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Case Presentation
A female patient in her early 40s presented to OBGYN as a new clinic consultation for a history of uterine leiomyomas with menorrhagia and iron deficiency anemia. Her examination noted an enlarged 30-week irregular uterus with a normal cervix; no other abnormality was palpable. Past surgical history was significant for an open abdominal myomectomy 8 years previously and an appendectomy 14 years previously. She had undergone a negative upper and lower gastro-intestinal endoscopy 3 months prior to this evaluation due to symptoms of gastro-esophageal reflux and constipation. No significant medical or family history was noted. Her body mass index was 44 kg/m2. Work-up included endometrial biopsy showing secretory endometrium with no neoplastic findings. Ultrasound noted 22.4×10.8×13.3 cm uterus with innumerable leiomyomas consistent with the physical examination. A contrast CT scan of the abdomen and pelvis was performed.
Dr Longo
The CT imaging showed an irregular 22.8×12×14.2 cm uterus with numerous intra-uterine masses ranging from 6 cm to 1 cm in size, consistent with possible leiomyomas. In addition, extensive enhancing peritoneal as well as mesenteric nodularity was worrisome for carcinomatosis (Figure 1). The nodularity was enhancing on the contrast phase along with stranding noted in the small bowel mesentery. The majority of the lesions were clustered in the pelvis and right lower quadrant; no significant upper abdominal or intra-parenchymal lesions were noted. A small amount of ascites was seen. The ovaries were not well visualized, but no cystic ovarian or other pelvic lesions were noted. Other than the uterus, no other obvious primary site was noted, with differential for the carcinomatosis including primary peritoneal carcinoma, unknown primary and metastatic leiomyosarcoma. An MRI of the pelvis with and without contrast was recommended for further evaluation along with referral to gynecologic oncology.
CT findings including enlarged uterus with leiomyomas and suspicion for carcinomatosis.
Dr Longo
MRI images again showed a markedly enlarged uterus measuring approximately 22.1×12.6×15.6 cm. Numerous uterine lesions compatible with leiomyomas were seen. They were round with distinct borders. The endometrium was obscured. No infiltrative process was seen. The ovaries were not clearly visualized, and no cystic masses were seen in the pelvis. Some of the leiomyomas showed an internal T1 hypointense/T2 hyperintense signal suggestive of degeneration, and some were hypoenhancing with the largest leiomyoma measuring 7.4×6.2 cm. Typical features of leiomyosarcoma including irregular borders, presence of restricted diffusion, and hemorrhage (increased T1-weighted signal intensity) were absent. There was a lobulated and nodular appearance of the peritoneal surfaces with multiple loculated fluid collections scattered throughout the abdomen and pelvis similar to CT findings compatible with carcinomatosis. No lymphadenopathy was noted. Overall, in addition to uterine fibroids, a separate disseminated process such as primary peritoneal carcinoma was favored to be the origin of the carcinomatosis ( Figure 2 ).
MRI findings including enlarged uterus with increased enhancement/nodularity in the mesentery and free fluid.
Gynecologic oncology evaluation included a tumor marker panel of which only CA 125 was abnormal (66 U/mL). A request for image-guided paracentesis and biopsy was made but deemed not feasible by radiology due to the scant amount of fluid and risk of bowel injury.
Dr Zaid: At this point, what was the differential diagnosis and what was the recommendation to the patient?
Given the elevated CA 125 with evidence of carcinomatosis, there was concern for a disseminated intra-abdominal malignancy. The primary source was questionable on radiologic imaging and the differential included gynecologic epithelial malignancies either of primary peritoneal or adnexal origin, in addition to disseminated smooth muscle neoplasms of the uterus including leiomyosarcoma. A synchronous metastatic gastrointestinal neoplasm was considered less likely given prior appendectomy and recent negative upper and lower gastro-intestinal endoscopy.
The patient was offered surgical exploration with a plan for total abdominal hysterectomy, frozen section evaluation, and possible tumor reduction as she was not seeking future fertility. She did request to retain ovarian function if the oncologic outcome was not compromised. On open surgical exploration, extensive involvement of the pelvic and abdominal cavity with innumerable solid rubbery nodules was noted ( Figure 3 ). This was not amenable to complete resection but was biopsied. The frozen section showed a bland smooth muscle neoplasm suggestive of leiomyomatosis. The patient underwent a total abdominal hysterectomy, bilateral salpingectomy, and omentectomy ( Figure 4 ). The right ovary was heavily involved and thus excised, while the left was left in situ after transposition to the paracolic gutter. The operative time was 100 min with blood loss of 200 mL. She had an uncomplicated recovery and was discharged home on post-operative day 3.
Intra-operative findings of abdominal disseminated disease.
Gross specimen morphology including uterus and omentum.
Dr Faroussi and Dr Deavers
The final pathology noted low-grade smooth muscle neoplasms involving all specimens, including the uterus. Histologic characteristics included no coagulative tumor cell necrosis or significant atypia, with focally increased mitotic activity >10 HPF in some nodules ( Figure 5 ). Immunohistochemical stains showed that tumor cells were ER/PR positive (patchy weak to moderate), p53 was wild type, p16 negative with variable Ki-67 expression. Differential included leiomyomatosis peritonalis disseminate versus low-grade leiomyosarcoma.
Histologic findings showing a representative nodule in the omentum.
Dr. Zaid: Given the findings of possible low-grade leiomyosarcoma, would you consider adjuvant treatment in the form of chemotherapy? Is there a role for targeted molecular therapy in these patients?
In addition to being very rare, low-grade leiomyosarcoma is a poorly defined clinicopathologic entity. There is significant overlap with the criteria for smooth muscle neoplasms of uncertain malignant potential (STUMP). The reported cases note an indolent course and high response rates to hormonal therapy. Hence, I would not recommend systemic chemotherapy in the adjuvant setting. Unfortunately, uterine smooth muscle neoplasms in general currently lack known druggable molecular targets with approved therapies. The pan TKI inhibitor pazopanib is approved in second-line treatment of high-grade leiomyosarcoma but would not be appropriate in this setting.
The patient was reviewed at a multi-disciplinary tumor board and leiomyomatosis was favored. She was started on oral progestin (megestrol acetate 80 mg twice daily) to be continued until menopause or disease progression, with a plan for imaging and clinical surveillance every 4–6 months.
Closing Summary
Disseminated peritoneal leiomyomatosis is a rare benign proliferation of extra-uterine leiomyomas throughout the peritoneal cavity.1 Approximately 200 cases have been reported in the literature since it was first described in 1952 by Wilson and Peale.2 It has been reported both independently and in association with prior open (as in this case) or minimally invasive myomectomy.3 Morcellation during minimally invasive myomectomy has been implicated as a risk factor, although data are limited to observational case series and case reports.4 5
Histologic findings are similar to intra-uterine leiomyoma with lack of coagulative tumor cell necrosis, significant atypia, and increased mitoses used to differentiate cases from other malignant histologies.6 Similar to uterine leiomyomas, they are usually ER/PR positive with wild type p53 expression and a low Ki-67 index.7 Radiologic distinction from malignant carcinomatosis may be difficult, as in this case, due to similarity with other diffuse neoplastic abdominal processes.8 MRI is useful to evaluate the presence of leiomyosarcoma as a differential.9
First-line treatment is typically surgical, but complete cytoreduction as in this case may not be feasible. Despite lack of high-quality data due to its rarity, hormonal treatment with a progestin or anti-estrogen agent is typically recommended to prevent recurrence, or for residual or relapsed disease not amenable to surgery.4 8 Unfortunately, no data are available to indicate the response rate of any single agent in this setting. Data from case reports note that successful treatment has been observed with oral progestins,10 aromatase inhibitors,11 and GnRH agonists.12 Hormonal suppression via oophorectomy can also be considered in select patients who cannot tolerate medical therapy.
Both clinical and radiologic surveillance is recommended as recurrences have been reported as far as 5 years from initial diagnosis.13 Interval and duration are extrapolated from customary practices associated with other smooth muscle uterine neoplasms (every 3–6 months for 5 years). If a recurrence is suspected, biopsy confirmation is advised to confirm histology, rule out progression to a higher-grade lesion, and obtain tissue for additional studies.7 For localized/resectable disease, surgical excision is both therapeutic and diagnostic. If a recurrence is confirmed, treatment with an alternate hormonal therapy is usually considered either after surgery or if resection is not feasible, although no consensus guidelines are available to guide the choice of agent.14 Treatment of unresectable disease resistant to hormonal treatment is particularly challenging, and individualized treatment based on the tumor molecular profile can be considered15 in addition to systemic chemotherapy.13
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Footnotes
Contributors KD: Preparation of manuscript draft, collection of case data. TZ: Final review and editing of manuscript, reference preparation; preparation of images and figures. EL: Interpretation of radiologic images, commentary in radiology section of presentation. SF and MD: Interoperation pathology and IHC data from case; commentary in pathology section of presentation.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.