. Irrigation of port sites with iodine, taurolidine, heparin, or normal saline does not offer protection in rat models [120].

Regulatory & agency statements

It is clear that guidance is required regarding morcellation for patients and providers. The Society of Gynecologic Oncology (SGO) released a position statement as early as December 2013 encouraging providers to avoid power morcellation in the presence of known or suspected malignancy, or even in risk- reducing surgery, and to consider mini-laparotomy or laparoscopic bag morcellation if possible [121]. SGO did underscore, however, that many of these malignant histologies offer an extremely poor prognosis even when not disseminated via morcellation.

Following widespread coverage in the news media, the FDA reviewed eighteen publications involving uterine sarcomas discovered after hysterectomy and deduced the rate of uterine sarcoma to be 1 in 427 women undergoing hysterectomy and the rate of leiomyosarcoma to be 1 in 568 using a random effects model [122]. In April 2014, the FDA then issued an advisory statement cautioning practitioners against the use of power morcellation during hysterectomy or myomectomy for fear of worsening long-term survival in women with unsuspected sarcoma [123]. The updated statement [124] reads:

Laparoscopic power morcellators are contraindicated:

For removal of uterine tissue containing suspected fibroids in patients who are peri- or postmenopausal, or are candidates for en bloc tissue removal, for example, through the vagina or mini-laparotomy incision;

In gynecologic surgery in which the tissue to be morcellated is known or suspected to contain malignancy.

Notably, the FDA estimations were derived from studies that were retrospective in nature, representative of single-institution referral centers, characterized by small sample sizes and not otherwise stratified based on risk according to age or other variables. Subsequent discontinuation of electromechanical morcellator sales by medical manufacturers such as Ethicon, who voluntarily recalled the Gynecare Morcellex, the Morcellex Sigma and the Gynecare X-Tract, contributed to additional scrutiny and cautious analysis of this technology.

In response to the FDA advisory, the AAGL assembled a task force to perform a thorough literature review regarding tissue morcellation. The AAGL published their comprehensive report describing morcellation modalities, risk profiles for uterine sarcoma, diagnostic and preoperative assessment, the consent process and recommendations for each level [125]. Based upon its findings, the AAGL continues to support the safe use of morcellation procedures provided that properly trained providers complete the appropriate and necessary preoperative workup and consider all factors in a patient's case, including but not limited to age, menopausal status and endometrial evaluation. The AAGL maintains that all methods of tissue extraction should remain available.

The American College of Obstetricians and Gynecologists (ACOG) released a special report and summary on morcellation and occult malignancies in May 2014 [126]. ACOG similarly supports a comprehensive preoperative evaluation process including cervical cytology, pelvic imaging and endometrial evaluation. ACOG underscores the need for a central national registry to allow for continued safety and outcomes research. As with other gynecologic organizations, ACOG recognizes the value of laparoscopic surgery and morcellation, when properly employed, in the treatment of women with uterine fibroids. Soon thereafter, the Society of Gynecologic Surgeons (SGS) [127] and American Urogynecologic Society (AUGS) also endorsed this statement [128].

Minimizing liability

A detailed discussion of medicolegal liability [129] is beyond the scope of this article. Briefly, one must prove not only a breach in standard of care but causality between this breach and the injury [130]. Failure to adhere to FDA labeling would support negligence, however, the FDA statement notably does not define ‘perimenopause’.

The authors recommend that morcellation remain available to providers and patients, but that a frank discussion of the risk stratification process occur with patients during preoperative counseling, and that risks, benefits and alternatives be outlined explicitly in balanced fashion on consent forms in order to satisfy requirements for informed consent, specifically:

The limitations of current technologies to identify malignancy with perfect accuracy;

Potential for upstaging of occult malignancy through morcellation, leading to compromised outcome;

Relative risks of wound complications, longer hospitalization and venous thromboembolism with laparotomy opposed to laparoscopy.

In the current medicolegal environment, patients who should probably not be offered uncontained morcellation at this time are those above 40 years with risk factors for sarcoma such as African–American race, tamoxifen/radiation therapy, or any woman with a hereditary predisposition to uterine cancer (e.g., hereditary leiomyomatosis, renal cell carcinoma syndrome, Lynch syndrome). Candidates for morcellation should also undergo preoperative imaging (preferably MRI with or without serum lactate dehydrogenase) and cytologic assessment (e.g., cervical cytology and endometrial biopsy).

Executive summary

Hysterectomy

Approximately 400,000–600,000 hysterectomies are performed annually in the USA.

Laparoscopic approaches have become more common as minimally invasive surgery offers less intraoperative blood loss, shorter hospitalization, fewer wound complications, and faster return to baseline activity relative to laparotomy.

Morcellation techniques

Morcellation is the fragmentation of solid tissue into smaller specimens to facilitate removal.

Manual morcellation can be accomplished with a scalpel:

– Transabdominally through extension of port sites or creation of a minilaparotomy;

– Transvaginally though the cuff or posterior colpotomy in the case of preservation of the cervix.

Electromechanical power morcellation has been approved for gynecologic indications since 1995; these devices generally utilize a spinning circular blade or radiofrequency energy at the end of a tube system through which tissue is fed using a grasper.

Risks of morcellation

Electromechanical power morcellation is associated with a higher incidence of bowel and vessel injury when compared with other forms of morcellation.

The potential for iatrogenic dissemination of benign and malignant disease remains one of the greatest limitations to tissue morcellation.

Measures to minimize risks associated with morcellation

Preoperative imaging (transvaginal ultrasound, MRI), endometrial sampling, and cervical cytology are imperfect approaches to the diagnosis of uterine malignancy, especially in instances of sarcoma.

Intraprocedural measures such as contained morcellation, use of intraoperative frozen section prior to morcellation and copious irrigation following specimen extraction have been proposed as measures to reduce risk.

Malignancy diagnosed following morcellation: subsequent management & prognosis

Due to a resultant milieu rich in growth factors, surgical wounds tend to enhance tumorigenicity of shed tumor cells to implant and may make intraperitoneal dissemination of tumor cells by means of morcellation particularly virulent.

In cases of postoperative diagnosis of malignancy, reoperation for completion staging and debulking of any disseminated disease is recommended and may guide additional adjuvant therapy.

Patients with morcellated cancer tend to have a poorer prognosis relative to counterparts with intact specimen delivery, especially in instances of leiomyosarcoma.

Port site metastases are a rare complication of laparoscopy performed in patients with cancer.

Regulatory & agency statements

In 2014, the US FDA issued an advisory statement cautioning practitioners against the use of power morcellation in peri- and postmenopausal during hysterectomy or myomectomy given concern for compromised long-term survival in women with unsuspected malignancy.

The Society of Gynecologic Oncologists suggests mini-laparotomy or laparoscopic bag morcellation be considered in cases of suspected malignancy and risk-reducing surgery.

The American Association for Gynecologic Laparoscopists and American Congress of Obstetricians and Gynecologists recommend comprehensive preoperative evaluation including cervical cytology, pelvic imaging and endometrial evaluation, appropriate patient selection based on risk stratification by age/menopausal status, as well as extensive informed consent, but support that all methods of tissue extraction should remain available.

Future perspectives

Dissemination of occult malignancy as a result of laparoscopic morcellation can have dire consequences. Compared with patients with delivery of intact specimens, patients who have undergone morcellation of malignancy may be up to four times more likely to have pelvic recurrences, may have recurrence-free survival that is compromised by up to 28 months, and may suffer a threefold increase in risk of death. Appropriate patient selection and preoperative evaluation can minimize this risk: endometrial biopsy may detect as many as 95% of endometrial carcinomas, and between a third and half of all submucosal leiomyosarcomas and endometrial stromal sarcomas; gadolinium-enhanced MRI in conjunction with serum LDH has reported sensitivity and negative/positive predictive values approaching 100%. An extensive informed consent process should occur between clinicians and patients. Series that compare survival outcomes in leiomyosarcoma treated with intact myomectomy versus morcellated myomectomy with or without completion hysterectomy are lacking. While intracorporeal morcellation by electromechanical means has received much focus, risk is currently understudied for manual morcellation and transvaginal delivery of nonintact specimens. Additional prospective evaluations of contained morcellation methods are required.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as:.

of interest.

Keshavarz

Hillis

Kieke

Hysterectomy surveillance-United States 1994–1999. MMWR Morb. Mortal. Wkly Rep. 51(SS05), 1–8 (2002).

CDC/NCHS National Hospital Discharge Survey. Number of all-listed procedures for discharges from short-stay hospitals, by procedure, category, and sex: United States, 2010. www.cdc.gov.

Baird

Dunson

Hill

High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am. J. Obstet. Gynecol. 188(1), 100–107 (2003).

Wright

Herzog

Tsui

Nationwide trends in the performance of inpatient hysterectomy in the United States. Obstet. Gynecol. 122(2), 233–241 (2013).

Sutton

. Hysterectomy: a historical perspective. Baillieres. Clin. Obstet. Gynaecol. 11(1), 1–22 (1997).

Rosero

Kho

Joshi

Comparison of robotic and laparoscopic hysterectomy for benign disease. Obstet. Gynecol. 122(4), 778–786 (2013).

Nieboer

Johnson

Lebathy

Surgical approach to hysterectomy for benign gynaecological disease. Cochrane Database Syst. Rev. (3), CD003677 (2009).

10.

Shen

Chen

Wang

Effects of laparoscopic versus minilaparotomic myomectomy on uterine leiomyomata: a meta-analysis. J. Minim. Invasive Gynecol. 22(2), 177–184 (2015).

11.

Sizzi

Rossetti

Malzoni

Italian multicenter study on complications of laparoscopic myomectomy. J. Minim. Invasive Gynecol. 14(4), 453–462 (2007).

12.

Glasser

. Minilaparotomy myomectomy: a minimally invasive alternative for the large fibroid uterus. J. Minim. Invasive Gynecol. 12, 275–283 (2005).

13.

Muzii

Basile

Zupi

Laparoscopic-assisted vaginal hysterectomy versus minilaparotomy hysterectomy: a prospective, randomized, multicenter study. J. Minim. Invasive Gynecol. 14(5), 610–615 (2007).

14.

Uccella

Cromi

Serati

Laparoscopic hysterectomy in case of uteri weighing ≥1 kilogram: a series of 71 cases and review of the literature. J. Minim. Invasive Gynecol. 21(3), 460–465 (2014).

15.

Chou

Sheu

Chang

Operating time and blood loss during laparoscopic-assisted vaginal hysterectomy with in situ morcellation. Acta. Obstet. Gynecol. Scand. 90(9), 985–989 (2011).

16.

Sobolewski

. Meeting Materials of the Obstetrics and Gynecology Devices Panel. Surgical treatment options for fibroids and their outcomes. www.fda.gov.

17.

Steiner

Wight

Tadir

Electrical cutting device for laparoscopic removal of tissue from the abdominal cavity. Obstet. Gynecol. 81, 471–474 (2013).

18.

Price

. Meeting material of the obstetrics and gynecology devices panel. regulation of laparoscopic power morcellators. www.fda.gov.

19.

Driessen

Arkenbout

Thurkow

Electromechanical morcellators in minimally invasive gynecologic surgery: an update. J. Minim. Invasive Gynecol. 21(3), 377–383 (2014).

20.

AAGL. Practice report: morcellation during uterine tissue extraction. J. Minim. Invasive Gynecol. 21(4), 517–530 (2014).

21.

Arkenbout

van den Haak

Driessen

Assessing basic “physiology” of the morcellation process and tissue spread: a time-action analysis. J. Minim. Invasive Gynecol. 22(2), 255–260 (2015).

22.

The authors objectively characterize scatter properties associated with power morcellators, and quantify magnitude of tissue spread that may occur secondary to power morcellation.

23.

Milad

. Laparoscopic morcellator-related complications. J. Minim. Invasive Gynecol. 21(3), 486–491 (2014).

24.

Rivard

Salhadar

Kenton

. New challenges in detecting, grading, and staging endometrial cancer after uterine morcellation. J. Minim. Invasive Gynecol. 19(3), 313–316 (2012).

25.

Bekkers

Willemsen

Schijf

Leiomyomatosis peritonealis disseminata: does malignant transformation occur. Gynecol. Oncol. 75(1), 158–163 (1999).

26.

Cucinella

Granese

Calagna

Parasitic myomas after laparoscopic surgery: an emerging complication in the use of morcellator? Description of four cases. Fertil. Steril. 96(2), e90–e96 (2011).

27.

Leren

Langebrekke

Qvigstad

. Parasitic leiomyomas after laparoscopic surgery with morcellation. Acta Obstet. Gynecol. Scand. 91(10), 1233–1236 (2012).

28.

Shakir

Hill

. Morcelloma formation following laparoscopic myomectomy and sub-%total hysterectomy. J. Minim. Invasive Gynecol. 19(6), S130 (2012).

