Mesenchymal and Mixed Epithelial–Mesenchymal Tumors of the Uterine Corpus and Cervix

Leiomyomas are the most common uterine tumor, being found in up to 75% of hysterectomy specimens. They are most common in the fourth and fifth decades; only about a third of tumors are symptomatic. Postmenopausal regression occurs in some cases.

The clinical manifestations are related to their number, size, and location, and include pelvic pain, abnormal vaginal bleeding, and uterine enlargement. Pedunculated submucosal tumors may present at the external os. Large tumors can produce pressure symptoms on adjacent pelvic organs (bowel, bladder) or complicate pregnancy or delivery.

Rare presentations include Meigs’-like syndrome, erythrocytosis due to erythropoietin production, and as a component of the hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome that is related to a fumarate hydratase mutation (see Leiomyomas with Rare Findings ).

Leiomyomas are multiple in ~75% of cases and are typically confined to the corpus; <2% are cervical. Rare tumors (that are usually microscopic) are confined to the endometrium.

Most leiomyomas are grossly evident, but some microscopic (‘seedling’) leiomyomas may be numerous. Sections should be taken from leiomyomas exhibiting other than the usual gross appearance and from the largest tumor because a leiomyosarcoma within a myomatous uterus is almost always the largest mass.

The tumors, which can be intramural, submucosal, or subserosal, are typically round, well-circumscribed, nonencapsulated masses (that can be enucleated) with white, whorled, bulging, solid cut surfaces.

Submucosal tumors are contiguous with or close to the endometrium.

• The overlying endometrium may be thinned out with glands running parallel (vs perpendicular) to the endomyometrial junction.

• The tumors may be nonpolypoid or polypoid; the latter may be sessile or pedunculated. Pedunculated tumors occasionally prolapse through the cervical os and/or undergo torsion.

• Ulcerative necrosis (see next heading) is occasionally found on the surface of some submucosal tumors.

Subserosal leiomyomas are contiguous with or close to the serosa. They are occasionally pedunculated; torsion of the pedicle may lead to infarction. Hemoperitoneum is a rare complication due to rupture of distended veins on the tumor's surface. Loss of attachment to the uterus accounts for most ‘parasitic’ leiomyomas (see corresponding heading).

Elongated spindle cells with eosinophilic cytoplasm and central, pale, fusiform nuclei are arranged in intersecting fascicles. Nuclear palisading is occasionally a prominent feature (‘schwannoma-like’ leiomyoma).

Variable amounts of collagen that typically increases with age separate the tumor cells (hence the term ‘fibromyoma’ used in older texts). Hyaline change is common and appears as acellular homogenized collagen that can form bands or plaques or replace large areas of the tumor. Nests and cords of tumor cells can be compartmentalized by collagen, resulting in pseudoepithelial patterns.

Some tumors have conspicuous vessels, including large muscular arteries, arterioles, and veins. Rare leiomyomas (‘angioleiomyomas’) contain numerous evenly distributed arteriole-like vessels with thick muscular walls and perivascular swirling of HMB45− tumor cells. Some may reach large sizes and/or be associated with extrauterine involvement (Muller and Lagstein).

Most leiomyomas have a sharp border with the myometrium, but occasionally it is somewhat infiltrative, a finding that is much more common in highly cellular leiomyomas (HCLs) (see below).

Necrosis within leiomyomas, which may be grossly visible, is infarct-type necrosis (ITN) in contrast to tumor cell necrosis (TCN) of leiomyosarcoma (LMS).

• ITN consists of necrotic mummified smooth muscle cells, often with hemorrhage. Vessels in the area may show fibrinoid change, perivascular inflammation, and luminal occlusion. Unlike TCN, a surrounding zone of granulation or fibrous tissue is typical of ITN but it may be absent or subtle.

• Early infarcts may consist of only single necrotic or apoptotic cells admixed with viable tumor cells.

• Viable smooth muscle cells around infarcts may show increased mitotic activity, a finding more common around ITN than TCN (Yang and Mutter).

• A trichrome stain can sometimes highlight fibrosis around ITN. Yang and Mutter found that the network of reticulin fibers around infarcts is lost with time but is preserved around foci of TCN.

• found that patchy p16 expression is common around ITN in leiomyomas, and rarely they show diffuse p16 positivity, a finding that can cause concern for LMS that are commonly p16 positive.

• A third type of necrosis (ulcerative necrosis), seen in submucosal leiomyomas, consists of numerous inflammatory cells and necrotic debris and in some tumors edema and occasionally myxoid change. Mitotic figures may be seen in the subjacent tumor.

Edema is common, at least in minor amounts. It may have a nonspecific appearance or have the particular characteristics of so-called ‘hydropic change’ (see below). A pattern that we refer to as ‘alveolar edema’ is considered under leiomyomas with bizarre nuclei.

Dystrophic calcification may be extensive, particular in postmenopausal women, and visible radiologically.

Leiomyomas typically stain for desmin and h-caldesmon, newer smooth muscle markers (oxytocin receptor, smooth muscle myosin heavy chain, histone deacetylase), and unlike most extragenital leiomyomas, WT1. Immunostaining is rarely required for diagnosis but occasionally can be helpful in tumors with unusual morphology.

‘Red degeneration’, which typically occurs in pregnancy or less commonly in oral contraceptive (OC) users, results in a beefy red appearance due to infarction and hemorrhage with subsequent hemolysis.

The following findings have been found in some but not all studies of tumors treated with gonadotropin-releasing hormone agonists (GnRHa):

• Irregular borders, focal hypercellularity, focal infarcts and/or hyalinization, and occasionally, massive lymphoid infiltrates.

• Vascular changes including decreased vessel number, decreased vessel caliber, mural smooth muscle proliferation, myxoid change, fibrinoid degeneration, and vasculitis.

• A decreased cellular proliferation index. After withdrawal of the GnRHa, however, there may be increased mitotic activity.

• A decrease in ER and PR immunoreactivity.

Specific changes referred to as ‘apoplectic’ leiomyomas are discussed later under the corresponding heading.

Uterine artery embolization (UAE) using particles or microspheres of polyvinyl alcohol (PVA) or tris-acryl gelatin microspheres (TGMs) is occasionally used to treat leiomyomas.

Microscopic changes vary with the post-UAE interval, but there is typically necrosis of infarct type.

• The cardinal finding is the presence of intra- or extravascular embolic material, often with a foreign-body granulomatous reaction, and in some cases thrombosis and partial to complete vessel destruction. These changes may occur within, around, or distant from the leiomyomas, including within the cervix, endometrium, tubes, and ovaries.

• PVA appears on H&E stained sections as a pale gray-blue fibrillar latticework (in its particulate form) or as oval structures (microspheres). PVA is PAS/PASD+ and black with the Elastic van Gieson (EVG) method. TGMs are red (H&E) or yellow-brown (EVG) spheroids with a PAS+ periphery.

Complications, which may necessitate hysterectomy, include hemorrhage, necrotizing endomyometritis, infarcts within the corpus, cervix, or vagina, and rarely permanent amenorrhea due to ovarian infarction.

Antifibrinolytic agents such as tranexamic acid, used in the treatment of menorrhagia and/or leiomyomas, can also produce thrombosis and infarction of leiomyomas.

• The infarcts may mimic TCN or necrosis of uncertain type, potentially leading to a misdiagnosis of leiomyosarcoma or smooth muscle tumor of uncertain malignant potential.

• Kudose and Krigman described intratumoral vasculopathy resembling acute atherosis in a leiomyoma treated with tranexamic acid.

Although these tumors (LMSs) account for 80% of uterine sarcomas (if malignant müllerian mixed tumors [MMMTs] are appropriately excluded), they account for only 1% of uterine cancers.

The patients are usually >40 years of age. Rare LMSs have been associated with tamoxifen treatment and hereditary retinoblastoma.

The presentation is usually nonspecific, with abnormal vaginal bleeding and an enlarged uterus; rare tumors may rupture with hemoperitoneum. Extrauterine extension is found at presentation in about a third of cases. Leukocytosis due to paraneoplastic production of granulocyte colony stimulating factor is a rare associated finding.

LMSs are typically solitary, but frequently coexist with uterine leiomyomas. In such cases, the LMS is almost always the largest mass (mean diameter of 10 cm). Two-thirds are intramural, one-fifth submucosal, and one-tenth subserosal; <5% arise in the cervix. Rarely an origin from a leiomyoma can be demonstrated.

LMSs are typically less well circumscribed than leiomyomas and unlike the latter usually cannot be easily enucleated. The cut surface is typically bulging, soft, fleshy, and focally necrotic and hemorrhagic, lacking the usual whorled appearance of a leiomyoma.

The tumors generally resemble their extrauterine counterparts, being typically composed of intersecting fascicles of mitotic spindle cells with eosinophilic fibrillar cytoplasm and elongated nuclei. An infiltrative border and vascular invasion are common. Some LMSs contain areas resembling leiomyoma (see below).

The combination of features that are diagnostic of LMS vs an atypical but benign smooth muscle tumor are: (1) hypercellularity of at least moderate degree; (2) diffuse moderate to marked nuclear atypia, usually appreciable at low-power magnification; (3) a high mitotic rate (≥10 mf/10 hpf is generally used); and (4) tumor cell necrosis (TCN) (we, like Hart, prefer ‘tumor cell necrosis’ to ‘coagulative tumor cell necrosis’ as the latter term leads to confusion with infarct-type necrosis). Most, but not all, LMSs exhibit all four features.

• found that any two of the last three features listed above are diagnostic of LMS. A smooth muscle tumor with even one of these three features in the initial sections should be thoroughly sampled to exclude the presence of the other features.

• TCN (present in 80% of LMSs) is characterized by an abrupt transition from viable cells to necrotic cells (without interposed granulation or fibrous tissue); ghost outlines and remnants of pleomorphic and hyperchromatic nuclei of the necrotic cells; and perivascular viable tumor cells. ITN is also commonly present.

• found interobserver agreement even amongst experienced gynecologic pathologists in the assessment of TCN to be only fair.

• found that mitotic counts in hypercellular areas and along fascicles (not cross-sections of fascicles) yield the highest count.

Yang and Mutter found significant differences between leiomyomas and LMSs in the reticulin/collagen networks as well as localization of mitoses.

• The normal myometrial honeycomb reticulin pattern was retained in the nonviable areas in ~90% LMSs but lost in ~60% of leiomyomas. Conversely, trichrome stains revealed that hyalinization was significantly more common in nonviable areas of leiomyomas than in LMSs.

• The same study found that mitotic activity in viable areas increased toward the interface with nonviable areas in LMSs but decreased toward the interface in leiomyomas.

Rare primary or metastatic LMSs contain a dedifferentiated component of high-grade pleomorphic cells (lacking smooth muscle differentiation) and/or heterologous elements that may include rhabdomyosarcoma, osteosarcoma, or liposarcoma.

• found loss of CDKN2A promoter methylation in the rhabdomyosarcomatous cells in some such cases.

• Tumors with liposarcomatous differentiation (‘lipoleiomyosarcoma’) may have myxoid and epithelioid features and/or foci of lipoleiomyoma or LBN.

LMS with a prominent component of osteoclastic-type giant cells may resemble benign or malignant giant cell tumor of bone or the giant cell variant of malignant fibrous histiocytoma. The giant cells appear to be due to high expression of receptor activator of nuclear factor κ B ligand within the tumor ( ).

Xanthomatous LMSs contain numerous large xanthomatous cells with abundant lipid-rich cytoplasm and multiple or multilobated nuclei, sometimes in a wreath-like arrangement.

Overt smooth muscle differentiation in most LMSs limits the need for smooth muscle markers (desmin, h-caldesmon), although their use can assist in poorly differentiated tumors (see below).

Immunostains usually show diffuse (>50%) p16 staining, diffuse (>50%) p53 staining, and a high (>10%) MIB1 index, in contrast to the rarity or absence of these findings in usual leiomyomas, leiomyoma variants, and STUMPs. ER and PR are present in about 40% of tumors.

Mitosis-specific markers MPM-2 and phospho-histone H3 (PHH3) can help assess mitotic activity.

found that half of LMSs showed strong cytoplasmic staining for IMP3 in contrast to an absence of staining in leiomyomas and, with rare exceptions, leiomyoma variants.

found that 75% of LMSs are c-kit positive, although no mutations in the gene have been yet identified. Reactivity for HMB-45 and/or melan A has been reported in some LMSs, suggesting an overlap with perivascular epithelioid cell tumors (see corresponding heading). Occasional LMS are DOG1+, a finding that could lead to a misdiagnosis of a GIST.

found that 70% of LMSs contained foci resembling typical leiomyoma or a leiomyoma variant and that typically lacked staining for Ki-67 and p53 but shared some genetic mutations with the LMS. Some such tumors may represent sarcomatous transformation of a leiomyoma ( ).

Some uterine LMSs are WT1+ in contrast to most extrauterine LMS which are WT1−. Thus WT1 staining favors a uterine primary when dealing with metastatic LMS of unknown origin, although WT1 negativity does not exclude a uterine origin.

found abnormal MMR protein expression in 10% of uterine LMSs.

found MED12 protein expression in all LMSs irrespective of MED12 exon 2 mutational status. found that 25% of LMSs had HMGA2 overexpression; no MED12 mutations were found in HMGA2+ LMSs. found FH -deletions that occur in some leiomyomas (see Leiomyomas with Bizarre Nuclei and HLRCC-related Leiomyomas) are also present in a minority of LMSs.

found that ~60% of LMSs expressed TOP2A; greater levels were found in ≥stage II tumors. All benign smooth muscle tumors had low TOP2A immunohistochemical expression.

found that deletion of COL4A5 and COLA46 occur in ~20% of LMSs resulting in loss of expression of these genes

have found that loss of ATRX and DAXX expression identifies poor prognosis in early stage LMSs.

Gene expression profiling can differentiate between primary uterine LMSs and their metastases ( ) as well as distinguishing LMSs from endometrial stromal sarcomas ( ).

Survival rates in most series range from 15% to 40% (most 20–30%) and median survivals of 13 to 43 months. Tumor-related deaths are usually due to distant metastases, frequently accompanied by local recurrence.

, studying 130 LMSs with distant metastases, found a wide variety of metastatic sites and highly variable median intervals to first metastasis (1 month to 26 years). By far the most frequent site of first metastasis was the lung; the next six most common sites, in order of frequency, were skin/soft tissue, cranial/intracranial, bone, liver, pancreas, and peritoneum. Metastases were histologically identical to the primary tumors.

Clinical prognostic factors:

• The most adverse prognostic factor is stage >I ( Table 9.2 ), although up to 76% of stage I tumors recur ( )

  Table 9.2

  FIGO staging for uterine sarcomas

  Stage I	Tumor limited to uterus
  IA	< or equal to 5 cm
  IB	> or equal to 5 cm
  Stage II	Tumor extends beyond uterus
  IIA	Adnexal involvement
  IIB	Involvement of other pelvic tissues
  Stage III	Tumor invades abdominal tissues
  IIIA	One site
  IIIB	More than one site
  IIIC	Metastasis to pelvic and/or para-aortic lymph nodes
  Stage IV
  IVA	Tumor invades bladder and/or rectum
  IVB	Distant metastases

• Using a variety of clinical and pathologic factors, developed a nomogram that outperformed AJCC and FIGO staging systems in predicting postresection 5-year OS.

• Other clinical adverse prognostic factors have included age >50 years, African-American race, and no primary surgical treatment.

Pathologic prognostic factors:

• Histologic grading of LMSs has not been prognostically helpful, as almost all LMSs are high-grade. found that 75% of tumors initially diagnosed as low-grade LMS did not meet current criteria for LMS, and were reclassified as atypical smooth muscle tumor (STUMP) or endometrial stromal tumor with smooth muscle differentiation.

• Poorer survivals have been associated with size ≥5 cm (see Table 9.2 ), ill-defined margin, >20 mf/10 hpf, an epithelioid or myxoid component, extensive TCN, diffuse high-grade atypia, lymphovascular invasion, p53 positivity, and absence of ER and PR. found that PR expression was associated with longer survival in stage I LMSs.

• Using size and mitotic index, identified three risk groups: low (≤10 cm, MI ≤10 mf/10 hpf), medium (>10 cm or >10 mf/10 hpf; 1.9-fold increased death risk), and high (>10 cm and >10 mf/10 hpf; 5.3-fold increased death risk).

• identified a better prognosis group (<10 cm, <20 mf/10 hpf, Ki67−, variable bcl-2 staining) and worse prognosis group (>10 cm, >20 mf/10 hpf, Ki67+, bcl-2−).

• found that desmin and CFL2 expression predicted improved survival on multivariate analysis and the presence of all four conventional smooth muscle markers (SMA, desmin, h-caldesmon, smooth muscle myosin) predicted improved survival on univariate analysis.

Leiomyoma variants (particularly mitotically active leiomyomas and leiomyomas with bizarre nuclei) and benign-appearing smooth muscle tumors with unusual growth patterns or behavior (see respective headings).

Smooth muscle tumors of uncertain malignant potential (STUMPs) (see corresponding heading).

Other sarcomas. Immunohistochemistry can usually aid in the differential diagnosis with these tumors that are covered under separate headings.

• Endometrial stromal sarcomas with smooth muscle differentiation. These tumors have an endometrial stromal component and a distinctive smooth muscle component that differs from LMS. In contrast to LMSs, p16 staining is absent or only focal ( )

• Undifferentiated endometrial sarcoma. These tumors definitionally lack smooth muscle differentiation.

• Rhabdomyosarcoma. These tumors definitionally contain rhabdomyoblasts, although some tumors may be admixed with leiomyosarcoma.

• PEComas (see corresponding heading).

These rare tumors are composed predominantly or entirely of polygonal cells. The designation ‘epithelioid’ should not be applied to otherwise typical spindle-cell smooth muscle tumors in which edema, hyalinization, or other changes result in epithelial-like patterns, such as nests and cords.

The clinical presentation is similar to that of patients with typical leiomyomas.

The tumors usually grossly resemble typical leiomyomas, but some benign tumors and some epithelioid leiomyosarcomas (LMSs) have worrisome gross features including a fleshy appearance, a poorly circumscribed margin, and hemorrhage or necrosis. Occasional tumors arise in the cervix.

The tumor cells are typically arranged in sheets, nests, or cords that may form a plexiform pattern. A tumor that is entirely plexiform and <1 cm (usually microscopic) is a ‘plexiform tumorlet’. The latter are often multiple and usually myometrial (often occurring at the endomyometrial junction) but occasionally involve or are confined to the endometrium.

The tumor cells are predominantly or exclusively round or polygonal with cytoplasm that is usually eosinophilic and granular, but occasionally clear; clear cells may predominate in some epithelioid leiomyomas and LMSs.

Spindle-shaped smooth muscle cells are present in 50% of the tumors. In such cases, the epithelioid cells may be scattered throughout a leiomyoma or LMS composed predominantly of spindle cells, a finding that can be mistaken for metastatic carcinoma.

The round or angular nucleus is typically central but may be eccentric, occasionally resulting in a signet-ring-like appearance. The nuclei exhibit variable degrees of pleomorphism that tend to parallel their malignant potential.

Rare findings include tumor cells with bizarre nuclei (similar to those in usual LBNs), osteoclastic-type giant cells, rhabdoid-type cells, and fat.

Mitotic figures are rare (0-1 mf/10 hpf) in benign tumors. In contrast, most epithelioid LMSs have at least 3 or 4 mf/10 hpf, but some clinically malignant tumors have only 2 mf/10 hpf (see next heading).

Stromal hyalinization may be slight and focal, or marked and diffuse, and occasional tumors have had a myxoid stroma.

Vascular invasion is present in occasional benign tumors as well as in epithelioid LMSs. Rare examples of intravenous leiomyomatosis are composed of epithelioid cells.

Immunostains may aid in diagnosis, but frequent negativity for desmin and h-caldesmon and occasional positivity for cytokeratin can lead to a misdiagnosis of an epithelial tumor.

• found that histone deacetylase, a smooth muscle marker, was consistently present in epithelioid smooth muscle tumors, and superior to desmin and h-caldesmon in this context.

• Occasional otherwise typical epithelioid LMSs contain clear cells that can be focally HMB-45+, suggesting overlap with PEComas (see corresponding heading below).

The proportion of tumors that are clinically malignant is higher than with spindle-cell smooth muscle tumors, and has ranged from 12% to 40% in the three largest series (predominantly consultation cases). In one study of metastasizing uterine LMSs (all histologic types included), 36% were epithelioid.

Tumors should be regarded as benign only when they have absent or mild (grade 1) nuclear atypia (excluding cells with bizarre nuclei as noted above), ≤ 2 mf/10 hpf, and no TCN. tentatively regard tumors with grade 2 nuclear features but without increased mitotic activity or TCN as ‘epithelioid smooth muscle tumor, probably benign’.

A diagnosis of epithelioid LMS is warranted in tumors that exhibit any two of: ≥5 mf/10 hpf, grade 2 or 3 nuclei; TCN.

Epithelioid LMSs may have a more protracted clinical course than typical LMSs. Patients may die from tumor, often after multiple recurrences, >5 or even >10 years after hysterectomy.

PEComas (see next heading).

Corded and hyalinized endometrioid carcinoma (see Chapter 8 ). In a limited sample, the hyalinized and occasionally myxoid stroma of this tumor resembles that of some epithelioid smooth muscle tumors. Glandular differentiation in well-sampled tumors excludes the latter diagnosis.

Poorly differentiated or undifferentiated carcinomas. These tumors overlap with epithelioid smooth muscle tumors on both routine and immunohistochemical staining (both may be CK+/EMA+ and negative for smooth muscle markers). A carcinoma is indicated in the presence of epithelial differentiation (glands, papillae, squamous elements, mucin) and/or staining for only epithelial markers.

Malignant melanoma. This diagnosis is indicated by the presence of cytoplasmic melanin pigment, melanoma markers (S100, HMB-45, Mart-1), and absence of smooth muscle markers.

Placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT). These tumors are usually associated with a history of a recent pregnancy, elevated serum hCG, permeative myoinvasion (PSTT), replacement of blood vessel walls (PSTT), extensive necrosis and hyalinization (ETT), and variable reactivity for inhibin, hPL, hCG, Mel-CAM, and in ETT, p63, but nonreactivity for smooth muscle markers.

Uterine tumors resembling ovarian sex cord tumors (see corresponding heading).

Endometrial stromal tumors with epithelioid cells. The presence of foci of typical EST points to the correct diagnosis.

Alveolar soft part sarcoma. This rare diagnosis is indicated by a typical alveolar pattern, PASD+ cytoplasmic granules and crystals, and reactivity for TFE3.

Uterine PEComas have occurred in women 9–79 (mean, 49) years of age, with presenting symptoms usually related to a uterine mass. Evidence of tuberous sclerosis and/or lymphangioleiomyomatosis (LAM) has been present in 15% of cases.

Tumor size has ranged from 1 to 30 (mean, 6) cm; 90% are within the corpus, the rest cervical. They are usually mural or subserosal, well to poorly circumscribed, and have cut surfaces that are leiomyoma-like or soft, fleshy, yellow, and/or focally necrotic. One tuberous sclerosis-associated tumor diffusely involved the myometrium and ovaries (‘PEComatosis’).

Epithelioid and/or spindle cells (usually both) with clear to pale eosinophilic cytoplasm are disposed in sheets, nests, and short fascicles, sometimes in a perivascular distribution. There is typically a prominent capillary network.

Rare features of uterine and extrauterine PEComas have included multinucleated cells, ‘spider cells’, rhabdomyosarcomatous differentiation, ganglion-like cells, stromal microcysts, myxoid change, and extensive stromal hyalinization (‘sclerosing’ PEComa). Atypical histologic features associated with malignant behavior are noted below.

PEComas typically stain for smooth muscle and melanocytic markers.

• found positivity for HMB-45 (in 92% of tumors), vimentin (85%), smooth muscle actin (80%), melan-A (72%), MiTF (microphthalmia transcription factor) (50%), and desmin (36%). Other markers tested for were S100 (33%), CK (13%), CD117 (5%), and CD34 (0%).

• (13 of 16 cases were uterine) found more frequent positivity for MiTF (92%) and desmin (100%); other markers included h-caldesmon (92%) and TFE3 (38%).

• found that cathepsin K strongly stained all PEComas, outperforming all other markers.

TFE3 gene fusions occur in a subset of PEComas. Such tumors occur at a younger age, lack association with tuberous sclerosis, and exhibit a predominant alveolar architecture, clear cell epithelioid cytology, and diffuse immunoreactivity for HMB45, cathepsin K, and TFE3 (nuclear staining). Not all tumors with the last finding have a TFE3 rearrangement. Melan-A staining is focal or absent and staining for smooth muscle markers is variably weak (except in any spindle cell areas).

Most PEComas harbor loss-of-function TSC1/TSC2 mutations. found novel RAD51B gene rearrangements in 8% of uterine PEComas.

About 40% of uterine PEComas with follow-up have been clinically malignant. In a study of PEComas from all sites, identified three prognostic groups based on histology:

• Malignant: tumors with any two of: size >5 cm, infiltrative borders, high nuclear grade, ≥1 mf/50 hpf, necrosis, vascular invasion.

• Uncertain malignant potential: tumors with only one of the above features.

• Benign: tumors with none of the above histologic features.

proposed a modification for classifying gynecologic PEComas using only five of the above criteria (infiltration was excluded): malignant (≥4 features), of uncertain malignant potential (1–3 features), benign (no atypical features). , however, found that the presence of only three of these features more reliably classified PEComas as malignant.

found that 50% of their TFE3 translocation-associated PEComas were clinically malignant.

Smooth muscle tumors (SMTs), especially of epithelioid type. SMTs and PEComas both contain spindled and/or epithelioid cells and exhibit variable staining for smooth muscle and melanoma-associated markers, although staining with the latter is usually more diffuse in PEComas.

• The following features favor a PEComa over a SMT ( ): pale eosinophilic to clear cytoplasm, an absence of perinuclear vacuoles, round to oval nuclei, a prominent capillary network, and extensive staining for Melan-A and MiTF. Evidence of tuberous sclerosis or LAM also favors PEComa. Cytokeratin and/or EMA staining may be seen in epithelioid SMTs but not in PEComas.

• HMB-45 positivity occurs in a third of tumors that with standard criteria would be considered epithelioid smooth muscle tumors. According to current approach, this finding would indicate PEComa and a potential association with tuberous sclerosis and/or LAM.

Endometrial stromal sarcoma (ESS). Although some PEComas have infiltrative patterns resembling those of ESS and rare ESSs contain epithelioid cells, ESSs, unlike PEComas, usually have endometrial involvement, overt endometrial stromal differentiation, and a CD10+/HMB-45 − immunoprofile.

Uterine extragastrointestinal stromal tumor (EGIST). EGISTs have an admixture of spindled and epithelioid cells and thus may resemble a PEComa. CD117 staining and negative staining for melanocytic markers supports a diagnosis of EGIST, although rare PEComas are CD117+ (as noted above).

Metastatic malignant melanoma. This diagnosis is supported by negative staining for smooth muscle markers and positivity for MUM-1 in addition to melanoma markers. found MUM-1 expression in 92.3% of primary melanomas and 81.3% of metastatic melanomas, whereas only weak positivity was seen in 25% of PEComas.

This uncommon tumor (IVL) is characterized by intravenous proliferations of benign-appearing smooth muscle outside the confines of a leiomyoma. Rare cases have been confined to the broad ligament without a uterine mass ( ).

The clinical presentation is usually similar to that of typical uterine leiomyomas. found an age range of 35 to 64 (mean, 46) years. Rare presentations include recurrent leiomyomas after repeated myomectomies, a retroperitoneal mass, or cardiac manifestations (see below).

Extrauterine extension into the veins of the broad ligament, or less often ovarian and vaginal veins, is found in 30% of cases. The extrauterine extension may be noticed intraoperatively or on gross examination of the hysterectomy specimen.

Rarely, intravascular tumor extends into the inferior vena cava, in some cases reaching the right side of the heart. Cardiac manifestations may be the presenting feature of IVL or recurrent tumor due to persistent growth of intravascular tumor years after hysterectomy.

Rare cases are associated with solitary metastases (lungs, pelvic lymph nodes), as in benign metastasizing leiomyoma (see below).

Gross examination reveals multinodular, rubbery, gray-white myometrial masses, at least some of which are worm-like plugs of tumor within myometrial and occasionally parametrial vessels. The intravascular involvement is sometimes only grossly appreciated upon re-examination of the uterus. Secondary changes similar to those seen in typical leiomyomas may be grossly apparent

On microscopic examination, endothelium-coated plugs of benign smooth muscle occupy the lumina of myometrial veins outside of leiomyomas.

• The intravascular tumor resembles typical or hydropic leiomyoma but potentially any variant of leiomyoma may be encountered.

• Rarely, endometrial glands and stroma may be admixed with the intravascular smooth muscle (‘intravascular adenomyomatosis’). In such cases, typical adenomyosis is also present.

• Common features of the intravascular tumor that may obscure its smooth muscle nature but should suggest IVL include a clefted or lobulated contour, extensive hydropic change, hyalinization, numerous thick-walled vessels, or combinations thereof.

Extravascular leiomyomas, which are usually present, are often less well circumscribed, occasionally dissecting, and more hydropic than usual leiomyomas. In rare cases, the extravascular tumor has had the gross and microscopic appearance of a dissecting cotyledonoid leiomyoma, as described above.

found that IVL exhibits recurrent chromosomal aberrations overlapping with those observed in uterine LMS. found that IVL shares some molecular cytogenetic characteristics with uterine leiomyomas, and expression profiles similar to that of LMSs.

Typical leiomyomas may be partly surrounded by slit-like spaces that may represent retraction artifact or compressed vascular spaces. In these cases the tumor does not have the intraluminal location or typical appearance of IVL.

Leiomyomas with perinodular hydropic change (see Hydropic Leiomyomas).

Endometrial stromal sarcomas (ESSs). ESSs, like IVL, are characterized by prominent intravascular growth, but unlike IVL, typically involve the endometrium, have permeative myoinvasion, lesional cells of endometrial stromal-type, and an arteriolar network. Additional features aiding the distinction of cellular IVL from ESS are the same as those that distinguish highly cellular leiomyomas from endometrial stromal tumors (see Table 9.1 ).

Leiomyosarcoma (LMS) vs IVL with bizarre nuclei. A high mitotic rate and tumor cell necrosis indicate LMS; also LMSs only very rarely have grossly visible venous invasion.

Myxoid LMS vs myxoid IVL. The former diagnosis is indicated if the extravascular tumor has infiltrative borders, atypia, mitoses, or tumor cell necrosis.

Epithelioid LMS vs epithelioid IVL. Atypia, mitoses, and tumor cell necrosis indicate the former diagnosis.

Leiomyoma with vascular invasion (see separate heading above).

Vessels within vessels. Arteries protruding into myometrial veins are an incidental microscopic finding in 50% of hysterectomy specimens and may be a cause of menorrhagia ( ). The distinctive appearance of this finding facilitates distinction from IVL.

Recurrences from growth of residual intravenous tumor may appear months to many years posthysterectomy. Approximately 10% of cases reported from three institutions recurred ( , , ).

The recurrences may be found within the pelvic veins, the inferior vena cava, or even the right side of the heart, sometimes with fatal consequences. Rarely the recurrences are as benign metastasizing leiomyoma (see next heading), with nodal or pulmonary involvement.

GnRH agonists and tamoxifen have been used successfully to treat unresectable tumor.

Posthysterectomy scans may be helpful in detecting and monitoring the presence and growth of residual intravascular tumor.

ESNs typically occur at a mean age of 53 years and have a nonspecific presentation (vaginal bleeding, enlarged uterus) or are an incidental finding.

Gross examination reveals a well-circumscribed, nonencapsulated, usually solitary, round to oval endomyometrial (or purely myometrial) mass (mean diameter, 7 cm). The usually soft, fleshy, and tan to yellow sectioned surface may exhibit focal necrosis, hemorrhage, and cystic change.

ESNs are usually well circumscribed on microscopic examination, but occasional finger-like projections of up to 3 mm are allowable.

• have described rare, otherwise typical ESNs with occasional tongue-like projections or satellite nodules of tumor that were up to 9 mm from the main border of the tumor (‘endometrial stromal tumor with limited infiltration’) (EST-LI).

• Vascular invasion is definitionally absent in ESNs and ESTs-LI.

ESNs and ESTs-LI are typically cellular tumors although about 20% are hypocellular due to fibrous regions or areas of edema or myxoid change (see ESTs with Unusual Pathologic Features).

The endometrial-stromal-type cells have bland nuclear features and usually <5 mf/10 hpf, but higher counts do not exclude the diagnosis.

There is typically a network of arterioles that may have hyalinized walls. Compared to HCLs (see Table 9.1 ), large thick-walled muscular vessels are uncommon and if present tend to be at the tumor's periphery. The cleft-like spaces of HCLs are not a feature of ESNs.

Foci of smooth muscle and sex cord-like differentiation are present in about half and a quarter of tumors, respectively, and rare ESNs have epithelioid cells with eosinophilic or foamy cytoplasm (see ESTs with Unusual Pathologic Features).

The immunohistochemical and molecular findings are identical to those in ESSs (see below).

ESNs are benign tumors adequately treated by hysterectomy. Rarely ESNs are a diagnostic consideration in a curettage specimen in a woman who desires to retain her uterus. If diagnostic imaging confirms that the lesion is well circumscribed, local excision can be occasionally successful.

The ESTs-LI reported by were clinically benign, presumably due to limited invasive growth. However, of two subsequently reported tumors, one was associated with metastases ( ) and another with possible metastases ( ).

Fragments of non-neoplastic endometrial stroma.

• Gland atrophy, particularly after menopause, can result in sizeable fragments of compact nonneoplastic stroma in a biopsy or curettage specimen.

• found that an aglandular fragment of endometrial-type stroma ≥5 mm is suggestive of an EST. Also, such fragments often appear distinct from normal stromal fragments and may exhibit unusual types of differentiation (see Unusual Pathologic Features of ESTs).

Endometrial polyp with cellular stroma ( Chapter 7 ).

Highly cellular leiomyoma (see Table 9.1 ).

Low-grade endometrial stromal sarcoma (LGESS).

• These tumors, unlike ESNs and ESTs-LI, usually exhibit extensive permeative myometrial invasion and often myometrial vascular invasion, a feature usually only evaluable in a hysterectomy specimen.

• In ESNs with metaplastic smooth muscle (see Unusual Pathologic Features of ESTs), an irregular admixture of the smooth muscle and endometrial stromal components can mimic a myoinvasive LGESS if the neoplastic smooth muscle is misinterpreted as myometrium. Appreciation that the true margin of the tumor is well circumscribed facilitates the diagnosis.

Uterine tumors resembling ovarian sex cord tumor (vs ESN with sex cord-like elements). These tumors (see corresponding heading) definitionally exhibit a predominance of sex cord or sex cord-like patterns, although focal endometrial stromal differentiation may be present.