Introduction
Sarcomas are malignant neoplasms of mesenchymal origin. They comprise many categories of tumors with unique clinical, pathologic, and radiologic features. Soft tissue sarcomas account for approximately 0.7% of all malignant tumors and are generally named according to their morphologic similarity to the tissue. Smooth muscle sarcoma is an aggressive soft tissue sarcoma that typically originates from smooth muscle cells of the uterus, gastrointestinal tract, or soft tissues and accounts for 5-10% of all soft tissue sarcomas.(1) It is generally believed that soft tissue smooth muscle sarcoma originates from smooth muscle cells in the walls of small blood vessels and can also originate from internal organs, including the gastrointestinal tract and uterus. Soft tissue smooth muscle sarcomas are discussed in this article, while similar uterine smooth muscle sarcomas are discussed in a separate article, and gastrointestinal lesions are not included in this discussion. Primary smooth muscle sarcoma of bone is a unique and rare type. Although the histologic features are similar, soft tissue smooth muscle sarcomas are often divided into 3 groups based on prognosis and therapeutic goals: soft tissue smooth muscle sarcomas of the body; cutaneous smooth muscle sarcomas and vascular smooth muscle sarcomas.(2) A group of smooth muscle sarcomas associated with immune dysfunction in patients was recently identified.(3) Smooth muscle sarcomas are aggressive tumors that are often difficult to treat, have a poor prognosis, and are a type of soft tissue sarcoma with a low survival rate. A type of soft tissue sarcoma with low survival rates.
Definitions: Many medical and other technical terms and phrases are underlined and shown in blue to enhance their more detailed content refer to the relevant definitions or articles.
Tissues and Cells: Human Tissues: An introductory site designed to give you an understanding of the basic characteristics and structure of tissues, including soft tissues. Go through each of the important characteristics of tissue categories and learning tissues. The booklet “Inside the Cell”, produced by the National Institute of Family Medicine, provides an easy-to-understand introduction to cells and tissues such as muscles. (The booklet can be read online or downloaded in Acrobat PDF format from the Internet).
Soft Tissue of the Body: The term “soft tissue of the body” is an anatomical term that helps describe the location of tumors and their origin. The term describes the normal tissues that comprise an entire type of tissue that, when altered, can cause a specific malignancy known as a “sarcoma. Another name for the “soft tissues of the body” can be “connective tissue”, which is roughly considered to be the tissue responsible for connecting all the structures of the body. Typical tissues in this category include: muscles, nerves, adipose tissue, blood vessels, and fibrous tissue. Although internal organs such as the liver, kidneys, etc., may be considered “soft”, they are composed of specific types of tissue with specific functions that allow them to perform certain functions within the body. Cancers originate from the epithelial cells that make up the internal organs, unlike sarcomas, and are therefore called “carcinomas”.
General clinical features
Soft tissue smooth muscle sarcoma has no specific clinical features that distinguish it from other soft tissue sarcomas. Generally, they occur more frequently in women than in men (2:1) and tend to occur between the ages of 50 and 60 years, a distinction that may reflect the different estrogen-associated smooth muscle cell proliferation in each sex. The treatment and prognosis of smooth muscle sarcoma varies depending on the location, stage, pathologic grade, and presence of metastasis of the tumor. The most common site of smooth muscle sarcoma is the retroperitoneal region, accounting for approximately 50% of cases (8). Symptoms in retroperitoneal lesions include abdominal masses, pain, swelling, weight loss, nausea or vomiting. Soft tissue smooth muscle sarcomas of the trunk, like other soft tissue sarcomas, tend to present as progressively larger, painless masses. Although these tumors are usually associated with small blood vessels, they usually have no obvious signs or symptoms of vascular compression. However, when a smooth muscle sarcoma arises from a larger blood, it can present with symptoms such as vascular compression or edema of the lower extremity, as well as numbness due to compression of the adjacent nerve (1). Soft tissue smooth muscle sarcoma mostly affects adults, but it can occur in children (2,3,5).
