Leiomyosarcomas account for 5% to 10% of soft tissue sarcomas. They are principally tumors of adults but are far outnumbered even in this age group by more common sarcomas, such as liposarcoma and undifferentiated pleomorphic sarcoma (malignant fibrous histiocytoma). Likewise, they are less common than leiomyosarcomas of uterine or gastrointestinal origin, and only some of the data gleaned from the collective experience with tumors in these two sites are directly applicable to the soft tissue counterpart. Few predisposing or etiologic factors are recognized for this disease. In general, these tumors are more common in women than men. About two-thirds of all retroperitoneal leiomyosarcomas and more than three-quarters of all vena caval leiomyosarcomas occur in women. The reasons for this are unclear, although growth and proliferation of smooth muscle tissue in women have been noted to coincide with pregnancy and estrogenic stimulation (see Chapter 15 ). Children rarely develop these tumors, and there is conflicting evidence as to whether leiomyosarcomas in children have a better prognosis. Many pediatric tumors reported as leiomyosarcoma appear to instead represent Epstein-Barr virus–related smooth muscle proliferations.
Leiomyosarcomas rarely occur after radiation therapy but may develop as a second malignancy in the setting of bilateral (hereditary) retinoblastoma. Because these tumors may occur at sites distant from the previously irradiated site, their pathogenesis is directly attributable to the RB1 mutation and not to irradiation. Deletions or mutations of the RB1 locus can be identified in a small number of leiomyosarcomas that occur on a sporadic basis as well. There is no evidence that leiomyomas undergo malignant transformation except in extraordinarily rare cases. Well-differentiated areas resembling leiomyoma are often found in a leiomyosarcoma, but this by no means proves that malignant transformation occurred. In fact, the predilection of leiomyosarcomas for deep soft tissue, in contrast to the superficial location of leiomyomas, provides some evidence to the contrary. As a group, leiomyosarcomas may have a poorer prognosis than other sarcomas when matched for other variables.
It is useful to divide leiomyosarcomas into several site-related subgroups because of significant clinical and biologic differences. In fact, site alone is one of the most important prognostic factors in assessing outcome in this disease. Leiomyosarcomas of the retroperitoneum and abdominal cavity are the most common subgroup and are associated with an aggressive clinical course. Leiomyosarcomas of somatic soft tissue are a second, but less common, subgroup associated with a better prognosis. There is increasing evidence that many, if not most, arise from small vessels, a relationship that may be important for defining the behavior and risk of metastasis. Although technically such lesions could be referred to as “vascular leiomyosarcomas,” this designation usually refers to a tumor arising from a major vessel so that clinical symptoms, radiographic findings, or both suggest the relationship preoperatively. A third subgroup comprises leiomyosarcomas of vascular origin. Again, this designation is used to refer to tumors arising from medium-size or large veins, in contrast to leiomyosarcomas for which vascular origin is identified on the basis of microscopic examination. Defined in this manner, these tumors are rare.
Primary tumors of the skin showing morphologic features of leiomyosarcoma have an excellent prognosis because of their superficial location and limited clinical stage. These lesions have historically been labeled “cutaneous leiomyosarcomas” but are now classified by the World Health Organization (WHO) as “atypical intradermal smooth muscle neoplasms.” Leiomyosarcomas may occur in an unusual soft tissue site, such as the head and neck and paratesticular region, but these are decidedly uncommon.
Retroperitoneal/Abdominal Leiomyosarcomas
About one-half to three-quarters of all soft tissue leiomyosarcomas arise in the retroperitoneum and a smaller number in the abdominal cavity or mediastinum. Two-thirds of affected patients are women, and peak incidence is in the seventh decade. The presenting signs and symptoms are relatively nonspecific and include an abdominal mass or swelling, pain, weight loss, nausea, or vomiting ( Fig. 16.1 ).
Gross and Microscopic Findings
Virtually all retroperitoneal tumors are more than 5 cm, and most are larger than 10 cm when first detected, in striking contrast to the majority of somatic soft tissue leiomyosarcomas. They usually involve other structures, such as the kidney, pancreas, and vertebral column by direct extension. Grossly, some have a white-gray whorled appearance resembling a leiomyoma on a cut section ( Fig. 16.2 ), whereas others are fleshy, white-gray masses with foci of hemorrhage and necrosis, indistinguishable from other sarcomas.
Histologically, the typical cell of a leiomyosarcoma is elongated and has abundant cytoplasm that varies tinctorially from pink to deep red in routinely stained sections. The nucleus is usually centrally located and blunt ended or cigar shaped ( Fig. 16.3 ). In some smooth muscle cells, a vacuole is seen at one end of the nucleus, causing a slight indentation, so the nucleus assumes a concave rather than a convex contour. In less well-differentiated tumors, the nucleus is larger and more hyperchromatic and often loses its central location. Multinucleated giant cells are common. Poorly differentiated leiomyosarcomas may consist of essentially undifferentiated-appearing pleomorphic spindled cells, resembling undifferentiated pleomorphic sarcoma, and requiring a careful search for more typical areas. Likewise, depending on the degree of differentiation, the appearance of the cytoplasm varies. Differentiated cells have numerous well-oriented myofibrils that are demonstrable as deep-red, longitudinally placed parallel lines running the length of the cell on Masson trichrome stain ( Fig. 16.4 ). In poorly differentiated cells the longitudinal striations are less numerous, poorly oriented, and therefore more difficult to identify. In some tumors the cytoplasm has a clotted appearance because of clumping of the myofilamentous material ( Fig. 16.5 ). When this phenomenon occurs, it may be difficult to identify linear striations. Leiomyosarcomas are typically composed of slender or slightly plump cells arranged in fascicles of varying size ( Figs. 16.6 to 16.9 ). In well-differentiated areas the fascicles intersect at right angles, so it is possible to see transverse and longitudinal sections side by side, similar to the pattern of a uterine myoma. However, in many areas, the pattern is not that orderly, and it more closely resembles the intertwining fascicular growth of an adult-type fibrosarcoma ( Fig. 16.10 ). In occasional leiomyosarcomas, the nuclei align themselves to create palisades, similar to a schwannoma ( Fig. 16.11 ). Hyalinization is a relatively common but usually focal feature of many leiomyosarcomas ( Fig. 16.12 ). Extensively hyalinized leiomyosarcomas largely lack typical morphologic features, requiring ancillary immunohistochemical studies for a definitive diagnosis. Some leiomyosarcomas may also show chiefly epithelioid features.
About 10% of retroperitoneal leiomyosarcomas are anaplastic tumors, which in the extreme case resemble an undifferentiated pleomorphic sarcoma ( Figs. 16.13 and 16.14 ). Some anaplastic leiomyosarcomas appear to arise abruptly from preexisting well-differentiated tumors; such tumors have been referred to as dedifferentiated leiomyosarcomas, although this term is not universally accepted. Anaplastic leiomyosarcomas contain numerous pleomorphic giant cells with deeply eosinophilic cytoplasm intimately admixed with a complement of more uniform-appearing spindle and round cells ( Figs. 16.15 and 16.16 ). In contrast to undifferentiated pleomorphic sarcoma, these tumors have less interstitial collagen and few inflammatory cells. In addition, it is usually possible to document myogenic differentiation in the less pleomorphic areas. Necrosis, hemorrhage, and mitotic figures are frequent in these pleomorphic tumors. Osteoclastic giant cells may rarely be seen in leiomyosarcomas, representing an unusual host response to the tumor. Some retroperitoneal leiomyosarcomas appear to represent dedifferentiated liposarcomas showing extensive heterologous differentiation.
Histologic Variants of Leiomyosarcoma
Inflammatory leiomyosarcoma is a rare entity defined as a leiomyosarcoma containing xanthoma cells and a prominent inflammatory infiltrate, usually lymphocytes but occasionally neutrophils ( Fig. 16.17 ). These tumors do not occur in any specific location and may be associated with constitutional or paraneoplastic symptoms such as anorexia, fever, night sweats, and diarrhea. Interestingly, whereas these tumors express desmin to a significant degree, they lack or only focally express other muscle markers, including muscle-specific actin, alpha smooth muscle actin, and caldesmon, suggesting that these lesions may not be true smooth muscle tumors. Most cases analyzed have displayed a near-haploid karyotype. Although originally associated with an excellent prognosis, recent cases have been reported with metastases.
Myxoid change may occur in leiomyosarcomas. When extensive, these tumors appear grossly gelatinous and are referred to as myxoid leiomyosarcoma. Although most common in the uterus, they develop in conventional soft tissue locations as well. The spindled muscle cells are separated by pools of hyaluronic acid, and in cross section the fascicles resemble the cords of tumor seen in a myxoid chondrosarcoma ( Figs. 16.18 and 16.19 ). Because these tumors are quite hypocellular relative to conventional leiomyosarcomas, mitotic rates estimated by counting high-power fields (hpf) are usually deceptively low, giving the false impression of a benign tumor. In general, myxoid leiomyosarcomas segregate toward the low-grade end of a grading spectrum. Of the 18 cases reported by Rubin and Fletcher, nine were considered grade 1, eight grade 2, and only one grade 3. Five of 13 patients experienced recurrences, often repeated, and two patients developed metastases. Spillage of the gelatinous matrix at surgery may contribute to the common phenomenon of local recurrence.
Rarely, leiomyosarcomas contain cells with granular eosinophilic cytoplasm (granular cell leiomyosarcomas). This change corresponds to the presence of numerous granules that stain positive on periodic acid–Schiff (PAS) and are diastase resistant. Ultrastructurally, these granules are similar to the phagolysosomes seen in granular cell tumors.
Immunohistochemical Findings
Although many leiomyosarcomas are easily diagnosed by light microscopy examination alone, poorly differentiated/anaplastic and extensively hyalinized tumors may require immunohistochemical confirmation of smooth muscle differentiation. It is important to keep in mind, however, that the distribution and intensity of muscle markers in highly pleomorphic areas of leiomyosarcoma are generally diminished compared to classic-appearing areas.
Antibodies to smooth muscle–specific actin (monoclonal antibody 1A4) and pan-muscle actin (monoclonal antibody HHF35) are positive in most leiomyosarcomas. Desmin, which is more variable, has been documented in one-half to almost 100% of tumors, depending on the series. Although there seems to be general agreement that the presence of desmin diffusely throughout a tumor usually indicates myoid differentiation, the presence of actin or desmin focally should not necessarily be equated with myoid lineage, because myofibroblasts in a variety of neoplastic and nonneoplastic conditions also display these phenotypes. The pattern of smooth muscle actin expression may be helpful in discriminating true smooth muscle from myofibroblasts, with the former typically showing robust expression within the entire cell and the latter showing wispy expression confined to the periphery of the cytoplasm (tram-track pattern). Other markers of smooth muscle differentiation, including heavy caldesmon (h-caldesmon) and smooth muscle myosin heavy chain, are less sensitive (approximately 40%) than muscle actins and desmin for the diagnosis of leiomyosarcoma, although they are less often expressed in myofibroblasts. However, these markers may be expressed in myoepithelial cells, a potential pitfall in locations such as the skin and breast.
The immunophenotype of leiomyosarcomas may vary according to their origin. For example, tumors arising from vascular smooth muscle often show a desmin-negative, h-caldesmon–positive phenotype, and those arising in somatic soft tissue locations more often express desmin and less often h-caldesmon. Anomalous keratin expression is relatively common in leiomyosarcomas, present in almost 40% of cases, and aberrant epithelial membrane antigen expression may also be seen. Keratin expression in leiomyosarcomas is limited to low-molecular-weight types (keratins 8 and 18). Leiomyosarcomas may also express CD34, S-100 protein, and estrogen and progesterone receptors. Hormone receptor expression is not confined to leiomyosarcomas of gynecologic type in women and is not of value in the distinction of tumors of gynecologic and nongynecologic origin. For reasons not entirely clear, some conventional leiomyosarcomas may show aberrant immunoreactivity for the melanocyte-associated marker HMB45, either in the primary tumor or in metastases ( Fig. 16.20 ).
The differential diagnosis of these rare tumors with perivascular epithelioid cell neoplasms is discussed in Chapter 29 .
Criteria of Malignancy
Criteria of malignancy in smooth muscle tumors are mentioned briefly in Chapter 15 . In general, the finding of significant nuclear atypia, even of a focal nature, is a cause for concern in soft tissue smooth muscle tumors and should lead to an evaluation of mitotic activity. By definition, leiomyosarcomas possess some degree of nuclear atypia, but mitotic activity varies considerably. However, even very low levels of mitotic activity (<1 figure/10 hpf) are accepted in the face of significant atypia as sufficient evidence of malignancy. In retroperitoneal lesions, coagulative necrosis also is usually present and can be extensive.
Differential Diagnosis
The differential diagnosis for leiomyosarcoma includes both nonpleomorphic spindle cell tumors, such as leiomyoma (of gynecologic and nongynecologic types), cellular schwannoma, gastrointestinal stromal tumor, synovial sarcoma, malignant peripheral nerve sheath tumor, and inflammatory myofibroblastic tumor, and a variety of other pleomorphic sarcomas. Leiomyomas of gynecologic-type smooth muscle are common in the pelvis and retroperitoneum and may achieve a large size at the time of diagnosis. As in the uterus, extrauterine gynecologic-type smooth muscle tumors may show mitotic activity but lack cytologic atypia and coagulative tumor cell necrosis (as distinct from infarct-type necrosis). Leiomyomas of gynecologic-type smooth muscle closely resemble uterine leiomyomas, with thick-walled blood vessels, trabecular and corded growth patterns, and occasionally fat. Leiomyomas of somatic soft tissue by definition are hypocellular, devoid of cytologic atypia, and essentially amitotic. Cellular schwannomas are encapsulated, cellular, fascicular proliferations of well-differentiated, S-100 protein–positive, actin- and (usually) desmin-negative Schwann cells, typically containing peripheral lymphoid aggregates, and intratumoral foamy macrophages. However, there have been exceptionally rare cases of cellular schwannoma exhibiting anomalous desmin immunoreactivity, apparently representing cross-reactivity with glial fibrillary acidic protein. Extraintestinal gastrointestinal stromal tumors show a lesser degree of cytoplasmic eosinophilia than in true smooth muscle tumors and typically express both CD117 (c-kit) and DOG1 (both positive in >90% of GISTs). Inflammatory myofibroblastic tumors usually arise in much younger patients than true smooth muscle tumors and show a prominent mixed chronic inflammatory cell infiltrate, stromal hyalinization, and calcifications. Strong expression of ALK1 protein is seen in many inflammatory myofibroblastic tumors but not in smooth muscle tumors. Monophasic synovial sarcomas show alternating zones of hypocellularity and hypercellularity, carrot-shaped nuclei, wiry collagen, a staghorn vascular pattern, and numerous stromal mast cells. Expression of TLE1 and keratins (focally), but not muscle markers, is typical of synovial sarcoma. Malignant peripheral nerve sheath tumors lack the diffuse cytoplasmic eosinophilia of leiomyosarcoma, have wavy or buckled nuclei, and show patchy expression of S-100 protein and/or SOX10 but not actins or desmin.
Genetic Findings
Karyotypic analyses of leiomyosarcomas typically show complex numeric and structural abnormalities, without consistent losses or gains. Frequently lost chromosome regions include 3p21-23, 8p21-pter, 13q12-13, 13q32-qter, with areas of frequent gain, including the 1q21-31 region. Comparative genomic hybridization studies have shown gain from chromosomes 1, 15, 17, 19, 20, 22, and X and loss from 1q, 2, 4q, 9p, 10, 11q, 13q, and 16. Gain of material from chromosomes 6q and 8q may be seen in larger tumors. At the molecular genetic level, methylation-related inactivation of cancer-associated genes such as RASSF1A and p16INK4 has been associated with poor prognosis in patients with leiomyosarcomas. The RB1 gene has been implicated in some cases of leiomyosarcoma, with frequent abnormalities in the Rb-cyclin D1 pathway. TP53 and MDM2 abnormalities have historically been thought to be less common in leiomyosarcoma than in other sarcoma subtypes, although alterations in these loci may be associated with a poor prognosis in leiomyosarcomas. A very recent whole exome and transcriptome sequencing study of leiomyosarcomas found TP53 inactivation in almost all studied cases. Other abnormalities identified in many cases in this study included RB1 inactivation, numerous DNA copy number alterations with chromothripsis, and frequent whole genome duplication. Alternative lengthening of telomeres, with recurrent alterations of ATRX, RBL2, and S-100 protein, were seen in more than 75% of cases. Leiomyosarcomas showing alternative lengthening of telomeres and ATRX expression reportedly have aggressive histologic features and poor outcome. In another recent targeting exome sequencing study of leiomyosarcomas, Agaram et al. found frequent losses of chromosomal regions involving a variety of tumor suppressor genes, including TP53 , PTEN , CDH1 , and RB1 , as well as rearrangements of the myocardin gene ( MYOCD ) in 20% of analyzed cases. MYOCD rearrangements have been reported in leiomyosarcomas in other studies as well.
Specific gene expression signature patterns may further help to predict outcome. Similarities between the gene expression patterns of leiomyosarcomas and undifferentiated pleomorphic sarcomas also suggest that some cases previously classified as the latter entity instead represent particularly poorly differentiated leiomyosarcomas. An interesting gene expression profiling study showed high-level expression of macrophage-associated genes in subsets of leiomyosarcomas, and a high density of tumor infiltrating macrophages was significantly associated with worse disease-specific survival in nongynecologic tumor.
Clinical Behavior
Retroperitoneal leiomyosarcomas are aggressive lesions that cause death not only by distant metastasis but also by local extension. The survival figures differ among series and are obviously influenced by the criteria of malignancy, proportion of high-grade versus low-grade tumors, and length of the follow-up. Early studies reflected mortality rates of 80% to 90% within 2 to 5 years of follow-up. However, a multiinstitutional study by the National Federation of Centers in the Fight Against Cancer (French Sarcoma Group, FNCLCC) detailing experience with 165 retroperitoneal sarcomas of all types indicates that an improvement in complete resection rates in retroperitoneal sarcomas has reduced local recurrence to 50% and improved survival rates to 50%. Factors that influence outcome in (nonliposarcomatous) retroperitoneal sarcomas include size, grade, and whether extension to bone and nerve is present. More recent studies have reported better outcome in retroperitoneal leiomyosarcomas treated with more aggressive surgical resection. A study of 586 leiomyosarcomas of head/neck, retroperitoneal, trunk, and extremity locations from the French Sarcoma Group found retroperitoneal location, tumor size larger than 5 cm, deep location, and grade greater than 1 to be independent adverse prognostic factors for metastasis-free and disease-free overall survival by multivariate analysis.
Leiomyosarcomas of Somatic Soft Tissue
Compared with retroperitoneal lesions, tumors arising from the soft tissues of the extremities and trunk are much less common and affect the sexes equally. Only 48 cases were identified by Gustafson et al. in a 22-year review of a Swedish population in Lund, and Farshid et al. studied 42 cases largely based on referred consultations. The Scandinavian Sarcoma Group (Leiomyosarcoma Working Group) series included 225 patients with leiomyosarcomas of nonvisceral soft tissue. The French Sarcoma Group series included 366 patients with extremity leiomyosarcomas. These tumors present as an enlarging mass, usually in the lower extremity. About half develop in the subcutis and the remainder in muscle. They have a circumscribed multinodular appearance and are significantly smaller (4-6 cm) than those in the retroperitoneum. When examined microscopically, at least one-third arise from a small vein causing expansion of the wall and protrusion into the lumen. Because many remain partially or completely confined by the adventitia, they give the impression of being discrete, encapsulated lesions, a feature that often leads to an inadvertent enucleation by the surgeon. Despite their vascular origin, few are associated with symptoms of vascular compromise as occurs with leiomyosarcomas arising from major vessels. The histologic features and criteria of malignancy in this group of leiomyosarcomas are similar to those in the retroperitoneum, with some minor exceptions. Although by definition all display some degree of atypia, the range of mitotic activity can be wide, with levels as low as less than 1 figure/10 hpf. Necrosis is rarely encountered to the extent seen in retroperitoneal leiomyosarcomas.
