—  SHORT COURSE #21  —

Mesenchymal Neoplasms of the Female Genital Tract

Case 2 - Mesodermal (Mullerian) Adenosarcoma

Teri Longacre, Esther Oliva and Robert Soslow


Introduction
Adenosarcoma is an uncommon, predominantly low-grade malignant biphasic tumor that is composed of sarcomatous stroma and benign epithelial elements. This tumor often represents a challenge for the pathologist due to significant overlap with adenofibroma and other forms of benign polyp on the one hand and with carcinosarcoma and sarcoma entrapping benign glands on the other. Indeed, the low-grade forms of adenosarcoma account for a significant proportion of malignant lesions within the female genital tract and peritoneum that are underdiagnosed by pathologists. [53]

Most adenosarcomas arise in the uterine corpus, but cervical, vaginal, tubal, ovarian and primary peritoneal adenosarcomas also occur. Although almost all adenosarcomas occur in women, mesodermal adenosarcoma has been reported in a boy with persistent mullerian duct syndrome and rarely, in the testis, seminal vesicle and prostate. [16, 27, 31, 33, 50] Involvement of additional extragenital sites in women has been linked to endometriosis. An association with unopposed estrogen and tamoxifen therapy has also been reported in uterine adenosarcoma. [4, 9] As with carcinosarcoma, a prior history of pelvic radiation has been implicated in a few cases. [6, 11]

Adenosarcomas are typically slowly growing, indolent tumors, but recurrences at five or more years following diagnosis are not unusual. In some instances, recurrence may not occur until 13 years or more years following definitive therapy. Recurrences tend to be local, with distant metastases following initial local recurrence(s). It has been suggested that these hematogenous metastases almost always contain only sarcomatous elements. [35] A subset of tumors may exhibit a more aggressive clinical course; these tumors often have stromal overgrowth or other features of a high-grade sarcoma and may resemble carcinosarcoma in their clinical behavior. In contrast, adenofibromas are considered to be clinically benign with little risk for recurrence once they are completely excised.

The adenofibroma-adenosarcoma-carcinosarcoma spectrum of biphasic mullerian tumors in the female gynecological tract resembles the fibroadenoma-phyllodes-metaplastic carcinoma spectrum in the breast. As in the breast, zones of histologic overlap exist and on occasion, areas of adenofibromatous, adenosarcomatous and/or carcinosarcomatous differentiation may be seen in the same neoplasm. Transformation of some adenosarcomas into carcinosarcomas has also been proposed. [41] Classification of each of these tumors is ultimately based on the most histologically malignant area, but it should not be surprising that just as there are gradations of histologic malignancy amongst these tumors, gradations of clinical behavior may also occur. Gradations of clinical behavior are also observed, depending on the site of origin (e.g., adenosarcomas arising in the ovary and peritoneum tend to behave more aggressively than those arising in the uterine corpus or cervix).

Clinical Features
Since adenosarcomas most commonly occur in the uterine corpus, most of the available clinical data reflects uterine tumors. However, since differences in clinical presentation, clinical behavior, and (in some instances) differential diagnosis do occur when adenosarcomas present at other sites, they are discussed separately.

Uterine Corpus
Most patients with uterine corpus adenosarcoma are postmenopausal, although this neoplasm may occur during the reproductive years. When they occur in the uterine body, adenosarcomas present as polyps or polypoid lesions which may protrude through the cervical os or appear to arise from the cervix or lower uterine segment with uterine enlargement; often there is a history of recurrent polyps, which on retrospect may represent early or subtle forms of adenosarcoma. The polyps vary in size from 1 to 17 cm (mean, 5 cm) and often exhibit microcystic architecture on cut section.

Approximately one-fourth of uterine corpus adenosarcomas are myoinvasive. Most patients with uterine adenosarcoma are cured by hysterectomy. However, deep myoinvasion, lymphovascular invasion, high-grade heterologous stroma, stromal overgrowth and extrauterine spread are associated with disease recurrence. The overall recurrence rate is 15-25% for tumors without stromal overgrowth and 45-70% for those with stromal overgrowth. Recurrent disease typically appears in the pelvis, although distant recurrences may develop many years after pelvic recurrence(s). Approximately 10-25% of patients with uterine adenosarcoma die of their disease. This figure rises to 54% for those whose tumors contain stromal overgrowth.

Surgery, including complete staging is the mainstay of therapy for uterine adenosarcoma with or without sarcomatous overgrowth. Additional therapy in the form of radiation, chemotherapy, or both has been reported; however, the superiority of any one modality has not been determined. Hormonal therapy has also been tried in the adjuvant setting in low stage disease.

Cervix
Cervical adenosarcomas tend to occur at a younger age than their uterine counterparts. [7, 23, 36, 39] Patients with primary cervical adenosarcomas range in age from 13 to 67 years (mean, 37 years). Most present during the reproductive years with abnormal bleeding, which is initially attributed to benign endocervical polyps. The polyps may be ectocervical or endocervical and range in size from 2 to 8 cm or more. A sarcoma botryoides appearance has been reported. [15]

The numbers are few and data is limited, but most cases appear to be cured by hysterectomy, possibly due to the early detection of low stage disease in the majority of patients. To date, less than 25 patients have been reported with endocervical adenosarcoma; recurrences have been reported in 18% while deaths due to disease occurred in 12%. [36, 39, 40] As in uterine corpus tumors, depth of invasion and sarcomatous overgrowth are adverse prognostic indicators.

It has been suggested that complete resection of the polyp alone may be adequate initial therapy for cervical adenosarcoma when it occurs in younger women, provided there is a stalk that is clearly uninvolved and there is no histologic evidence of invasion. [7] Although this is controversial and there is little supporting data, conservation of reproduction and/or hormonal function should always be considered in such cases. Adenosarcomas may be hormonally responsive, but there appears to be no justification for oophorectomy in the younger patients at this time. [17]

Ovary
Ovarian adenosarcoma occurs in reproductive and postmenopausal women from 30 to 84 years of age (mean, 55 years). Almost half occur in women <50 years of age. [14] Patients present with the usual signs and symptoms of an ovarian tumor mass, most commonly abdominal discomfort and distention. Most are unilateral, even when presenting at high stage disease. The tumors range in size from 5.5 to 50 cm (mean, 14 cm) and are more solid and cystic than polypoid. An association with endometriosis may be present in some cases, but this is not as firmly established as in extragenital sites.

In contrast to the cervical and uterine corpus tumors, adenosarcomas arising in the ovary often have a worse prognosis, presumably due to the greater ease of peritoneal spread at this location. In the Eichhorn series, the overall recurrence rate for ovarian adenosarcomas was 77% at five or more years, and the 5-, 10-, and 15-year survival rates were 64%, 46%, and 30%, respectively. [14] As in the uterine tumors, high-grade sarcoma, high-grade sarcomatous stromal overgrowth, and advanced stage, including tumor rupture are adverse prognostic factors. Age <53 years at diagnosis is also a risk factor for disease recurrence, possibly due to increased likelihood of hormonal stimulation. Mitotic index and low grade stromal overgrowth do not predict recurrence in stage I tumors. Synchronous uterine or extragenital adenosarcomas may occur in some patients. [14]

Primary Peritoneal and Extragenital Sites
Adenosarcoma arising within the peritoneum and other extragenital sites is uncommon. In many of the reported cases, a history of hysterectomy many years prior to presentation clouds the picture, and it is not clear how many of these cases represent true de novo tumors or metastases from previously unrecognized adenosarcomas. At least some cases appear to be primary, most of which are associated with endometriosis. [13, 22, 28, 35, 38] The pluripotent mesothelial and mesenchymal cells of the pelvic/abdominal cavity have been cited as the site of origin for those cases in which no endometriotic or other primary foci can be identified. [5, 25, 51] Sites of involvement include bladder, colon or rectum, omentum, recto-vaginal septum, pouch of Douglas, liver, retroperitoneum and vaginal wall. Multiple sites of peritoneal involvement may be present at initial presentation. [13]

A recent literature review by Murugasu and colleagues suggests that extragenital and peritoneal tumors occur at a slightly younger age than uterine adenosarcomas (mean age, 41 years) with a significant proportion developing in women less than 30 years of age. [35] Data is limited, but the presence of adenosarcoma in the peritoneum appears to be an adverse risk factor regardless of histology. [35] The reported overall rate of recurrence is 60% and death due to tumor occurs in almost 40% of patients. [35] It is not clear why the extragenital tumors behave more aggressively, but local complications due to bowel obstruction, larger tumor size at presentation, inability to achieve complete surgical excision and exposure to the entire peritoneum have all been proposed as possible contributing factors.

Histologic Features
Most adenosarcomas feature uniformly distributed, often cystic and irregularly contoured glandular elements, often with internal papillations scattered throughout a variably cellular stroma. The stroma forms a characteristic hypercellular collar or cuff (so called "cambium layer") around the glands, which often exhibit mixed differentiation, including endometrioid, endocervical, ciliated, eosinophilic and squamous. The epithelium typically appears benign or less often, atypical, simulating complex hyperplasia or adenocarcinoma in situ. Asymmetric growth of stroma may compress the epithelial component to produce irregular stellate glandular configurations; sometimes, when this asymmetry is extreme, polypoid invaginations are produced. Stromal foam cells may be present. The classic adenosarcoma exhibits a frondlike growth pattern, resembling phyllodes tumor of the breast. Adenosarcomas fall into three general groups, depending on the atypicality of the stroma and the presence of stromal overgrowth:

Group 1: The first and most common type of adenosarcoma resembles adenofibroma, but possesses more cellular and more mitotically active stroma (= low-grade adenosarcoma). In most cases, the stromal component is nondescript, but in some instances the stromal cells are arranged in cordlike patterns reminiscent of sex cord elements in uterine tumors resembling sex cord stromal tumors. The recommended mitotic index thresholds for classifying a tumor as adenosarcoma vary between 2 MF/10 HPF to 4 MF/10 HPF. [11, 55] The latter criterion is recommended, unless a particular tumor exhibits prominent stromal cellularity or cytologic atypia, in which case the tumor should be classified as uncertain malignant potential. An alternative approach is to classify these tumors as low grade adenosarcoma (or low malignant potential) with the understanding that such tumors will probably either not recur at all or may only recur many years after diagnosis. The distinction is most important in women of reproductive age, for whom a hysterectomy may not be the treatment of choice.

Group 2: The second group features histologically malignant stroma (= high-grade adenosarcoma), most often manifested by rhabdomyosarcomatous differentiation, but chondroid, smooth muscle and undifferentiated sarcoma may also be seen. This group of tumors often contains numerous mitotic figures, including atypical mitoses. Stromal overgrowth is not present.

Group 3: The third group features stromal overgrowth (= adenosarcoma with stromal overgrowth). By definition, tumors with stromal overgrowth should contain pure stroma comprising more than 25% of the tumor volume. Most, but not all of this group also contain high-grade sarcomatous stroma, often with heterologous differentiation (typically rhabdomyosarcoma). These latter tumors are associated with a uniformly poor prognosis. In some tumors, the stroma in the areas of stromal overgrowth is low grade or bland as in the first type of adenosarcoma and these tumors, despite the presence of stromal overgrowth may be associated with a more indolent disease course, with long disease free intervals punctuated by intermittent localized recurrences. The mitotic count almost always exceeds 4 MF/10 HPF in tumors with stromal overgrowth, although exceptions do rarely occur, typically in the group with low-grade sarcomatous overgrowth.

Recurrent adenosarcomas may continue to exhibit a biphasic phenotype or may be composed of stroma only. In some instances, recurrences may transform to higher grade sarcoma or develop heterologous elements that were not apparent in the primary tumor. [46] The transformation to higher grade sarcoma or sarcomatous overgrowth is usually associated with increased tempo of disease with increased frequency of recurrence and involvement of multiple sites. Hematogenous metastases, typically to the lung, may occur and are often comprised only of stromal elements.

Immunohistologic Features
The immunophenotype of most adenosarcomas resembles that of endometrial stromal tumors (positive for ER, PR, WT1, and CD10, with variable expression of muscle markers, androgen receptors and cytokeratin). ER, PR, and CD10 expression are commonly lost in cases showing stromal overgrowth [1, 2, 43]. The stroma of adenosarcomas, particularly the low-grade tumors, is often CD10 positive and so this marker cannot be used to differentiate endometrial stromal sarcoma with benign glands from a low-grade adenosarcoma. [2, 34]

Molecular Features
A complex karyotype involving multiple chromosomes was identified by cytogenetic and molecular cytogenetic analysis of an adenosarcoma from a 15-year-old girl. [8] Neither p53 nor HER-2/neu appears to play a significant role in this disease. [6, 45]

Differential Diagnosis
The differential diagnosis of adenosarcoma includes adenofibroma and other clinically benign processes with little or no recurrent potential at the benign end of the spectrum and carcinosarcoma and other clinically malignant processes with significant recurrent and metastatic potential at the malignant end of the spectrum.

Adenofibroma vs Adenosarcoma
Adenofibromas typically harbor paucicellular, fibromatous or fibrotic stroma and are distinguished from adenosarcoma on the basis of low cellularity and low mitotic index. Adenosarcomas without stromal overgrowth may have the typical low-power appearance of a benign adenofibroma but differ from that lesion in that the stroma is more cellular (particularly the cambium-layer-like cuff immediately adjacent to the epithelium) and is mitotically active. The presence of periglandular stromal condensation, increased stromal cellularity and/or increased mitotic index distinguish adenosarcomas with recurring potential from adenofibromas with little or no potential for recurrence. In the case of the uterine tumors, the distinction can usually be made when the entire uterus is available for examination, although there is some controversy concerning the level of mitotic activity that predicts potential for recurrence in the absence of high-grade sarcomatous elements. