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An Introduction to Uterine Leiomyosarcomas

Uterine sarcomas are a rare and aggressive form of uterine cancer. They arise from the endometrial lining or the myometrium in the uterus. Compared to the more common endometrial carcinomas, uterine sarcomas behave more aggressively and are associated with a poorer prognosis.

In this review, we shall focus on one subset - uterine leiomyosarcomas (ULMS), although it is noteworthy to mention that leiomyosarcoma can arise from other gynecological primary sites. ULMS are rare smooth muscle tumors accounting for approximately 1% of patients with uterine cancer1 with an estimated annual incidence of 0.64 per 100,000 women.2 ULMS are considered neoplasms of high metastatic potential with 5-year overall survival rates varying between 0 and 73%.3-5 These discrepancies may be attributable to inconsistent definitions and variable sample sizes for diagnostic criteria. Additionally, this adds to the dilemma of addressing survival rates given the variable time periods of these studies.

ULMS occur primarily in women 40 to 60 years of age. The most frequent presenting symptoms are abnormal vaginal bleeding and pelvic or abdominal pain. The amount of bleeding ranges from spotting to menorrhagia and is often associated with foul-smelling vaginal discharge. Less common symptoms include weight loss, weakness, lethargy, and fever.5-7 On pelvic examination, the uterus is often enlarged, and in some cases part of the tumor may prolapse through the cervical os and into the vaginal canal. Diagnosis is usually not made before surgery, thus many patients present with advanced disease.

ULMS Figure 1

Figure 1: A uterus has been cut showing a large, soft leiomyosarcoma...

The rarity of these tumors has prevented the performance of large epidemiological studies to identify risk factors. Data regarding parity, onset of menarche, or age at menopause as risk factors are inconclusive. Based on available United States data, there is approximately a two- to three-fold higher incidence of ULMS among African-American women compared to Caucasian women.2,8,9 A history of pelvic irradiation is noted in 5-10% of patients.10

Benign leiomyomas (fibroids) and ULMS often coexist in the same uterus, but are genetically distinct entities. ULMS are much less common and not hormonally driven. See Figure 1 and Table 1.

Table 1: Gross pathological comparison of 
Leiomyoma and Leiomyosarcoma
Leiomya Leiomyosarcoma
Usually multiple
Often solitary
Variable size, usually 3-5cm
Large, often >10cm
Firm, whorled surface
Soft, fleshy cut surface
White
Yellow or tan
Hemorrhage and necrosis infrequent
Hemorrhage and necrosis frequent

The belief that the risk of ULMS is elevated among women with a "rapidly growing" uterus or leiomyoma was proven false in a study of 1322 women admitted to two community hospitals for hysterectomy or myomectomy. Fibroids rarely, if ever, degenerate into ULMS.12

Classification

Tissues and Cells

These sites will help readers to better understand this article: The Tissues of the Human Body and Inside the Cell

The Gynecologic Oncology Group (GOG) uses a classification scheme for uterine sarcomas that divides them into five categories:

  • Mixed homologous mullerian sarcoma
  • Mixed heterologous mullerian sarcoma
  • Leiomyosarcoma
  • Endometrial stromal sarcoma
  • Other

ULMS Figure 2

Figure 2: Cut surface of this leiomyosarcoma showing...

Homologous refers to similarity to endometrial stroma or myometrium, while heterologous indicates similarity to other cell types, including fat, muscle, etc. Malignant mixed mullerian tumors, now called carcinosarcomas, arise from endometrial adenocarcinoma, but resemble sarcoma on histology.

The typical gross appearance is a large (>10cm), poorly circumscribed mass with a soft, fleshy consistency and a variegated cut surface that is grey-yellow to pink, with foci of hemorrhage and necrosis.13 The histologic classification of uterine sarcomas is based upon homology to normal cell types and include ULMS (analogous to myometrium), stromal sarcoma (analogous to endometrial stroma), and other heterologous cell types (i.e., osteosarcoma, liposarcoma). See Figures 2 and 3.

ULMS Figure 3

Figure 3: Cut surface of this leiomyoma with infarction...

Microscopically, most ULMS are overtly malignant, with hypercellularity, coagulative tumor cell necrosis, abundant mitoses (>10 to 20 mitotic figures (mf) per 10 high power fields (hpf)), atypical mitoses, cytologic atypia, and infiltrative borders. Mitotic rate is the most important determinant of malignancy, but is modified by the presence of necrosis and cytologic atypia. The diagnosis of ULMS may be made in the presence of tumor necrosis and any mitoses. In the absence of tumor necrosis, the diagnosis can be made with moderate to severe cytologic atypia and a mitotic index greater than 10mf/10hpf. Without tumor necrosis and significant atypia, a high mitotic index is compatible with a benign clinical course, however, data is limited.14 See Definitions Sidebar. See Figures 4, 5, and Table 2.

ULMS Figure 4

Figure 4: Tumor necrosis consists of ghosts (no nuclei) of tumor...

One study looked at the expression of particular markers that are of interest in gynecological cancers (p53, Epidermal Growth Factor, and Platelet Derived Growth Factor) in tissue samples from patients who had ULMS or benign leiomyomas. Their data demonstrated significant and molecular differences between benign and malignant smooth muscle tumors of the uterus. The study also suggested a prognostic interrelationship between expression of p53 and stage in ULMS.15

A subset of smooth muscle tumors will not be easily classified based on the criteria and are designated as smooth muscle tumors of uncertain malignant potential (STUMP). The literature is unresolved on whether special studies such as proliferation index or stains for p53 add to the discriminating power of the basic criteria of mitoses, necrosis and cytologic atypia in determining the malignant potential of STUMP lesions. In practice, however, these stains are uncommonly used, and definitive diagnosis of sarcoma is never reported based on these stains alone.16,17

ULMS Figure 5

Figure 5: Mitosis (center of slide)....

Limited data has allowed some tumors, formerly classified as STUMP, into the leiomyoma category and should be distinguished from their sarcomatous counterparts.

Tumors now in the leiomyoma category include: mitotically active, cellular, epithelioid, myxoid, atypical (pleiomorphic, bizarre, or symplastic) tumors. Mitotically active leiomyomas can occur in pre-menopausal women and have the typical macroscopic and histologic appearance of a leiomyoma with the exception that they have > 5mf/hpf. Cellular leiomyomas tend to have hypercellularity and can suggest the diagnosis of ULMS, but they lack tumor cell necrosis, cytologic atypia and mitotic figures. Epithelioid leiomyomas are yellow or grey and may contain visible areas of hemorrhage and necrosis, and tend to be solitary and softer than the usual leiomyoma. Myxoid leiomyomas have myxoid material separating the tumor cells. They are soft and translucent with circumscribed margins with neither cytologic atypia nor mitotic figures. Atypical leiomyomas lack all the other components with the exception of atypia and have little recurrence potential.14 See Figure 6.

Table 2: Diagnostic Criteria for LMS, 
Adapted from 2003 WHO Guidelines14
  Standard smooth muscle Differentiation Epithelioid differentiation Myxoid differentiation
Histology Cigar-shaped spindled cells with scanty to abundant eosinophilic cytoplasm Rounded cells with central nuclei, and clear to eosinophilic cytoplasm Spindle shaped cells set within an abundant myxoid matrix
Criteria for LMS Any coagulative tumor cell necrosisIn the absence of tumor cell necrosis, the diagnosis required diffuse, moderate to severe cytological atypia and a mitotic index of > 10mf/10hpf*. If the mitotic index is < 10mg/10hpf, the chance of recurrence is low (less than 2-3%). In the absence of coagulative tumor cell necrosis and significant atypia, a high mitotic index is compatible with a benign clinical course. *mf/hpf = mitotic figures/high power fields Any coagulative tumor cell necrosis In the absence of tumor cell necrosis, the diagnosis requires diffuse, moderate to severe cytological atypia and a mitotic index of >5mf/10hpf. Any coagulative tumor cell necrosis In the absence of tumor cell necrosis, the diagnosis requires diffuse, moderate to severe cytological atypia and a mitotic index of >5mf/10hpf.

ULMS Figure 5

Figure 6: Atypia is seen...

Unlike smooth muscle tumors at other sites, uterine smooth muscle tumors are generally not graded. Rather, clinical behavior is defined by the designation to categories of ULMS, leiomyoma, or STUMP. The distinction is important since grading ULMS based on criteria at other body sites is misleading.

Diagnostic Evaluation

Patients with abnormal uterine bleeding or a suspicious uterine lesion should undergo endometrial sampling. Imaging studies and/or clinical findings are not specific for ULMS versus other uterine tumors. Ultrasound examination, magnetic resonance imaging (MRI), or computed tomography (CT) do not reliably distinguish between sarcoma, leiomyoma, endometrial cancer, lymphoma, intravenous leiomyomatosis, or adenomyosis.18

MRIs and Diagnosis

The utility of MRI for diagnosis is being addressed in case reports. Contrast resolution in soft tissues (better than ultrasonography) and lack of ionizing radiation show great promise as an imaging tool to evaluated LMS. The findings of atypical degeneration with irregular contours should bring LMS into the differential when evaluating leiomyomas (or other pelvic masses).19-21 One study looked at patients (including nine patients with pathologically proven LMS and three with STUMP) in order to study the magnetic resonance characteristics of non-benign uterine smooth muscle tumors. Additionally, they analyzed twelve cases of benign leiomyomas in which the gynecologists had suspected LMS. Size, location, signal intensity, and contrast enhancement of the tumors were studied on an individual basis. With some exceptions, the authors concluded that more than 50% of high signal on T2-weighted images and the presence of any small high-signal areas on T1-weighted images with un-enhanced pockets were considered MRI suggestive for STUMPS and LMS.22

Staging

Staging is based on surgical, not clinical findings. Extensive local growth is a hallmark of ULMS and spread of these tumors occur by local, lymphatic, and hematogenous routes (see Figure 2). Metastasis frequently involves the lung. If the diagnosis of ULMS is known preoperatively, chest imaging is necessary to evaluate for metastatic disease.

