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.

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.

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

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

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.

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.

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

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.

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

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.

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

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.

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:

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

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

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.

An ESUN Article By Michael J. Weaver, MD and John A. Abraham, MD
Also available in Chinese and Spanish.

An Introduction to Leiomyosarcoma of the Bone and Soft Tissue

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

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. PET 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.

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

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

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).

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

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

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 ifosfamide, gemcitabine 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 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.