Imaging and initial work-up plan
Usually, once a suspicious lesion is considered a sarcoma, its diagnosis and staging should be determined simultaneously. Initial imaging should include X-rays of the affected area and MRI and CT scans of the chest. As with other soft tissue sarcomas of the extremities, MRI is preferred to study the anatomic extent of tumor extension. CT imaging is useful to assess the extent of retroperitoneal tumor and the invasion of adjacent structures. Angiography is a useful method of adherence when major vessels are involved. CT scan of the chest is useful to evaluate pulmonary metastases of the lesion. PET-CT studies of smooth muscle sarcoma are not yet available, but this study is promising in other sarcomas. PET and PET/CT examinations are particularly useful to determine the presence of local recurrence or to assess the presence of distant metastases. Biopsy is necessary for a definitive diagnosis of smooth muscle sarcoma, mostly CT-guided puncture biopsy, and in most cases this biopsy technique reduces the disabling rate of open biopsy.
Biopsies, immunohistochemistry and pathology reports: biopsies are necessary for a definitive diagnosis of smooth muscle sarcoma. Click here for some biopsy knowledge and information.
The physician’s website contains several pages that can help you understand a pathology report. In addition, for a variety of tissue sections and pathology reports, please click here. To read about immunohistochemical staining procedures, click here.
Classification
Histologically, soft tissue smooth muscle sarcomas that occur in different anatomical locations are similar. However, because of the different locations, treatment and prognosis may differ. Therefore, depending on the location, soft tissue smooth muscle sarcomas are mostly classified into four categories. There are also sporadic clinical cases reporting rare primary smooth muscle sarcomas of bone.
Soft tissue smooth muscle sarcoma of the retroperitoneal trunk
Smooth muscle sarcomas of cutaneous origin
Smooth muscle sarcoma of vascular origin (large vessels)
Smooth muscle sarcoma in immunocompromised hosts
Smooth muscle sarcoma of bone
Smooth muscle sarcoma of soft tissue
Immunohistochemical analysis indicates that the origin of smooth muscle sarcoma cells is smooth muscle cells. The most common site of soft tissue smooth muscle sarcoma is the posterior peritoneal cavity, accounting for approximately 50% of cases (8). Smooth muscle sarcomas originating from the abdominal organs and the uterus are considered to be different types of disease. Other sites of smooth muscle sarcoma include types of deep soft tissue origin in the extremities, known as soft tissue smooth muscle sarcoma of the body. It was once thought that soft tissue smooth muscle sarcoma was of smooth muscle tumor origin, but this is now considered extremely rare. Most smooth muscle sarcomas arise independently of the associated benign tumor. Pathologic studies of soft tissue smooth muscle sarcomas have shown that the vast majority of lesions arise directly from the smooth muscle of the small vessel wall.
Tumors that occur in the retroperitoneum tend to present with vague abdominal discomfort, abdominal masses and weight loss. Lesions located in the periphery tend to be progressively larger, painless masses, often without very severe symptoms. Smooth muscle sarcomas in the retroperitoneum tend to present as much larger masses than limbic lesions due to inaccessibility as well as large cavities. Retroperitoneal smooth muscle sarcoma is an aggressive lesion that often does not allow for complete surgical excision.
Smooth muscle sarcoma of cutaneous origin
Smooth muscle sarcomas can occur in the dermis, and those that occur in these areas should be classified as cutaneous smooth muscle sarcomas. Unlike other forms of smooth muscle sarcoma, cutaneous lesions occur in males and females in a 2:1 ratio (11). These lesions of the skin are usually small (1-2 cm) at the time of initial diagnosis and the prognosis is generally good (12). Smooth muscle sarcomas that occur in the dermis are mostly thought to be from the erector spinae of the dermis (20). When tumors occur in tiny vessels in the dermis, they should be considered smooth muscle sarcomas of the soft tissues of the body, and the behavior of these tumors is mostly consistent with lesions from deeper sites. When lesions are limited to the dermis, metastasis does not usually occur (11). Thirty to 40% of lesions in deeper tissues can metastasize, mostly through the bloodstream to the lungs (12). Treatment of cutaneous smooth muscle sarcoma includes extensive excision, and lesions of any histologic grade are curable when limited to the dermis.
Smooth muscle sarcomas originating from blood vessels
Smooth muscle sarcomas rarely occur directly in large blood vessels; however, once a tumor originates in a large blood vessel, it is called a vascular smooth muscle sarcoma. To date, only a few hundred cases of smooth muscle sarcoma of vascular origin have been reported. In a review of 86 cases, smooth muscle sarcomas of vascular origin occurred mostly in the vessels of the low pressure system, most commonly in the larger veins (68 cases), especially in the inferior vena cava (33 cases), less frequently in the pulmonary artery (10 cases), and rarely in the peripheral arteries (8 cases) (13).