Surgical staging for ULMS is the same as for endometrial carcinoma (see Figure 7). The surgery includes peritoneal washings for cytology, extrafascial total abdominal hysterectomy, bilateral salpingo-oophorectomy, removal of enlarged lymph nodes, and biopsy or any suspicious areas. Some oncologists recommend omentectomy and pelvic and paraaortic lymph node sampling. See Figure 7.

Figure 7: The International Federation of Gynecology 
and Obstetrics (FIGO) Staging of ULMS
Stage I Tumor confined to corpus uteri 
IA Tumor limited to the endometrium 
IB Tumor invades up to or less than 50% of the myometrium 
IC Tumor invades more than 50% of the myometrium 

Stage II Tumor invades cervix but does not extend beyond uterus 
IIA Endocervical glandular involvement only 
IIB Cervical stroma invasion 

Stage III Local and/or regional spread 
IIIA Tumor involves uterine serosa and/or adnexa (direct extension or metastasis) 
IIIB Vaginal involvement (direct extension or metastasis) 
IIIC Metastasis to the pelvic and/or para-aortic lymph nodes 

Stage IV 
IVA Tumor invades the bladder mucosa and/or bowel mucosa 
IVB Distant metastasis(excluding metastasis to vagina, pelvic serosa, or adnexa. Including metastasis to intra-abdominal lymph nodes other than para-aortic, and/or inguinal lymph nodes) 

LMS should be grouped with regard to the degree of differentiation as follows: 
G1 5 percent or less of a nonsquamous or nonmorular solid growth 
G2 6 percent to 50 percent of a nonsquamous or nonmorular solid growth 
G3 More than 50% of a nonsquamous or nonmorular solid growth

The importance of lymph node dissection is controversial.23 Though the involvement of lymph nodes is of prognostic significance, lymphadenectomy has not been shown to be therapeutic. Outcomes have been comparable among similarly staged patients who did or did not undergo lymphadenectomy.23 Based on these results, most perform lymph node dissection only in patients with clinically suspicious nodes. Patients with ULMS confined to the uterus have a low risk of occult nodal disease (2.4%).24 When ULMS is diagnosed postoperatively, re-exploration for surgical staging is probably unnecessary since this risk of metastasis to lymph nodes and beyond is minimal.

Ovarian conservation may be an option for premenopausal women who wish to retain ovarian function. Two studies have suggested that retention of the ovaries may not adversely affect prognosis in women with Stage I ULMS.23 Informed consent as to the uncertainty of outcome with conservative surgery and close follow-up is clearly needed.

Treatment for Localized Disease

Surgical treatment

At a minimum, surgical treatment of a patient with a ULMS of the uterus should include a total hysterectomy and removal of the cervix.

Adjuvant radiotherapy

The benefit of postoperative adjuvant radiotherapy (RT) in ULMS is unclear. The European Organization for Research and Treatment of Cancer (EORTC) randomly assigned 222 patients with stage I or II uterine sarcoma (including 103 patients with ULMS) to pelvic external beam radiation or observation. The preliminary report in 2003 suggested a lower rate of local recurrence in the irradiated group but no improvement in overall survival.25

Retrospective studies provide conflicting data. Most studies that group all uterine sarcomas together note better pelvic control with adjuvant RT. In GOG protocol 20, women with stage I or II uterine sarcoma were randomized to a trial of adjuvant doxorubicin with or without adjuvant RT. The majority of these patients had carcinosarcoma. Results showed that the irradiated group of patients had a significantly lower rate of pelvic failure, but no improvement in overall survival.26 Smaller retrospective studies suggest the possibility of a survival benefit as well as an improvement in local control.27-30 The largest series evaluated 103 women with stage I-IV uterine sarcoma (42% ULMS) who received RT at the discretion of their physician. Irradiated patients had a significantly better five-year pelvic control (76% versus 36%) and overall survival (73% versus 37%). The significance of improved survival and pelvic control remained in multivariate analysis after controlling for stage, histology, tumor grade, and presence of lymphvascular invasion.29

A major obstacle with ULMS is that even if pelvic control is achieved, the majority of women develop distant extraabdominal metastases.31

Guidelines from the National Comprehensive Cancer Network (NCCN) suggest that adjuvant RT can be considered for all women with resected stage I or stage II ULMS. For stage III ULMS with positive lymph nodes, the NCCN recommends consideration of adjuvant chemotherapy and pelvic RT, vaginal brachytherapy, and/or adjuvant chemotherapy.32

NCCN: The National Comprehensive Cancer Network

NCCN is an alliance of twenty cancer centers that work together to, among other things, develop treatment guidelines for most cancers. NCCN is also dedicated to research that improves the quality, effectiveness, and efficiency of cancer care. The NCCN Clinical Practice Guidelines in Oncology™ are viewed by many as the standard for clinical policy. See the article, Options and Follow-up Care for Women with Uterine Sarcomas, by Suzie Siegel which appeared in ESUN.

The use of RT needs to be balanced with the negative effects of therapy. Short term or immediate side effects include vaginal bleeding, vaginal discharge, skin reactions, hair loss, urinary problems, diarrhea and pain. Long term side effects include changes in bowel/bladder function and sexual function.

Adjuvant Chemotherapy

With the high rate of distant metastatic spread in ULMS, adjuvant systemic therapy is controversial. Some observational studies suggest a benefit,33, 34 while most do not.32 35-38 To date, no prospective studies are available that focus on patients with ULMS, and there is no definitive evidence that adjuvant chemotherapy improves overall survival. Therefore, it cannot be recommended as the standard of care, and should be considered in individual circumstances.

Three observational studies suggest that the combined use of postoperative RT and chemotherapy may provide benefit after resection of uterine sarcoma. Two of the studies involved patients with carcinosarcomas. The third study had 41 patients with uterine sarcoma who received either pelvic RT or RT plus adjuvant chemotherapy. Three-year survival rates were significantly better in the chemotherapy group (66% versus 36%).39

Neoadjuvant chemotherapy can be used to improve respectability of advanced disease, in the appropriate setting. The data is limited, at best.

Treatment for Recurrent, Advanced or Metastatic Disease

Surgery

Recurrent ULMS is diagnosed by the new development of symptoms. Most relapses occur in the pelvis, followed by the lung and abdomen. Bone and brain metastases are uncommon.23 Surgical resection should be considered in patients with localized single foci recurrences, either local or metastatic. In a report of 41 women who underwent resection for recurrent uterine ULMS (29% pulmonary, 41% pelvis), two-year survival was 71 percent among those who had a disease-free interval between resection of the primary and the development of metastatic disease of 12 months or longer.40-42 In a study evaluating metastatic disease, Lenvenback et al showed that 71% had unilateral lesions, 51% had one lesion, and 70% had nodules greater than 2 cm. After pulmonary resection, unilateral versus bilateral disease was a significant predictor of survival (p = 0.02). Size, number of metastases, disease-free interval, and patient age were not significant.42

With regard to Radiofrequency Ablation (RFA) and Video Assisted Thoracic Surgery (VATS), there is limited literature on sarcomas and more studies are needed prior to recommendations.

Radiofrequency Ablation (RFA) and Video Assisted Thoracic Surgery (VATS)

There are a few case reports in the literature of RFA and VATS for metastatic lesions to the liver and lung. Most of these studies have small numbers and, within those, even fewer with lesions from a uterine primary. Nevertheless, these approaches provide an alternative local therapy for metastatic lesions, and more studies will be needed to establish its role in LMS.43-47

Chemotherapy

Though unproven in the adjuvant setting, single agent doxorubicin is an effective drug for advanced ULMS. Objective response rates are between 16 and 25 percent, lasting generally less than 6 months.48-52

Two randomized trials have examined the benefit of doxorubicin single agent therapy versus in combination. Doxorubicin alone was compared to doxorubicin plus cyclophosphamide. Response rates were similar in both arms for patients with measurable disease (19%), as was the progression-free and median overall survival (median 11.6 versus 10.9 months).49

The second trial compared doxorubicin with and without dacarbazine. Although combined therapy was associated with a significantly higher response rate overall, there were no significant differences between the two groups in terms of progression-free survival or overall survival (7.7 versus 7.3 months). Combination therapy was associated with more hematologic and gastrointestinal toxicity.48

Ifosfamide has limited activity as a single agent with a response rate of 17%.53 Its combination with doxorubicin increased the objective response but added substantial toxicity.54,55

The combination of gemcitabine and docetaxel is the most effective chemotherapy regimen for ULMS patients with advanced disease described to date. In one report, patients with unresectable uterine or other primary site ULMS received gemcitabine plus docetaxel and granulocyte colony stimulating factor. Of the 34 patients in the study, complete response was seen in 3 patients and partial response in 15, for an overall response rate of 53%. Seven patients had stable disease. Despite the use of granulocyte colony stimulating factor, grade 3 or 4 neutropenia and febrile neutropenia developed in 21 and 6 percent, respectively. The toxicity profile was otherwise mild.53 A second series with 35 patients reported 7 of 12 patients (2 with ULMS) had a response.56

To date, there has not been a phase III trial comparing doxorubicin plus ifosfamide versus gemcitabine plus docetaxel. Historical comparison shows at least equivalent response, with improved toxicity with gemcitabine plus docetaxel. Therefore gemcitabine plus docetaxel can be considered for first line use in the appropriately selected patient.

Temozolomide is also modestly active. In an observational series with 12 patients (most of whom had received two prior chemotherapy regimens), one patient had a prolonged partial response and one a near complete response after 13 months.57 In a second study, responses were seen in 5 of 11 patients with gynecologic ULMS.58 Response lasted for longer than one year in four patients.

A potentially new agent being investigated in the treatment of soft tissue sarcomas is Trabectedin (ecteinascidin), or ET-743. It is the active component of extracts from Caribbean tunicate, Ecteinascidia tubinata. ET-743 binds to the guanine residue within the minor groove of DNA causing a bend in the major groove which interferes with the DNA binding proteins and transcription factors in the cancer cell. Several phase II studies have demonstrated some activity in advanced soft tissue sarcomas, including ULMS. Response rates range between 4-17%.59 This drug and its potential future combination with additional active agents will be investigated in a future GOG phase II trials.

Certain uterine tumors are responsive to hormonal therapy because they express estrogen and/or progesterone receptors. However, this is not the case in ULMS and adjuvant hormonal therapy is not recommended for any stage of ULMS.

Patients with metastatic ULMS have limited options with regards to chemotherapy and enrollment in clinical trials is appropriate. Chemotherapy is palliative and should be used to relieve symptoms. Options include single agent doxorubicin, doxorubicin and ifosfamide, single agent gemcitabine, and gemcitabine and docetaxel. Considering that there is no survival benefit with our current chemotherapeutic options, toxicity versus symptom management should be evaluated on a case by case basis with full informed consent.

Summary and Recommendations

ULMS are rare tumors with a limited body of literature to help guide treatment. Patient care should be individualized. Further investigation is needed to improve the treatment options for our patients with this disease.

Surveillance32

  • Physical exam every 3 months for 2 years, then every 6-12 months.
  • Chest imaging every 3-6 months for 2 years, then annually.
  • CT/MRI as clinically indicated.
  • Patient education regarding symptoms.

Surgical

  • Extrafascial total abdominal hysterectomy with bilateral salpingo-opherectomy and formal surgical staging.
  • Fertility-sparing in young women who wish to preserve childbearing potential with low grade ULMS may be considered.

Adjuvant Therapy

  • RT appears to improve local control while it is unclear whether it provides survival benefits. Adjuvant chemotherapy is of uncertain benefit.

Questions, Comments & Counterpoints

Two letters about this article

We have received two letters regarding this article. The first letter was received from Dr. Ian Judson of Royal Marsden Hospital, London, and reads:

To the authors: This is an excellent and comprehensive review of a highly aggressive sarcoma and it is important that awareness be drawn to this disease entity. However, I would caution against the blanket statement that ULMS is unresponsive to oestrogen. I know of cases of ULMS that express oestrogen and progesterone receptors and have responded to oestrogen withdrawal measures. It has been assumed that this phenomenon is restricted to low grade endometrial stromal sarcoma. This appears not to be the case and there are grounds for believing that pathologists should examine all ULMS cases for ER and PgR expression. 

The second letter was received from Shirley Collings, a leiomyosarcoma survivor who lives in the UK. It reads:

Dear Bruce and ULMS survivors, 

First of all may I refresh your memories about the article in the ESUN Apr 07 on Uterine Leiomyosarcomas. In particular the three following extracts: "Benign leiomyomas (fibroids) and ULMS often coexist in the same uterus, but are genetically distinct entities. ULMS are much less common and not hormonally driven. "

"Fibroids rarely, if ever, degenerate into ULMS12"

"Certain uterine tumors are responsive to hormonal therapy because they express estrogen and/or progesterone receptors. However, this is not the case in ULMS and adjuvant hormonal therapy is not recommended for any stage of ULMS." 

I am sure I speak for a number of women on this and the Sarcoma UK lists, who disagree vehemently with these three statements. Through personal experience with diagnoses from fibroids, ER/PR positivity and subsequent treatment with aromatase inhibitors many of us can prove these statements wrong. I am shocked and disappointed that four such eminent doctors can attach their names publicly to these misleading statements in an otherwise very interesting article. 

Bruce, would you kindly contact Drs Gosh, Hecht, Ferzandi and Awtry and ask them if they would be willing to respond to and comment on this email in the next edition of ESUN.

The Authors' Reply

We thank the Dr. Ian Judson for his thoughts and Mrs. Collings for her passionate comments and offer further data from the literature to clarify the issues raised.

The distinction between benign leiomyomata (fibroids) and smooth muscle sarcomas in the uterus is clear.1 The genetic changes in sarcomas are more complex than in fibroids [many references over 20 years, available on request]. Interestingly, the specific genetic aberration detected may vary from cell to cell suggesting a high level of genomic instability. This instability can also be detected by techniques that measure allelic imbalance such as comparative genomic hybridization, and is not present in benign fibroids.2 Some changes are unique to sarcomas such as a heterozygosity for the long arms of chromosomes 10 and 13 that is found in more than half of sarcomas.

Although hormone manipulation with agents such as leuprolide (a gonadotropin-releasing hormone –GnRH agonist) or aromatase inhibitors (an agent that reduces circulating estrogen) have a clear role in treatment of benign leiomyoma, the response of sarcomas is highly variable, and is not part of the primary therapy offered to women with sarcoma [treatment recommendations for sarcoma based on stage are available at the NCI website].

We could not find publications describing even anecdotal experiences with anti-estrogens for treatment of leiomyosarcoma. We suspect that such options are used when conventional therapy fails. There is no evidence that hormone receptor status correlates with response and those stains are not routinely performed. Rare reponses to antiprogestins has been reported. [Koivisto-Korander R, Leminen A, Heikinheimo O. Mifepristone as treatment of recurrent progesterone receptor-positive uterine leiomyosarcoma. Obstet Gynecol. 2007;109:512-4.]

Many cases of leiomyosarcoma express hormone receptors and the association between hormone receptor expression and sarcoma growth has been examined. The largest study has com from Memorial Sloan-Kettering Cancer Center. They show that the expression of estrogen and progestin receptor was less frequent in uterine sarcoma compared with leiomyoma. Progesterone and androgen receptor expression appeared to be associated with disease-free survival but were not found to correlate with overall survival. [Leitao MM, Soslow RA, Nonaka D, Olshen AB, Aghajanian C, Sabbatini P, Dupont J, Hensley M, Sonoda Y, Barakat RR, Anderson S. Tissue microarray immunohistochemical expression of estrogen, progesterone, and androgen receptors in uterine leiomyomata and leiomyosarcoma. Cancer. 2004 Sep 15;101(6):1455-62.]

Another category of uterine sarcoma, uterine stromal sarcoma, may have some overlap in microscopic appearance and be confused with leiomyosarcoma. In addition, rare sarcomas have mixed differentiation (smooth muscle and stromal). Stromal sarcomas are more likely to express progesterone receptors and progesterone therapy may have some role in treating recurrent stromal sarcomas. [Katz L, Merino MJ, Sakamoto H, et al.: Endometrial stromal sarcoma: a clinicopathologic study of 11 cases with determination of estrogen and progestin receptor levels in three tumors. Gynecol Oncol 26 (1): 87-97, 1987.]

Dr. Judson's Response

Thank you for giving me the opportunity to respond to the comments both of Mrs. Collings and the authors of the review on uterine sarcomas.

Over the last 20 years there has been a gradual change in the approach to the hormonal manipulation of gynecological sarcomas. Progestogens have been used for more than 25 years, to my knowledge, in the management of the rare condition of metastasising leiomyoma, which is really low grade leiomyosarcoma. I first met a patient with the disease who had responded to medroxyprogesterone acetate (MPA) in 1983. She required pulmonary metastasectomy in the 1990s for progressive disease that was no longer responding but remains alive and well. I have other patients with the same condition whose disease fluctuates but remains essentially stable. We recently saw a case of grade I leiomyosarcoma of the vulva that had grown dramatically during pregnancy. Such lesions are acknowledged to be hormonally driven. We know that leiomyosarcomas represent a broad spectrum of malignancy from STUMP to high grade disease. It is assumed that hormonal dependence is lost with increasing grade. While there is no literature on the treatment of frankly malignant leiomyosarcoma with estrogen deprivation therapy, clearly in some cases it can be effective. What is particularly important is that doctors and patients alike should be aware of the potentially detrimental effect of hormone replacement therapy (HRT), suggesting that it might be helpful to know the ER/PgR status of all such tumours.

As acknowledged in the article, the position regarding endometrial stromal sarcoma (ESS) is clearer, although the literature is still sparse. Progestogens used to be the mainstay of hormonal therapy for these tumours. Since the advent of potent aromatase inhibitors it is much more logical, as well as highly effective, to use these agents that are better tolerated and provide a reliable way of reducing oestrogen levels in the menopausal / post-oophorectomy state. A brief review of our own experience of treating metastatic endometrial stromal sarcoma reveals 4 patients with response / prolonged stable disease on MPA, ranging from 4-10 years, 3 patients responding to withdrawal of HRT or oophorectomy lasting 18+months, 3 and 6 years respectively and 6 patients responding to an aromatase inhibitor (usually letrozole) of 1-5 years in duration. Recurrent well-differentiated ESS that expresses ER and PgR can be expected to respond to withdrawal of HRT (which should not be given in the first place), oophorectomy if this has not been performed, or administration of an aromatase inhibitor with a high degree of confidence. Tamoxifen should not be used since it is pro-estrogenic in the uterus and I have seen exacerbation of the disease with this agent.

It would appear that further research is required to address the true response rate of ESS to aromatase inhibitors and to examine their potential role in the treatment of a proportion of less agressive uterine leiomyosarcomas.

The Authors' Closing Reply

We appreciate the depth and insight of Dr. Judson's comments. As Dr Judson mentioned, the literature on this issue is sparse. In this review, we have attempted to outline guidelines for evidence-based standard of care for uterine LMS. We do recognize that in individual cases and case-series, there has been reponse to hormonal therapy, dependent on grade. Although in rare circumstances that the therapy may be indicated, until sufficient data exists, we were careful not to project this as routine treatment. However, the physician has a duty to serve his/her patients with the data available and that the patient must be given full informed consent thereof.

Last revised and medically reviewed: 8/2007

By Sue Ghosh, MD
Clinical Instructor, Department of Obstetrics and Gynecology
Harvard Medical School, Beth Israel Deaconess Medical Center
Boston, Massachusetts

Jonathan L. Hecht, MD, PhD
Assistant Professor of Pathology, Harvard Medical School,
Beth Israel Deaconess Medical Center in Boston, Massachusetts

Tanaz R. Ferzandi, MD, MA
Fellow, Division of Urogynecology
Clinical Instructor, Department of Obstetrics and Gynecology
Harvard Medical School, Mount Auburn Hospital / Beth Israel Deaconess Medical Center
Boston, Massachusetts

Christopher S. Awtrey, MD
Co-Director Minimally Invasive Gynecologic Surgery, Instructor of Obstetrics and Gynecology
Division Gynecologic Oncology, Harvard Medical School, Beth Israel Deaconess Medical
Center Boston, Massachusetts

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15. Anderson SE, Nonaka D, Chuai S, Olshen AB, Chi D, Sabbatini P, Soslow RA. P53, epidermal growth factor, and platelet-derived growth factor in uterine leiomyosarcoma and leiomyomas. Intl J Gynecol Cancer. 16:849-853, 2006.

16. Layfield LJ, Liu K, Dodge R, Barsky SH. Uterine smooth muscle tumors: utility of classification by proliferation, ploidy, and prognostic markers versus traditional histopathology. Arch Pathol Laboratory Med. 124(2):221-7, 2000.

17. Mittal K, Demopoulos RI. MIB-1 (Ki-67), p53, estrogen receptor, and progesterone receptor expression in uterine smooth muscle tumors. Hum Pathology. 32(9):984-7, 2001.

18. Rha SE, Byun JY, Jung SE, et al. CT and MRI of uterine sarcoma and their mimickers. Am J Roentgenol 181: 1369, 2003.

19. Janus C, White M, Dottino P, Brodman M, Goodman H. Uterine Leiomyosarcoma – magnetic resonance imaging. Gynecology Oncology. 1989 Jan 3(1): 79-81.

20. Takemori M, Nishimura R., Sugimura K. Magnetic Resonance Imaging of Uterine Leiomyosarcoma. Arch Gynecol Obstetrics. 1992; 251 (4): 215-218. 21. Pattani SJ, Kier R, Deal R, Luchansky E. MRI of Uterine Leiomyosarcoma. Magnetic Resonance Imaging, 1995; 13 (2): 331-3.

22. Tanaka YO, Nishida M, Tsunoda H, Okamoto Y, Toshikawa H. Smooth muscle tumors of uncertain malignant potential and leiomyosarcomas of the uterus: MR findings. J. Magnetic Resonance Imaging. 2004 Dec; 20(6): 998-1007.

23. Guintoli RL, Metzinger DS, DiMarco CS, et al. Retrospective review of 208 patients with leiomyosarcoma of the uterus: prognostic indicators, surgical management, and adjuvant therapy. Gynecol Oncol 89: 460, 2003.

24. Leitao MM, Sonoda Y, Brennan MF, Barakat RR, and Chi DS. Incidence of lymph node and ovarian metastases in leiomyosarcoma of the uterus. Gynecol Oncol 91: 209, 2003

25. Reed NS, Mangioni C, Malmstrom H, et al. First results of a randomized trial comparing radiotherapy versus observation postoperatively in patients with uterine sarcomas. An EORTCGCG study (abstract) Int J Gynecol Cancer 13: 4, 2003

26. Hornback NB, Omura G, Major FJ. Observations on the use of adjuvant radiation therapy in patients with stage I and II uterine sarcoma. Int J Radiat Onc Bio Phys 12: 2127, 1986.

27. Moskovic E, MacSweeney E, Law M, Price A. Survival patterns of spread and prognostic factors in uterine sarcoma: a study of 76 patients. Br J Radiol 66:261, 1993.

28. Knocke, TH, Kucera H, Dorfler D, et al. Results of postoperative radiotherapy in the treatment of sarcoma of the corpus uteri. Cancer 83: 1972, 1998.

29. Ferrer F, Sabater S, Farrus B, et al. Impact of radiotherapy on local control and survival in uterine sarcomas: a retrospective study from the Group Oncologic Catala-Occita. Int J Radiat Oncol Bio Phys 44:47, 1999.

30. Soumarova R, Horova H, Seneklova Z, et al. Treatment of uterine sarcoma. A survey of 49 patients. Arch Gynecol Obstet 266:92, 2002.

31. Major FJ, Blessing RA, Silverberg SG, et al. Prognostic factors in early-stage uterine sarcoma. A Gynecologic Oncology Group study. Cancer 71: 1702, 1993.

32. The NCCN Guidelines Uterine Cancer. Clinical Practice Guidelines in Oncology (version V.2.2006). www.nccn.org.

33. Soh LT, Chew SH, Ang L. Uterine leiomyosarcoma: a Singapore experience. Aust N Z J Obstet Gynaecol 39:246, 1999.

34. Wu TI, Chang TC, Hsueh S, et al. Prognostic factors and impact of adjuvant chemotherapy for uterine leiomyosarcoma. Gynecol Oncol 21:220, 1985.

35. Nordal RN, Kjorstad KE, Stenwig AE, Trope CG. Leiomyosarcoma (LMS) and Endometrial stromal sarcoma (ESS) of the uterus. A survey of patients treated in the Norwegian Radium Hospital 1976-1985. Int J Gynecol Cancer 3:110, 1993.

36. Barter JF, Smith ED, Szpak CA, et al. Leiomyosarcoma of the uterus: clinicopathologic study of 21 cases. Gynecol Oncol. 21: 220, 1985.

37. Bodner K, Bodner-Adler B, Kimberger O, et al. Evaluating prognostic parameters in women with uterine leiomyosarcoma. A clinicopathologic study. J Reprod Med 48:95, 2003.

38. Dinh TA, Oliva EA, Fuller AF, et al. The treatment of uterine leiomyosarcoma. Results form a 10-year experience (1990-1999) at the Massachusetts General Hospital. Gynecol Oncol 92:648, 2004

39. Tore G, Topuz E, Blice N, et al. The role of adjuvant chemotherapy in the treatment of uterine sarcoma patients. Eur J Gynaecol Oncol. 11: 307, 1990.

40. Anraku M, Yokoi D, Nakagawa K, et al. Pulmonary metastases from uterine malignancies : results of surgical resection in 133 patients. J Thoracic Cardiovascular Surg 127: 1107, 2004.

41. Leitao MM, Brennan MF, Hensley M, et al. Surgical resection of pulmonary and extrapulmonary recurrences of uterine leiomyosarcoma. Gynecol Oncol 87: 287, 2002.

42. Levenback C, Rubin SC, McCormack PM, et al. Resection of pulmonary metastases from uterine sarcomas. Gynecol Oncol 45: 202, 1992.

43. Ambrogi MC, Lucchi M, Dini P, Melfi F, Fontanini G, Faviana P, Fanucchi O, Mussi A. Percutaneous radiofrequency ablation of lung tumours: results in the mid term. Eur J Cardiothoracic Surgery. 30:177, 2006.

44. Lin JC, Wiechmann RJ, Szwerc MF, Hazelrigg SR, Ferson PF, Naunheim KS, Keenan RJ, Yim AP, Rendina E, DeGiacomo T, Coloni GF, Venuta F, Macherey RS, Bartley S, Landreneau RJ. Diagnostic and therapeutic video-assisted thoracic surgery resection of pulmonary metastases. Surgery. 216: 636, 1999.

45. Chow DH, Sinn LH, Ng KK, Lam CM, Yuen J, Fan ST, Poon RT. Radiofrequency ablation for hepatocellular carcinoma and metastatic liver tumors: a comparative study. J Surg Oncology. 94:565, 2006.

46. Berber E, Siperstein AE. Perioperative outcome after laparoscopic radiofrequency ablation of liver tumors: an analysis of 521 cases. Surg Endoscopy. 8 (epub), 2007.

47. Lawes D, Chopada A, Gilliams A, Lees W, Taylor I. Radiofrequency ablation as a cytoreductive strategy for hepatic metastasis from breast cancer. Ann R Coll Surg England. 88:639, 2006.

48. Omura GA, Major FJ, Blessing JA et al. A randomized study of adriamycin with and without dimethyl trizenoimidazole carbozamide in advanced uterine sarcomas. Cancer 52: 626, 1983.

49. Muss HB, Bundy B, DiSaia PJ, et al. Treatment of recurrent or advanced uterine sarcoma. A randomized trial of doxorubicin versus doxorubicin and cyclophosphamide ( a phase III trial of the Gynecologic Oncology Group). Cancer 55, 1648, 1985.

50. Kanjeekal S, Chambers A, Fung MF, Verma S. Systemic therapy for advanced uterine sarcoma: a systematic review of the literature. Gynecol Oncol 97: 624, 2005.

51. Hannigan EV, Freedman RS, Elder KW, Rutledge FN. Treatment of advanced uterine sarcoma with adriamycin. Gynecol Oncol 16: 101, 1983.

52. Sutton GP, Blessing JA, Hanjani R, Kramer P. Phase II evaluation of liposomal doxorubicin (Doxil) in recurrent or advanced leiomyosarcoma of the uterus: a Gynecology Oncology Group study. Gynecol Oncol 96:749, 2005.

53. Hensley ML, Maki R, Venkatraman E, et al. Gemcitabine and Docetaxel in patients with unresectable leiomyosarcoma: the result of a phase II trial. J Clin Oncol 20:2824, 2002.

54. Sutton GP, Blessing JA, Barrett RJ, McGehee R. Phase II trial of ifosfamide and mesna in leiomyosarcoma of the uterus: a Gynecologic Oncology Group Study. Am J Obstet Gynecol. 166: 556, 1992.

55. Sutton GP, Blessing JA, Malfetano JH. Ifosamide and doxorubicin in the treatment of advanced leiomyosarcomas of the uterus: a Gynecologic Oncology Group study. Gynecol Oncol 62: 226, 1996.

56. Lei KM, Ostruszka LJ, Shewach D. Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by doxetaxel in the treatment of sarcoma. J Clin Oncol 22: 1706, 2002.

57. Anderson S, Aghajanian C. Temozolomide in uterine leiomyosarcomas. Gynecol Oncol. 98: 99, 2005.

58. Garcia D, Muro X, Lopez-Pousa A, Martin J, et al. A phase II trial of Temozolomide as a 6-week, continuous, oral schedule in patients with advanced soft tissue sarcoma. Cancer 104: 1706, 2005.

59. Tewari D, Saffari B, Cowan C, Wallick A, Koontz MZ, Monk BJ. Activity of trabectedin (ET-743, Yondelis) in metastatic uterine leiomyosarcoma. Gynecol Oncol. 102: 421, 2006.

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An Introduction to Leiomyosarcoma of the Bone and Soft Tissue

Tissues and Cells

These sites will help readers to better understand this article: The Tissues of the Human Body and Inside the Cell

Leiomyosarcoma is an aggressive soft tissue sarcoma derived from smooth muscle cells typically of uterine, gastrointestinal or soft tissue origin. Sarcomas are malignant tumors arising from mesenchymal cell lines. They comprise a heterogeneous group of cancers, each with unique clinical, histologic, and radiographic characteristics. Soft tissue sarcomas account for 0.7% of malignancies. Sarcomas are generally classified according to the normal cell line that they most closely resemble. Of all soft tissue sarcomas, approximately 5-10% are leiomyosarcomas.1 Leiomyosarcoma of soft tissue is thought to arise from the smooth muscle cells lining small blood vessels. Leiomyosarcoma can also arise directly from the viscera, including the gastrointestinal tract and uterus.

Leiomyosarcoma of soft tissue is discussed in this article, while the companion article (linked in the above panel) addresses the uterine form of this disease. Gastrointestinal lesions are not included in this discussion. Primary leiomyosarcoma of bone is a distinct entity which is quite rare. While histologically similar, soft tissue leiomyosarcoma has classically been subdivided into three groups for prognostic and treatment purposes: leiomyosarcoma of somatic soft tissue, cutaneous leiomyosarcoma and leiomyosarcoma of vascular origin.4 A group of patients with leiomyosarcoma in the setting of immune dysfunction is also being discovered.5 Leiomyosarcomas are aggressive tumors that are often difficult to treat. The prognosis is poor, with survival rates among the lowest of all soft tissue sarcomas.7

General Clinical Features of LMS

There are no specific clinical features diagnostic of leiomyosarcoma of soft tissue that distinguish these tumors from other soft tissue sarcomas. Women are affected more than men (2:1), with the disease typically occurring in the 5th and 6th decades of life. This gender distribution may reflect the proliferation of smooth muscle that can occur in response to estrogen. Prognosis and treatment varies on the location, stage and grade of the primary tumor as well as the presence of metastatic disease. The most common site of involvement of leiomyosarcoma is the retroperitoneum, accounting for approximately 50% of occurrences.8 In the case of retroperitoneal tumors, presenting signs and symptoms can include an abdominal mass, pain, swelling, weight loss, nausea or vomiting. Leiomyosarcoma of somatic soft tissues, like other soft tissue sarcomas, often present as an enlarging, painless mass. Although these tumors are generally associated with small blood vessels, they usually do not present with signs or symptoms of vascular compression. However, when leiomyosarcoma arises from a major blood vessel, symptoms of vascular compromise or leg edema may be present, as well as neurologic symptoms such as numbness from compression of an adjacent nerve. Soft tissue leiomyosarcoma typically affects adults, however it can present in childhood.2,3,5

Figure 1

Figure 1: Leiomyosarcoma of soft tissue of the wrist...

LMS Imaging and Initial Workup

Typically, once a lesion suspicious for a sarcoma has been discovered, diagnosis and staging studies are performed simultaneously. Initial imaging should include plain radiographs of the affected area, an MRI of the lesion, and a chest CT scan. As with other soft tissue sarcomas in the extremities, MRI is the study of choice for the evaluation of the anatomic extent of the tumor. Important considerations are the involvement of adjacent structures such as bone, nerves or compression of vascular structures. CT imaging is useful in evaluating the extent of retroperitoneal tumors and specifically the involvement of adjacent structures. Angiography may be a useful modality in cases involving a major blood vessel. CT scanning of the chest is useful to evaluate for the presence of metastatic disease in the lungs. The role of PET scanning has not been studied in particular reference to leiomyosarcoma, but has been studied in other soft tissue sarcomas with early promising results. Video: Biopsy for SarcomasPET and PET/CT may prove particularly useful in evaluating patients who have undergone surgery in looking for local disease recurrence, or in the search for metastatic lesions. Biopsy is necessary to establish a specific diagnosis of leiomyosarcoma, and is often accomplished using a CT guided core needle biopsy. This technique can be performed in most cases with less morbidity than an open incisional biopsy.

Classification

Histologically, soft tissue leiomyosarcomas that arise in different anatomic locations are similar. However, based on the location of the tumor, prognosis and possible treatments differ. For this reason leiomyosarcoma of soft tissues is divided into four groups. Furthermore there are sporadic case reports of primary leiomyosarcoma of bone, a clinically distinct entity.

  1. Leiomyosarcoma of Soft Tissue Retroperitoneal Somatic soft tissue
  2. Leiomyosarcoma of Cutaneous Origin
  3. Leiomyosarcoma of Vascular Origin (large vessel)
  4. Leiomyosarcoma in the Immunocompromised Host
  5. Leiomyosarcoma of Bone

Leiomyosarcoma of Soft Tissue

Immunohistochemical analysis suggests that the cell line of origin of leiomyosarcoma is the smooth muscle cell. The most common site of leiomyosarcoma of soft tissue is the retroperitoneum, accounting for 50% of all cases.8 Smooth muscle sarcomas arising from the abdominal viscera or uterus are considered to be distinct disease entities. Other sites of involvement include the deep soft tissues of the extremities and are referred to as leiomyosarcoma of somatic soft tissue.4 Soft tissue leiomyosarcoma was at one time believed to arise from leiomyomas, however, this is now thought to be an extremely rare occurrence. Most malignant leiomyosarcomas arise independently, and are not associated with benign tumors. Histologic studies of somatic soft tissue leiomyosarcomas have shown that many, if not all, of these tumors arise directly from the smooth muscle cells lining small blood vessels.

Figure 2

Figure 2: Retroperitoneal Leiomyosarcoma...

When the retroperitoneum is involved, presenting symptoms are usually vague abdominal discomfort, an abdominal mass and weight loss. Peripherally located masses present as an enlarging mass, often painless, with few constitutional signs. Due to the deep inaccessible location and large volume of the abdominal cavity, leiomyosarcomas of the retroperitoneum tend to be significantly larger than those of the extremities at presentation. Retroperitoneal leiomyosarcoma is an aggressive disease that is often not amenable to complete surgical resection.

Leiomyosarcoma of Cutaneous Origin

Leiomyosarcoma can arise within the dermis. When this occurs it is referred to as cutaneous leiomyosarcoma. Unlike other forms of leiomyosarcoma, men are affected more than women at a ratio of 2:1.11 These lesions are typically small when first diagnosed (1-2 cm), and prognosis is generally good.12 When leiomyosarcoma develops within the dermis itself it is thought to be derived from the pilar arrecti.20 Tumors that develop within subcutaneous tissue arise from small or microscopic vessels and should be considered leiomyosarcoma of somatic soft tissue. The behavior of these tumors is more consistent with that of deeper tumors than intradermal tumors. When the lesion is confined to the dermis, metastasis typically does not occur.11 Deeper lesions can metastasize in up to 30-40% of cases, usually hematogenously to the lungs.12 Treatment consists of wide resection, and is often curative when the lesion is initially confined to the dermis, regardless of histologic grade.

Leiomyosarcoma of Vascular Origin

Leiomyosarcoma rarely arises directly from major blood vessels, however, when it does, it is termed leiomyosarcoma of vascular origin. There have been only a few hundred published reports of leiomyosarcoma of vascular origin. In one review of 86 cases, leiomyosarcoma of vascular origin was shown to have a propensity for lower pressure systems. Most commonly affected were the larger veins (68 cases), specifically the inferior vena cava (in 33 cases), and less commonly the pulmonary artery (10 cases) and rarely peripheral arteries (8 cases).13

If the tumor develops in the inferior vena cava in the supra-hepatic segment, Budd-Chiari syndrome develops: hepatomegaly, jaundice, and ascites. These tumors are usually not surgically resectable. Tumors that arise in the inferior vena cava below the liver present with lower extremity edema and vague abdominal pain. Symptoms are defined by the anatomic location of the lesion, and the local vascular physiology and drainage patterns.

Arterial leiomyosarcoma usually affects the pulmonary artery. Patients will typically complain of dyspnea and chest discomfort, relating to the arterial obstruction. Symptoms are related to the vascular distribution of the affected artery and the presence or absence of collateral blood flow.

Leiomyosarcoma in the Immunocompromised Host

Since the 1970s there have been a number of cases of leiomyosarcoma reported in immunocompromised patients having undergone transplantation and treated with immunosuppressive regimens.15 More recently, there have been further case reports involving people infected with the HIV/AIDS virus.6 There appears to be a relationship between these immunocompromised patients and super-infection with Epstein-Barr virus (EBV). Case reports of synchronous multiple leiomyosarcoma have been published where clonal analysis have shown that the individual tumors arose independently from each other.16 It is not known what interaction exists between immuno-incompentence and EBV infection that predisposes to leiomyosarcoma.

Leiomyosarcoma of Bone

Figures 3A and 3B

Figures 3A - 3B: Leiomyosarcoma of the distal radius...

Primary leiomyosarcoma of bone is extremely rare. There have been approximately 90 cases reported since initially described in 1965.22,23 Many cases that are thought to represent primary disease of bone, after further investigation, actually represent metastatic disease from another site or bony invasion from a neighboring soft tissue lesion. Most cases of leiomyosarcoma of bone reported so far have been in the metaphysis of long bones. These lesions are thought to arise from the smooth muscle cells lining the intraosseous vessels or from pluripotent mesenchymal cells. The histology is the same as leiomyosarcoma of soft tissue. These tumors have an equal or slightly male-predominant gender distribution. The radiographic appearance of these tumors is typically a radiolucent lesion in the metaphysis of a long bone, although the tumor has been described in other locations as well. A permeative appearance is characteristic.24 There are no specific radiographic features that can diagnose leiomyosarcoma by radiography alone.

Leiomyosarcoma Staging

Figure 4

Figure 4: Metastatic retroperitoneal leiomyosarcoma to bilateral proximal...

Staging of leiomyosarcoma is important both in guiding treatment and in providing prognostic information. While many staging systems exist for soft tissue sarcoma, the most commonly used system is the AJCC system.9 This system classifies the tumor based upon histologic grade, the tumor size, location as superficial or deep, and the presence or absence of metastatic disease (see Table 1).

The Surgical Staging System of the Musculoskeletal Tumor Society (MSTS) is also used. It is utilized for staging bone and soft tissue sarcomas, including leiomyosarcoma.10 This staging system classifies tumors as Ia, Ib, IIa, IIb, or III based upon the histologic grade of the tumor, its local extent and the presence or absences of macroscopic distant metastatic disease. If the tumor is localized to a single anatomic compartment, it is said to be confined. If it has spread locally beyond its initial compartment, then it is said to be unconfined (see Table 2).

Table 1: AJCC staging system
Stage Histological
Grade
Size Location 
(Relative to fascia)
Systemic / Metastatic 
Disease Present
IA Low < 5cm Superficial or Deep No
IB Low ≥ 5cm Superficial No
IIA Low ≥ 5cm Deep No
IIB High < 5cm Superficial or Deep No
IIC High ≥ 5cm Superficial No
III High ≥ 5cm Deep No
IV Any Any Any Yes
Table 2: MSTS Staging system
Stage Histological
Grade
Local Extent of Disease Systemic / Metastatic 
Disease Present
Ia Low Confined No
Ib Low Unconfined No
Ia High Confined No
Ib High Unconfined No
III Any Any Yes

Figures 5A-5C

Figure 5a,b,c: Low grade Leiomyosarcoma of Soft Tissue...

Histology

The histologic appearance of leiomyosarcoma of soft tissue exhibits significant variability. Typical features include a highly cellular field, with abundant pink to deep red cytoplasm on H&E staining. Cells are arranged in fascicles, and in well-differentiated tumors these fascicles are often arranged at right angles, allowing identification of both longitudinal and cross-sectional areas within one field. The nuclei are usually centrally located, and are classically described as cigar-shaped. One of the key features is the presence of myofibrils that are longitudinal and run the length of the cell. As the cells become increasingly de-differentiated, they become disorganized, and begin to lose their distinguishing characteristics.4

Differentiation

Pathologists and oncologists often describe a particular tumor’s potential for aggressive behavior in terms of "differentiation." Differentiation of any cell is a description that means that a given cell type has certain characteristics that make it unique, or "different" from other cell typed. For instance, a fat cell is different from a cartilage cell, because these two cell types have many characteristics that differ from each other. Many types of connective tissue cells come from common precursor cells, but as they get signals to express certain proteins and develop certain characteristics, they fall into a unique cell type category. Sarcoma cells are cells that resemble or are derived from these cell types, but have undergone a transformation into a malignancy. That is, they have developed the capacity to metastasize. 

Differentiation is a description of how closely the tumor resembles its cell of origin on the histologic (microscope) evaluation and gives a guide to the treating physicians of how aggressive a behavior to expect from a given patient’s tumor. A well-differentiated tumor very closely resembles the cell line that it is derived from, whereas a poorly differentiated tumor has very few characteristics of its cell line of origin. This is an important distinction, as well-differentiated tumors have a lower potential for aggressive or aberrant behavior than poorly differentiated tumors, which can behave very aggressively. Additionally, the term "dedifferentiated" is usually used to describe a tumor that no longer has any detectable relationship to its origin cell line, and can only be diagnosed as being related to that cell line based on the background it is found in. For instance, a patient with a well-differentiated liposarcoma has a tumor that closely resembles adipose, or fat, tissue and has little propensity, if any, to metastasize. However, within that patient’s well differentiated liposarcoma if there were to be found a defined area that no longer has any resemblance to fatty tissue, but has the more characteristic appearance of an aggressive malignant spindle cell neoplasm, this area would then likely be considered a dedifferentiated area of the well-differentiated liposarcoma, or an area of dedifferentiated liposarcoma. It is important to note that these dedifferentiated tumors, since they behave differently from their related tumor type, may need to be treated quite differently than that related tumor type.

Figures 6A-6C

Figure 6a,b,c: High grade Leiomyosarcoma of Soft Tissue...

Leiomyosarcoma of somatic soft tissue has a number of histologic subtypes including epithelioid leiomyosarcoma, myxoid leiomyosarcoma, inflammatory leiomyosarcoma, granular cell leiomyosarcoma and dedifferentiated leiomyosarcoma.4 The clinical importance of these subtypes has not been well studied.

Histologic features under light microscopy are the most important factors in making the diagnosis of leiomyosarcoma. However, adjunctive modalities including immunohistochemisty and electron microscopy play an important confirmatory role. Immunohistochemistry helps support the diagnosis by demonstrating the presence of muscle specific markers including: desmin, muscle specific antigen (HHF35), cytokeratin (CK) and epithelial membrane antigen (EMA). While not required to make the diagnosis, one or more of these markers is usually found in specimens of leiomyosarcoma. Electron microscopy is useful in further elucidating the classic nuclear morphology seen in this tumor. Cytogenetic analysis of large series of soft tissue sarcoma, including leiomyosarcoma, has not shown a consistent chromosomal aberration or translocation.18

Figures 7A and 7B

Figure 7a,b: Leiomyosarcoma of bone...

Size, cellularity, atypia, necrosis, and mitoses per high power field are indicators that help define the difference between a benign smooth muscle tumor and leiomyosarcoma. Of these indicators, mitoses per high-powered field is considered the most reliable.25 It is important to note that the threshold of mitotic rates that would qualify a tumor as malignant in soft tissue leiomyosarcoma is lower than that used in uterine leiomyosarcoma. When considering soft tissue smooth muscle tumors, the presence of any mitotic figures should raise suspicion of a malignancy, especially in the presence of cellular atypia or focal necrosis.

Leiomyosarcoma Treatment

Due to the rarity of these tumors, and the need for a multi-specialty treatment team, treatment is best carried out in a specialized center with expertise in sarcoma care. At our institution, treatment planning begins with a multi-disciplinary review of the patient’s history, all available radiographic imaging, and the pathologic results from biopsy. A treatment plan is then formulated based upon the input from orthopedic and general surgeons, musculoskeletal radiologists, pathologists, medical oncologists, and radiation oncologists.

Surgery

Local control of soft tissue sarcomas is usually achieved with surgical resection. Pre-operative planning based upon radiographic and pathologic information is important to ensure adequate surgical margins. Achieving wide surgical margins is important in preventing local recurrence.

Radiation Therapy

Many tumors involve or are directly adjacent to vital structures. In these cases achieving a wide surgical margin is impossible. Radiation therapy is an important additional treatment for improving rates of local control when surgical margins are close, especially in high-grade sarcomas. Radiation therapy can be delivered either pre-operatively (neoadjuvant) or post-operatively (adjuvant). Radiation therapy can also be utilized as a means of palliative local control in cases where extensive metastasis has already occurred.

Chemotherapy

The primary role of chemotherapy is in the treatment of metastatic disease. While not curative, it may slow the progression of systemic disease. Agents that are used in some sarcoma centers include: doxorubicin and ifosfamidegemcitabine and taxotere (docetaxel), dacarbazine, and ecteinascidin. There are currently investigational studies underway to identify other agents that may prove useful in the treatment of leiomyosarcoma. Chemotherapy is sometimes used as an adjuvant in the treatment of localized sarcomas. No clear survival benefit has been demonstrated in retroperitoneal leiomyosarcomas. However, pre-operative chemotherapy may help to shrink a tumor away from vital structures, and improve the ability of surgeons to successfully remove a large tumor. In localized leiomyosarcoma of the extremities, there may be a survival benefit for adjuvant chemotherapy using doxorubicin-based regimens.28 Both retrospective and prospective studies have shown a benefit for neoadjuvant doxorubicin and ifosfamide based regimens in patients with large (>8cm) high-grade sarcomas.

Prognosis and Outcomes

Retroperitoneal Leiomyosarcoma

In a recent review of smooth muscle tumors of soft tissue, Weiss has compiled data from the current series on retroperitoneal leiomyosarcomas (see table 3). These tumors seem to display very aggressive biology. Neither size nor mitotic activity correlated with outcome, which may represent a reflection of the fact that most of these tumors are quite large on presentation.

Table 3: Summary of published case series 
of retroperitoneal/abdominal leiomyosarcomas
Author Number of Cases Atypia Necrosis Minimum Mitotic Rate Size Died of Disease (DOD)
Hashimoto 44 All 68 1-4/10HPF 90% > 10cm 79%
Rajani 17 All 12/17 3/10HPF 82% > 10cm 88%
Ranchod 13 12/13 7/13 0-4/10HPF 85% > 10cm 92%
Shmookler 36 ? ? 1-4/10HPF 100% > 7cm 77%
Wile 16 ? ? 2/10HPF 93% > 5cm 93%

(Table reproduced with permission from Weiss SW. Smooth muscle tumors of soft tissue. Advances in Anatomic Pathology. 9(6):351-359. Copyright 2002, Loppincott Williams & Wilkins.)

Soft Tissue Leiomyosarcoma

The patient numbers of most case series are small, and there is no published meta-analysis available to provide clear prognostic data. Small case series have been published, however, that do provide some insight into the prognostic significance of some patient variables. Deep soft tissue leiomyosarcomas are usually detected before they reach the large size of many retroperitoneal tumors. About half of these patients die of metastatic disease. The factors that are associated with worse prognosis include age >62 years, size greater than 4cm, tumor necrosis, French Federation Nationale des Centers de Lutte Contre le Cancer (FNCLCC) grade, vascular invasion, or previous intralesional surgery.1,17 Mitotic rate has not been directly correlated to worse outcome, although mitotic rate is clearly a useful parameter in differentiating malignant tumors from benign ones. In a retrospective study of 66 patients with soft tissue leiomyosarcoma, Mankin, et al found a significant effect of MSTS stage and size on outcome but not gender, age, site, adjuvant therapy, or presence of local recurrence.7 Overall reported survival for patients diagnosed with soft tissue leiomyosarcoma range from 50% 3-year survival to 64% 5-year survival, making this tumor one of the more aggressive soft tissue sarcomas.1,7

Cutaneous Leiomyosarcoma

True intradermal leiomyosarcoma is thought not to metastatsize, and therefore presents more of a local control issue than a problem of metastatic disease. Published series on this tumor have often included small subcutaneous tumors as well as truly intradermal tumors which alters the reporting of the natural history of this disease subtype. Wide excision of truly intradermal tumors, if achievable, is curative.

Vascular Leiomyosarcoma

Leiomyosarcoma of vascular origin has a poor prognosis. Because they are rare, definitive diagnosis is often delayed and complete resection is usually not possible. Local complications of the primary tumor are the main cause of morbidity and mortality. Metastatic disease to the liver and lungs occurs in 54%, in approximately the same percentage as other forms of leiomyosarcoma.14

Leiomyosarcoma in the Immunocompromised Host

Little is known about the specific prognostic implications of this rare entity, as no case series have been compiled. However, as in most other cases of leiomyosarcoma it appears to behave aggressively.

Leiomyosarcoma of Bone

The largest current series did not demonstrate any difference between wide surgical resection and surgery plus radiation and/or chemotherapy in the treatment of primary leiomyosarcoma of bone. In this study, local recurrences were seen in 24% of cases, and metastases developed in 24% of cases, all in the lung. Overall survival was 77% at 3 years and 68% at 5 years.29

Pediatric Patients

Leiomyosarcoma in the pediatric age group is rare. In a series of 20 tumors in patients under 16 years of age, there was no gender predilection.5 Tumors were evenly distributed between the head and neck, upper extremity, lower extremity, and trunk. Most of the lesions (85%) in this series were considered low-grade. Local recurrence occurred in two patients, and none of the patients had died by the end of the study. The prognosis of children afflicted by leiomyosarcoma appears to better than adults.2,3,5

Conclusion

Leiomyosarcoma is an aggressive sarcoma that can arise in a number of locations. Although advances have been made in treatment protocols, leiomyosarcoma remains one of the more difficult soft-tissue sarcomas to treat. Accurate diagnosis, classification, and multi-modality treatment by physicians who are familiar with these tumors are essential to favorable outcome.

The rarity of these tumors makes definitive studies difficult to perform. For instance, there is very little published data available on patients with leiomyosarcoma of somatic soft tissues. There have only been a limited number of small case series published. This fact has prompted us to look at the experience we have had with this tumor at our institution, and we are currently preparing to publish the treatment and outcome of over 120 patients with leiomyosarcoma of soft tissue. These types of reviews, along with carefully designed prospective randomized clinical trials, may help further define the best treatment of these tumors in the future.

Currently, however, in general local control is obtained with wide surgical excision. Neoadjuvant or adjuvant radiation therapy is appropriate in some circumstances where local control is an issue. Chemotherapy is employed for the treatment of systemic disease. Ongoing clinical trials may identify agents that may improve the overall and disease-free survival of patients suffering from this disease.

Last revision and medical review: 4/2007

By Michael J. Weaver, MD
Harvard Combined Orthopedic Surgery Program
Boston, MA

John A. Abraham, MD
Center for Bone and Soft Tissue Oncology
Dana Farber Cancer Institute
Brigham and Women’s Hospital
Instructor of Orthopedic Surgery,
Harvard Medical School
Boston, MA

References

1. Gustafson P, Willen H, Baldetrop B, et al. Soft tissue leiomyosarcoma: a population-based epidemiologic and prognostic study of 48 patients, including cellular DNA content. Cancer 70:114, 1992.

2. Lack EE. Leiomyosarcomas in childhood: a clinical and pathologic study of 10 cases. Pediaric Pathology 6:181, 1986.

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Leiomyosarcoma Stories and Support

Lynn, survivor of uterine LMS, writes about her journey

Lynn, leiomyosarcoma survivorI was in surgery within two hours of arriving at the hospital. The tumor had caused other issues, so I had to have a procedure on my kidney within ten days of my surgery. I was a mess. But when they got the results back, it was like a sucker punch. All I could think and say was, "This can't happen; I take care of myself! I eat right and exercise daily! How could this happen to me?"

When my doctor told me what type of cancer it was, a uterine leiomyosarcoma, I said, "I don't have a uterus!" I had a hysterectomy 11 years prior, and this cancer had evidently grown from fibers of uterine muscle that remained in my abdomen. The doctor said, "It is rare and aggressive." My response was, "I'm rare and aggressive!" Read Lynn's story.

Alan, survivor of recurrent LMS, shares his thoughts

Alan, leiomyosarcoma survivor

I have advised some friends I have met who are battling sarcomas and other rare cancers. My advice mirrors what the LMS listserve and the Liddy Shriver Sarcoma Initiative website stress: Be seen at a cancer center that specializes in sarcomas. Educate and empower yourself to be a full partner in the development of a treatment plan. Engage and seek the support of others who are fighting similar battles. Finally, I would stress the importance of addressing the emotional needs of family and friends who are providing care and support. Emotionally and psychologically dealing with LMS has been much harder on my wife than it has been on me. I think if our roles were reversed that I, too, would have a much harder time. Read Alan's story.

Amy writes about strength

No matter how much you try, you’re never ready to lose ALL your hair! The night I stepped into the shower and began "shedding," I lost more than half my hair. I stood there, feeling the hair wash down over me, and thought, "Now everyone will know. No more hiding." My friends and family all knew of course, but now the strangers in restaurants and at the grocery store would know. It was as good as if I’d screamed out to the world "I have Cancer!" My private fight was becoming public.

After I stepped out of the shower and scraped the remains of my blonde curls from the drain, I had my husband, Bryan (the love of my life), shave my head…into a Mohawk!!!! He and I went upstairs, woke up the kids (ages 8 & 11), and let them take pictures of Mommy with a Mohawk. We all laughed a lot, took turns rubbing the bald sides of my head and fluffing through the tufts of hair remaining on the top. Later that night, Bryan shaved it all off, but I knew it would be better for all of us if mommy didn’t go to bed "with hair" and wake up bald.

It’s all about keeping it normal for my kids. They look to us for direction on how to handle the tough stuff in life, and uterine leiomyosarcoma is tough. But, they’ve learned, we’ve all learned, that together we are strong, and that prayer, love and laughter will get us all through this.

The words of a metastatic LMS survivor, Warren

Warren, leiomyosarcoma survivorOn April 10th, 2008, at the age of 62, I won the Alaska State Racquetball Championships in all ages at the highest level. A few months later I placed 3rd in the International Championships in Milwaukee, Wisconsin.

What makes April 10th so special is that exactly 7 years earlier to the day my Racquetball days were coming to a close. That’s when I had my first of 5 major major surgeries on my right thigh for the attempted removal of a rare cancer called leiomyosarcoma. A few months later, I would find out there were numerous mets in both lungs. Not only did I have 5 major surgeries on my leg, I had radiation, 40 treatments of hyperbarics for wound healing, chemotherapy, partial removal of left lung for mets, 4 detached retinas, and 3 major infections! Because I was stage lV, my wife & I spent the first 4 1/2 years at a Sarcoma Center 2500 miles away from home in Seattle.

At some point I made up my mind to "stay in the game" of life, fight and continue with racquetball at some level, never thinking that my body would respond in ways that seemed unattainable. I now use Racquetball to raise money, give speeches and raise awareness around the country of these rare cancers called sarcomas.

A moment in leiomyosarcoma from Di...

It’s January 2009, and I’m walking along the Euston Road in London to my yearly check up at the sarcoma clinic. I’m thinking back nearly seven years to a moment in 2002 when I was in this same place.

An ambulance hadn’t arrived to bring me back to my ward from a pre-chemo hearing check in another part of the city. I’d had to haul myself out of my wheelchair and into a cab. This had proved difficult because I’d just had an above-knee amputation for the leiomyosarcoma in my tibia. I sat looking out at the crowded pavement where I’d often walked on my way from Euston Station. The cab stopped in the traffic in front of a construction site, and I realised that the building beginning to rise through the scaffolding was the new University College Hospital, which would eventually house the Middlesex hospital’s oncology department.

In that moment I was sure I would not live long enough to see the hospital completed, to be treated there or ever again be a part of the crowd walking freely along the street. That was one of my lowest moments.

