Uterine fibroids (leiomyomas): Variants and smooth muscle tumors of uncertain malignant potential

INTRODUCTION — Uterine fibroids (leiomyomas) are benign tumors that exhibit various forms of smooth muscle differentiation. The classic (conventional or typical) spindled form of leiomyoma is the most common pelvic tumor in females [1-3]. Occasionally, patients with a uterine mass presumed to be a leiomyoma are subsequently diagnosed with a leiomyoma variant or leiomyosarcoma. There is a broad spectrum of leiomyoma variants: some have a single histologic finding that is associated with leiomyosarcoma, such as an increased mitotic index or severe cytologic atypia, while other growth pattern variants are defined by their capacity to spread to peritoneal surfaces or solid organs but are histologically benign. Finally, some smooth muscle tumors do not satisfy histologic criteria as being unequivocally benign or malignant and are, therefore, classified as having uncertain malignant potential.

This topic will review variants of uterine leiomyomas; smooth muscle tumors of uncertain malignant potential (STUMP); leiomyomas with a disseminated, intravascular, or metastatic growth; and female genital tract leiomyomas associated with genetic disorders. The diagnosis and management of classic uterine leiomyomas, approaches to differentiating leiomyomas from various sarcomas, and tumors of uncertain malignant potential are discussed separately.

●(See "Uterine fibroids (leiomyomas): Epidemiology, clinical features, diagnosis, and natural history".)

●(See "Uterine fibroids (leiomyomas): Treatment overview".)

●(See "Uterine fibroids (leiomyomas): Differentiating fibroids from uterine sarcomas".)

CRITERIA FOR CLASSIFICATION OF UTERINE SMOOTH MUSCLE TUMORS AS BENIGN OR MALIGNANT — Smooth muscle tumors are classified by their histologic features as benign, malignant, or, in some cases, of uncertain malignant potential. Gross characteristics may suggest that a tumor is benign or malignant, but microscopic examination is essential for proper classification since benign and malignant tumors can have overlapping macroscopic features. Disseminated peritoneal leiomyomatosis and metastasizing leiomyoma present with extrauterine spread, and such growth patterns should not be considered pathognomonic of malignancy. The 2020 World Health Organization classification system is shown in the table (table 1) [4].

●Histologic features – Three histologic features are considered when microscopically evaluating a uterine smooth muscle tumor:

•Mitotic index (counted per 10 high power fields)

•Degree of cytologic atypia (graded as mild, moderate, severe)

•Presence of tumor cell necrosis, also known as coagulative necrosis

In general, most spindled leiomyomas (also referred to as classic, typical, or conventional leiomyomas) have the following features:

•Mitotic index of fewer than five mitotic figures per 10 high power fields

•Mild cytologic atypia

•No tumor cell necrosis

A diagnosis of leiomyosarcoma requires at least two of the following three features [5]:

•Mitotic index of ≥10 mitotic figures per 10 high power fields

•Moderate to severe cytologic atypia

•Presence of tumor cell necrosis

●Definition of tumor cell necrosis – Tumor cell necrosis has a sharp transition between viable and nonviable tumor without intervening granulation tissue-like response resulting in the appearance of irregular "geographic shapes" [5]. It must be distinguished from ischemic or hyaline-type necrosis, which is much more common and usually due to ischemia or hormonal changes. In some instances, necrosis can be ambiguous or have overlapping features of tumor cell necrosis and ischemic necrosis; in these cases, cytologic atypia and mitotic index may provide insight into the type of necrosis and possibly allow the pathologist to favor one type or the other.

●Impact of interpretation – It should be appreciated that while the above histologic features are considered objective values, there is an aspect of subjectivity in their interpretation based on the pathologist's experience and personal threshold for classification. For example, a study of interobserver variability in the interpretation of tumor cell necrosis among experienced gynecologic pathologists found only moderate agreement (kappa = 0.436) [6]. Awareness of these issues is important for cases near the threshold for each parameter or tumors with unusual or difficult to classify features. Management of such cases may benefit from a dialogue between the clinician and pathologist and/or review by an expert gynecologic pathologist at a referral center.

PATHOLOGIC CONSIDERATIONS

Epidemiology — Classic spindled uterine leiomyomas are very common, in contrast to leiomyoma variants, which have an estimated incidence of 1 to 2 percent in aggregate [7]. Leiomyosarcoma is also rare compared with leiomyomas, although the exact incidence is controversial [8,9]. (See "Uterine sarcoma: Classification, epidemiology, clinical manifestations, and diagnosis", section on 'Epidemiology'.)

Clinical implications — It is challenging to use clinical methods to differentiate tumors as benign or malignant and, therefore, be able to provide appropriate evaluation and treatment. The rarity of leiomyoma variants limits epidemiologic study and, by extension, data to guide diagnosis and treatment. Since most variants are defined by their histologic features, they are diagnosed only after surgical removal. Thus, the management of variants is primarily clinically relevant following myomectomy or hysterectomy that involved intraperitoneal morcellation of the uterine corpus, where persistence or recurrence is a possibility. Increasingly, abnormal magnetic resonance imaging may suggest atypical features in a presumed smooth muscle tumor and prompt surgical excision. (See 'Management' below.)

Expertise in these lesions varies among institutions, pathology laboratories, and gynecologists specializing in uterine smooth muscle tumors, and, if questions remain, pathology may benefit from review at a referral center. Gynecologic and medical oncologists may have additional expertise, particularly for tumors of uncertain malignant potential or disseminated or metastatic leiomyomas.

VARIANTS OF LEIOMYOMAS — Histologic variants of leiomyomas exhibit the same symptoms and signs as classic leiomyomas. There are no imaging modalities that distinguish histologic variants from classic spindled leiomyomas. Variants are diagnosed by pathologic examination following myomectomy or hysterectomy.

Histologic variants

Cellular leiomyoma

●Definition and classification – Cellular leiomyoma is defined as having increased cellularity relative to background myometrium (picture 1). Careful evaluation is important to make this diagnosis correctly and differentiate this tumor from low-grade endometrial stromal sarcoma. Cellular leiomyomas are believed to make up no more than 5 percent of all leiomyomas [10]. When diagnosed by hysterectomy, thoroughly sampled, and appropriately classified, cellular and hypercellular leiomyomas are benign with no risk of recurrence. However, since earlier studies have suggested that there may be rare cases of cellular leiomyomas with some molecular evidence of sarcoma-like signature, short-term surveillance is indicated in patients who underwent a uterine-sparing or intraperitoneal morcellating procedure due to risk of tissue remnant or misclassification [11]. (See 'Management' below.)

There is not a specific quantitative minimum degree of cellularity for a tumor to be considered cellular, and application of the term varies among pathologists. Marked cellularity resembling that of a typical endometrial stromal nodule or low-grade endometrial stromal sarcoma is sometimes referred to with the terms "cellular leiomyoma," "highly cellular leiomyoma," or, less commonly, "hypercellular leiomyoma." Care must be taken not to misclassify low-grade endometrial stromal sarcoma as cellular/hypercellular leiomyoma. (See "Endometrial stromal sarcomas, related tumors, and uterine adenosarcoma", section on 'ESN and LG-ESS'.)

Cellular leiomyomas often have different gross appearance than conventional leiomyoma: their cut surface is generally more tan and less firm or rubbery. The spindle cells of cellular leiomyomas are arranged in bundles (fascicles) whereas the cells of low-grade endometrial stromal tumors are not bundled; instead, they are more haphazard in their architecture. Cellular leiomyomas, like classic leiomyomas, have thick-walled vessels. By contrast, classic low-grade endometrial stromal tumors have numerous spiral arterioles resembling those in proliferative phase endometrium.

●Differential diagnosis – Immunohistochemistry and molecular cytogenetic testing can be helpful in difficult cases. Cellular leiomyomas express contractile proteins like smooth muscle actin, h-caldesmon, and desmin whereas classic low-grade endometrial stromal tumors express IFITM1 and more robustly express CD10. Since several of these markers may be expressed by both categories of tumors, testing a panel of markers is most useful. Cytogenetic evaluation, often by way of fluorescence in situ hybridization, can facilitate classification. Classic low-grade endometrial stromal tumors can have recurrent chromosomal translocations, the most common being t(7;17)(p15;q21), which involves rearrangement of JAZF1 and SUZ12 (formerly JJAZ1). Another more common rearrangement in low-grade endometrial stromal tumors is PHF1. In most tumors, identification of a JAZF1, SUZ12, or PHF1 rearrangement is diagnostic of a low-grade endometrial stromal tumor, but PHF1 and JAZF1 rearrangements have been reported in ossifying fibromyxoid tumor [12,13], a rare soft-tissue tumor of intermediate malignancy that has yet to be reported as a primary uterine tumor.

Leiomyoma with bizarre nuclei

●Definition and classification – Leiomyoma with bizarre nuclei has focal, multifocal, or diffuse severe cytologic atypia in the form of nuclear enlargement, pleomorphism, hyperchromasia, multilobulated nuclei, and/or multinucleation (picture 2). The recurrence risk of leiomyomas with bizarre nuclei after myomectomy is approximately 2 percent [14].

The 2020 World Health Organization (WHO) recommends the term "leiomyoma with bizarre nuclei" rather than symplastic leiomyoma, atypical leiomyoma, or pleomorphic leiomyoma [4]. The term "atypical leiomyoma" has been used inconsistently to describe different entities, including as a synonym for STUMP, which has a risk of recurrence, and as a synonym for leiomyoma with bizarre nuclei, which has no risk of recurrence when diagnosed by hysterectomy, appropriately sampled (such as one section/block per 1 cm of tumor), and correctly classified.

●Differential diagnosis – Since leiomyoma with bizarre nuclei by definition has severe or significant cytologic atypia, STUMP and leiomyosarcoma should be excluded as part of the differential diagnosis. Smooth muscle tumors with significant cytologic atypia and a mitotic index of 10 or greater figures per 10 high power fields should be classified as leiomyosarcoma. Tumors with significant cytologic atypia that have fewer than 10 but a mitotic count near the threshold may be classified as STUMP; however, regardless of mitotic index, if tumor cell necrosis is present in a tumor that has severe cytologic atypia, it should be classified as leiomyosarcoma.

•(See 'Smooth muscle tumors of uncertain malignant potential' below.)

•(See 'Criteria for classification of uterine smooth muscle tumors as benign or malignant' above.)

Leiomyomas with bizarre nuclei and fumarate hydratase (FH)-deficient leiomyomas have overlapping morphologic features. FH-deficient leiomyomas show a spectrum of prominent nucleoli, perinucleolar clearing, binucleation (in some instances, resembling Reed-Sternberg cells), eosinophilic intracytoplasmic inclusions, pseudoalveolar edema, and staghorn or hemangiopericytic vasculature. A comparative study of leiomyomas with bizarre nuclei and FH-deficient leiomyomas found staghorn vasculature as the only statistically significant feature by multivariate analysis of FH-deficient leiomyomas. FH immunohistochemistry can be helpful in distinguishing these two variants, but the immunostain is not 100 percent sensitive for all genetic alterations of FH. (See 'Fumarate hydratase deficiency' below.)

Mitotically active leiomyoma

●Definition and classification – This variant is defined by the 2020 WHO Classification of Female Genital Tumors [4] as an otherwise classic spindled leiomyoma (mild cytologic atypia, no tumor cell necrosis) but has an increased mitotic index >10 mitotic figures per 10 high power fields (picture 3). Some pathologists use a threshold of >5 mitotic figures per 10 high power fields. Progesterone is thought to influence the mitotic index of smooth muscle tumors. Leiomyomas are more likely to have an increased mitotic count if they are excised during the secretory phase of the menstrual cycle, during pregnancy, or when patients are receiving exogenous progestins [15-17]. Clinical manifestation and management of mitotically active leiomyomas are the same as for classic leiomyomas.

●Differential diagnosis – Mitotically active leiomyomas may have increased cellularity. Before making a diagnosis of cellular mitotically active leiomyoma, STUMP and low-grade endometrial stromal tumor should be excluded. Smooth muscle tumors with high mitotic counts (>15 per 10 high power fields) are uncommon, and some have demonstrated aggressive behavior. Such tumors that have >15 figures per 10 high power fields, are cytologically bland, and lack tumor cell necrosis should be classified as STUMP. (See 'Smooth muscle tumors of uncertain malignant potential' below.)

Myxoid leiomyoma

●Definition and classification – Myxoid leiomyomas have an extracellular matrix composed of proteoglycans and glycosaminoglycans [18]. This matrix is gray to blue by light microscopy, has a viscous quality, and separates spindled tumor cells into single cells and small clusters. Myxoid stroma can be present in various quantities and even found focally in otherwise classic leiomyomas. Generally, tumor volume is at least 50 percent myxoid to classify a tumor as myxoid leiomyoma [19].

Myxoid smooth muscle tumors are classified as leiomyoma when the tumor is well-circumscribed, has uniformly mild cytologic atypia, <2 mitotic figures per 10 high power fields, and no tumor cell necrosis [19]. In comparison, myxoid leiomyosarcoma has historically required two of three features to be present: significant cytologic atypia, ≥2 mitotic figures per 10 high power fields, and tumor cell necrosis. However, a study of uterine myxoid smooth muscle tumors emphasized the interface between tumor and surrounding myometrium as a critical prognostic feature: while most myxoid leiomyosarcomas infiltrate myometrium, in patients whose tumors satisfy criteria for myxoid leiomyosarcoma but were well-circumscribed, none experienced recurrence [20]. Although data are limited, the authors suggested that a designation of STUMP may be more appropriate for what may typically be a well-circumscribed myxoid leiomyosarcoma. Optimal management of these lesions is unclear as the case reports are limited to small numbers of patients. (See 'Smooth muscle tumors of uncertain malignant potential' below.)

