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Uterine Smooth Muscle Tumors
Introduction
Smooth muscle tumors of the uterus are very common and the vast majority are benign leiomyomas. In contrast, leiomyosarcomas are rare and constitute only 1.3% of uterine malignancies ( Figure 19.1 ). Nevertheless, leiomyosarcoma is the most frequent malignant mesenchymal tumor of the uterus, accounting for almost 60% of uterine sarcomas. Whereas almost all leiomyosarcomas are high-grade tumors and their diagnosis is straightforward, a small fraction of uterine smooth muscle tumors show atypical histologic features that are insufficient for the diagnosis of malignancy or have an unpredictable clinical behavior. The term smooth muscle tumors of uncertain malignant potential (STUMP) has been used to describe these neoplasms; however, we prefer to call them atypical smooth muscle tumors in view of their favorable behavior in most cases. The latter term simply describes the morphologic findings avoiding the words ‘uncertain’ and ‘malignant,’ which undoubtedly create unnecessary concern for the patient. A classification of smooth muscle tumors of the uterus is given in Table 19.1 .
Table 19.1
Classification of Smooth Muscle Tumors
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Leiomyoma
Leiomyoma is a benign smooth muscle tumor that most commonly occurs in the uterus, but may also be found in the cervix, uterine ligaments, and, rarely, the ovary or fallopian tube.
Incidence
Leiomyomas are clinically evident in 20–30% of women over 30 years of age, rising to more than 40% in those over 40 years old. In a series of 1000 uteri that were serially examined, over 56% contained leiomyomas. In other studies, 69–77% of women who underwent hysterectomy for non-cancerous conditions were found to have leiomyomas. The clinical presentation depends on their size and location. Most are asymptomatic while others present abnormal uterine bleeding, pain, and/or abdominal enlargement.
Leiomyomas are more common in black than in Caucasian women. Recently, a higher prevalence for genetic polymorphisms in the estrogen receptor (ER)-α and catechol- O -methyltransferase (an enzyme involved in estrogen metabolism) was observed in black women with leiomyomas, but it is unknown whether these polymorphisms account for the higher tumor incidence in these patients. In fact, a number of nuclear receptors are differentially expressed by leiomyomas in black women compared to other ethnic groups.
Like the contribution of race, familial patterns of inheritance also suggest that genetic risk factors are important in the pathogenesis of leiomyomas.
Etiology
The precise etiology of leiomyomas is unknown, but the hormonal milieu is pivotal. Recent evidence confirms that estrogens and progesterone receptors (ERs and PRs) are important in their pathogenesis. Studies comparing gene expression in leiomyomas with that in normal myometrium show that leiomyomas maintain a high level of sensitivity to estrogen during the estrogen-dominated proliferative phase of the menstrual cycle. Furthermore, cultured cells from leiomyomas have a significantly higher response to estrogen than do matched cultures of myometrial cells from the same patient, particularly if the tissue is taken for culture in the proliferative phase. Semiquantitative immunohistochemistry for ERs and PRs correlates with tumor growth rate. Accelerated growth, sufficient to require hysterectomy, also occurs in women taking tamoxifen for breast cancer treatment.
Further information on the origin of leiomyomas has come from studying their clonality. Originally, glucose-6-phosphate dehydrogenase isoforms were used as a marker for X chromosome inactivation, but this has been supplanted by newer molecular biologic techniques that exploit methylation differences between polymorphic loci on the active and inactive X chromosomes. These methods confirm that each leiomyoma derives from a single transformation event. Interestingly, these studies also suggest that each tumor is a distinct clone, reinforcing the notion that smooth muscle tumorigenesis is an exceedingly common event.
The genetic mechanisms by which initiation and growth of leiomyomas occur so frequently are not fully understood. Cytogenetic analysis of these benign smooth muscle tumors, however, has revealed important clues. Nearly one-half of leiomyomas have chromosomal rearrangements large enough to be seen in G-banded karyotypes. These chromosomal rearrangements are generally simple, which is in sharp contrast to the aberrations seen in leiomyosarcoma. To date, recurrent aberrations have allowed the definition of seven cytogenetic subgroups: t(12;14)(q14–15;q23–24), del(7)(q22q32), rearrangements of 6p21 and 10q22, trisomy 12, and deletions of 3q and 1p. Of these, the translocation between chromosomes 12 and 14 and the rearrangements involving chromosome 6 are perhaps the best understood. Both rearrangements involve genes for two closely related non-histone chromatin proteins: HMGA1 at 6p21 and HMGA2 at 12q15. Rearrangements involving HMGA1 and HMGA2 are also associated with lipomas, endometrial polyps, vulvar aggressive angiomyxoma, and several other benign mesenchymal neoplasms. Evidence suggests that inappropriate expression of AT-hook DNA binding domains from HMGA2 are relevant in uterine leiomyoma. Interestingly, rearranged 10q22 disrupts a gene for another class of chromatin protein, namely the histone acetyltransferase MYST4 , which raises the possibility that chromatin regulation more broadly is important in the pathogenesis of uterine leiomyoma. Beyond such mechanistic insights, cytogenetic studies may also have some practical significance. Tumors with chromosomal rearrangements are on average larger and often within the uterine wall. In addition, some aberrations are associated with specific variants of uterine leiomyomas.
An autosomal dominant syndrome, Reed syndrome (Mendelian Inheritance in Man #150800 and #605839), exhibits a predisposition toward cutaneous and uterine leiomyomas as well as renal cell carcinoma. This syndrome has inactivated fumarate hydratase, an enzyme of the Krebs cycle. Germline fumarate hydratase mutations behave like those in classical tumor-suppressor genes. Some non-syndromic (i.e., typical ‘garden variety’) leiomyomas also have a subset, particularly those from symptomatic younger women, which may have deleted fumarate hydratase.
Transcriptional profiling has been used to study uterine smooth muscle tumors. While lists of dysregulated genes produced by various groups overlap to some degree, and while much more study is needed to understand fully the significance of these transcriptional profiles, it seems that the transcriptional profiles for uterine leiomyomas are much closer to myometrium than to leiomyosarcoma and atypical leiomyomas, and that malignant transformation appears to coincide in downregulation of gene expression more frequently than upregulation. Three potential mechanisms proposed to account for differential gene regulation in the smooth muscle transcriptome include: (1) differential expression of non-histone chromatin proteins such as HMGA2 and MYST4 ; (2) altered expression of tuberin and the glucocorticoid receptor; and (3) abnormal regulation of micro-RNAs, which in turn might regulate HMGA2 .
Gross Features
Leiomyomas occur anywhere within the myometrium and are multiple in about two-thirds of cases. They also occur occasionally in the cervix (see Chapter 13 ). The most frequent location is within the myometrial wall where, if numerous or large, they can also grossly distort the uterus ( Figure 19.2 ). Those situated close to the endometrium or the serosa are referred to as submucosal and subserosal, respectively. Submucosal leiomyomas are frequently ulcerated and may lead to intermenstrual bleeding ( Figure 19.3 ). A subserosal, pedunculated leiomyoma may, on rare occasions, lose its connection with the uterus and become attached to another pelvic structure, such as the omentum, bowel, or peritoneum (‘parasitic’ leiomyoma), which must not be mistaken for a metastasis from a malignant smooth muscle tumor. Leiomyomas are round, firm, and rubbery and they rise above the surrounding myometrium from which they are easily shelled out. The cut surface is typically white to tan, with a whorled, spiral pattern. A striking feature is the very sharp demarcation between it and the surrounding normal myometrium. Several degenerative changes may occur in leiomyomas. Hemorrhage and necrosis are frequent in leiomyomas, particularly if they are large or occur in women who are pregnant or receiving progestogen. Whereas the hemorrhagic areas appear dark, necrotic zones are yellow. Cystic change and calcification also occur.
Microscopic Features
A leiomyoma consists of intersecting bundles of smooth muscle cells. The margins are well circumscribed ( Figure 19.4 ). The smooth muscle cells are markedly elongated and have eosinophilic cytoplasm and tapered, cigar-shaped nuclei. In a typical leiomyoma, the nuclei are uniform and mitotic figures absent or sparse ( Figure 19.5 ). Abundant reticulin is present. The smooth muscle cells of a leiomyoma are usually more closely packed than those of the surrounding myometrium, so that the tumor usually appears more cellular and the small blood vessels appear compressed and less randomly distributed. Such increased cellularity is often particularly striking in women past menopause. The nuclei in a leiomyoma are generally arranged in a fascicular fashion, but occasionally there is palisading resulting in a pattern similar to that seen in a neurilemmoma (schwannoma) ( Figure 19.6 ).
Marked attenuation of overlying endometrium may be seen in some mucosal leiomyomas ( Figure 19.4 ). By extension, the presence of aglandular functionalis in curettings is a hint that dysfunctional uterine bleeding might be due to a nearby leiomyoma.
Hyaline change is common in leiomyomas, particularly in postmenopausal women, and edema or marked hydropic change is found in half of them. The areas of hemorrhage are usually well circumscribed. Hypercellularity, hemorrhage, edema, and myxoid change occur in leiomyomas in women who are pregnant or taking progestogens. Progestational agents are associated with increased mitotic activity but mitoses appear normal.
Variants of Leiomyoma
Mitotically Active Leiomyoma
In premenopausal women, otherwise typical leiomyomas may occasionally show 5 or more mitotic figures per 10 HPF. These tumors have a benign clinical course (even when treated by myomectomy). They are typically small (<10 cm) and have a benign gross appearance. Approximately 60% of mitotically active leiomyomas are submucosal. Microscopically, they have 5–14 mitotic figures per 10 HPF when counted in the most active area. This increased proliferative rate is frequently, but not always, diffusely distributed ( Figure 19.7 ). In submucosal leiomyomas, ulceration, inflammation, or necrosis may be accompanied by a focal increase of proliferation and mitotic activity. Increased proliferation has also been associated with higher progestin levels, such those seen during the secretory phase. Malignant tumors exhibiting severe nuclear atypia, abnormal mitoses, or geographic necrosis should not be diagnosed as mitotically active leiomyomas.
Cellular Leiomyoma
A cellular leiomyoma is a benign smooth muscle tumor that has a cellularity greater than the surrounding myometrium and the majority of leiomyomas. Grossly, cellular leiomyoma may resemble typical leiomyoma but often has a fleshier and softer sectioned surface and the color tends to be tan or creamy yellow rather than pinkish white. Microscopically, cellular leiomyomas almost always have <5 mitotic figures per 10 HPF and are cytologically bland. A fascicular pattern is present in some areas. The tumor is markedly cellular, and the cells are small and round to spindle shaped ( Figure 19.8 ). The blood vessels are typically large with thick muscular walls and cleft-like spaces are often seen, possibly representing compressed vessels or edema. Unlike the usual leiomyoma, cellular leiomyomas often show focal extensions into and appear to merge with the adjacent myometrium.
Differential Diagnosis
Cellular leiomyomas may resemble endometrial stromal tumors. Helpful features in the differential diagnosis include: (1) coexistence of the highly cellular areas with a fascicular growth pattern typical of smooth muscle tumors; (2) reticulin stains with fibers that tend to parallel the cell bundles in leiomyomas but surround individual tumor cells in endometrial stromal tumors; (3) vessels of large caliber with thick muscular walls, in contrast to the prominent network of small blood vessels typical of endometrial stromal tumors; (4) presence of cleft-like spaces and the absence of foamy histiocytes, which are often present in endometrial stromal tumors; and (5) strong and multifocal or diffuse immunoreactivity for smooth muscle markers such as desmin and h-caldesmon.
In the absence of vascular invasion, the distinction is between two benign lesions, i.e., cellular leiomyoma and endometrial stromal nodule. However, when there is intravascular tumor, the differential is clinically relevant, i.e., intravenous leiomyomatosis versus endometrial stromal sarcoma. In young women wishing to retain their fertility or in older women with high surgical risk, hysteroscopy, imaging studies, or repeat sampling should be considered before hysterectomy.
The cellular leiomyoma must also be distinguished from leiomyosarcoma. The cellular leiomyoma lacks geographic tumor cell necrosis, nuclear atypia, and mitotic activity, all characteristic of leiomyosarcoma.
Cytogenetic Features
The cellular variant may be associated with two chromosomal aberrations: deletion of 1p and rearranged 10q22. Whether all cellular leiomyomas have these or related chromosomal aberrations is unknown.
Hemorrhagic Cellular Leiomyoma and Hormone-Induced Changes
Hemorrhagic cellular leiomyoma, or ‘apoplectic leiomyoma,’ occurs in pregnancy and during treatment with oral contraceptive or gonadotrophin-releasing hormone agonists (GnRHa). Grossly, hemorrhage and cystic change are frequently seen ( Figure 19.9 ). Microscopically, the leiomyoma is densely cellular and contains stellate zones of recent hemorrhage. Mitotic activity may be increased (up to 8 mitotic figures per 10 HPF), but there is no atypia and necrosis generally is not present. Vascular changes may be prominent. Leiomyomas treated with GnRHa, to reduce their size prior to their removal, may exhibit the features of apoplectic leiomyomas and vascular changes (i.e., myxoid change, fibrinoid change, mural thickening, luminal narrowing, and thrombosis). Leiomyomas removed several weeks after withdrawal of GnRHa treatment may have increased mitotic activity.
The most striking feature that may be present is geographic (coagulative) necrosis exhibiting nuclear pyknosis, karyorrhexis, karyolysis, and markedly increased cytoplasmic eosinophilia. This may affect a small group of cells or extensive areas within the leiomyoma and be surrounded by a rim of inflammatory cells. Apoptosis may be prominent. Changes in cellularity are not significant and both decreased and increased cellularity have been reported. A massive lymphocytic infiltration and thickening of blood vessel walls with narrowing of the lumen may also be seen. A study of cell proliferation indices (Ki-67 and proliferating cell nuclear antigen) suggests that the reduction in size of leiomyomas treated by GnRHa is due to a reduction in the number of cycling cells, presumably secondary to reduced levels of ERs and PRs.
Degenerated Leiomyoma
A variety of degenerative changes can occur in leiomyomas. By far the most common form of degeneration is hyaline change whereby expanded septa have lost their fibrillary structure, assuming a uniform, pale eosinophilic, ground-glass appearance ( Figure 19.10 ). This change may be localized or it may affect extensive areas of the tumor, occasionally even the whole of it. This form of degeneration may be accompanied by surviving muscle cells oriented into lacework patterns. The blood vessels within an area of hyaline necrosis undergo the same change and can be seen as pale outlines, a point of distinction from the geographic tumor cell necrosis seen in leiomyosarcoma where the vessels are often spared. Degenerated areas may liquefy, resulting in hydropic or cystic degeneration . When extreme, such a degenerated leiomyoma may take on a peculiar multinodular appearance. Mucoid and myxoid degeneration are also common. In myxoid change, the scattered nuclei are embedded in an amorphous, slightly amphophilic matrix whereas in mucoid degeneration the matrix appears to be mucinous in nature. The mucoid and myxoid forms of degeneration lack practical importance and the two terms are often used interchangeably.
Red degeneration ( necrobiosis ), on the other hand, occurs characteristically but not exclusively in pregnancy and often causes pain and fever. Necrobiosis results in the cut surface taking on a more homogeneous look with loss of the whorled appearance. At the same time, the color becomes a deeper pink or red (due to staining by fresh blood pigment) and the consistency softer ( Figure 19.11 ). Over time, the periphery of a leiomyoma that has undergone red degeneration may become white and calcified. Unlike hyaline change, the microscopic appearance in red degeneration shows the ghosts of the muscle cells and their nuclei. Uncommonly, a leiomyoma may undergo necrosis, resulting in a soft, structureless, pale gray mass. This change is seen most often in submucous leiomyomas that protrude into the endometrial cavity.
Calcific degeneration is seen more frequently in women after the menopause.
Fatty degeneration is rare. In most circumstances fat in a myometrial mass is part of a lipoleiomyoma. In these tumors, the fat is within recognizable adipocytes; in contrast, fatty degeneration discloses the lipid in the smooth muscle cells themselves or in histiocytes.
In general, benign forms of necrosis tend to be unifocal, centrally located, rounded in shape, and relatively uniform in color and consistency of the gross cut surface. The microscopic border exhibits a gradual transition from viable to fully necrotic tumor. Inflammation, granulation, and early hyaline change may be found in these transitional areas. Atypical ghost cells should not be present. Vascular sparing within larger areas of degeneration is unusual. Not infrequently, thrombosis may be seen in the tumor. The overall impression rendered is that of an ongoing or chronic process with a corresponding host reaction. These features are important to recognize and distinguish degenerated leiomyomas from the geographic pattern of necrosis found in leiomyosarcomas.
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