Each year now when I walk from Euston station to UCH on my brilliant high-tech leg, I remember that moment and feel a huge amount of gratitude toward every one of the people who helped me get to this point, especially the oncologist at my local hospital who swiftly referred me to UCH’s sarcoma specialists for diagnosis and treatment.

A moment in leiomyosarcoma from Kim...

I was diagnosed with metastatic leiomyosarcoma as a young mother of three while in my last year of nursing school. I had the whole world ahead of me, or so I thought. What I hadn’t realized was that my soon-to-be-found sarcoma would change my life forever, bringing experiences and friendships from around the world that I would never have experienced otherwise.

Once I realized I was not alone in my battle, I began networking. I was amazed that my very personal diagnosis, fears and need for a shoulder could be shared with so many with just a few keystrokes on my computer. My networking brought me to realize that sarcoma was not always best treated in the country which I resided. Instead, my eyes were opened to what was to become a 3.8 year (and counting) extension to my original prognosis of three months to live.

My extensive research led me to a thoracic surgeon in Coswig, Germany, who, seemingly hidden away other than through his published papers, had been saving the lives of many patients having tumors of the lung since the early 1990′s. My faith in God and confidence in a world of His people, having much to offer each other, led me to have not one, but both lungs operated on by him, removing 269 tumors from my lungs. My research had brought me almost 1/3 of the way around the world to a culture to which I did not belong to place my life in the hands of a surgeon I did not know. But through that experience I made a connection that will live with me forever.

The online leiomyosarcoma support group at ACOR

This online support group provides a network of friends who are dealing with issues related to leiomyosarcoma. An ACOR "Mailing List" is a free, non-moderated discussion mechanism for patients, caregivers, researchers, and medical professionals to exchange messages with each other. Messages are "posted" by someone on the list (i.e., a member of the support group) and cover a wide range of topics, e.g., patient experiences, research articles, clinical trials, current treatment practices and alternative treatments. A posting often results in an "online discussion" of the topic. Sometimes, one or more medical professionals are members of a support group and may comment on a posting.

Find treatment and support resources

We maintain listings of sarcoma treatment centers, local support groups and organizations that provide financial assistance to sarcoma patients and their loved-ones.

Leiomyosarcoma (LMS) Cancer Research

The Liddy Shriver Sarcoma Initiative is pleased to support LMS research. Leiomyosarcomas are tumors that develop in the smooth muscles of the body. Like many sarcomas, they can be difficult to diagnose and treat. It is our hope that research will lead to newer and better treatments for those who are diagnosed with LMS.

The following research studies were funded by the Initiative after sarcoma experts agreed that they were clinically relevant and scientifically sound:

Developing Novel Therapeutic Options for Leiomyosarcoma

Deletion Of Type 4 Collagens And Smooth Muscle Sarcomagenesis$150,000 Grant: In this study, researchers at Stanford University aim to determine whether three proteins that are expressed at various levels in LMS tumors can be used as targets for novel therapies. The investigators hope that this research will eventually lead to clinical trials of targeted treatments for LMS patients.

This study was funded by the LeioMyoSarcoma Direct Research Foundation and the Liddy Shriver Sarcoma Initiative in September 2013. It was made possible, in part, by a very generous donation from Laura Somerville.

Deletion Of Type 4 Collagens And Smooth Muscle Sarcomagenesis

Deletion Of Type 4 Collagens And Smooth Muscle Sarcomagenesis$50,000 Grant: In this study, researchers at Harvard Medical School will look for the early genetic changes that lead to the development of leiomyosarcomas. The scientists hope that their research will lead to better diagnostic testing and targeted drugs to treat leiomyosarcoma.

This study was funded by the Liddy Shriver Sarcoma Initiative in February 2013. It was made possible, in part, by a very generous donation from Laura Somerville.

The Effect of Mir-17-92 Dysregulation in Leiomyosarcoma-Genesis

Effect of Mir-17-92 Dysregulation in Leiomyosarcoma-Genesis$50,000 Grant: In this study, Eva Hernando, PhD continues her research on LMS at NYU School of Medicine. The study should lead to a better understanding of the molecular basis of LMS and reveal potential new therapeutic targets for LMS treatment.

This study was co-funded by the Liddy Shriver Sarcoma Initiative and the Leiomyosarcoma Direct Research Foundation in April 2011. It was made possible, in part, by donations made to the Liddy Shriver Sarcoma Initiative from the Jim Hauser Sarcoma Foundation in memory of Jim Hauser.

A Preclinical Mouse Model for Uterine Leiomyosarcoma

A Preclinical Mouse Model for Uterine Leiomyosarcoma$25,000 Grant: In this study, investigators at Cedars-Sinai Medical Center and Massachusetts General Hospital are using a mouse model for the evaluation of therapies that target the BRCA1 pathway in uterine leiomyosarcoma. Researchers expect that this research will provide justification for the development of PARP-1 inhibitor clinical trials for ULMS patients and, ultimately, lead to a safe and effective treatment option for women with ULMS.

This study was funded by the Liddy Shriver Sarcoma Initaitive in August 2009. It was made possible, in part, by generous donations made in memory Suzanne Kurtz and Teal Harris, who lost their lives to leiomyosarcoma; and by generous donations made by the family and friends of Jim Hauser, who is fighting leiomyosarcoma.

MicroRNA Deregulation in Mesenchymal Transformation and Sarcomagenesis

MicroRNA Deregulation in Mesenchymal Transformation and Sarcomagenesis $50,000 Grant: In this study, Eva Hernando, PhD developed and characterized an in vitro model of smooth-muscle cell (SMC) differentiation, identified the miRNA ‘signature’ of this differentiation and began to develop tools to investigate the role that these miRNAs (and their targets) play in SMC differentiation.

This study was co-funded by the Liddy Shriver Sarcoma Initiative and the Leiomyosarcoma Direct Research Foundation in June 2007.

Study of Tissue Samples in Conjunction with a Phase II Trial of Dasatinib

$25,000 Grant: This tissue study was performed in conjunction with a clinical trial on several types of sarcoma, including LMS.

  • Figure 1: Leiomyosarcoma of soft tissue of the wrist.
    The importance of MRI is demonstrated in this case, as the pathology was initially suggestive of a cutaneous leiomyosarcoma. This gadolinium enhanced T-1 weighted image with fat saturation shows the deep extension of the tumor nearly to the bone, placing this tumor in the category of leiomyosarcoma of soft tissue.
  • Figure 2: Retroperitoneal Leiomyosarcoma.
    In this oral and IV contrast enhanced CT image, a large heterogenous soft tissue mass arising from the retroperitoneum is demonstrated (red circle). Core needle biopsy confirmed the diagnosis of leiomyosarcoma.
  • Figure 3A and 3B: Leiomyosarcoma of the distal radius.
    The permeative appearance often seen with leiomyosarcomas of bone is demonstrated in these AP and lateral radiographs of the wrist. This tumor had no extension outside the bone.
  • Figure 4: Metastatic retroperitoneal leiomyosarcoma to bilateral proximal femurs.
    Non-contrast T-1 weighted MRI image demonstrates extensive disease in both femurs, which in this case necessitated surgical intervention to prevent fracture
  • Figure 5A,B,C: Low grade Leiomyosarcoma of Soft Tissue
    (a) Low, (b) Medium, and (c) High power. Classic features of leiomyosarcoma including cigar shaped nuclei and arrangement of cells in fascicles are seen.
  • Figure 6A,B,C: High grade Leiomyosarcoma of Soft Tissue:
    (a) Low, (b) Medium, and (c) High power. High grade tumors demonstrate marked atypia and cellularity with multiple mitoses present.
  • The tumor demonstrated the features of leiomyosarcoma, and is found entirely within the bone. Staging studies demonstrate no other sites of disease.
    Figure 7A and 7B: Leiomyosarcoma of bone.
  • Figure 1: A uterus has been cut showing a large, soft leiomyosarcoma...
    Figure 1: A uterus has been cut showing a large, soft leiomyosarcoma with irregular borders noted to be invading the myometrium (LS, arrows) adjacent to a small, firm leiomyoma with a hemorrhagic center which is sharply demarcated (single arrow) (11).
  • Figure 2: Cut surface of this leiomyosarcoma showing hemorrhage and necrosis.
    Benign leiomyomas, in contrast, have a solid white whorled cut surface. Although typically spreading to distant sites through vascular invasion, tumors like the one shown may be locally infiltrative and cause adhesions to large bowel (arrow). Courtesy of Jonathan L. Hecht, M.D., Ph.D. (Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA).
  • Figure 3: Cut surface of this leiomyoma with infarction.
    Notice the rim of residual solid white whorled cut surface surrounding the area of necrotic debris. Common causes include embolization or torsion. Courtesy of Jonathan L. Hecht, M.D., Ph.D. (Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA).
  • Figure 4A and 4B: Tumor necrosis...
    Figure 4: Tumor necrosis consists of ghosts (no nuclei) of tumor and an abrupt transition from live to dead tumor (left panel) without an inflammatory response. Degenerative changes contain either liquefaction necrosis (no cell ghosts as seen in the lower panel here), edema, or an inflammatory response at the boundary with viable tissue. Courtesy of Jonathan L. Hecht, M.D., Ph.D. (Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA)
  • Figure 5: Mitosis (center of slide).
    Criteria for malignancy relies on necrosis, and mitotic count. Courtesy of Jonathan L. Hecht, M.D., Ph.D. (Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA).
  • Figure 6: Atypia is seen...
    Figure 6: Atypia is seen characteristically and lowers the required number of mitoses to meet criteria for malignancy. Atypical (a.k.a. symplastic) leiomyoma is a benign smooth muscle tumor with atypia only, lacking mitoses or necrosis. Courtesy of Jonathan L. Hecht, M.D., Ph.D. (Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA).