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  Table of Contents    
REVIEW ARTICLE  
Year : 2011  |  Volume : 54  |  Issue : 2  |  Page : 243-253
Uterine mesenchymal tumors


1 Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT, USA
2 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

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Date of Web Publication27-May-2011
 

   Abstract 

Uterine mesenchymal tumors are a heterogeneous group of neoplasms that can frequently be diagnostically challenging. Differentiation between the benign and malignant counterparts of mesenchymal tumors is significant due to differences in clinical outcome, and the role of the surgical pathologist in making this distinction (especially in the difficult cases) cannot be underestimated. Although immunohistochemical stains are supportive toward establishing a final diagnosis, the morphologic features trump all the other ancillary techniques for this group of neoplasms. This review therefore emphasizes the key morphologic features required to diagnose and distinguish uterine mesenchymal tumors from their mimics, with a brief description of the relevant immunohistochemical features.

Keywords: Adenosarcoma, carcinosarcoma, leiomyosarcoma, mesenchymal, stromal sarcoma, tumors, uterus

How to cite this article:
Sangle NA, Lele SM. Uterine mesenchymal tumors. Indian J Pathol Microbiol 2011;54:243-53

How to cite this URL:
Sangle NA, Lele SM. Uterine mesenchymal tumors. Indian J Pathol Microbiol [serial online] 2011 [cited 2019 Sep 17];54:243-53. Available from: http://www.ijpmonline.org/text.asp?2011/54/2/243/81582



   Introduction Top


Uterine mesenchymal tumors are a heterogeneous group of neoplasms that can frequently be diagnostically challenging. Majority of these tumors (uterine smooth muscle and endometrial stromal) show homologous mesodermal tissue differentiation. However, on occasions, it is not uncommon to see differentiation toward heterologous elements like cartilage, skeletal muscle, bone, etc. Differentiation between the benign and malignant counterparts of mesenchymal tumors is significant due to differences in clinical outcome, and the role of the surgical pathologist in making this distinction (especially in the difficult cases) cannot be underestimated. Herein, we have also described the mixed epithelial and mesenchymal tumors, which are predominantly classified based on the morphologic assessment of their epithelial and mesenchymal components. Although immunohistochemical stains are supportive toward establishing a final diagnosis, the morphologic features trump all the other ancillary techniques for this group of neoplasms. This review therefore emphasizes the key morphologic features required to diagnose and distinguish uterine mesenchymal tumors from their mimics, also giving a brief description of the relevant immunohistochemical features.


   Mesenchymal Tumors Top


Smooth Muscle Tumors

Leiomyoma

Leiomyoma is one of the commonest visceral neoplasms affecting women in their reproductive age group (mean age = 35 years). The clinical presentation is dependent on the location of the tumor within the uterine corpus (submucosal, intramural or subserosal); however, the most common clinical complaints include menorrhagia, dysmenorrhea, abnormal uterine bleeding, lower abdominal/pelvic pain or mass, and/or reproductive dysfunction. [1] "Fibromyoma", "fibroid" and "myoma" are some terms synonymously used for this benign neoplasm; however, their use should be discouraged since the terms are not specifically representative. Grossly, these are well-circumscribed, firm, gray-white masses which bulge out on slicing and demonstrate a whorled appearance over its cut surface. The macroscopic appearance, if more heterogenous and different from the classic appearance as described, would mandate a more thorough sampling. Histologic sections are characterized by a uniform spindled population of cells with moderately eosinophilic cytoplasm, long blunt-ended nuclei with smooth nuclear contours and fine uniform chromatin with occasional inconspicuous nucleoli. The cells are tightly packed in fascicles and are indistinguishable from the adjacent normal myometrium. Even to the uninitiated eye, these classic microscopic findings are easy to document and cause no difficulties in the histologic diagnosis of leiomyoma. The appearance of certain microscopic findings - mitotic activity, tumor cell necrosis, diffuse nuclear atypia - should prompt the pathologist to entertain the diagnosis of a malignant neoplasm, leiomyosarcoma in particular. [2] The uncommon and potentially confounding histologic features of leiomyomas and their differential diagnostic considerations are discussed in the subsequent section of this article.

Leiomyosarcoma

Leiomyosarcomas are amongst the most frequent malignant uterine neoplasms and account for up to 25% of the uterine mesenchymal tumors. [3] In contrast to leiomyomas, these occur in women over 40 years of age. [4] The clinical presentation is largely similar to that of leiomyoma. Grossly, a large (often >10 cm in greatest dimension), poorly circumscribed, firm, solitary mass is identified within the uterine corpus. The cut surface of such a mass appears variegated with areas of hemorrhage, necrosis and degenerative changes. [5] Extensive sampling (at least 1 section per centimeter of tumor) is usually required to identify all the histologic components within the tumor. Leiomyosarcoma is characterized by hypercellularity, increased mitotic activity [>10 mitoses/10 high power fields (HPFs)], diffuse nuclear atypia and coagulative tumor cell necrosis. At least two of the latter three features need to be present to establish a diagnosis of conventional (spindle cell) leiomyosarcoma, with some exceptions as detailed below. [6]

Mitotic count: It is recommended that only abnormal mitotic figures be considered significant - this is to eliminate the erroneous inclusion of "mitotic-like" elements (apoptotic cells, karyorrhectic or pyknotic nuclei, cellular debris, lymphocytes or precipitated hematoxylin) from being counted toward the total mitotic count. To be counted as an abnormal mitotic figure requires hair-like extension of the chromatin from a central denser chromosome core, absence of nuclear membrane and moderate amounts of cytoplasm. This provides a standardized approach toward the abnormal mitotic count (>10 per 10 HPFs) is considered significant). [6]

Nuclear atypia: This should be significant enough to be noticeable on low magnification [Figure 1]a, b and should be diffuse and widespread. The presence of pleomorphic nuclei, nuclear membrane irregularity, multiple/prominent nucleoli and nuclear hyperchromasia are counted toward significant atypia. [6],[7] Comparison of nuclear features in the tumor areas with those in the non-tumor regions is helpful.
Figure 1: (a) Note the presence of significant nuclear atypia with nuclear enlargement, irregular nuclear contours, hyperchromasia and coarse chromatin easily recognizable at low-medium power (H and E stain, ×200); (b) note the absence of significant nuclear atypia to contrast with the image seen in Figure 1a (H and E stain, ×200)

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Coagulative tumor cell necrosis (CTCN): This type of necrosis has to be distinguished from ischemic-type necrosis occurring secondary to vascular insufficiency [Figure 2]a, b. Ischemic-type necrosis is characterized by the presence of hemorrhage, fibrosis, and hyalinized or granulation tissue interposed between the tumor and the non-tumor areas. Leiomyosarcomas are characterized by tumor cell necrosis, which shows an abrupt transition between the necrotic and non-necrotic areas. Since ischemic-type necrosis occurs due to insufficient blood supply, it can be seen in any rapidly growing tumor. The very early infarct-type necrosis is however difficult to distinguish from tumor cell necrosis. [6],[7],[8],[9]
Figure 2: (a and b) Coagulative tumor cell necrosis. The necrotic area is sharply demarcated from the viable region (a, H and E stain, ×100) and has apoptotic nuclei that may at times cause confusion when viewing the slide at low power (b, H and E stain, ×200)

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Other microscopic findings to be included in the final report include extent of invasion, hypercellularity, and lymphovascular space invasion, but these are not considered among the diagnostic criteria for leiomyosarcoma.

The three key histologic features of mitotic count, tumor cell necrosis and nuclear atypia may be seen individually in some cases of leiomyomas, causing diagnostic difficulty. Mitotically active leimoyomas are characterized by a mitotic count between 10 and 20 per 10 HPF. However, these tumors demonstrate neither diffuse nuclear atypia nor tumor cell necrosis, which helps to distinguish them from spindle cell leiomyosarcoma. There is limited data with regards to leiomyomas with >20 mitoses per 10 HPFs, and therefore, some authors classify these tumors as "leiomyoma with increased mitotic activity, but experience limited" or smooth muscle tumors of uncertain malignant potential (STUMP). [6],[8],[10] Apoplectic leiomyomas characteristically occur in women during their reproductive years, during or after pregnancy. The histologic features include focal areas of recent hemorrhage and ischemic-type necrosis, occasionally demonstrating nucleomegaly, prominent nucleoli and an increased mitotic count. [11],[12] The increased mitotic count is, however, usually identified in the vicinity of the area of hemorrhage. This feature is important to recognize to avoid misclassifying such neoplasms. Occasional patients receive gonadotrophin-releasing hormone analogs (GnRHa) prior to surgery for tumor size reduction. These tumors on microscopic examination demonstrate infarct-type necrosis; however, they lack nuclear atypia or high mitotic activity. [1] Leiomyomas can occasionally demonstrate bizarre nuclear features with pleomorphism, conspicuous nucleoli, and pseudoinclusions [Figure 3]. Such leiomyomas with bizarre nuclear features are, however, not associated with a high mitotic count or CTCN. These tumors carry an excellent prognosis and hence need to be accurately distinguished from leiomyosarcomas. [4] One feature that is often helpful is to note that the cells with atypical or bizarre nuclei are lying adjacent to numerous bland (benign) smooth muscle cells. The atypia is, therefore, focal and not diffuse. Similarly, highly cellular leiomyomas without diffuse significant nuclear atypia, CTCN or high mitotic count are encountered on occasions, and carry an equally good prognosis. On the other hand, the presence of diffuse nuclear atypia in a spindle cell smooth muscle neoplasm without CTCN or a high mitotic count requires the designation of "atypical leiomyoma" or STUMP since the behavior of such tumors cannot be predicted with certainty.
Figure 3: Leiomyoma with bizarre nuclei. Note the presence of bland non-bizarre nuclei in the background, which serve as a clue to the diagnosis (H and E stain, ×200)

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The histologic criteria used for diagnosing spindle cell leiomyosarcoma are not applicable to myxoid or epithelioid smooth muscle tumors. The myxoid variant of leiomyosarcoma typically has a gelatinous cut surface and often demonstrates a deceptively well-defined border from the surrounding myometrium on gross examination. On microscopic examination, these lesions appear hypocellular, with spindled, ovoid and stellate cells embedded in a loose myxoid and edematous stroma. Often, the myxoid areas are focal, and elsewhere, infiltrating areas with relatively diffuse nuclear atypia and tumor cell necrosis can be identified. It is recommended that a diagnosis of myxoid leiomyosarcoma be rendered in the presence of marked nuclear atypia and/or CTCN, irrespective of the mitotic count; or in the absence of nuclear atypia and CTCN, the presence of >2/10 HPF mitoses is enough to establish the diagnosis. [13],[14] Another rarely encountered histologic variant includes the epithelioid leiomyosarcoma. This variant is characterized by round, ovoid, epithelial-like cell types with moderate eosinophilic cytoplasm. Epithelioid tumors of smooth muscle origin [Figure 4] are considered malignant if they demonstrate >5 mitoses per 10 HPFs, along with either CTCN or diffuse nuclear atypia. [15] The epithelioid variant of leiomyosarcoma may stain positively in a significant number of cases for pan-cytokeratin and EMA, in addition to the smooth muscle markers (desmin and smooth muscle actin). [16] Rare malignant neoplasms such as melanoma, alveolar soft part sarcoma, and rhabdomyosarcoma may enter the histologic differential diagnosis of epithelioid leiomyosarcoma; however, these are readily differentiated by immunohistochemical stains. The differentiating features between leiomyosarcoma and endometrial stromal sarcoma are discussed below.
Figure 4: Epithelioid smooth muscle tumor. Note the striking resemblance to epithelial cells required to classify the tumor as epithelioid (hematoxylin and eosin stain, ×400)

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Endometrial stromal sarcoma

Neoplasms that arise from endometrial stroma include the benign endometrial stromal nodule, low-grade endometrial stromal sarcoma (previously designated as endolymphatic stromal myosis), and undifferentiated endometrial sarcoma. Majority of these neoplasms are seen in the relatively younger, premenopausal women in their fourth or fifth decade. [17] The most common clinical presentation is abnormal vaginal bleeding and occasionally pelvic pain. Endometrial stromal nodules are soft, usually yellow masses that on microscopic examination are composed of cells resembling endometrial stromal cells [Figure 5] and have a well-circumscribed interface with the adjacent normal myometrium. In contrast, low-grade endometrial stromal sarcomas are characterized by an infiltrative ("tongue-like") pattern often associated with lymphovascular space invasion [Figure 6] and are composed of spindled and ovoid cells with regular nuclear membranes and inconspicuous nucleoli. Some endometrial stromal nodules may show minimal (usually <3 areas, each of <3 mm in depth) interdigitation at the tumor/myometrial junction. [6] Interestingly, even a greater degree of infiltration that still falls short of the more frank "tongue-like" pattern of invasion (of a low-grade endometrial stromal sarcoma) has been reported with a favorable outcome on limited follow-up. [18] The term "endometrial stromal tumor with limited myometrial invasion" is used to describe such tumors. [18] Endometrial stromal nodules cannot be differentiated from low-grade endometrial stromal sarcomas based on cellularity or mitotic count. An unequivocal evidence of the absence of myometrial or lymphovascular space invasion is essential to diagnose stromal nodules. [19] This is why this distinction cannot be made in a curettage sample. [20],[21] Some endometrial stromal nodules may demonstrate areas of fibrosis, areas of hyalinization, myxoid change, fatty and skeletal muscle metaplasia and also smooth muscle metaplasia. [18],[22] The latter may be quite extensive and may at times be nodular in appearance with a central area of hyalinization with collagen bundles radiating toward the periphery with smooth muscle cells embedded in them, creating a starburst like appearance. [18] The smooth muscle metaplasia seen within or at the periphery of the tumor may be misinterpreted as myometrial smooth muscle [Figure 7]a, b. A haphazard pattern of smooth muscle metaplasia (within the tumor) alternating with the more typical "blue" appearance of an endometrial stromal nodule may be misconstrued as myometrial invasion and thus results in a misdiagnosis. This potential pitfall can be avoided by screening the slides at low power to recognize the smooth tumor-myometrial interface [Figure 7]b and also correlating the site of the sections as noted on gross inspection with the histologic features.
Figure 5: Endometrial stromal tumor. Note the resemblance to endometrial stroma. This may represent a benign nodule or a low-grade sarcoma. The distinction cannot be made on cytologic grounds (H and E stain, ×200)

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Figure 6: Endometrial stromal sarcoma, low grade. Note the tongue-like pattern of invasion of the myometrium with areas of lymphovascular space invasion (H and E stain, ×40)

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Figure 7: (a and b) Endometrial stromal nodule with smooth muscle metaplasia as seen in the center and right (a, H and E stain, ×200) and as seen on low power with a smooth interface with normal myometrium (H and E stain, ×40)

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Rare cases of low-grade endometrial stromal sarcomas can demonstrate increased mitotic activity; however, these should not be associated with moderate/severe (significant) cytologic atypia. If there is striking cytologic atypia, the term high-grade endometrial sarcoma is used. The cellular component of these tumors is admixed with arborizing capillaries (reminiscent of a pericytomatous vascular pattern); spiral arteriole like vessels are also present. [23] A majority of endometrial stromal tumors demonstrate immunohistochemical staining for hormone receptors (estrogen and progesterone receptors), CD10 and WT1. Occasional tumors also stain for smooth muscle actin (SMA), but are commonly negative for desmin and h-caldesmon. [24],[25] Translocation t(11;17) involving the JAZF1 and JJAZ1 is identified in up to 80% of low-grade endometrial stromal sarcomas. [26] Stage is the most important prognostic factor; organ confined tumors (stage I) carry a good prognosis, while the prognosis of higher stage tumors is much worse. [23] Undifferentiated stromal sarcomas are cytologically high grade with frequent mitoses (>10 per 10 HPFs). [23]

A highly cellular leiomyoma may enter the differential diagnosis of a low-grade endometrial stromal sarcoma. Histologically, leiomyomas demonstrate thick-walled blood vessels, a more fascicular arrangement, and are positive for desmin and h-caldesmon (which is almost always negative in endometrial stromal sarcomas). [6] One feature that is quite helpful is the presence of cleft-like spaces [Figure 8] which are typically seen in smooth muscle tumors including the highly cellular leiomyoma but not in endometrial stromal tumors. Epithelioid smooth muscle tumors can resemble endometrial stromal sarcomas; however, the former lacks the characteristic arteriole-like and plexiform vascular pattern of endometrial stromal sarcomas. Also, immunophenotyping is generally helpful. [27] Morphologically bland endometrioid glands can also be found within an endometrial stromal sarcoma and can cause diagnostic difficulty with uterine adenosarcoma and also adenomyosis. The endometrioid glands, when present in the former, are however, focal and haphazardly placed. In contrast, uterine adenosarcomas show stromal condensation around the glandular component and display a phyllodes-like (leaf-like) architecture. [23] Adenomyosis can at times be quite difficult to distinguish from an endometrial stromal sarcoma with endometrioid glands. An invasive pattern and the presence of lymphovascular space invasion may help in identifying the lesion as a sarcoma. Distinguishing low-grade stromal sarcoma from a solitary fibrous tumor (SFT) can be challenging due to similar plexiform capillary (pericytomatous) pattern. In addition, positivity for CD10 and progesterone receptors can be observed in SFT. However, CD34 staining observed in SFT has not been reported in endometrial stromal sarcomas. [23]
Figure 8: Highly cellular leiomyoma. Note the cleft-like spaces that help distinguish this tumor from an endometrial stromal neoplasm (H and E stain, ×100)

