Are You Confident of the Diagnosis?
Although this chapter will focus on leyomiosarcomas of cutaneous or subcutaneous origin, for a better understanding of the pathophysiology of the disease, comments on leiomyosarcoma of soft tissue are included.
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% to 10% are leiomyosarcomas.
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. Primary leiomyosarcoma of bone is a distinct entity that is quite rare. While histologically similar, soft tissue leiomyosarcoma has classically been subdivided into three groups for prognostic and treatment purposes: leiomyosarcoma of soft tissue, cutaneous leiomyosarcoma and leiomyosarcoma of vascular origin. 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.
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 fifth and sixth 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. In the case of retroperitoneal tumors. Presenting signs and symptoms can include an abdominal mass, pain, swelling, weight loss, nausea or vomiting. Leiomyosarcoma of soft tissues, like other soft tissue sarcomas, often presents 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 but can present in childhood.
Characteristic findings on physical examination
The clinical symptoms accompanying the diagnosis of cutaneous and subcutaneous leiomyosarcomas are nonspecific. The most common finding at presentation is a painless, gradually enlarging mass (Figure 1). The size of the tumor at diagnosis varies according to the site; tumors of the distal limbs and head or neck are usually smaller because they are likely to be noticed earlier.
The growth rate of soft-tissue sarcomas including cutaneous and subcutaneous leiomyosarcomas varies with the aggressiveness of the tumor. Low-grade tumors may evolve over a long period and may be mistaken for benign tumors, especially dermatofibromas. Such a mistake may delay referral to a specialist center. Indeed, the identification relies on clinical examination, imaging, and histologic analysis. Examination and imaging can be used to define the tumor’s relationship to surrounding structures.
Expected results of diagnostic studies
Typically, once a lesion suspicious for a sarcoma has been discovered, diagnosis and staging studies are performed simultaneously. Initial imaging should include a magnetic resonance image (MRI) of the lesion and a chest computed tomography (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 muscle, nerves or compression of vascular 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 in those cases of subcutaneous leiomyosarcoma. This technique can be performed in most cases with less morbidity than an open incisional biopsy.
Who is at Risk for Developing this Disease?
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. 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 soft tissue.
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. These lesions are typically small when first diagnosed (1 to 2cm), and prognosis is generally good. When leiomyosarcoma develops within the dermis itself it is thought to be derived from the pilar erector. 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. Deeper lesions can metastasize in up to 30% to 40% of cases, usually hematogenously to the lungs. Treatment consists of wide resection and is often curative when the lesion is initially confined to the dermis, regardless of histologic grade.
What is the Cause of the Disease?
Soft-tissue sarcomas account for only about 1% of all cancers. Approximately 8700 new cases of soft-tissue sarcoma are diagnosed each year in the United States and about 1500 in the United Kingdom. The relative frequency and response of each subtype vary according to age. Most soft-tissue sarcomas are sporadic; few have an identifiable cause. There is an association between certain viral infections (notably Epstein–Barr virus in those with AIDS) and leiomyosarcoma.
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 surgical oncologists, radiologists, pathologists, medical oncologists, and radiation oncologists.
Surgery is the mainstay of treatment for all soft-tissue sarcomas and, supplemented when necessary by adjuvant radiotherapy, is often curative for localized leiomyosarcomas. Treatment is best planned in a multidisciplinary setting, which facilitates consideration of the need for preoperative induction treatment, discussion of reconstructive strategies, and planning for rehabilitation. This assessment should include histologic review by an expert on soft-tissue sarcoma to verify or alter the classification or grade of the tumor; a change in the grade or class may necessitate a change in the treatment plan (Figure 2, Figure 3).
Surgical resection involving wide margins, with or without radiotherapy, offers the best chance of cure in the absence of metastatic disease. The operation should be planned by an experienced surgical team after careful study of the scans. Because cutaneous and subcutaneous leiomyosarcoma can occur at any site, every operation will be different, though common surgical oncologic principles prevail (Figure 4, Figure 5, Figure 6, Figure 7).
Soft-tissue sarcomas expand spherically and along tissue planes and their centrifugal growth creates a false capsule, or pseudocapsule, of compressed surrounding tissue. Malignant cells penetrate this pseudocapsule. Simple removal of visible tumor in this plane leaves microscopic disease in situ, and 90% of tumors recur unless there is further treatment. Over 30% will recur even after further excision of the tumor bed, and the subsequent use of radiotherapy does not compensate for the presence of unplanned positive histologic margins. Thus, the goal of surgery is to resect the tumor with wide (2 to 3cm) margins when possible, removing at least one uninvolved tissue plane circumferentially.
Most patients with a cutaneous or subcutaneous leiomyosarcoma and wide resection margins will not require further treatment (including radiotherapy). It is rarely necessary to reconstruct major vessels or to resect major nerves unless they are encased by tumor.
Surgical margins should be documented by both surgeon and the pathologist in evaluating a resected specimen. If surgical resection margins are positive on final pathology, surgical re-resection to obtain negative margins should strongly be considered if it will not have a significant impact upon functionality. If it is safe from an oncologic perspective, preserving one innervated muscle in any compartment results in better function than a more radical approach.
Although tumors are usually smaller in the distal limbs than in the proximal limbs, it is more difficult to preserve function in the distal limbs, especially the forearms and hands. Preoperative induction treatment may reduce the size of tumors of distal limbs and facilitate better functional results.
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 preoperatively (neoadjuvant) or postoperatively (adjuvant). Radiation therapy can also be utilized as a means of palliative local control in cases where extensive metastasis has already occurred.
The cytotoxic effects and therapeutic role of radiotherapy in treating soft-tissue sarcomas are well described. Radiotherapy should be considered for high-grade tumors of the limbs (unless margins are very wide) and for intermediate-grade tumors of the limbs with close or positive histologic margins. Radiotherapy has little role in primary low-grade soft-tissue sarcoma, although it should be considered for a recurrence.
Radiotherapy is delivered as either external-beam therapy or brachytherapy. The latter involves the insertion of radioactive “seeds” or wires (usually iridium-192) into surgically placed catheters traversing the tumor bed. Brachytherapy has theoretical advantages postoperatively, given the hypoxic nature of the wound and the radiobiologic characteristics of the inverse-square law (local doses are high, but the dose decreases proportionally with increasing distance from the tumor).
These advantages are even more important in patients who have already undergone external-beam radiotherapy. No randomized clinical trial has compared these types of delivery. Not all sites are suitable for brachytherapy, and many prefer to perform external-beam therapy with its use of standardized fields. Occasionally, both methods are combined — for example, when a large external-beam field is used with a brachytherapy boost to a specific area.
Radiotherapy alone is considered when surgery is inappropriate or declined by the patient; it achieves rates of local control of 30% to 60%. More commonly, operative treatment is coupled with adjuvant radiotherapy on the basis of evidence demonstrating similar survival rates after limb-conserving surgery with radiotherapy and after amputation.
Optimal timing remains unclear. A lower total dose of radiotherapy (50Gy) is required when it is delivered preoperatively. Postoperatively, a total of 60 to 66Gy is usually delivered to maximize killing of hypoxic tumor cells. One trial of external-beam therapy in patients with soft-tissue sarcoma of the limbs demonstrated similar effectiveness whether therapy was administered preoperatively or postoperatively. Functional outcome in the group treated preoperatively was slightly better but was associated with a doubling in the incidence of wound-healing problems. Counterintuitively, delaying postoperative radiotherapy does not significantly worsen the rate of late control of local disease.
Enhanced targeting and delivery of radiotherapy with the use of intensity-modulated techniques represent a potential advance of this treatment.
Whereas the goal of surgery and radiotherapy is local control of the tumor, the aim of chemotherapy is systemic control, which may be therapeutic, adjuvant, or palliative. Although some subtypes of soft-tissue sarcoma are sensitive to chemotherapeutic agents, the outcome of therapeutic chemotherapy is unsatisfactory overall, and the use of adjuvant chemotherapy is controversial. A meta-analysis of adjuvant chemotherapy did not demonstrate an overall survival advantage, although progression-free survival improved.
Although local treatment of primary cutaneous and subcutaneous leiomyosarcoma influences the likelihood of local recurrence and functional outcome, the metastatic potential is mainly determined by the grade and size of the primary tumor. There is little evidence that local recurrence increases the likelihood of metastatic spread, although debate on this point continues. Except for rhabdomyosarcomas and Ewing’s sarcomas, the use of adjuvant chemotherapy generally does little to influence the natural history of the soft tissue sarcomas.
The use of traditional generic approaches to chemotherapy belies the heterogeneity of soft-tissue sarcomas. Chemosensitivity varies according to the tumor subtype, and the likelihood of a response and survival is further influenced by the tumor grade, the patient’s age, performance status, and the timing of metastatic disease. Leiomyosarcoma, for example, responds variably to conventional chemotherapy, depending on the site and grade of the tumor. 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, preoperative 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. Both retrospective and prospective studies have shown a benefit for neoadjuvant doxorubicin- and ifosfamide-based regimens in patients with large (>8cm) high-grade sarcomas.
Targeted molecular therapy
Encouraging progress is occurring with the use of therapies directed against specific molecular targets associated with soft-tissue sarcoma, however, at this moment there is not a specific molecular alteration to be targeted in cutaneous or subcutaneous leiomyosarcomas.
Optimal Therapeutic Approach for this Disease
Soft tissue sarcomas may be heterogeneous, so adequate tissue should be obtained via carefully planned biopsy being either core-needle or incisional biopsy for microscopic examination to determine histologic type and tumor grade. Careful planning of the initial biopsy is important, placed along planned future resection axis with minimal dissection and careful attention to hemostasis to avoid compromising subsequent curative resection.