Epithelioid leiomyoma

●Definition and classification – Epithelioid smooth muscle tumors are composed of rounded to polygonal cells that appear similar to epithelial cells and comprise at least 50 percent of the tumor [21-23]. There are limited data on morphologic features as predictive of malignant potential. An epithelioid smooth muscle tumor is classified as leiomyoma when it is well-circumscribed, lacks significant cytologic atypia, has a mitotic index of <3 figures per 10 high power fields, and lacks tumor cell necrosis [23]. Epithelioid smooth muscle tumors with significant nuclear atypia and either necrosis or >5 mitotic figures per 10 high power fields are best considered leiomyosarcoma [22,23].

●Differential diagnosis – Aside from excluding carcinoma as part of the differential diagnosis when evaluating a potential epithelioid smooth muscle tumor, perivascular epithelioid cell (PEComa) tumor should also be considered. Like epithelioid smooth muscle tumors, PEComa forms nests and/or sheets of epithelial-like cells and spindle cells that have clear to granular eosinophilic cytoplasm [24,25]. PEComa is variably positive for smooth muscle immunohistochemical markers (desmin, h-caldesmon, smooth muscle actin) and melanocytic immunohistochemical markers (HMB45 and melan-A). Epithelioid smooth muscle tumors can be positive for HMB45 but are usually negative for melan-A [26]. (See "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis", section on 'Perivascular epithelioid cell (PEComa)'.)

Management — The rarity of leiomyoma variants limits the amount of data available to guide management. In general, patients who underwent hysterectomy do not require additional follow-up, but those who underwent myomectomy, or procedures with risk of myometrial cell spread, warrant surveillance.

●Prior hysterectomy – Hysterectomy by any route is considered curative for cellular leiomyoma, leiomyoma with bizarre nuclei, mitotically active leiomyoma, myxoid leiomyoma, and epithelioid leiomyoma as long as any uterus morcellation was performed outside of the peritoneum or within a containment system. No additional follow-up of these patients is needed. Patients who underwent supracervical hysterectomy should also be considered cured, unless the incision at the level of the cervix also incised the leiomyoma. Patients in whom the leiomyoma was incised when removing the uterine corpus have a risk of recurrence and are followed as if they had a myomectomy, which is discussed below.

●Prior myomectomy or intraperitoneal morcellation without containment – Patients who underwent myomectomy or intraperitoneal uterine morcellation without a containment system have a potential risk of persistence or recurrence of leiomyoma variant tumors. For patients with leiomyoma that are cellular, mitotically active, or have bizarre nuclei, surveillance imaging is performed to exclude residual tumor or recurrence, but the optimal frequency and duration of imaging are not known. The authors perform serial ultrasound examinations of the uterus for patients who underwent myomectomy and abdominal/pelvic magnetic resonance imaging for patients in whom there could have been intraabdominal dissemination at the time of the primary surgery.

Epithelioid and myxoid smooth muscle tumors may be difficult to unequivocally classify as benign when myomectomy is performed due to potential intratumoral heterogeneity. The mitotic count threshold for diagnosing epithelioid and myxoid leiomyosarcomas is comparatively lower (5 and 2 mitotic figures/10 high power fields, respectively) than classic spindled leiomyosarcoma (10 mitotic figures/10 high power fields). In addition, data on myxoid smooth muscle tumors suggest myometrial infiltration is an important predictor of malignant potential [20]. It is recommended that patients who underwent a uterine-sparing procedure or hysterectomy with uncontained intraperitoneal morcellation have annual surveillance, most commonly by pelvic ultrasound, and, if findings are concerning, pelvic magnetic resonance imaging.

SMOOTH MUSCLE TUMORS OF UNCERTAIN MALIGNANT POTENTIAL

Classification — Uterine STUMP are a histologically and biologically heterogeneous collection of smooth muscle tumors that have features that do not satisfy defined criteria for leiomyoma, a leiomyoma variant, or leiomyosarcoma, although they do have features that raise concern for leiomyosarcoma. While these tumors have various combinations of cytologic atypia, mitotic index, and tumor cell necrosis, their overall findings are subdiagnostic of leiomyosarcoma but go beyond those of a typical leiomyoma or leiomyoma variant. (See 'Criteria for classification of uterine smooth muscle tumors as benign or malignant' above.)

Clinical features and management — The clinical presentations of STUMP are the same as uterine leiomyomas and leiomyosarcomas (ie, uterine mass, abnormal uterine bleeding, and pelvic pain/pressure). Likewise, there is no imaging modality that can reliably distinguish these lesions. (See "Uterine fibroids (leiomyomas): Differentiating fibroids from uterine sarcomas".)

STUMP is diagnosed by pathologic evaluation of hysterectomy or myomectomy specimens. There are no guidelines regarding whether hysterectomy, if not previously performed, is required in patients diagnosed with STUMP by myomectomy. Similarly, the optimal management of the ovaries is not known. For such patients, a detailed discussion should be held with the patient to review tumor characteristics and the patient's plans for future pregnancy. Management options include hysterectomy or annual surveillance with pelvic imaging. More frequent surveillance, such as every four to six months, may be warranted, especially in the first several years after initial presentation and depending on the histologic features of the tumor and/or other factors (eg, the tumor was incompletely excised or was morcellated). If pelvic imaging is used, transvaginal ultrasound is recommended to detect the presence of new uterine masses and magnetic resonance imaging with gadolinium is recommended to evaluate the characteristics of any new uterine masses. (See "Uterine fibroids (leiomyomas): Differentiating fibroids from uterine sarcomas", section on 'Imaging'.)

Risk of recurrence — Though the malignant potential of STUMP is difficult to predict by conventional morphologic analysis, all tumors appropriately classified as STUMP should be regarded as having some recurrent potential, even in patients who have undergone hysterectomy with an intact corpus.

While data are limited, the recurrence risk of STUMP appears to vary with histologic features. In the 2020 World Health Organization (WHO) Classification of Female Genital Tumors, among the combinations of features found in STUMP, tumors that lack cytologic atypia and have a low mitotic index but have tumor cell necrosis carry the greatest risk of recurrence (up to 28 percent) [4]. By contrast, tumors that lack cytologic atypia and tumor cell necrosis but have a high mitotic index (>15 figures per 10 high-power fields) carry the lowest risk of recurrence (0 percent). These outcome data are aggregated from relatively small case series ranging from a total of 18 to 42 cases. Nevertheless, they underscore the diversity of tumors that can be classified as STUMP and that this category includes a range of smooth muscle tumors from exceptionally unusual leiomyomas, "low-grade" leiomyosarcomas, and developing "high-grade" leiomyosarcomas.

In most instances, STUMPs that recur have declared their malignant potential and should be treated as sarcomas. Typical management includes surgical resection with or without removal of the ovaries depending on estrogen receptor (ER) status, age of the patient, and presences of metastatic disease. (See "Uterine sarcoma: Classification, epidemiology, clinical manifestations, and diagnosis", section on 'Classification' and "Endometrial stromal sarcomas, related tumors, and uterine adenosarcoma".)

LEIOMYOMAS WITH DISSEMINATED, INTRAVASCULAR, OR METASTATIC GROWTH PATTERNS — There are distinctive growth patterns of smooth muscle tumors that have histologic features identical to classic uterine leiomyomas but with a capacity to disseminate through the peritoneal cavity, extend into the pelvic veins and vena cava, or metastasize to other distant sites, such as the lungs.

Disseminated peritoneal leiomyomatosis — Disseminated peritoneal leiomyomatosis (DPL; previously also called leiomyomatosis peritonealis disseminata) manifests as multiple nodules that occur across pelvic and peritoneal surfaces, often giving the impression of carcinomatosis [27]. Although this disorder is benign, it appears that a small proportion (approximately <5 percent) of DPL cases undergo malignant transformation.

DPL primarily occurs in reproductive-age patients, although it has been described in postmenopausal patients and in a few male patients [28]. Most patients are asymptomatic, and disease is usually discovered incidentally at the time of surgery. Symptoms, if present, may include abdominal mass or distension. DPL has also been reported in patients who do not have a history of uterine leiomyomas [28]. A diagnosis of DPL is based upon histologic examination and correlation with operative/radiologic findings.

Asymptomatic disease does not require treatment. Periodic regression and recurrence can occur, and medications that lower estrogen levels have been reported to resolve lesions for periods of time [29]. Patients have been reported to develop recurrence, despite prior oophorectomy, after initiation of postmenopausal hormone therapy. Surgical resection is a reasonable approach in cases of large, symptomatic nodules. Hysterectomy is not indicated unless uterine symptoms are present.

Clusters of disease within families have been described and suggest a hereditary element [28,30]. Some data [31-33] suggest DPL originates from hormonally driven transformation of subperitoneal mesenchyme while molecular studies propose that DPL is a clonal, metastatic process and has cytogenetic alterations similar to classic uterine leiomyomas [30].

DPL is biologically different from iatrogenic seeding of the peritoneal cavity due to morcellation of leiomyoma(s) at the time of minimally invasive surgical procedures although the clinical presentation and management are similar [34,35]. (See "Uterine tissue extraction by morcellation: Techniques and clinical issues".)

Intravenous leiomyomatosis — Intravenous leiomyomatosis (IVL) is characterized by proliferations of histologically bland smooth muscle that extend in a plug-like fashion into uterine and pelvic veins, vena cava, and sometimes as far as the heart [36].

IVL is found primarily in patients of reproductive age, although some cases have been described in postmenopausal patients [21,29]. Patients with IVL may present with pelvic, abdominal, or cardiac symptoms, depending on the degree of extension of tumor plugs. Pelvic or abdominal symptoms include pain, abnormal uterine bleeding, and abdominal distension [29]. A minority of patients present with significant dyspnea, an intracardiac mass, or evidence of right ventricular dysfunction (congestive heart failure, dyspnea, and syncope) [21,37].

IVL is diagnosed by pelvic imaging with computed tomography or magnetic resonance imaging showing a leiomyomatous or distorted uterus with projections into vasculature (image 1); intracardiac evaluation is performed by cardiac echocardiography [38,39]. In some instances, the diagnosis is made following hysterectomy, when macroscopic and microscopic tumor plugs are present in vascular structures beyond the vicinity of an associated leiomyomatous mass. Treatment by surgical resection of the intravascular mass is required in most cases [40-42].

IVL can be associated with uterine leiomyomas, but some cases of IVL are not. IVL macroscopically and microscopically resembles typical leiomyomas [21,43], although some histologic variants have been reported, such as tumors that are cellular, epithelioid, have a component of mature adipocytes, or a component of endometrial glands and stroma [44,45]. Karyotypic findings in IVL are similar to the high-mobility group AT-hook (HMGA2) subgroup of classic leiomyomas [46,47].

The understanding of the pathogenesis of IVL suggests contiguous spread from the uterus to the vascular tree; hysterectomy is likely indicated at the time of surgical intervention. There are reports of improvement in symptoms with use of medications that decrease estrogen levels (eg, gonadotropin-releasing hormone agonists, aromatase inhibitors) [48,49]. Since tumor recurrence has been reported from 7 months to 15 years after hysterectomy [50,51], posttreatment surveillance by abdominal or thoracic imaging is suggested. There is some evidence that plugs of smooth muscle lesions may detach from IVL and travel hematogenously to the lung, resulting in a lesion suggestive of metastasizing leiomyoma, indicating necessity of serial chest imaging.

Metastasizing leiomyoma — Metastasizing leiomyoma is an uncommon condition in which solitary or multiple cytologic bland and mitotically inactive smooth muscle tumors are present at a distant location, most commonly the lungs (ie, pulmonary benign metastasizing leiomyoma [PBML]) [52]. Such tumors are hormone dependent and express estrogen and progesterone receptors [52,53].

Metastasizing leiomyoma occurs predominantly in patients of reproductive age or older. Most patients have a previous or current history of uterine leiomyomas. Patients can be asymptomatic (with incidental discovery by chest radiograph) or symptomatic (eg, chest pain, dyspnea, cough). In a review including 65 patients (median age at diagnosis 39 years) with PBML, respiratory symptoms and bilateral lesions occurred in over half of the patients (54 and 61 percent, respectively) [52]. Median time to diagnosis of PBML from initial uterine leiomyoma surgery was six years (range <1 to 14 years).

Clonality studies suggest that metastasizing leiomyoma is derived from uterine leiomyomas [54,55]. Further cytogenetic data identified recurrent 19q and 22q deletions in both uterine and metastasized leiomyomas, indicating a subset may be predisposed to disseminate [11,56]. Given data supporting a clonal process originating from uterine leiomyomas, it is likely that metastasizing leiomyoma spreads by vascular or lymphatic channels. Instances of metastasizing leiomyoma in patients with IVL have been reported.

Metastasizing leiomyoma must be distinguished from pulmonary lymphangioleiomyomatosis (LAM), which presents with somewhat histologically similar lung lesions but with a more severe clinical phenotype. LAM, however, is a progressive proliferation of perivascular epithelioid cells (or LAM cells) along bronchial interstitium rather than usually inert nodular aggregates of conventional smooth muscle cells that involve alveolar parenchyma. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation".)

Many patients with metastasizing leiomyoma experience an indolent course, but significant morbidity may occur [29,57]. Expectant management is an option for asymptomatic disease. Surgical intervention (eg, oophorectomy, resection of metastatic lesion), use of agents that decrease estrogen (eg, gonadotropin-releasing hormone agonists, selective estrogen receptor modulators with antagonistic activity in the uterus, aromatase inhibitors) or progestins (eg, progesterone receptor antagonists), or anti-angiogenesis agents (anti-vascular endothelial growth factor [VEGF]) have resulted in tumor regression [52,53,58]. While hysterectomy may not be required to treat extrauterine disease, if the patient has a uterine mass or masses, hysterectomy may be necessary to exclude a sarcoma.

FEMALE GENITAL TRACT LEIOMYOMAS ASSOCIATED WITH GENETIC DISORDERS

Fumarate hydratase deficiency — Fumarate hydratase (FH) deficiency can occur as both a sporadic (ie, nonhereditary) event in leiomyomas or as a manifestation of hereditary leiomyomatosis and renal cell carcinoma (HLRCC), previously known as Reed syndrome [59].

FH encodes fumarase, an enzyme that participates in the tricarboxylic acid cycle. The mechanism by which FH acts as a tumor suppressor is not fully understood, but other tricarboxylic acid cycle genes are known to act as tumor suppressors for other tumors, such as hereditary paragangliomas and succinate dehydrogenase. One mechanistic hypothesis posits that activation of hypoxia-induced metabolic pathways is involved in oncogenesis [60,61].

Morphologic features of leiomyomas affected by FH deficiency include prominent nucleoli, perinucleolar clearing, binucleation or multinucleation (in some instances, resembling Reed-Sternberg cells), eosinophilic intracytoplasmic inclusions, pseudoalveolar edema, and staghorn or hemangiopericytic vasculature (picture 4). Whether a tumor is from a patient with a sporadic or hereditable deficiency cannot be distinguished by these morphologic features alone; dermatologic and medical genetic consultation are recommended for patients with uterine leiomyomas that have FH-deficient features [62,63].

●Fumarate hydratase-deficient leiomyomas – FH-deficient leiomyomas can occur in patients in whom no personal or family history of FH deficiency exists; a somatic mutation of one allele in a uterine myocyte results in the leiomyoma, leading all cells in the tumor to manifest FH deficiency. One explanation of FH-deficient leiomyomas is that marked metabolic stress drives their development [64].

When available, FH immunohistochemistry can be helpful to support a diagnosis of an FH-deficient leiomyoma (it shows loss of nuclear expression in FH-deficient tumors), but it is not 100 percent sensitive since some FH missense mutations still result in retained protein expression. The frequency remains to be determined of nonsyndromic FH loss due to chromosome 1 ring formation (deleting the copy of the FH gene on that chromosome) resulting in an FH-deficient histologic phenotype. [59-62,64].

●Hereditary leiomyomatosis and renal cell carcinoma – HLRCC is an autosomal dominant inherited disorder in which affected patients may develop cutaneous leiomyomas, uterine leiomyomas, and an aggressive form of papillary renal cell carcinoma. While it was originally thought that cutaneous leiomyomas were ubiquitous in this syndrome, subsequent reports suggest that cutaneous lesions are present in less than one-half of affected individuals [65,66]. The lifetime risk of renal cell cancer in such patients is lower (ie, 15 to 20 percent), but screening and regular surveillance renal imaging is an important aspect of HLRCC management. (See "Hereditary kidney cancer syndromes", section on 'Hereditary leiomyomatosis and renal cell cancer syndrome' and "Hereditary leiomyomatosis and renal cell cancer (HLRCC)".)

HLRCC is caused by alterations in one copy of FH. Molecular studies have found different germline mutations associated with HLRCC, but they all result in absent or truncated proteins or changes in highly conserved amino acids. The second (normal) allele is usually deleted in tumor cells (ie, somatic loss of heterozygosity), confirming the role of FH as a tumor suppressor [67-69]. Patients homozygous for FH mutations have a profound constitutional FH deficiency [67,69]. The genotype-phenotype relationships for FH are an example of phenotypic heterogeneity.