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   Mixed Epithelial and Mesenchymal Tumors Top


Adenosarcoma

Up to 2-3% of the malignant uterine corpus tumors are sarcomas. [3] Mullerian adenosarcomas are relatively rare uterine sarcomas and represent approximately 8% of the uterine sarcomas. [28] Adenosarcomas are best categorized as mixed epithelial and mesenchymal tumors, and they are so designated due to their varying compositions of benign epithelial component, admixed with a low-grade malignant sarcomatous stromal component. [29] This neoplasm is uncommon, and shows a wide age predilection from second through tenth decade, with most cases occurring in the sixth decade (median age 58 years). [30],[31],[32] A racial predilection has not been demonstrated. [33] The commonest clinical presentation is an abnormal vaginal bleeding, an enlarged uterus, and in some cases, a pelvic mass or tissue is seen protruding through the external os. [30],[31],[32],[34] Patients may present with a history of recurrent polyps, and in some cases, the tumor may be correctly diagnosed only after the re-excision of such a recurrent polypoidal lesion. [30] Exogenous or endogenous factors causing an uninterrupted and prolonged hyperestrogenic state are risk factors for development of epithelial as well as mixed epithelial and mesenchymal tumors. [35],[36],[37],[38],[39],[40],[41],[42] Breast cancer patients who receive tamoxifen therapy as part of their therapeutic regimen are are at risk for this tumor. [43] Adenosarcomas are unifocal, solitary polypoidal masses that generally arise from the uterine fundus. In some instances, they may arise from the lower uterine segment or the cervix. In majority of the cases, these grow within the endometrial cavity, while some may prolapse through the cervical os. [30],[31],[32],[43],[44],[45] Most adenosarcomas do not invade the myometrium; however, rarely they may arise within the myometrium from a focus of adenomyosis. [34] The cut surface of these tumors is tan brown and variegated with foci of hemorrhage and necrosis. The low-power examination of these lesions is characteristic and includes a pattern resembling "phyllodes tumor of the breast", with leaf-like architectural projections lined by non-neoplastic epithelium [Figure 9]a. [29] The epithelial component is represented by dilated and compressed glands lined by benign/bland cuboidal or stratified epithelium with or without focal metaplastic squamous, columnar, mucinous or tubal differentiation. [19] The mesenchymal component is represented by hypercellular spindled stroma with varying degree of atypia. The stromal component typically exhibits >2 mitoses/10 HPFs [Figure 9]b. The stromal component shows distinct condensation around the epithelial glands, reminiscent of a cambium layer. [29] These areas of stromal condensation exhibit the maximum degree of cellular atypia and mitotic activity. [34] The mesenchymal component is generally homologous, showing endometrial stromal or fibrous differentiation, supported by hormone receptors [estrogen receptor (ER)/progesterone receptor (PR)] and CD10 positivity. [29] On occasions (in up to 10-15% cases), heterologous differentiation in the form of skeletal muscle, fat, cartilage, and sex-cord differentiation may be identified. In majority of the cases, the stromal component is low grade, while the cases with higher histologic grade bear resemblance to undifferentiated sarcoma. The histomorphologic appearances are diagnostic, and immunohistochemistry is not particularly contributory toward the diagnosis of adenosarcoma. The epithelial component stains well with a broad spectrum of cytokeratin antibodies, and the mesenchymal component shows focal and variable immunoreactivity to CD10, smooth muscle markers, desmin and caldesmon . [34]
Figure 9: (a and b) Adenosarcoma. Note the phyllodes-like pattern on low power (a, H and E stain, ×40) and mitotic figures subjacent to the epithelium within the condensed stroma (b, H and E stain, ×400)

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A broad variety of tumors can bear morphologic resemblance to adenosarcoma. The differential diagnostic considerations include adenofibroma, carcinosarcoma, low-grade endometrial stromal sarcoma with glandular differentiation, endometrial polyp and atypical polypoid adenomyoma (APA). Uterine adenofibroma is the benign counterpart of adenosarcoma and is therefore composed of benign/non-neoplastic epithelial and mesenchymal component. The stromal atypia and mitoses identified in adenosarcoma are absent in adenofibroma. [46] Carcinosarcoma is another mixed epithelial and mesenchymal tumor, which is more common than adenosarcoma; however, the epithelial component in carcinosarcoma is morphologically malignant. Also, the leaf-like glandular contours and stromal condensation of adenosarcoma is not readily identified in carcinosarcoma. The mesenchymal component in carcinosarcoma is typically higher grade (cf. adenosarcoma in which it is generally low grade). An endometrial stromal sarcoma may contain non-neoplastic endometrioid appearing glands. These are generally focal, lack the glandular contours and do not demonstrate the periglandular stromal cuffing which is characteristic of adenosarcoma. [47] Certain endometrial polyps might contain atypical features in the form of stromal condensation, characteristic glandular contours and stromal atypia. Since these can be morphologically very difficult to distinguish from an adenosarcoma, a close clinical follow-up and sampling of any residual polyp(s) is recommended. [48] APA is characterized by extensive squamous metaplasia of the glandular epithelium and a fibromyomatous stroma and lacks the typical architectural features of an adenosarcoma.

Adenosarcomas are low-grade malignant neoplasms with potential for local recurrences. Clement et al., [30] in their largest case series, had approximately 25% adenosarcomas with local recurrence, with vagina, pelvis, and abdomen being the most common sites. The most important histologic poor prognostic indicators are the presence of deep myometrial invasion and sarcomatous overgrowth. Sarcomatous overgrowth is defined by the presence of >25% high-grade stromal component, with loss of expression of hormone receptors and CD10. It is uncommon to see vascular invasion; but if present, it generally represents a poorer prognosis. [29],[34] In one series, distant metastases were identified in 5% of cases, with the metastatic component solely represented by the sarcomatous element. [30]

Adenofibroma

Adenofibromas belong to the mixed epithelial and mesenchymal neoplasm category and are composed of non-neoplastic epithelial and mesenchymal elements. Adenofibroma is less common than adenosarcoma and is often seen in the postmenopausal women, with rare cases occurring in the younger population. [46] The risk factors are similar to those of adenosarcoma and include hyperestrogen states, with some cases associated with tamoxifen therapy used in women with breast cancer. [49] These tumors grossly appear polypoidal and have a firm gray-white cut surface. As the name implies, these tumors microscopically demonstrate an admixture of benign epithelial and mesenchymal components. The two components are present in varying proportions, giving a papillary or club-like growth pattern. Cleft-like spaces similar to those identified in adenosarcoma are often present. The lining epithelium is low cuboidal or columnar, but occasional cases can demonstrate endometrioid, tubal or squamoid patterns. The mesenchymal component is fibroblastic, and occasionally, differentiation toward smooth muscle or endometrial stromal components may be identified. Heterologous differentiation of the mesenchymal component can be represented by skeletal muscle, mature fat, cartilage, etc.; however, this is rarely seen. [50],[51]

The main differential diagnostic consideration for this tumor is adenosarcoma. The absence of periglandular stromal cuffing or cytologic atypia and a mitotic count of <2/10 HPFs precludes the diagnosis of adenosarcoma. Adenofibromas are benign lesions; however, because rare incidences of recurrence and possible metastasis have been reported, some authors recommend that all adenofibromas should be categorized as adenosarcomas with low malignant potential. [29]

Carcinosarcoma

Carcinosarcoma is a neoplasm composed of an admixture of malignant-appearing epithelial and mesenchymal components. Synonyms for this tumor include malignant mixed Mullerian tumor (MMMT) and recently, metaplastic carcinoma. Carcinosarcoma is still classified in many pathology textbooks as a "mixed epithelial and mesenchymal tumor"; recent studies, however, suggest that the mesenchymal component is derived from sarcomatoid differentiation of the carcinomatous component. [52],[53],[54],[55] Allelic imbalance patterns have shown that the tumor cell origin is epithelial rather than mesenchymal. [56] Genetic studies have demonstrated these tumors to be of a monoclonal nature. [57],[58] Carcinosarcoma is most frequently seen in the postmenopausal women (median age 65 years), with occasional cases occurring in the younger population. [59] Various studies have reported the association of tamoxifen therapy with carcinosarcoma. [36],[39],[60],[61] Some patients with carcinosarcoma have antecedent history of pelvic radiation exposure, this being particularly true for the younger women. [62],[63],[64] Like any other endometrial carcinoma, carcinosarcoma also presents with abnormal vaginal bleeding; however, at times, it may present as a polypoid mass protruding through the cervical os. Grossly, these tumors are bulky, polypoid, with foci of necrosis and hemorrhage. Myometrial invasion and penetration is not uncommon. [34] These tumors demonstrate biphasic morphology and consist of an admixture of malignant-appearing epithelial and mesenchymal elements. The epithelial component has a glandular architecture and may have an endometrioid, clear-cell, serous, mucinous, yolk-sac or mesonephric differentiation. [65],[66] In the series published by Soslow et al., [23] FIGO (International Federation of Gynecology and Obstetrics) grade 3 was the commonest grade that was assigned to most cases. Some cases may have a predominance of the epithelial or sarcomatous component; however, extensive sampling of the tumor in such cases is helpful to identify the second component. The sarcomatous component can be either homologous or heterologous. The homologous elements are generally high grade and are commonly represented by undifferentiated sarcoma, fibrosarcoma, leiomyosarcoma or endometrial stromal sarcoma. The heterologous elements are uncommon and are most frequently represented by chondroid [Figure 10] or rhabdomyoblastic differentiation and less frequently by adipocytic, osteoid, melanocytic, neuroendocrine, neuroectodermal and/or angiomatoid elements. [67],[68],[69],[70] The cases with demonstrable carcinosarcoma metastases have predominantly an epithelial component, with only rare cases demonstrating a sarcoma-only metastasis. [23] The epithelial component demonstrates strong and diffuse immunoreactivity with pan-cytokeratin. The mesenchymal component shows patchy and focal staining with the epithelial antibodies, supporting the epithelial origin of this component. The epithelial and mesenchymal components show concordant staining for p53, again supporting their common clonal origin. [23],[34] Carcinosarcomas express epidermal growth factor receptor (EGFR), but amplification of EGFR has not been demonstrated. [71] KIT expression by these tumors has also been reported. However, no mutations of c-kit have been identified, suggesting that these tumors will likely not benefit from Gleevec therapy. [72]
Figure 10: Carcinosarcoma. Note the sharply demarcated sarcomatous region with malignant cartilage (bottom) contrasting with the adenocarcinoma (top) (H and E stain, ×200)

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The two main tumors which enter the differential diagnostic considerations include adenosarcoma and endometrioid adenocarcinoma with spindle cell elements. Adenosarcomas carry a benign epithelial component (cf. carcinosarcoma in which the epithelial component is malignant). Even when the adenosarcomas display sarcomatous overgrowth, the sarcomatous component is generally low grade. The presence of "phyllodes-like" growth pattern and non-neoplastic epithelial component should sway the pathologist away from making a diagnosis of carcinosarcoma. [23] Endometrioid adenocarcinomas may contain varying degrees of spindle cell elements which fuse imperceptibly with the epithelial component. [73],[74] In carcinosarcomas, the epithelial and mesenchymal elements do not merge with one another and are typically sharply demarcated. [23] There is a general agreement that carcinosarcomas carry a worse prognosis than poorly differentiated endometrial carcinoma. Whether the grade of epithelial component - high-grade carcinoma, including serous and clear-cell types - bears prognostic implications is debatable. Also, recent studies have suggested that the histologic features of the mesenchymal component carry no prognostic significance. [75] The most promising prognostic markers include the extent of myometrial invasion, the presence of lymphovascular space invasion, the extent of sarcomatous differentiation and the grade of the epithelial and mesenchymal components. [75],[76]

Adenomyoma Including Atypical Polypoid Adenomyoma


Adenomyoma is characterized by an admixture of non-neoplastic epithelial and mesenchymal components. A variant of adenomyoma, APA, is characterized by glandular architectural complexity, with or without cytological atypia. APA is commonly seen in the young population; however, rare cases are encountered in women of all age groups. [77],[78] Grossly, these are polypoid, firm masses within the uterine cavity, usually submucosal in location. Rare cases may demonstrate deeper myometrial or subserosal location. The APA shows a predilection for the lower uterine segment or the upper cervix. [79] The epithelial component is represented by benign endometrial-type glands admixed with a fibromyomatous mesenchymal component. The epithelial component can show a spectrum of metaplastic changes such as tubal, mucinous, or squamoid. The endometrial glandular component is often surrounded by varying amounts of endometrial-type stroma. [79] APA shows a complex glandular architecture, with the epithelial elements demonstrating varying degrees of cytological atypia. A helpful clue is the presence of extensive squamous and/or morular metaplasia [Figure 11]. The mesenchymal component is represented by fibromyomatous stroma. Clement et al. have demonstrated association of APA with Turner's syndrome. [80]
Figure 11: Atypical polypoid adenomyoma. Note the presence of crowded glands with squamous metaplasia (H and E stain, ×200)