29.

Sepilian

. Iatrogenic endometriosis caused by uterine morcellation during a supracervical hysterectomy. Obstet. Gynecol. 102, 1125–1127 (2003).

30.

Donnez

Jadoul

Squifflet

Iatrogenic peritoneal adenomyoma after laparoscopic subtotal hysterectomy and uterine morcellation. Gynecol. Oncol. 132, 360–365 (2014).

31.

Takeda

Mori

Sakai

Parasitic peritoneal leiomyomatosis diagnosed 6 years after laparoscopic myomectomy with electric tissue morcellation: report of a case and review of the literature. J. Minim. Invasive Gynecol. 14(6), 770–775 (2007).

32.

Takeda

Masuhara

Kamiura

. Successful management of a leiomyomatosis peritonealis disseminatawith an aromatase inhibitor. Obstet. Gynecol. 112(2 Pt 2), 491–493 (2008).

33.

Zyla

Dzieniecka

Kostrzewa

Leiomyomatosis peritonealis disseminata of unusual course with malignant transformation: case report. Acta Obstet. Gynecol. Scand. 94(2), 220–223 (2015).

34.

Sharma

Chaturvedi

Gupta

Leiomyomatosis peritonealis disseminata with malignant change in a post-menopausal woman. Gynecol. Oncol. 95(3), 742–745 (2004).

35.

Bell

Kempson

Hendrickson

. Problematic uterine smooth muscle neoplasms: a clinicopathologic study of 213 cases. Am. J. Surg. Pathol. 18(6), 535–558 (1994).

36.

Sutton

Kavanagh

Wolfson

Uterine corpusmesenchymal tumors. In: Principles and Practice of Gynecologic Oncology (5th Edition). Lippincott, Williams and Wilkins, PA (2009).

37.

Seidman

Oduyebo

Muto

Peritoneal dissemination complicating morcellation of uterine mesenchymal neoplasms. PLoS ONE 7(11), e50058 (2012).

38.

Han

Chew

A clinicopathologic study of uterine smooth muscle tumors of uncertain malignant potential (STUMP). Ann. Acad. Med. Singapore 39, 625–628 (2010).

39.

Peters

Howard

Andersen

Uterine smooth muscle tumors of undetermined malignant potential. Obstet. Gynecol. 83, 1015–1020 (1994).

40.

Dall'Asta

Gizzo

Musaro

Uterine smooth muscle tumors of uncertain malignant potential (STUMP), pathology, follow-up, and recurrence. Int. J. Clin. Exp. Pathol. 7(11), 8136–8142 (2014).

41.

Guntapalli

Ramirez

Anderson

Uterine smooth muscle tumor of undetermined malignant potential: a retrospective analysis. Gynecol. Oncol. 113, 324–326 (2009).

42.

Mowers

Skinner

McClean

Effects of morcellation of uterine smooth muscle tumor of uncertain malignant potential (STUMP) and endometrial stromal sarcoma (ESS), case series and recommendations for clinical practice. J. Minim. Invasive Gynecol. 22(4), 601–606 (2015).

43.

Roque

Santin

. Updates in therapy for uterine serous carcinoma. Curr. Opin. Obstet. Gynecol. 25, 29–37 (2013).

44.

Lee

Kim

Outcomes of ovarian preservation in a cohort of premenopausal women with early-stage endometrial cancer: a Korean Gynecologic Oncology Group study. Gynecol. Oncol. 13(12), 289–293 (2013).

45.

Mariani

Webb

Keeney

Low-risk corpus cancer: is lymphadenectomy or radiotherapy necessary?

Am. J. Obstet. Gynecol. 182, 1506–1519 (2000).

46.

Hill

Carroll

Matthews

. Unanticipated uterine pathologic finding after morcellation during robotic-assisted supracervical hysterectomy and cervicosacropexy for uterine prolapse. Female Pelvic Med. Reconstr. Surg. 20(2), 113–115 (2014).

47.

National Comprehensive Cancer Care Network. Clinical Practice Guidelines: genetic/familial high-risk assessment: colorectal. Version 2. 2014. www.nccn.org.

48.

Parker

Berek

. Uterine sarcoma in patients operated on for presumed leiomyoma and rapidly growing leiomyoma. Obstet. Gynecol. 83, 414–418 (1994).

49.

Launonen

Vierimaa

Kiuru

Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc. Natl Acad. Sci. USA 98(6), 3387–3392 (2001).

50.

Bansal

Herzog

Burke

The utility of preoperative endometrial sampling for the detection of uterine sarcomas. Gynecol. Oncol. 110, 43–48 (2008).

51.

Leibsohn

d'Ablaing

Mishell

Leiomyosarcoma in a series of hysterectomies performed for presumed uterine leiomyomas. Am. J. Obstet. Gynecol. 162(4), 968–974 (1990).

52.

Buttram

Jr Reiter

. Uterine leiomyomata: etiology, symptomatology and management. Fertil. Steril. 36(4), 433–445 (1981).

53.

Kosary

. SEER monograph: cancer of the corpus uteri. www.igcs.org 942.

54.

Leath

Huh

Hyde

A multi-institutional review of outcomes of endometrial stromal sarcoma. Gynecol. Oncol. 105(3), 630–634 (2007).

55.

Perri

Korach

Sadetzski

Uterine leiomyosarcoma: does the primary surgical procedure matter?

Int. J. Gynecol. Cancer 19(2), 257 (2009).

56.

Leung

Terzibachian

Gay

Hysterectomies performed for presumed leiomyomas: should the fear of leiomyosarcoma make us apprehend non-laparotomic surgical routes?

Gynecol. Obstet. Fertil. 37(2), 109–114 (2009).

57.

Theben

Schellong

Altgassen

Unexpected malignancies after laparoscopic-assisted supracervical hysterectomies (LASH), an analysis of 1,548 LASH cases. Arch. Gynecol. Obstet. 287, 455–462 (2013).

58.

Takamizawa

Minakami

Usui

Risk of complications and uterine malignancies in women undergoing hysterectomy for presumed benign leiomyomas. Gynecol. Obstet. Invest. 48, 193–196 (1999).

59.

Ehdaivand

Simon

Sung

Incidental gynecologic neoplasms in morcellated uterine specimens: a case series with follow up. Hum. Pathol., pii: S0046–8177 (2014).

60.

Pritts

. Meeting Materials of the Obstetrics and Gynecology Devices Panel. General public presenter. www.fda.gov.

61.

Major

Blessing

Silverberg

Prognostic factors in early-stage uterine sarcoma. Cancer 71, 1702–1709 (1993).

62.

Hensley

Ishill

Soslow

Adjuvant gemcitabine plus docetaxel for completely resected stages I-IV highgrade uterine leiomyosarcoma: results of a prospective study. Gyneol. Oncol. 112, 563–567 (2008).

63.

Rauh-Hain

del Carmen

. Endometrial stromal sarcoma: a systematic review. Obstet. Gynecol. 122(3), 676–683 (2013).

64.

Wright

Tergas

Burke

Uterine pathology in women undergoing minimally invasive hysterectomy using morcellation. J. Am. Med. Assoc. 312(12), 1253–1255 (2014).

65.

The authors derive incidence of uterine cancer among a multi-institutional insurance database of over 232,000 women undergoing minimally invasive hysterectomy from 2006–2012. This is one of the larger databases published. Among the 36,470 women who underwent morcellation, there were 27 per 10,000 with occult malignancy.

66.

Wang

Wieslander

Hansen

Thin endometrial echo complex on ultrasound does not reliably exclude type II endometrial cancers. Gynecol. Oncol. 101(1), 120–125 (2006).

67.

Kim

Lee

Choi

. Sonographic findings of uterine endometrial stromal sarcoma. Korean J. Radiol. 7(4), 281–286 (2006).

68.

Kurjak

Kupesic

Shalan

Uterine sarcoma: a report of 10 cases studied by transvaginal color and pulsed Doppler sonography. Gynecol. Oncol. 59(3), 342–346 (1995).

69.

Aviram

Oscshom

Markovitch

Uterine sarcoma versus leiomyomas: gray-scale and Doppler sonographic findings. J. Clin. Ultrasound 33(1), 10–13 (2005).

70.

Rha

Byun

Jung

Am. J. Roentgenol. 181(5), 1369–1374 (2003).

71.

Schwartz

Zawin

Carcangiu

Does pelvic magnetic resonance imaging differentiate among the histologic subtypes of uterine leiomyomata?

Fertil. Steril. 70(3), 580–587 (1998).

72.

Tanaka

Nishida

Tsunoda

Smooth muscle tumors of uncertain malignant potential and leiomyosarcomas of the uterus: MR findings. J. Magn. Reson. Imaging 20(6), 998–1007 (2004).

73.

Namimoto

Yamashita

Ketal

Awai

. Combined use of T2-weighted and diffusion-weighted 3–T MR imaging for differentiating uterine sarcomas from benign leiomyomas. Eur. Radiol. 19(11), 2756–2764 (2009).

74.

Koh

Collins

. Diffusion-weighted MRI in the body: application and challenges in oncology. Am. J. Roentgenol. 188, 1622–1635 (2007).

75.

Sato

Yuasa

Fujita

Clinical applications of diffusion-weighted imaging for preoperative differenation between uterine leiomyoma and leiomyosarcoma. Am. J. Obstet. Gynecol. 210(4), 368. e1–82013 (2014).

76.

Tasaki

Asatani

Umezu

Differential diagnosis of uterine smooth muscle tumors using diffusion-weighted imaging: correlations with the apparent diffusion coefficient and cell density. Abdom. Imaging 40(6), 1742–1752 (2014).

77.

Cornfeld

Israel

Martel

MRI appearance of mesenchymal tumors of the uterus. Eur. J. Radiol. 74(1), 241–249 (2010).

78.

Thomassin-Naggara

Deehoux

Bonneau

How to differentiate benign from malignant myometrial tumours using MR imaging. Eur. Radiol. 23, 2306–2314 (2013).

79.

Seki

Hoshihara

Nagata

. Leiomyosarcoma of the uterus: ultrasonography and serum lactate dehydrogenase level. Gynecol. Obstet. Invest. 33, 114–118 (1992).

80.

Takeuchi

Minami

. Serum lactate dehydrogenase and degenerative patterns in ultrasonography for differential diagnosis between uterine leiomyomas and meiomyosarcomas. J. Japan. Assoc. Rural Med. 47(5), 718–723 (1999).

81.

Goto

Takeuchi

Sugimura

Usefulness of Gd-DTPA contrast-enhanced dynamic MRI and serum determination of LDH and its isozymes in the differential diagnosis of leiomyosarcoma from degenerated leiomyoma of the uterus. Int. J. Gynecol. Cancer 12(4), 354–361 (2002).

82.

The authors described the relative improvements in preoperative discrimination of leiomyosarcomas from degenerating leiomyomas using MRI, versus gadolinium-enhanced MRI, versus gadolinium-enhanced MRI and serum biomarkers.

83.

Stovall

Photopulos

Poston

Pipelle endometrial sampling in patients with known endometrial carcinoma. Obstet. Gynecol. 77(6), 954–956 (1991).

84.

Sany

Jha

Singh S

. Correlation between preoperative endometrial sampling and final endometrial cancer histology. Eur. J. Gynaecol. Oncol. 33(2), 142–144 (2012).

85.

Ramm

Gleason

Segal

Utility of preoperative endometrial assessment in asymptomatic women undergoing hysterectomy for pelvic floor dysfunction. Int. J. Urogynecol. 23(7), 913–917 (2012).

86.

McPencow

Erekson

Guess

Cost-effectiveness of endometrial evaluation prior to morcellation in surgical procedures for prolapse. Am. J. Obstet. Gynecol. 209(1), e1–e9 (2013).

87.

Schwartz

Diamond

Schwartz

. Leiomyosarcomas: clinical presentation. Am. J. Obstet. Gynecol. 168(1 Pt 1), 180–183, (1993).

88.

Van den Bosch

Vandendael

Wranz

Cervical cytology in menopausal women at high risk for endometrial disease. Eur. J. Cancer Prev. 7(2), 149–152 (1998).

89.

Tulandi

Ferenczy

. Biopsy of uterine leiomyomata and frozen section before laparoscopic morcellation. J. Minim. Invasive Gynecol. 21(5), 963–966 (2014).

90.

Huang

Chang

Huang

. Iatrogenic parasitic myoma: a case report and review of the literature. Taiwan J. Obetet. Gynecol. 53(3), 392–396 (2014).

91.

Kho

Anderson

Nezhat

. Intracorporeal electromechanical tissue morcellation: a critical review and recommendations for clinical practice. Obstet. Gynecol. 124, 787–93 (2014).

92.

Yustein

. Meeting Material of the Obstetrics and Gynecology Devices Panel. Additional data: power morcellators and specimen bags. www.fda.gov.

93.

Rassweiler

Stock

Frede

Organ retrieval systems for endoscopic nephrectomy: a comparative study. J. Endourol. 129(4), 325–333 (1998).

94.

Eichel

Abdelshehid

Lee Di

In vitro comparison of burst tension and puncture pressure in commonly used organ retrieval bags. J. Am. Coll. Surg. 199(1), 166–169 (2004).

95.

Cohen

Greenberg

Wang

Risk of leakage and tissue dissemination with various contained tissue extraction (CTE) techniques: an in vitro pilot study. J. Minim. Invasive Gynecol. 21(5), 935–939 (2014).

96.

Serur

Lakhi

. Laparoscopic hysterectomy with manual morcellation of the uterus: an original technique that permits the safe and quick removal of a large uterus. Am. J. Obstet. Gynecol. 204(6), 566. e1–2 (2011).

97.

Cohen

Einarsson

Wang

Contained power morcellation within an insufflated isolation bag. Obstet. Gynecol. 124(3), 491–497 (2014).

98.

McKenna

Kanade

Choi

The Sydney Contained In Bag Morcellation technique. J. Minim. Invasive Gynecol. 21(6), 984–985 (2014).

99.

Favero

Anton

Silva e Silva

Vaginal morcellation: a new strategy for large gynecological malignant tumor extraction: a pilot study. Gynecol. Oncol. 126(3), 443–447 (2012).

100.

Montella

Riboni

Cosma

A safe method of vaginal longitudinal morcellation of bulky uterus with endometrial cancer in a bag at laparo. scopy. Surg. Endosc. 28(6), 1949–1953 (2014).

101.

Dvorak

. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1959 (1986).

102.

Demicheli

Retsky

Hrushesky

WJM

The effects of surgery on tumor growth: a century of investigations. Ann. Oncol. 19, 1821–1828 (2008).

103.

Hofer

SOP

Molema

Hermens

AEC

The effect of surgical wounding on tumour development. Eur. J. Surg. Oncol. 25, 231–243 (1999).

104.

Oduyebo

Rauh-Hain

Meserve

The value of re-exploration in patients with inadvertently morcellated uterine sarcoma. Gynecol. Oncol. 132, 260–365 (2014).

105.

The authors provide their retrospective experience with surgical re-exploration following morcellation of occult leiomyosarcoma and STUMP. They recommend all patients undergo formal staging for purposes of prognostication.

106.

Rowland

Lesnock

Edwards

Occult cancer in patients undergoing laparoscopic hysterectomy with morcellation. Gynecol. Oncol. 127(1), S29 (2013).

107.

Einstein

Barakat

Chi

Management of uterine malignancy found incidentally after supracervical hysterectomy or uterine morcellation for presumed benign disease. Int. J. Gynecol. Cancer 18, 1065–1070 (2008).

108.

In this retrospective case series, the authors outline their institutional experience with re-exploration after unanticipated finding of malignancy following morcellation following supracervical hysterectomy. They estimate that approximately 15% of patients who are re-explored by laparotomy with staging are upstaged.

109.

Berchuck

Rubin

Hoskins

Treatment of uterine leiomyosarcoma. Gynecol. Oncol. 71, 845–850 (1988).

110.

Lissoni

Cormio

Bonazzi

Fertility-sparing surgery in uterine leiomyosarcoma. Gynecol. Oncol. 70, 348–350 (1998).

111.

Davis

. Myomectomy: surgical technique and results in a series of 1,150 cases. Am. J. Obstet. Gynecol. 63(3), 592–604 (1952).

112.

Van Dinh

Woodruff

. Leiomyosarcoma of the uterus. Am. J. Obstet. Gynecol. 144, 817–823 (1982).

113.

Comio

Loizzi

Carriero

Conservative management of uterine leiomyosarcoma: report of a failure. Eur. J. Gynaecol. Oncol. 30(2), 206–207 (2009).

114.

Park

Kim

The impact of tumor morcellation during surgery on the prognosis of apparently early uterine leiomyosarcoma. Gynecol. Oncol. 122, 255–259 (2011).

115.

The authors quantify the adverse effect of morcellation on otherwise early-stage uterine leiomyosarcoma using best available data.

116.

Salman

Guler

Kucukali

Fertility-sparing surgery for low-grade uterine leiomyosarcoma with subsequent pregnancy. Int. J. Gynaecol. Obstet. 98(2), 160–161 (2007).

117.

Hagemann

LiVolsi

Risk of occult malignancy in morcellated hysterectomy: a case series. Int. J. Gynecol. Pathol. 30(5), 476–483 (2011).

118.

Pritts Parker

Brown

Outcome of occult uterine leiomyosarcoma after surgery for presumed uterine fibroids: 944 a systematic review. J. Minim. Invasive Gynecol. 22(1), 26–33 (2014).

119.

In this systematic review, the authors attempt to address whether (1) en bloc removal of an intact uterus improves recurrence rates and survival in instances of occult leiomyosarcoma and (2) to quantify differences in outcome between women with leiomyosarcoma who undergo morcellation by electromechnical versus other means. The analysis is restricted to patients undergoing hysterectomy for presumed uterine fibroids.

120.

George

Barysauskas

Serrano

Retrospective cohort study evaluating the impact of intraperitoneal morcellation on outcomes of localized uterine leiomyosarcoma. Cancer 120(2), 3154–3158 (2014).

121.

Park

Kim

The impact of tumor morcellation during surgery on the outcomes of patients with apparently early low-grade endometrial stromal sarcoma of the uterus. Ann. Surg. Oncol. 18, 3453–3461 (2011).

122.

The authors quantify the adverse effect of morcellation on otherwise early-stage uterine endometrial stromal sarcomas using best available data.

123.

Morice

Rodriguez

Rey

Prognostic value of initial surgical procedure for patients with uterine sarcoma: analysis of 123 patients. Eur. J. Gynaecol. Oncol. 24(3–4), 237–240 (2003).

124.

Favero

. Response to vaginal morcellation: a new strategy for large gynecological malignant tumors extraction – a pilot study. Gynecol. Oncol. 128(1), 151 (2013).

125.

Ota

Huang

Sicam

Unusual trocar site metastasis in a uterine leiomyosarcoma after laparoscopic hysterectomy. J. Minim. Invasive Gynecol. 19(2), 252–254 (2012).

126.

Clark

Thomas

. Portsite recurrence after laparoscopy for staging of retroperitoneal sarcoma. Surg. Laparosc. Endosc. Percutan. Tech. 13(4), 290–291 (2003).

127.

Walker

Piedmonte

Spirtos

Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. J. Clin. Oncol. 27, 5331–5336 (2009).

128.

Ndofor

Soliman

Schmeler

Rate of portsite metastasis is uncommon in patients undergoing robotic surgery for gynecologic malignancies. Int. J. Gynecol. Cancer 21(5), 936–940 (2011).

129.

Rindos

Curry

Tabbara

Port-%site metastases after robotic surgery for gynecologic malignancy. JSLS 18(1), 66–70 (2014).

130.

Wittich

Mearadji

Marquet

Irrigation of port sites: prevention of post site metastases. J. Laparoendosc. Adv. Surg. Tech. 14(3), 125–129 (2004).

131.

Society of Gynecologic Oncologists. SGO position statement: morcellation. www.sgo.org.

132.

Jones

. Meeting Material of the Obstetrics and Gynecology Devices Panel. Quantitative assessment of risks of uterine power morcellation. www.fda.gov.

133.

Food and Drug Administration. Laparoscopic uterine power morcellation in hysterectomy and myomectomy: FDA safety communication. www.fda.gov.

134.

Food and Drug Administration. UPDATED laparoscopic uterine power morcellation in hysterectomy and myomectomy: FDA safety communication. www.fda.gov.

135.

American Association of Gynecologic Laparoscopists. AAGL statement to the FDA on power morcellation. www.aagl.org/.

136.

American College of Obstetricians and Gynecologists. www.acog.org.

137.

Society of Gynecologic Surgeons. Special report. https://sgs.memberclicks.net.

138.

American Urogynecologic Society. AUGS position statement: laparoscopic uterine power morcellation in hysterectomy and myomectomy FDA safety communication and ACOG special report. www.augs.org.

139.

Ton

Killic

Phelps

. A medicolegal review of power morcellation in the face of the recent FDA warning and litigation. J. Minim. Invasive Gynecol. 22(4), 564–572 (2015).

140.

Rosenbaum

. Medical errors, medical negligence, and professional liability reform. Public Health Rep. 118, 272–274 (2003).