Compared with retroperitoneal tumors, the behavior of somatic soft tissue leiomyosarcomas has been relatively poorly defined as a result of the smaller number of reported cases. In the Scandinavian series, 84% of patients with localized disease at presentation remained free of locally recurrent disease at a median of 5.5 years of follow-up, with distant metastases in 34% and death from disease in 51% of patients, respectively. In the recent French series, approximately 40% of patients with extremity leiomyosarcomas were metastasis free at 140 months, compared with 75%, 60%, and 25% of patients with tumors in trunk wall, head/neck, and retroperitoneal locations, respectively. Older series have shown local recurrence rates of 10% to 25% and metastatic rates of 44% to 45%, with 5-year survival of 64%. Most metastases develop in the lung and rarely in lymph nodes.
A number of variables affect the prognosis in somatic soft tissue leiomyosarcomas, but their relative importance differs, depending on the study. Gustafson et al. found that age over 60 years and vascular invasion were independent risk factors for death from the tumor, whereas others have reported depth, tumor size, and stage as independent factors. In the Farshid study, factors predictive of metastasis at 36 months in a multivariate analysis were grade (FNCLCC system) and whether the tumor had been violated surgically (disruption). However, disruption also correlated with size and depth and therefore could represent a surrogate marker for both. On the other hand, this group of soft tissue sarcomas requires special scrutiny because their frequent origin from vessels may grant them greater accessibility to the bloodstream and hematogenous dissemination. This phenomenon was underscored by Berlin et al., who reported metastasis from all six extremity leiomyosarcomas that originated from veins. One patient with a small (3 cm) mass arising from the saphenous vein died 1 month after surgery with liver and lung metastases. Data from the Scandinavian group showed that decreased metastasis-free survival was associated with higher tumor grade, larger tumor size, and deeper tumor location, with higher tumor grade also significantly associated with decreased overall survival. The most important prognostic factors for extremity leiomyosarcomas identified in the French Sarcoma Group study were size more than 5 cm, grade greater than 1, and a high genome complexity score using the CINSARC (complexity index in sarcomas) 67 gene expression panel.
Leiomyosarcomas of Vascular Origin
Leiomyosarcomas of vascular origin are a seemingly rare group of tumors, with only a few hundred cases reported in the literature and only isolated instances recorded in several large autopsy series. Hallock et al. noted one case in 34,000 autopsies, Abell reported two in 14,000 autopsies, and Dorfman and Fisher found none in 30,000 autopsies. Several features of this disease probably significantly affect its detection, diagnosis, and incidence. Lesions arising from major vessels, such as the vena cava, are likely to produce symptoms leading to their detection. Conversely, tumors arising from small vessels, vessels subserved by ancillary tributaries, or vessels in deep locations probably go unrecognized in a significant percentage of cases. It is therefore difficult to be certain what percentage of leiomyosarcomas of the retroperitoneum or other deep soft tissue sites may actually be of vascular origin. Hashimoto et al. documented that, in their experience, at least one-fourth of leiomyosarcomas of peripheral soft tissue arose from or involved a vessel; this has been observed in at least one-third of cases. Therefore, the recorded experience with vascular leiomyosarcomas is biased, which probably underestimates the true incidence and possibly conveys a false impression of clinical behavior.
Clinical Findings
The distribution of vascular leiomyosarcomas parallels in a crudely inverse fashion the pressure in the vascular bed. Leiomyosarcomas are most common in large veins such as the vena cava, far less common in the pulmonary artery, and rare in systemic arteries. In the extensive review by Kevorkian and Cento, of cases reported up to the early 1970s, a total of 33 cases arose in the inferior vena cava, and 35 collectively affected other medium-size or large veins; 10 occurred in the pulmonary artery alone, and 8 arose in systemic arteries. One report has indicated the unique occurrence of a leiomyosarcoma in a surgically created arteriovenous fistula. The symptoms related to these tumors are diverse and are determined by the location of the tumor, rate of growth, and degree of collateral blood flow or drainage in an affected part.
Inferior Vena Cava Leiomyosarcoma
Inferior vena cava leiomyosarcomas occur during middle or late adult life, at an average age of about 50 years; 80% to 90% of patients are women. The location of the tumor in the vessel is significant because it determines the symptoms and surgical resectability. Based on material submitted to the International Registry of Inferior Vena Cava Leiomyosarcomas, most tumors arise in the lower (44.2%) or middle (50.8%) portion, with only a small number (4.2%) arising from the upper third or suprahepatic region. Patients with upper-segment tumors develop Budd-Chiari syndrome, with hepatomegaly, jaundice, and massive ascites. Nausea, vomiting, and lower-extremity edema may also be present. These tumors are surgically unresectable. Tumors of the middle segment involve the region between the renal veins and hepatic veins; they produce symptoms of right upper quadrant pain and tenderness, frequently mimicking biliary tract disease. Extension into the hepatic veins may cause some of the symptoms of Budd-Chiari syndrome, whereas extension into the renal veins results in varying degrees of renal dysfunction, from mild elevation of blood urea nitrogen to nephrotic syndrome. Some of these lesions are surgically resectable. Lesions arising below the renal veins cause lower-leg edema, but unless they have spread extensively beyond the confines of the vessel, they are often amenable to surgical excision.
To date, the long-term outlook for this disease is poor. A large study comparing caval wall resection with a more extended segmental resection of the vessel demonstrated no significant difference in 5-year (55% vs. 37%) or 10-year (42% vs. 23%) survival. This seems to indicate that, at clinical detection, the disease is relatively advanced and not curable by surgery in most patients. Improved outcome was reported in a small series of Korean patients, with a multidisciplinary approach, including resection, prosthetic inferior vena cava grafting, chemotherapy, and radiotherapy. Similar findings were reported from two large Brazilian hospitals Metastatic disease is seen most often in the lung, kidney, pleura, chest wall, liver, and bone.
Leiomyosarcomas of Other Veins
Unlike vena cava lesions, those in other veins affect the sexes equally and most often arise in the veins of the lower extremity, including the saphenous, iliac, and femoral veins. They usually present as mass lesions of variable duration that occasionally produce lower-leg edema. Pressure on nerves coursing close to the affected vessel may produce additional symptoms of numbness. Angiographically, the lesions are highly vascular and create compression of the accompanying artery. The compression appears to result from entrapment of the artery that resides in the same preformed fibrous sheath (conjunctiva vasorum) as the vein. Because an incisional biopsy of intravascular sarcomas can result in considerable seeding of tumor by hemorrhage, thorough radiographic evaluation should be followed by a needle biopsy in select cases. The behavior of this group of leiomyosarcomas has been a controversial topic. Although one series suggested that small intravascular leiomyosarcomas might have a relatively good prognosis, all six patients reported by Berlin et al. developed metastases, even those with relatively low mitotic rates. However, all but one of the tumors exceeded 4 cm in diameter.
Pulmonary Artery Leiomyosarcoma
Pulmonary artery leiomyosarcomas are the most common form of arterial leiomyosarcoma. They occur in adults and display no sex predilection. Their symptoms are referable to decreased pulmonary outflow and include chest pain, dyspnea, palpitations, dizziness, syncopal attacks, and eventual right-sided heart failure. Until recently, the diagnosis was inevitably made at autopsy. Most of these tumors arise at the base of the heart and grow distally into the left and right main pulmonary arteries.
Gross and Microscopic Findings
In almost all reported cases, vascular leiomyosarcomas are described as polypoid or nodular masses that are firmly attached to the vessel at some point and have spread for a variable extent along its surface ( Fig. 16.21 ). However, some reported cases describing extensive spread along the vena cava into the right side of the heart may represent misdiagnosed intravenous leiomyomatosis (see Chapter 15 ). In the case of thin-walled veins, extension to the adventitial surfaces and adjacent structures is a relatively early event, whereas in arteries the integrity of the internal elastic lamina is often preserved so that no spread occurs outside the vessel. Histologically, the tumors are similar to those in the retroperitoneum, although they usually do not exhibit as much hemorrhage or necrosis ( Fig. 16.22 ). Mitoses are rather easy to identify in these tumors, and the histologic criteria of malignancy previously discussed are equally applicable to these lesions. True leiomyomas arising from vessels are rare, and this diagnosis should be made with extreme caution and only after the lesion has been sampled extensively.