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To the uninitiated eye, it might be difficult to distinguish adenomyoma and APA from common uterine lesions such as endometrial polyp and endometrioid adenocarcinomas with myometrial invasion. Presence of a minor component of smooth muscle within an endometrial polyp should not make one consider a diagnosis of adenomyoma. Endometrioid adenocarcinomas show pronounced cytologic and architectural atypia and a desmoplastic response in cases of myometrial invasion, which differentiates it from the aforementioned entities. Adenomyoma and APA are benign entities and carry no metastatic potential. Cases of APA that are not completely excised may recur. Rare cases might have an underlying associated endometrioid adenocarcinoma, in which case, the malignant component generally dictates the prognosis. [81]


   Miscellaneous Mesenchymal Tumors Top


Perivascular Epithelioid Cell Tumors

Perivascular epithelioid cell (PEC) tumors are characterized by immunoreactivity for Melan-A and/or HMB-45. Other tumors that belong to this category include epithelioid angiomyolipoma, clear-cell "sugar" tumor, lymphangioleiomyomatosis, and clear-cell myelomelanocytic tumor of ligamentum teres. [82] When PEC tumors involve the female genital tract, uterus is the most common site. [83],[84] PEC tumors are composed of intermediate sized cells containing clear to granular cytoplasm, located in the vicinity of blood vessels [Figure 12]a. They vary in their proportions of spindled and epithelioid components. Two growth patterns are described - one in which the tumor cells show a solid infiltrative growth and the other in which the tumor cells show finger-like permeation of the uterine wall. [82] A rich vascular network similar to clear-cell renal carcinoma of the kidney, wreath-like cells and "spider" cells are the additional distinguishing features for this tumor. [85],[86] The tumor cells show diffuse and uniform staining for HMB-45 and/or Melan-A. [82] Variable degree of tumor cell immunoreactivity is identified for desmin, estrogen and progesterone receptors, and actin. Staining for AE1/AE3, CAM 5.2, EMA, chromogranin, vimentin, S100, CD31 and CD34 is usually negative. [87] A high index of suspicion is essential to make a correct diagnosis of PEC tumors in the uterus. Some authors recommend immunostaining for HMB-45 on all uterine malignancies with clear and epithelioid features. [87]
Figure 12: (a and b) Perivascular epithelioid cell tumor of the uterus. Note the striking epithelioid appearance (a, H and E stain, ×200) and an area of coagulative tumor cell necrosis (top) in a malignant example (b, H and E stain, ×200)

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Certain uterine malignancies bear morphologic resemblance to PEC tumors and include clear and epithelioid smooth muscle tumors, endometrial stromal sarcomas, and metastatic melanoma. The smooth muscle tumors (particularly epithelioid leiomyosarcoma) may occasionally exhibit morphologic resemblance to PEC tumor; however, the former do not show immunoreactivity to Melan-A, and in contrast, may show reactivity to keratins. [82],[88] Melanoma stains for HMB-45; however, PEC tumors that stained positive with S100 protein were also positive for SMA. [85] The latter marker (SMA) is typically negative in melanoma. PEC tumors can behave in a malignant manner. A mitotic count of >1/10 HPFs and/or presence of CTCN [Figure 12]b have been reported to be suggestive of a definite potential for aggressive behavior. [86]

Other Rare Mesechymal Tumors

A variety of rare uterine neoplasms that are not smooth muscle or endometrial stromal derived are described in the literature. When these entities arise in the uterus, they are histologically identical to their counterparts arising in more usual sites. The rare malignant mesenchymal tumors include angiosarcoma, liposarcoma, osteosarcoma, Ewing tumor, malignant peripheral nerve sheath tumor, malignant pigmented neuroectodermal tumor of infancy, chondrosarcoma, alveolar soft part sarcoma, and peripheral primitive neuroectodermal tumor. Immunohistochemistry is useful in arriving at the correct diagnosis of these common entities, when they arise at uncommon locations such as the uterus. Similarly, a variety of benign lesions, such as lipoma, hemangioma, rhabdomyoma, and lymphangioma, are on rare occasions encountered in the uterus.

 
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Correspondence Address:
Subodh M Lele
Department of Pathology and Microbiology, 983135 Nebraska Medical Center, Omaha, NE 68198-3135
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DOI: 10.4103/0377-4929.81582

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