Günter Köhler, Katja Evert, Marek Zygmunt and Matthias Evert

1Variants of leiomyoma (angio- and lipoleiomyoma, cotyledonoid and cellular leiomyoma, leiomyoma with bizarre nuclei, mitotically active, epithelioid and myxoid leiomyoma), smooth muscle tumors with uncertain malignant potential (atypical smooth muscle tumors), disseminated peritoneal leiomyomatosis, benign metastasizing leiomyoma, intravenous leiomyomatosis

1.1Angioleiomyoma (Angiomyoma, vascular leiomyoma)

1.1.1General, epidemiology, etiology, pathogenesis, pathological-anatomical findings

The current WHO Classification (183) does not list uterine ALM as a variant of LM. However, the clinical features of ALM justify that they are discussed in the context of LM. ALM is a smooth muscle tumor and is thus deemed a soft tissue tumor (261). Most ALM arise in the skin of the extremities (89%) and in the vicinity of the head (9%) (82). Women are noticeably more frequently affected than men are. One striking feature of ALM is its ample degree of vascularization. Furthermore, ALM have clinical features that are suggestive of malignant behavior, but do not fulfill the malignancy criteria. This applies to the frequent localization of such tumors in the lower extremity in particular. These suspicious clinical findings can lead to (even intraoperative) confusion with a malignant mesenchymal tumor.

Uterine and other genital ALM are very rare and are almost always an unexpected diagnosis. There is one account of a large ALM in the ligamentum latum in a 52-year-oldwoman (44). The uterine variant typically arises during pubescence. The few available data suggest that extrauterine forms occur slightly later, in the 5th and 6th decade of life (260), though there is a known case of an enormous ALM in a 19-year-oldwoman (222). Very little is known about this unusual LM in terms of pathogenesis and etiology. It appears to develop from the smooth musculature of the veins.

The strong degree of vascularity lends such tumors a brownish-red to deep red/blueish-red (Fig. 1.1.1 (A)), sometimes pink to yellowish macroscopic appearance. The presence of ample dilated vessels renders ALM relatively soft compared to ordinary uterine LM, and elastic like rubber. The so-called solid type can also be relatively coarse in comparison. ALM often have a lobulated appearance, but can nonetheless be clearly delineated from surrounding tissues. Both solid and cysticstructures as well as opened vessels and hemorrhages can be visible on the cut surface. Very large tumors often exhibit necrosis. An abundance of larger vessels can also give the cut-surface a sponge-like look (88). These macroscopic features often give the impression of a malignant tumor. Like ordinary LM, multiple ALM can arise synchronously. Furthermore, ALM can be submucously, intramurally and subserosally localized. Subserosal ALM can develop extraperitoneally into the ligamentum latum or the abdominal cavity via pedicular growth, and clinically mimic a solid, relatively soft adnexal tumor (36, 84). There are reports of tumors reaching diameters of up to 28 cm (100). ALM easily bleed when touched. Since the definitive diagnosis cannot be made on the basis of clinical criteria alone, the unusual appearance of ALM should give rise to intraoperative histologic clarification via frozen section.

ALM are also microscopically well-delineated from their surroundings. They typically have noticeably elevated numbers of large, thick-walled, arteriole-like vessels. The uniform spindle-like smooth muscle cells are often swirled around the vessels (36). ALM are histologically differentiated into the solid/capillary, cavernous and venous subtypes. Cavernous and venous ALM are characterized by strongly dilatated vascular spaces with narrow media and the ample presence of vessels with thick muscular walls (82, 117). Necroses, mitoses and atypia are usually not observed, and when they are, they do not account for a substantial share of the tumor’s total volume (Fig. 1.1.1 (B)).