HLRCC has been associated with an increased risk of leiomyosarcoma in early literature. However, the distinctive morphology of FH-deficient leiomyomas may have led to their misclassification as leiomyosarcoma. Nevertheless, the risk of sarcoma associated with HLRCC is unclear, and, until there are more data, surveillance of patients who have undergone myomectomy for HLRCC appears to be indicated. HLRCC is discussed in detail separately. (See "Hereditary kidney cancer syndromes", section on 'Hereditary leiomyomatosis and renal cell cancer syndrome'.)

Cowden syndrome — Cowden syndrome (also known as Cowden disease or multiple hamartoma syndrome) is a multisystem disorder caused by germline mutation of the PTEN tumor suppressor gene that manifests with a range of hamartomatous lesions and benign tumors that involve mucocutaneous sites, the gastrointestinal tract, thyroid, and genitourinary tract. Those affected are also at an increased risk of developing endometrial, thyroid, and breast carcinoma [70]. A systematic review of published cases of Cowden syndrome and other PTEN-related syndromes found uterine leiomyomas reported in 21 to 38 percent of patients [71,72]. Data are conflicted as to whether there is a significantly increased incidence of uterine leiomyomas in Cowden syndrome relative to the general population. PTEN mutation is not thought to play a pivotal role in sporadic uterine leiomyoma pathogenesis. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Cowden syndrome'.)

Diffuse leiomyomatosis (Alport syndrome) — The X-linked form of Alport syndrome, defined by nephropathy, deafness, and sometimes ocular anomalies, is caused by germline mutation of COL4A5. Patients with Alport syndrome who also develop diffuse leiomyomatosis (which can involve the esophagus, tracheobronchial tree, vulva, and/or uterus) have an underlying germline deletion of both COL4A5 and COL4A6, typifying the definition of a contiguous gene syndrome [73]. On chromosome Xq22.3, genes for the alpha-5 and alpha-6 monomers of nonfibrillar basement membrane (type IV) collagen (COL4A5 and COL4A6) are arranged in a head-to-head fashion and share a common promoter region. Pathogenetic, submicroscopic deletions of the overlapping promoters and adjacent 5' regions may be as small as 13.4 kb [74]. Interestingly, the mRNA of COL4A6 is increased approximately twofold in nonsyndromic typical uterine leiomyomas but decreased nearly 14-fold in uterine leiomyosarcomas relative to myometrium [75]. (See "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Uterine fibroids (leiomyomas)".)

SUMMARY AND RECOMMENDATIONS

●Malignant potential of uterine smooth muscle tumors is currently assessed by degree of cytologic atypia, mitotic index, and presence of tumor cell necrosis. Uterine leiomyoma variants can have the same clinical presentations as classic uterine leiomyomas and sarcomas, such as a solitary mass or numerous masses, abnormal uterine bleeding, and pelvic pain/pressure. No imaging modality reliably distinguishes these leiomyoma variants from classic leiomyoma or sarcomas. (See 'Criteria for classification of uterine smooth muscle tumors as benign or malignant' above.)

●Histologic variants of leiomyomas include cellular, bizarre nuclei, mitotically active, epithelioid, and myxoid, among others. They are diagnosed following myomectomy or hysterectomy. Although their management is generally the same as classic leiomyomas, surveillance with pelvic imaging may be required if incompletely removed. (See 'Variants of leiomyomas' above.)

●Smooth muscle tumors of uncertain malignant potential (STUMP) have some features of leiomyosarcoma, but they do not satisfy diagnostic criteria. Furthermore, the features of STUMP go beyond what is expected in established leiomyoma variants. STUMP is diagnosed following myomectomy or hysterectomy. There are no definitive guidelines regarding whether hysterectomy, if not already performed, is required in patients with this diagnosis, but long-term follow-up is required at minimum. Optimal management of the ovaries is also not known. (See 'Smooth muscle tumors of uncertain malignant potential' above.)

●Conditions such as metastasizing leiomyoma and intravenous leiomyomatosis present with symptoms related to involved disease sites, such as lung and vena caval lesions causing dyspnea. Many of these conditions are responsive to antiestrogenic therapy. (See 'Leiomyomas with disseminated, intravascular, or metastatic growth patterns' above.)

●Some cases of leiomyomas are associated with genetic disorders. Pathologic reporting of a fumarate hydratase-deficient leiomyoma should prompt discussion of referral to a genetic counselor for risk evaluation of hereditary leiomyomatosis renal cell carcinoma in the patient and family members and initiation of surveillance for renal cell cancer. (See 'Fumarate hydratase deficiency' above and 'Cowden syndrome' above and 'Diffuse leiomyomatosis (Alport syndrome)' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Bradley Quade, MD, PhD, and Rochelle Garcia, MD, who contributed to earlier versions of this topic review.