If tumors occur in the inferior vena cava around the liver, they are likely to present with Buga syndrome: hepatomegaly, jaundice and ascites, and these tumors are usually not completely surgically resectable. If the tumor is located at the level of the subhepatic area, it presents with vaguely localized abdominal pain and lower extremity edema, and the symptoms vary depending on the anatomic location of the lesion, its vascular physiology and drainage pattern.
Arterial smooth muscle sarcomas usually affect the pulmonary arteries, and patients often complain of dyspnea and chest discomfort due to arterial obstruction, which is related to the distribution of blood flow and collateral circulation.
Smooth muscle sarcoma in immunocompromised hosts
Since the 1970s, there have been many reports of smooth muscle sarcomas in immunocompromised and immunosuppressed patients after transplantation (15). More recently, there have been numerous case reports of lesions occurring in patients with HIV and AIDS (6). EBV and tumorigenesis have also been reported. A study of multiple smooth muscle sarcoma cases reported that simultaneous clonal analysis showed that multiple tumors were independent of each other (16). The relationship between factors such as immunodeficiency and EBV and the development of smooth muscle sarcoma is unclear.
Smooth muscle sarcoma of bone
Primary smooth muscle sarcoma of bone is very rare. Approximately 90 cases have been reported since it was first described in 1965 (22, 23). Many cases were initially thought to be primary smooth muscle sarcoma of bone, but later, after further study, many cases were found to be mostly bone invasion of nearby soft tissues or metastatic lesions of bone. Most of the reported cases of smooth muscle sarcoma of bone are found in the epiphysis of long bones, and these lesions are thought to originate from small intravascular smooth muscle cells or pluripotent mesenchymal stem cells in bone, and their histologic appearance is identical to that of soft tissue smooth muscle sarcoma. Although there are reports of this tumor occurring in other parts of the bone, the radiographic appearance of these tumors is mostly typical of lesions in the epiphysis of long bones (24). X-rays and other imaging data alone cannot establish the diagnosis of smooth muscle sarcoma.
Staging
The staging of smooth muscle sarcoma is important both in guiding treatment and in providing information for prognosis. Although many staging systems exist for soft tissue sarcomas, the most commonly used system is the AJCC system (9). This staging system is based on histologic grading, tumor size, superficial or deep location, and the presence or absence of metastases.
The Musculoskeletal Tumor Society (MSTS) surgical staging system is commonly used in the staging of bone and soft tissue sarcomas and also smooth muscle sarcomas (10). This staging system classifies tumors into stages I, IIA, IIB, and III based on their pathologic grading, the extent of local invasion, and the presence or absence of metastases. If the tumor is confined to a single interstitial compartment, it is mostly considered limited. If it is beyond a localized interstitial compartment, then it is mostly considered as a non-confined lesion.
Retroperitoneal smooth muscle sarcoma metastasizing to the bilateral proximal femur. Non-contrast T – 1 weighted MRI images show lesions metastasizing to both femurs, and in this case surgical intervention is necessary to prevent fracture.
Staging: The American Cancer Consortium (AJCC) was established to develop and publish systematic cancer classifications, including staging and final outcome reports, that are most accepted and chosen for use by the medical community to select treatment options, evaluate prognosis and assess cancer control measures. In soft tissue tumors, the Enneking Surgical Staging System grade is based on histologic grading (G), tumor location (T) and metastasis (M), as determined by pathologic, imaging and clinical features. It is the most widely used staging system in soft tissue sarcomas and is included by the Musculoskeletal Oncology Society (see the eMedicine website for staging and treatment planning for musculoskeletal tumors).
Histology
The histopathologic features of smooth muscle sarcoma are variable and typically include an area with abundant cells, H&E staining for pink to dark red areas, and abundant cytoplasm. The cells are arranged in a fenestrated pattern and well-differentiated tumor cells are often arranged at the right angle to distinguish the polarity of a region. The nucleus is usually located in the center of the cell and is typically cigar-like. One of the features of smooth muscle sarcoma is the presence of important myofibers that are distributed along the long axis of the cell and run the full length of the cell. As the cells become less differentiated, the arrangement of the cells becomes disorganized and loosely characterized (4).
