Uterine leiomyosarcomas are the most common uterine sarcomas. For clinicians, they are difficult tumours to manage. Preoperative detection is difficult because of the similarity in clinical presentation to ordinary fibroids. They are highly aggressive tumours and the effectiveness of adjuvant therapy remains controversial with surgery remaining the mainstay of treatment. Despite treatment, disease frequently recurs. For pathologists, diagnosis of most leiomyosarcomas using current diagnostic criteria is usually straightforward, as most tumours often possess two or more diagnostic microscopic features, including diffuse atypia, high mitotic count and tumour cell necrosis. Diagnostic difficulties usually relate to tumours having only one of these worrisome features, with or without other additional unusual morphologic findings. These latter tumours have been labelled as uterine smooth-muscle tumours of uncertain malignant potential. Those that are followed by a recurrence are biologically low-grade leiomyosarcomas. Epithelioid and myxoid leiomyosarcomas are less common, and their diagnostic criteria are different to tumours of usual spindle cell differentiation. In this review, we discuss the pathology of leiomyosarcomas, including an update on smooth-muscle tumours of uncertain malignant potential, with emphasis on the controversy of labelling of atypical leiomyomas. The problems with histologic diagnosis, immunohistochemical studies and molecular pathology are reviewed.
Leiomyosarcoma
Uterine leiomyosarcomas (LMS) are rare, and represent only 1% of all uterine malignancies; notwithstanding, they are still the most common uterine sarcomas. Affected women are usually over 40 years of age, and typically present with symptoms almost identical to ordinary leiomyomas. Because of this, preoperative detection of malignancy is often difficult. Rarely, the presentation is that of uterine rupture and haemoperitoneum.
It has been estimated that only 1 in 800 uterine smooth-muscle tumours is malignant, making it statistically unlikely that LMS arise from pre-existing leiomyomas. It is partly for this reason that most investigators believe that most LMS are sporadic and arise de novo . This hypothesis is supported by recent studies involving microRNAs, in which the miRNA expression profiles between LMS and leiomyomas have been shown to be different (see subsequent section on molecular pathology). Conversely, the presence of leiomyoma-like areas in LMS (specifically, cellular and symplastic areas), with discovery of additional genetic aberrations in the sarcoma, differences in immunohistochemical profile between the benign and sarcomatous areas within the same tumour, and demonstration of identical pattern of X-chromosome inactivation between benign and malignant tumours suggest that a minority of tumours indeed originate from pre-existing leiomyomas.
Pathology
Most uterine LMS are solitary, with a mean diameter of 10 cm. Most are located intramurally. Less than 5% of tumours are cervical in origin. When concurrent multiple leiomyomas occur, the malignant lesion is almost always the largest lesion. The border of a LMS is usually infiltrative or irregular. Instead of the typical whorled appearance of a leiomyoma, the cut surface is usually soft and fleshy, alternating with areas of necrosis and haemorrhage ( Fig. 1 A).
Uterine LMS are classified into different histologic subtypes, based on cellular characteristics and constituents of the intercellular stroma. Most are of spindle cell type (usual differentiation). Leiomyosarcomas with epithelioid or myxoid differentiations are less common, and their diagnostic criteria are different. Clinically, malignant tumours of these latter differentiations usually show a lesser degree of cytologic atypia and lower mitotic counts ( Table 1 ).