Fig. 1.1.1: (A) angiomyoma – vaginal hysterectomy with morcellation under the preoperative diagnosis of ordinary leiomyoma. Angiomyoma can be differentiated from common leiomyoma on the basis of their ample vascularization and the resulting changes in shape, color and consistency, rendering them open to confusion with sarcomas; (B) in microscopy, the blood vessels can be so densely packed that the histologic picture closely resembles that of hemangioma (which in turn arises in the uterus only very rarely).

The spindle cells are positive for SMA, desmin, vimentin, caldesmon, ER and PGR (36, 58, 84, 91, 154). Cytokeratins are not expressed. The vascular component is immunoreactive for CD34 (84), though there are also reports of CD34 negative tumors (58). Immunostaining for CD10 and HMB45 is negative in ALM.

1.1.2Clinical presentation, diagnostics, imaging, differential diagnostics

ALM largely correspond to LM in terms of clinical symptomatology and findings, though there are some noteworthy particularities. Bleeding, predominantly as heavy menstrual bleeding, is often severe and can swiftly result in anemia. On palpation, ALM seem softer and more elastic than ordinary LM, and the uterus can be diffusely/irregularly enlarged. Like ordinary LM, ALM can reach enormous dimensions. They can literally fill the entire lower abdomen, and occasionally be equivalent in size to 40 weeks’ gestation (84, 88, 129, 222). Rapid growth is not uncommon. Large cavernous ALM can contain ample amounts of blood. In one case, a cavernous ALM weighed 5.1 kg and contained 2 liters of blood (129). Intratumoral bleeding with clotting occasionally results in consumptive coagulopathy (88). The large amount of blood can “mimic” rapid growth, cause pains in the lower pelvis and justify a suspected diagnosis of sarcoma. Otherwise, pains are rather the exception in patients with genital ALM, and more frequently occur when the tumor is localized in the extremities. Curettage indicated for AUB as well as twisting off pedunculated submucosal ALM can result in severe bleeding that can be difficult to arrest, if need be viaHE. There are accounts in which tumors have spontaneously ruptured, causing massive bleeding and hemoperitoneum (51). They can mimic a ruptured ectopic pregnancy. Taking all of the presented findings and features together should suffice to at least suspect ALM. However, the proper diagnosis is only rarely reached preoperatively, even when there are typical symptoms.

In the majority of cases, ALM are subjected to further diagnostics because of (hyper)menorrhagia or a “rapidly growing uterus”. Besides palpatory examination, curettage and HSC appear to be the primary methods of choice in practice due to the AUB. However, the correct diagnosis can often not be reached on the basis of curettage, unless myometrium could also be retrieved via very sharp or “vigorous” curettage, or unless the tumor is submucosal.

Ordinary LM is the most important DD. A rubbery consistency should be deemed suggestive of ALM. On occasion, soft DLM can masquerade as ALM. Pedunculated subserosal ALM can reach considerable dimensions and are barely discernible from mobile ovarian tumors on palpation (84). Compared to malignant ovarian tumors, however, ascites is absent and CA-125 values are not elevated in ALM (22, 84, 102).

Sonography reveals a well-circumscribed uterine mass with heterogeneous echogenicity, solid components and numerous anechoic voids that correspond to vessels (58, 91, 100). These voids are noticeably larger in cavernous ALM, and can achieve the size of small cysts. Doppler sonography shows a diffuse distribution of vessels throughout the entire tumor. Blood flow speed is elevated and the resistant index is low. Ultimately, LM with pronounced vascularity should be deemed suspicious of being ALM. Sarcoma would be a justifiable differential diagnostic consideration in these cases. Strongly vascularized tumors also clearly present as such in sonography when localized in the ligamentum latum (44).

ALM often appear as heterogeneous lobulated tumors in CT. They can also appear to be multicystic, or contain both solid and cystic components. The borders between these two components can be irregular, i.e. the components can exhibit a certain degree of “blending” (84, 91, 100). In CECT, the presence of prominent, wound, vessellike enhancing structures in tissue masses that are well-delineated from the uterine wall should be regarded as being suggestive of ALM.

T2W-MRI reveals a tumor with both hyperintense fluid-filled and solid hypointense areas that correspond to the smooth musculature. These two structures irregularly blend into each other. The solid components show strong enhancement in T1WC (91). The solid structures thus correspond to the MRI picture of LM. However, neither DLM nor a malignant tumor can be properly ruled out via diagnostic imaging (187). Larger, mixed solid and multicystic ALM are sometimes not discernible from ovarian tumors in MRI (80). The PET-CT shows no increase of activity (91). It is very effective in differentiating ALM from malignant tumors.

In summary, the simultaneous presence of cystic and solid structures is the decisive feature in imaging diagnostics. The solid structures exhibit the MRI characteristics of LM. The combined context of medical history, clinical findings and diagnostic imaging justifies at least a suspicion of ALM.

The coincidence of a uterine tumor and rapid growth can arouse a suspicion of uterine sarcoma, not least because the latter also have a softer consistency than ordinary LM. In contrast to the very rare uterine ANS (see also ANS, Vol. 2, Chapter 1), ALM do not express CD34 (58). The implications of a rapidly growing uterus are discussed at length in the chapter on LMS (Chapter 2). DLM can bear close gross resemblance to ALM in terms of consistency and color. From a clinical perspective, very rare uterine hemangioma is another differential diagnostic possibility. However, hemangiomas and ALM differ in that the former is usually not well-delineated from its surroundings, neither macroscopically nor microscopically. Arteriovenous malformations have similar features and appearance to hemangiomas (84). PEComa can be ruled out on the basis of HMB45 negativity (58).

While the cystic components revealed in diagnostic imaging are suggestive of ALM, they are usually a sign of LM degeneration. Such findings sometimes also constitute a cystic adenomyoma, or innate intrauterine cysts (204).

Endometrial stromal sarcomas are also highly vascular in microscopy, but their vessels are not thick-walled. The very rare uterine ANS macroscopically differ from ALM in that they are poorly circumscribed, while microscopy reveals pronounced cellular pleomorphism and positive immunostaining for ERG and CD31. In contrast to the suspicious clinical and macroscopic findings, the risk of mistaking ALM with sarcoma in histology is low.

1.1.3Course, prognosis, primary surgery, systemic and radiogenic therapy

ALM are without doubt benign. Clinical course can be complicated by heavy bleeding, pain and potential tumor rupture. ALM subjected to surgery have an excellent prognosis that corresponds to that for LM. ALM have a Ki67 index of between 0 und 25% (mean 2%) (156). Only two cases have been reported in which local recurrence developed after surgery on extragenital ALM, though no mention is made of the surgical procedures applied (82).

The (usually strong) menorrhagia and the risk of tumor rupture require that the threshold for surgery be set more generously than for ordinary LM. Once the proper diagnosis has been reached, further surgical treatment should be performed according to the criteria for LM surgery. THE is the standard surgical procedure. Bleeding can be ample in the course of surgery, rendering endoscopic procedures rather inadequate. There is no indication for BSO. Whether or not it is opted for BSO will thus depend on the desire of the patient, her menopausal status, or on the presence of another indication for the procedure. Since ALM are without doubt benign, patients can also undergo conservative, uterus-sparing surgery. The large volumes of blood involved can complicate tumor enucleation or morcellation procedures.

Adjuvant or additive therapy is not indicated, because ALM are without doubt benign.

There is no indication for primary RT or CHT. No data have been published on the treatment of ALM with progestins, antiprogestins, GnRH analogues and UPA. In the event that a certain amount of time needs to be bridged until surgery can be performed, analogous to ordinary LM, there is currently no reason not to administer GnRH analogues or UPA as a means of symptom control, i.e. stopping bleeding. Due to its good adverse effect profile, UPA might be particularly adequate for treating strong hypermenorrhea. In a recent study, applying the AI letrozole (2.5mg over 3mo) to premenopausal LM patients (aged 30–55 years) achieved a tumor volume reduction of > 50% and significant symptomatology improvements (63). AI apparently inhibits aromatases and, subsequently, the production of estradiol within LM (63). Administering 10mg mifepristone vaginally daily achieved similar clinical results in a comparable sample (273). In Germany, AI and mifepristone are only eligible for off-label use.

No data are available regarding the application of invasive-conservative procedures like embolization and high-frequency ultrasound therapy, not least because ALM are so uncommon.

1.1.4Aftercare, recurrences, metastases and their treatment

1.2Lipoleiomyoma

1.2.1General, pathogenesis, pathological-anatomical findings

Under WHO Classification, LLM is regarded as an independent variant of LM (183). LLM contain a mixture of mature adipocytes and smooth muscle cells. They appear to predominantly arise in postmenopausal women (259). Chromosomal aberrations have been observed in a number of LLM (175). LLM account for 0.28% of all LM. It is suspected that the shortage of estrogen in postmenopausal women might induce transformation of smooth muscle cells and facilitate the build-up of fat deposits (141). The results provided by a working group of the DKSM reveal that LLM account for 0.98% of LM (126). Affected women frequently have disorders in their fat-related metabolism and are often heavy by comparison. LLM are relatively soft tumors with a whitish-yellowish color on the cut surface. Purely adipocytic areas appear yellow and are very soft. LLM have an average diameter of 4.6 cm. Fat tissue can account for strongly varying shares of total tumor volume (Fig. 1.2.1), ranging from microscopic amounts to almost the entire tumor (43). Lipoblasts, mitoses and atypia are absent (see also Tab. 1.9.1).

Fig. 1.2.1: Histologic aspect of a lipoleiomyoma. The tumor is characterized by a stroma with mediate collagen levels. Small fascicles of leiomyocytes and small groups of univacuolar fat cells, all without atypia, are embedded in the stroma.

Tumors with a pronounced vascular component consisting of arteries, veins or undefinable vessels are referred to as angiolipoleiomyoma (275). The latter has nothing to do with angiomyolipoma from the PEComa family (cf. PEComa, Vol. 2, Chapter 4). LLM can also arise in the vicinity of the ligamentum latum (260).

1.2.2Clinical presentation, diagnostics, imaging, differential diagnostics

As is the case for all adipocytic tumors, sonography reveals more or less expansive hyperechoic areas in an otherwise hypoechoic uterine mass (191). In native CT and CECT, the adipocytic accumulations are recognizable, both natively and within the enhancing LM, on the basis of their weaker attenuation (191). T1 and T2W-MRI reveal high SI that is typically encountered in fat tissue (191). Hypointense sections correspond to the smooth muscle component. A diagnosis of an adipocytic tumor can be secured via fat suppression (13, 149). Malignant uterine and extrauterine genital adipocytic sarcomas are the most important DD in diagnostic imaging.

1.2.3Course, prognosis, primary surgery, systemic and radiogenic therapy

LLM is a benign tumor. Constituting a variant of LM, the “International Classification of Diseases for Oncology” deems LLM benign and codes it with “0” (183). However, malignant transformation appears to be generally possible (182). HE constitutes the therapeutic measure of choice. Conservative, organ-sparing surgery is also possible.

There is no indication for adjuvant or additive RT, CHT or HT. The same applies for primary or neoadjuvant CHT and/or RT in generally inoperable cases.

1.3Cotyledonoid dissecting leiomyoma

1.3.1General, pathogenesis, pathological-anatomical findings

Cotyledonoid LM is listed as an independent variant of LM in the current WHO Classification (183). Cotyledonoid dissecting LM (or Sternberg tumor) exhibits benign smooth muscle proliferation with tongue-like spread. This tumor thus belongs to the group of LM with unusual growth patterns. Affected women are aged between 23 and 73 years (mean 44, median 46). Atypia, mitoses and tumor necrosis are not present in cotyledonoid dissecting LM (121, 224). Growth beyond the uterus into the ligamentum latum is frequently observed (121, 187, 204). Cotyledonoid dissecting LM can also fill the entire pelvis (75). There are also known accounts of entirely extrauterine growth (152, 215). Adhesions with neighboring organs without infiltration are not uncommon (224). Intravascular involvement is observed in 21% of cases (152, 224). Accordingly, tumors vary considerably in size, ranging from 4 to 41 cm, with a mean widest diameter of 14.2 cm. Cotyledonoid LM generally exhibit prominent vessels and strong hydroponic change. Combined with the edemas and vessels, the tumor’s dark-red color and sponge-like structure render it similar to placental cotyledons when it has spread beyond the uterus (hence the name). Based on their appearance, cotyledonoid LM are sometimes also referred to as grape-like tumors (182, 211, 275). Epithelioid variants have been described (32). Despite the tumor’s “threatening” macroscopic and microscopic spread characteristics, including VI, it remains benign and can be discerned from STUMP and LMS (see below) on the basis of its macroscopy and the defined histologic criteria (absence of TCN, atypia and mitoses) (see also Tab. 1.9.1).

1.3.2Clinical presentation, diagnostics, imaging, differential diagnostics

Symptoms most closely resemble those of LM. Cotyledonoid dissecting LM has a noticeable rubbery consistency on palpation. Severe pelvic pain can arise when there is spread within the pelvis. Cotyledonoid LM is largely identical to ordinary LM in sonography (121) and MRI (152). The tumor is homogeneously isointense to surrounding myometrium and neighboring LM in T1W-MRI. T2W shows moderate heterogeneous SI that is higher than that of neighboring LM, but lower than that of normal myometrium. In T1WC, cotyledonoid dissecting LM shows strong enhancement with minimal heterogeneity, as do neighboring LM. However, SI is slightly higher than in ordinary LM (152, 224). There are ample noticeable signal voids that correspond to the high degree of vascularity (203). Cotyledonoid LM can be clinically mistaken with adnexal tumors. The macroscopic, placenta-like appearance might be deemed suggestive of malignancy or sarcoma (32, 121, 187). DPLM, IVLM or parasitic LM are further possible DD.

1.3.3Course, prognosis, primary surgery, systemic and radiogenic therapy

Cotyledonoid LM are without doubt benign. As a variant of LM, the “International Classification of Diseases for Oncology” deems such tumors benign and codes them with “0” (183). THE is the therapeutic measure of choice. In general, given the unusual growth pattern of these tumors, recurrences need to be reckoned with when conservative surgery is opted for. Organ-sparing operations should, therefore, only be performed upon critical deliberation, and should leave no microscopic residual disease. There are two reports of cases in which recurrences arose, reportedly as a result of residual disease (211, 237). Continuous growth with uncontrollable AUB were observed in a case of a patient who underwent incomplete surgery (210). However, there are also reports of cases in which there was no recurrence despite R1 resection and the presence of LVI (81, 224). In one case, a patient in whom a superficial tumor had been incompletely resected gave birth via cesarean section after an uneventful pregnancy. No residual tumor was found (215). In another case, a cotyledonoid LM was excised completely at 14 weeks of gestation, and cesarean section to term revealed that the uterus was disease-free (152). Judging by the presented experiences, it appears as though recurrences only occur in patients with at least microscopic residual disease. Reresection/completion surgery should, therefore, be considered in cases in which there is microscopic or macroscopic residual tumor.

There is no indication for adjuvant or additive RT, CHT or HT. The same applies for primary and neoadjuvant CHT and/or RT in generally inoperable cases.

In one case report, applying GnRH analogues achieved a (albeit minor) remission (215). Temporary treatment with GnRH analogues can, therefore, be adequate for bridging the time until surgery or impending menopause.

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