The concept of “dedifferentiation”: Pathologists and oncologists often use differentiation to describe tumors with the potential for aggressive behavior. Cellular “differentiation” is a description that refers to a specific cell type having specific characteristics that make it “different” from other cell types. For example, an adipocyte is different from a chondrocyte because these two types of cells have many different characteristics. Many types of connective tissue cells come from a common precursor cell, but they get different signals while expressing certain proteins and develop certain characteristics that turn them into unique cell types. Sarcoma cells come from these types of cells but undergo a malignant transformation. In other words, they already have the ability to metastasize.
Differentiation is the microscopic description of the histological differences between a tumor and its cells of origin, and this description provides the basis for the physician to assess the aggressive behavior of the tumor and the patient’s prognosis. Well-differentiated tumors closely resemble the tissue of their origin, whereas hypodifferentiated tumors rarely have the characteristics of their cells of origin. The important difference is that well-differentiated tumors rarely have invasive metastatic potential, whereas hypofractionated tumors can exhibit invasive and metastatic capabilities. In addition, the term “dedifferentiation” is often used to describe a tumor that no longer has any relationship to its cells of origin. For example, a patient with a well-differentiated liposarcoma has a tumor that closely resembles fat or adipose tissue and has no tendency to metastasize. It is important to note that these dedifferentiated tumors may require a completely different approach.
Pathologic subtypes of soft tissue smooth muscle sarcoma of the body include epithelioid smooth muscle sarcoma, mucinous smooth muscle sarcoma, inflammatory smooth muscle sarcoma, granulocytic smooth muscle sarcoma, and dedifferentiated smooth muscle sarcoma (4). The clinical significance of these subtypes has not been well studied.
Histologic features under optical microscopy are the most important decision factor in the diagnosis of smooth muscle sarcoma, however other modalities such as immunohistochemistry and electron microscopy also play an important role. Immunohistochemical markers that help support the diagnosis include actin, nodulin, MSA (HHF35), cytokeratin (CK), and epithelial membrane antigen (EMA). Although not required for diagnosis, one or more of these markers are often found in smooth muscle sarcoma specimens. Electron microscopy often further elucidates the classic nuclear morphology of the tumor. Genetic analysis of soft tissue smooth muscle sarcoma cells in bulk cases does not reveal consistent chromosomal translocations or aberrations (18).
Tumor size, cell morphology, anisotropy, necrosis, and high magnification field nuclear division images can help identify benign smooth muscle tumors and smooth muscle sarcomas. The number of mitoses per high magnification field of view is considered to be the most reliable of these indicators (25). It is important to note that when considering soft tissue smooth muscle tumors, the cut-off value for the nuclear division index is lower than the standard used in uterine smooth muscle sarcoma. The presence of nuclear schizograms should raise a high suspicion of malignancy, especially when there is cellular anisotropy or the presence of focal necrosis.
Treatment
As these tumors are relatively rare, they mostly require a multidisciplinary team and treatment is best performed in a sarcoma center with extensive experience. At our treatment center, treatment planning begins with the patient’s history, a multidisciplinary consultation, all available x-ray imaging, and pathologic findings on biopsy. A treatment plan is developed with the participation of orthopedic surgeons, general surgeons, musculoskeletal radiologists, pathologists, oncologists, and radiation oncologists.
Surgery
Local control of soft tissue sarcomas is usually achieved by surgical excision. Preoperative planning based on x-ray and pathology is important to ensure that adequate safe surgical margins are available. Extensive safe surgical margins are an important surgical modality to prevent local recurrence.
Radiation Therapy
Many tumors directly invade adjacent vital structures, in which case extensive resection is not possible. Radiation therapy is an important tool to improve local control of high-grade sarcomas, especially in those with inadequate margins. Radiotherapy can be given before surgery (neoadjuvant) or after surgery (adjuvant). Radiotherapy can also be used as a palliative treatment for extensive metastatic lesions.
Chemotherapy
The primary role of chemotherapy is in the treatment of metastatic disease, and although not curative, it can slow the progression of systemic disease. Drugs commonly used in some sarcoma centers include: Adriamycin, isocyclophosphamide, Kenzyme and Tysodi (doxorubicin), and dacarbazine. Chemotherapy is sometimes used as an adjuvant treatment for localized sarcomas. There is no clear evidence of survival benefit from chemotherapy for retroperitoneal smooth muscle sarcoma; however, preoperative chemotherapy may help shrink the tumor away from vital structures, improving the surgical resection rate for large tumors. In focal smooth muscle sarcoma of the extremities, there is a survival benefit with adjuvant adjuvant chemotherapy based regimens using adriamycin (28). Both retrospective and prospective studies have shown that neoadjuvant chemotherapy using an adriamycin+isocyclophosphamide based regimen in high-grade sarcomas larger than 8 cm improves survival.
Prognosis and outcome
Retroperitoneal smooth muscle sarcoma
In a recent review of soft tissue smooth muscle tumors, Weiss compiled a series of data on retroperitoneal smooth muscle sarcomas (see Table 3). The results show that these tumors are highly biologically aggressive. Neither tumor size nor mitosis was associated with outcome which also precludes the effect of these tumors being bulky lesions at the time of initial diagnosis on the overall outcome.
Soft tissue smooth muscle sarcoma
In most cases, the number of patients reported is small, and no meta-analysis has been published to provide definitive prognostic data. Deep soft tissue sarcomas are often detected before they reach the volume of the retroperitoneal lesion, and approximately half of these patients die from metastatic disease. Factors associated with poor prognosis include age > 62 years, tumor volume > 4 cm, tumor necrosis, high FNCLCC grade, vascular invasion, or prior intra-focal resection (1, 17). Mitotic index has no direct correlation with prognosis but is a useful parameter to identify benign and malignant tumors. In a retrospective study of 66 cases of soft tissue smooth muscle sarcoma, Mankin found that MSTS stage and tumor volume had a significant impact on prognosis, but gender, age, site, adjuvant therapy, and the presence of local recurrence did not have a significant impact on prognosis (7). Most reports show a 3-year survival rate of 50% and a 5-year survival rate of 64% for soft tissue smooth muscle sarcoma, thus making it a highly malignant soft tissue sarcoma (1, 7).
Cutaneous smooth muscle sarcoma
True intradermal smooth muscle sarcoma is considered to be nonmetastatic and therefore the issue of local control of the disease is paramount. Intradermal tumors are curable, and surgery can resolve the problem.
Vascular smooth muscle sarcoma
Smooth muscle sarcomas of vascular origin have a poor prognosis. Because of their rarity, definitive diagnosis is often delayed and complete resection is usually not possible. Local complications of the primary tumor are a major cause of high disability and mortality, with metastases to the liver and lungs occurring in 54% of patients and having approximately the same metastatic rate as other forms of smooth muscle sarcoma (14).
Smooth muscle sarcoma in immunocompromised hosts
Because of the absence of information such as case compilations, little is known about the specific prognosis of this rare sarcoma. However, in most cases the biological behavior of this smooth muscle sarcoma is aggressive, as shown in the reports.
Smooth muscle sarcoma of bone
In the largest case series study to date, extensive surgical resection did not show any difference in the treatment of primary smooth muscle sarcoma of bone compared with surgery plus radiation and/or chemotherapy. In this study, local recurrence occurred in 24% of cases and metastases occurred in 24% of cases, all to the lungs. 3- and 5-year survival rates were 77% and 68% (29).
Pediatric patients
The occurrence of smooth muscle sarcoma in children is rare. In a study of 20 smooth muscle sarcomas in patients under the age of 16 years, no gender preference was found (5). The tumors were distributed in the head and neck, upper extremities, lower extremities, and trunk, with no site differences. Most of the lesions in this study (85%) were low grade, with 2 cases of local recurrence, and no patient died at the end of this study, and the prognosis of smooth muscle sarcoma in children seems to be better than in adults (2, 3, 5).
Conclusion
Smooth muscle sarcoma is a highly aggressive sarcoma that can occur at any site. Despite significant advances in treatment options, smooth muscle sarcoma remains one of the more difficult soft tissue sarcomas to treat. Accurate diagnosis, classification, and a physician familiar with these tumors are essential for a favorable outcome.
Because of their rarity, many studies of these tumors are difficult to perform. As an example, few data have been published on patients with soft tissue smooth muscle sarcoma of the trunk. This fact has prompted us to review those tumors treated at our very experienced treatment facility, and we are currently preparing to publish data on the treatment and prognosis of over 120 patients with soft tissue smooth muscle sarcoma. These retrospective analyses, along with well-designed prospective randomized clinical trials, may help to further determine the best treatment for these tumors in the future.
Local overall control is currently achieved by extensive surgical resection, and neoadjuvant or adjuvant radiation therapy is an additional means of local control. Chemotherapy is indicated for the treatment of systemic disease. Ongoing clinical trials may identify certain agents to improve the overall and disease-free survival of patients with this disease.