| Histologic subtype | Diagnostic criteria | Additional features |
|---|---|---|
| Spindle cell (usual) | Any two of the following features: diffuse moderate-to-severe atypia; ≥ 10 mitotic figures per 10 high power fields; tumour–cell necrosis. | |
| Epithelioid | Either moderate-to-severe atypia and ≥ 5 mitotic figures per 10 high power fields or tumour–cell necrosis and ≥ 5 mitotic figures per 10 high power fields. | > 50% cells must be epithelial cell-like |
| Myxoid | Any one of the following features: moderate-to-severe atypia; ≥ 2 mitotic figures per 10 high power fields; tumour–cell necrosis. | Hypocellular, stroma stained with alcian blue. Usually has infiltrative border |
| Other rare morphology | Any of the above three subtypes may contain areas with sex cord-like elements, xanthomatous cells, rhabdomyoblasts, osteoclastic giant cells and lipoblasts. |
Leiomyosarcomas of usual (spindle cell) differentiation
The current approach to diagnosis was derived by the Stanford investigators after studying 213 cases of problematic uterine smooth-muscle tumours, which has formed the basis for the current World Health Organization classification. Most clinically malignant tumours usually show a combination of diffuse moderate-to-severe nuclear atypia, greater than10 mitotic figures (MF) per 10 high power fields (HPF), and presence of (coagulative) tumour-cell necrosis ( Fig. 1 B). Tumours that have any two of these features are also sufficient to be diagnosed as LMS ( Table 1 ). Additionally, clinically malignant tumours are usually hypercellular and have an infiltrative border. Vascular invasion may sometimes be encountered, but it is not a common finding and its presence alone is not always indicative of malignancy.
Tumour-cell necrosis, the ‘bad necrosis’, is a common finding in 80% of LMS, characterised by an abrupt transition from viable to necrotic cells. Infarct-type (or hyaline) necrosis, the ‘good necrosis’, may be seen in benign leiomyomas and LMS, is characterised by the presence of a zone of reparative granulation tissue separating the viable and devitalised tissue. Tumours that appear histologically benign, with only tumour-cell necrosis, can occasionally be clinically malignant ; it is, therefore, important to distinguish this from infarct-type necrosis. Having said that, the distinction may not be easy, especially in early infarcts in which there may be little or no reparative granulation tissue. When there is difficulty in determining the type of necrosis (also known as ‘necrosis of an uncertain type’) in a tumour without atypia or a high mitotic count, a smooth-muscle tumour of uncertain malignant potential (STUMP) diagnosis is warranted (see subsequent section on STUMP).
Epithelioid leiomyosarcomas
Epithelioid LMS do not differ grossly from those of the spindle cell subtype. Histologically, they are defined by the presence of rounded or polygonal cells that have a microscopic appearance of ‘epithelial cells’ in at least 50% of the tumour ( Fig. 1 c). Immunohistochemical study is sometimes necessary to confirm the smooth-muscle nature. Unfortunately, the tumour cells in about 20% of epithelioid smooth-muscle tumours express cytokeratins (as in carcinomas) and less often myogenic markers such as desmin. Histone deacetylase 8 and myocardin have recently been shown to be superior markers for epithelioid smooth-muscle tumours compared with desmin or h-caldesmon. The diagnostic criteria for epithelioid LMS are listed in Table 1 .
Epithelioid smooth-muscle tumours that are composed of clear cells may show overlapping features with perivascular epithelioid cell tumours (PEComas). PEComas are composed of perivascular epithelioid cells that have no known normal cellular counterpart. They typically show focal association with blood-vessel walls, and shows immunophenotypic features of both smooth muscle and melanocytic differentiation. A subset of tumours is found in women who also have lymphangiomyomatosis, angiomyolipomas of various visceral organs, and tuberous sclerosis. The lesional cells have clear to eosinophilic granular cytoplasm, and are arranged in nests or cords separated by a hyalinised stroma (resembling an epithelioid smooth-muscle tumour). Characteristically, PEComas show immunoreactivity for HMB-45, Melan-A, or both. In one-third of cases, there is also expression of myogenic markers, and distinction from epithelioid LMS may be difficult. Extensive immunoreactivity for MiTF has been reported in PEComas but not in epithelioid smooth-muscle tumours.
Myxoid leiomyosarcomas
Myxoid LMS have a gelatinous gross appearance and often a deceptively well-circumscribed border. Histologically, they are tumours that contain abundant, acellular stroma caused by the accumulation of hyaluronic acid-rich glycosaminoglycans that can be confirmed by alcian blue stain ( Fig. 1 d).
Pathologic assessment of malignancy is more difficult in myxoid smooth-muscle tumours because of the hypocellularity, difficulty in assessment of tumour border, and the fact that tumour-cell necrosis is less often encountered. Hypocellularity causes the tumour cells to be widely separated, resulting in a lower mitotic count. The cells may be more oval or stellate with less cytoplasm, and the atypia is less conspicuous. Sometimes, even the recognition of their smooth-muscle nature may be difficult, and confirmation with immunostains is necessary. An infiltrative border is known to be associated with malignant behaviour in myxoid smooth-muscle tumours; however, in one study, one-third of benign cases also showed this feature. The diagnotic criteria for myxoid LMS are listed in Table 1 .
Leiomyosarcomas with rare morphology
Rare cases of LMS may contain sex cord-like elements, xanthomatous cells, rhabdomyoblasts and osteoclast-like giant cells. Nevertheless, the clinical significance of their additional presence is unknown. The presence of lipoblasts usually indicates an underlying liposarcoma; some of these may have originated from a pre-existing lipoleiomyoma.
Pathology
Most uterine LMS are solitary, with a mean diameter of 10 cm. Most are located intramurally. Less than 5% of tumours are cervical in origin. When concurrent multiple leiomyomas occur, the malignant lesion is almost always the largest lesion. The border of a LMS is usually infiltrative or irregular. Instead of the typical whorled appearance of a leiomyoma, the cut surface is usually soft and fleshy, alternating with areas of necrosis and haemorrhage ( Fig. 1 A).
Uterine LMS are classified into different histologic subtypes, based on cellular characteristics and constituents of the intercellular stroma. Most are of spindle cell type (usual differentiation). Leiomyosarcomas with epithelioid or myxoid differentiations are less common, and their diagnostic criteria are different. Clinically, malignant tumours of these latter differentiations usually show a lesser degree of cytologic atypia and lower mitotic counts ( Table 1 ).
| Histologic subtype | Diagnostic criteria | Additional features |
|---|---|---|
| Spindle cell (usual) | Any two of the following features: diffuse moderate-to-severe atypia; ≥ 10 mitotic figures per 10 high power fields; tumour–cell necrosis. | |
| Epithelioid | Either moderate-to-severe atypia and ≥ 5 mitotic figures per 10 high power fields or tumour–cell necrosis and ≥ 5 mitotic figures per 10 high power fields. | > 50% cells must be epithelial cell-like |
| Myxoid | Any one of the following features: moderate-to-severe atypia; ≥ 2 mitotic figures per 10 high power fields; tumour–cell necrosis. | Hypocellular, stroma stained with alcian blue. Usually has infiltrative border |
| Other rare morphology | Any of the above three subtypes may contain areas with sex cord-like elements, xanthomatous cells, rhabdomyoblasts, osteoclastic giant cells and lipoblasts. |
Leiomyosarcomas of usual (spindle cell) differentiation
The current approach to diagnosis was derived by the Stanford investigators after studying 213 cases of problematic uterine smooth-muscle tumours, which has formed the basis for the current World Health Organization classification. Most clinically malignant tumours usually show a combination of diffuse moderate-to-severe nuclear atypia, greater than10 mitotic figures (MF) per 10 high power fields (HPF), and presence of (coagulative) tumour-cell necrosis ( Fig. 1 B). Tumours that have any two of these features are also sufficient to be diagnosed as LMS ( Table 1 ). Additionally, clinically malignant tumours are usually hypercellular and have an infiltrative border. Vascular invasion may sometimes be encountered, but it is not a common finding and its presence alone is not always indicative of malignancy.
Tumour-cell necrosis, the ‘bad necrosis’, is a common finding in 80% of LMS, characterised by an abrupt transition from viable to necrotic cells. Infarct-type (or hyaline) necrosis, the ‘good necrosis’, may be seen in benign leiomyomas and LMS, is characterised by the presence of a zone of reparative granulation tissue separating the viable and devitalised tissue. Tumours that appear histologically benign, with only tumour-cell necrosis, can occasionally be clinically malignant ; it is, therefore, important to distinguish this from infarct-type necrosis. Having said that, the distinction may not be easy, especially in early infarcts in which there may be little or no reparative granulation tissue. When there is difficulty in determining the type of necrosis (also known as ‘necrosis of an uncertain type’) in a tumour without atypia or a high mitotic count, a smooth-muscle tumour of uncertain malignant potential (STUMP) diagnosis is warranted (see subsequent section on STUMP).
Epithelioid leiomyosarcomas
Epithelioid LMS do not differ grossly from those of the spindle cell subtype. Histologically, they are defined by the presence of rounded or polygonal cells that have a microscopic appearance of ‘epithelial cells’ in at least 50% of the tumour ( Fig. 1 c). Immunohistochemical study is sometimes necessary to confirm the smooth-muscle nature. Unfortunately, the tumour cells in about 20% of epithelioid smooth-muscle tumours express cytokeratins (as in carcinomas) and less often myogenic markers such as desmin. Histone deacetylase 8 and myocardin have recently been shown to be superior markers for epithelioid smooth-muscle tumours compared with desmin or h-caldesmon. The diagnostic criteria for epithelioid LMS are listed in Table 1 .
Epithelioid smooth-muscle tumours that are composed of clear cells may show overlapping features with perivascular epithelioid cell tumours (PEComas). PEComas are composed of perivascular epithelioid cells that have no known normal cellular counterpart. They typically show focal association with blood-vessel walls, and shows immunophenotypic features of both smooth muscle and melanocytic differentiation. A subset of tumours is found in women who also have lymphangiomyomatosis, angiomyolipomas of various visceral organs, and tuberous sclerosis. The lesional cells have clear to eosinophilic granular cytoplasm, and are arranged in nests or cords separated by a hyalinised stroma (resembling an epithelioid smooth-muscle tumour). Characteristically, PEComas show immunoreactivity for HMB-45, Melan-A, or both. In one-third of cases, there is also expression of myogenic markers, and distinction from epithelioid LMS may be difficult. Extensive immunoreactivity for MiTF has been reported in PEComas but not in epithelioid smooth-muscle tumours.
Myxoid leiomyosarcomas
Myxoid LMS have a gelatinous gross appearance and often a deceptively well-circumscribed border. Histologically, they are tumours that contain abundant, acellular stroma caused by the accumulation of hyaluronic acid-rich glycosaminoglycans that can be confirmed by alcian blue stain ( Fig. 1 d).
Pathologic assessment of malignancy is more difficult in myxoid smooth-muscle tumours because of the hypocellularity, difficulty in assessment of tumour border, and the fact that tumour-cell necrosis is less often encountered. Hypocellularity causes the tumour cells to be widely separated, resulting in a lower mitotic count. The cells may be more oval or stellate with less cytoplasm, and the atypia is less conspicuous. Sometimes, even the recognition of their smooth-muscle nature may be difficult, and confirmation with immunostains is necessary. An infiltrative border is known to be associated with malignant behaviour in myxoid smooth-muscle tumours; however, in one study, one-third of benign cases also showed this feature. The diagnotic criteria for myxoid LMS are listed in Table 1 .
Leiomyosarcomas with rare morphology
Rare cases of LMS may contain sex cord-like elements, xanthomatous cells, rhabdomyoblasts and osteoclast-like giant cells. Nevertheless, the clinical significance of their additional presence is unknown. The presence of lipoblasts usually indicates an underlying liposarcoma; some of these may have originated from a pre-existing lipoleiomyoma.
Immunohistochemistry and molecular pathology
Diagnosis of most LMS can usually be made by light microscopic examination. In tumours with uncertain or poor differentiation, or when distinction from other neoplasms is required, a combination of markers, including desmin, smooth-muscle actin and h-caldesmon, may be used to confirm the smooth-muscle origin. Additional markers for epithelioid tumours have already been discussed in the preceding section, epithelioid LMS.
The overexpression of p16 has been identified in 86.7%, 86% and 51% of uterine LMS in three studies. The frequency of overexpression of p53 protein in uterine LMS has been variable and has ranged from 13–56.5%, with one study reporting a frequency of 71.4% (five out of seven cases). Therefore, absence of p53 staining in uterine smooth-muscle tumours does not exclude a diagnosis of LMS. Overexpression of p53 in LMS was an adverse prognostic factor in some studies. In one, it was significantly associated with recurrence in stage I–II disease. In another, overexpression of p53 was apparently associated with a shorter patient survival, although such results were not statistically significant on multivariate analysis. A higher proliferative index (ki-67) was found in LMS compared with leiomyomas or STUMPs that did not recur. O’Neill et al. determined that a ki-67 greater than 30% was indicative of an LMS, although 29% of their LMS had values lower than this, leading them to conclude that ki-67 staining lacks sensitivity for malignancy.
Oestrogen, progesterone and androgen receptors are expressed in about 30–40% of LMS. Immunoreactivity with these markers may provide a target for treatment. Even though some LMS show immunoreactivity for CD117 (C-KIT) but there is no underlying KIT oncogenic mutation or KIT phosphorylation, targeted treatment with imatinib is ineffective.
LMS are genetically unstable tumours characterised by complex chromosomal abnormalities and highly disturbed gene regulation. Currently, no specific chromosomal translocation or gene mutation has been identified, except in women with germline mutations involving the fumarate hydratase gene. These women are reported to develop multiple cutaneous and uterine leiomyomas at a young age, and have an increased risk for developing LMS and renal cell carcinoma.
Nearly all LMS are karyotypically complex, with imbalances involving several chromosomes, but there is no consistent pattern of gains or losses.
Unlike benign leiomyomas and normal myometrium, most LMS show differential expression of many genes involved in cell proliferation and regulation of the cell cycle. In particular, upregulation of CDKIN2A enables the immunohistochemical detection of p16, the protein to which it encodes. p16 is therefore a useful marker for differentiating between malignant and benign smooth-muscle tumours, as noted in the preceding section.
MicroRNA (miRNA) expression is becoming recognised as a possible epigenetic mechanism in the pathogenesis of uterine smooth-muscle tumours. MiRNAs are 20–25 nucleotide non-coding RNAs that exhibit the translation of targarted mRNAs. They have been shown to recapitulate the cell lineage or tissue of origin reliably, and could therefore be used to subclassify tumours. The miRNA expression profiles between LMS and leiomyoma have been shown to be different. The former have been shown to be closely related to mesenchymal stem cell, whereas the latter are similar to mature smooth-muscle cells, indicating that they are in fact two separate entities. Additionally, the expression of miR-21 levels is higher in LMS compared with uterine leiomyomas or benign metastasising leiomyomas in other studies.
Behaviour
High-grade LMS are highly aggressive tumours, with survival rates in most studies ranging from 15–30%, and median survival ranging from 13–43 months. As many as 70% of women with stage I–II disease, and almost all women with stage III–IV disease will develop a recurrence between an interval of 8–16 months. Clinical and pathological features reported to be associated with poor prognosis and decreased long-term survival in several studies include age (greater than 50 years), a high mitotic count (greater than 15–19 MFs/10 HPFs), absence of residual disease at the time of initial surgery, presence of vascular space invasion, tumour-cell necrosis and presence of an epithelioid component and myxoid differentiation. None of these, however, are consistent. The most powerful predictor for an adverse outcome is the stage. For early stage tumours, the lack of gross circumscription, tumour size greater than 10 cm and greater than 10 MFs/10 HPFs were independent prognostic factors by multivariate analysis. In another study involving a large number of tumours, stage and histologic grade were shown to be independent prognostic factors. Histologic grading of LMS nonetheless is still controversial, with no universally accepted grading system. Tumour size greater than 5 cm was a major prognostic indicator in two studies. This last parameter has now been incorporated into the 2009 International Federation of Gynecology and Obstetrics staging for uterine LMS.
Uterine smooth-muscle tumour of uncertain malignant potential
The term STUMP was first used by Kempson in 1973 for tumours that were clinically malignant, but by using the available diagnostic criteria at the time, a correct diagnosis of sarcomas could not have been made. The criteria for these tumours have evolved over the ensuing 38 years, as our knowledge of the behaviour of uterine smooth-muscle tumours with varying combinations of atypical features has accrued. For example, tumours that were once considered STUMPs because of only an unusually high mitotic rate, or the presence of bizarre giant cells, but with no other worrisome features, are now regarded as benign variants of leiomyoma, respectively, as ‘mitotically active leiomyoma’ and ‘bizarre leiomyoma’ (we prefer the term ‘leiomyoma with bizarre nuclei’ as it is a better reflection of its nature). Conversely, 17 years ago, Bell et al. recognised that an otherwise benign-appearing uterine smooth-muscle tumour containing only tumour-cell necrosis can occasionally be clinically malignant, and thus such tumours are now appropriately considered STUMPs. According to the current WHO classification, if a tumour shows any unusual combinations of histologic features that do not satisfy the Stanford criteria for LMS, a diagnosis of uterine STUMP is appropriate. Although it is also stated that the term should not be used as a diagnosis for difficult cases, the lack of clearly defined criteria could potentially lead to pathologists having differing interpretations.
Clinical features
Women with STUMPs usually present with the same clinical picture as those with ordinary leiomyomas, and the age at presentation is similar to those with LMS and benign leiomyomas. Women diagnosed with STUMP followed by a subsequent recurrence, however, seem to be younger than those with an uneventful follow up. In two studies, the mean age of women with recurrent disease was 44.5 and 33.7 years, respectively, compared with 47.5 and 43.9 years in those without.
Pathology
Histological diagnosis of smooth-muscle tumour of uncertain malignant potential
In the Stanford study involving 213 problematic uterine smooth-muscle tumours, the term ‘STUMP’ was not used ; however four histologic subgroups of uterine smooth-muscle tumours that had a low or uncertain malignant potential were delineated: (1) ‘atypical leiomyoma with limited experience’, if the tumour showed focal or multifocal moderate-to-severe atypia, less or equal to 10 MFs/10 HPFs and no tumour cell necrosis; (2) ‘smooth-muscle tumour with low malignant potential’, if the tumour showed tumour-cell necrosis, but absent-to-mild atypia and less than10 MFs/10 HPFs; (3) ‘atypical leiomyoma with low risk of recurrence’, if there was diffuse moderate-to-severe atypia, less than 10 MFs/10 HPFs, and no tumour cell necrosis; and (4) ‘mitotically active leiomyoma with limited experience’, if the only worrisome feature is a mitotic count of greater or equal to 20/10 HPFs. Cases with different histologic combinations that have been classified as STUMPs are presented in Table 2 , although it is not exhaustive. Other investigators would also include tumours with any other unusual combination of histologic features, such as uncertain differentiations (i.e. epithelioid or myxoid) and tumours with uncertain type of necrosis or mitotic counts. Nonetheless, the number of such cases reported is too small and their true recurrence rate is unknown. Many cases with necrosis of an uncertain type are usually early infarcts; under most circumstances, a drug-induced cause could often be found.
| Authors | Histologic subtype used | Atypia | Mitotic figures (MF) per 10 high power fields (HPFs) | Tumour cell necrosis | Cases reported with recurrence |
|---|---|---|---|---|---|
| Tumors with necrosis only | |||||
| Bell , Rosai , Clement and Young , Oliva , Quade and Robboy , Nucci , Hendrickson , Zaloudek | STLMP | None | <10 | Yes | 26.7% (4 of 15 cases) |
| Clement and Young , D’Angelo and Prat , Oliva , Hendrickson | STUMP | None | ≥10 | Uncertain | None |
| Tumours without necrosis and no atypia | |||||
| Bell , Clement and Young , Longacre , Nucci | MAL-LE or STUMP | None | ≥15 | No | 0% (0 of 3 cases) |
| Tumours without necrosis but with atypia | |||||
| Bell , Longacre | AL-LE | Focal/multifocal moderate-to-severe | ≤10 | No | 17.4% (4 of 23 cases) |
| Zaloudek | STUMP | Focal moderate-to-severe | ≥5 | No | None |
| Rosai | STUMP | Focal moderate-to-severe | >10 | No | None |
| Quade and Robboy | STUMP | Focal moderate-to-severe | <15 | No | None |
| Bell , Longacre , Quade and Robboy , Rosai , Hendrickson , Zaloudek a | AL-LRR | Diffuse moderate-to-severe | <10 | No | 4.8% (3 of 63 cases) |
| Nucci | STUMP | Diffuse/multifocal moderate-to-severe | >7 to <10 | No | None |
| D’Angelo and Prat , Oliva , Hendrickson | STUMP | Diffuse/multifocal moderate-to-severe | Borderline (8–9) | No | None |
| D’Angelo and Prat , Oliva | STUMP | Any | Uncertain | No | None |
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