Since the selection of treatment is determined by the grade of the tumor, it is essential to have a careful review of the biopsy tissue by a pathologist who is experienced in diagnosing sarcomas. Complete staging and treatment planning by a multidisciplinary team of cancer specialists is required to determine the optimal treatment for patients with this disease. In most cases, a combined modality approach of preoperative or postoperative radiation therapy is used, rather than the radical surgical procedures that were used in the past.
The role of chemotherapy is less well defined. Because of the evolving nature of the state of the art in the treatment of this disease, all patients with such lesions should be included in a clinical trial whenever possible.
Post-treatment surveillance (by means of clinical examination and chest radiography or CT) is recommended to detect treatable recurrence and metastasis. Recurrence rates of 5% to 10% might be expected after optimal treatment of soft-tissue sarcomas of the limbs. The utility of CT and MRI for detecting subclinical local recurrence has not been established, but these approaches may be more useful for detecting deep lesions. Since two thirds of recurrences occur within 2 years, follow-up should be most intense during this period.
Options for Advanced Disease
All three major approaches to treatment — systemic chemotherapy, radiotherapy, and surgery — may prove useful in patients with advanced disease, depending on the circumstances. Systemic chemotherapy has a palliative role, as discussed earlier. Radiotherapy may provide substantial control of symptoms, particularly for patients with inoperable localized symptomatic disease. Surgery with a goal of limb salvage is useful for locally recurrent disease. Reconstruction is more frequently needed in this setting. Amputation should be considered in patients with advanced disease, if severe pain, fungation, or bleeding is present.
Unusual Clinical Scenarios to Consider in Patient Management
When the diagnosis of leiomyosarcoma is made, an inquiry should be made regarding a family history of such lesions, uterine fibroids, and renal cancer to determine if any further investigation should be made for the possiblity of hereditary leoimyomatosis and renal cell carcinoma syndrome.
What is the Evidence?
McClain, KL, Leach, CT, Jenson, HB, Joshi, VV, Pollock, BH, Parmley, RT. “Association of Epstein–Barr virus with leiomyosarcomas in young people with AIDS”. N Engl J Med. vol. 332. 1995. pp. 12-8. (Study that links EBV infections in HIV-positive individuals that have developed leiomyosarcoma. Nine patients with smooth muscle tumors were evaluated. Only one was located in the subcutaneous tissue. The rest were intracranial or intraspinal.)
Jemal, A, Tiwari, RC, Murray, T, Ghafoor, A, Samuels, A, Ward, E. “Cancer statistics, 2004”. CA Cancer J Clin. vol. 54. 2004. pp. 8-29. (Annual review of all cancer statistics from the United States. Reviewed over 1.3 million cases of cancer diagnosed in 2004.)
Rydholm, A. “Improving the management of soft tissue sarcoma: diagnosis and treatment should be given in specialist centres”. BMJ. vol. 317. 1998. pp. 93-4. (Excellent review of the diagnostic criteria used for soft-tissue tumors and their management, both surgical and medical.)
” Adjuvant chemotherapy for localized resectable soft-tissue sarcoma of adults: meta-analysis of individual data”. Lancet. vol. 350. 1997. pp. 1647-54. (Study of the use of chemotherapy in the treatment of adult soft-tissue tumors including leiomyosarcomas. Uses a meta-analysis to compare therapies.)
Hensley, ML, Maki, R, Venkatraman, E, Geller, G, Lovegren, M, Aghajanian, C. “Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial”. J Clin Oncol. vol. 20. 2002. pp. 2824-31. (Phase II trial results using these two agents to treat unresectable leiomyosacomas. This chemotherapy was tolerable and highly active in treating leiomyosarcomas.)
Whooley, BP, Gibbs, JF, Mooney, MM, McGrath, BE, Kraybill, WG. “Primary extremity sarcoma: what is the appropriate followup?”. Ann Surg Oncol. vol. 7. 2000. pp. 9-14. (Nice discussion on the follow-up management of sarcomas of the extremity with expert opinion on management.)
Stojadinovic, A, Leung, DH, Allen, P, Lewis, JJ, Jaques, DP, Brennan, MF. “Primary adult soft tissue sarcoma: time-dependent influence of prognostic variables”. J Clin Oncol. vol. 20. 2002. pp. 4344-52. (Review of adult soft-tissue sarcomas. Looks at many variables and tries to correlate with prognosis. Leiomyosarcomas are discussed.)
“NCCN Guidelines Version 1.2011 Soft Tissue Sarcomas”. (Standardized guidelines for the treatment of most types of cancer. This section is for the treatment of soft-tissue sarcomas.)
Clark, MA, Fisher, C, Judson, I, Thomas, JM. ” Soft-tissue sarcomas in adults”. N Engl J Med. vol. 353. 2005. pp. 701-11. (The best review of the diagnosis, management and treatment of soft-tissue sarcomas.)
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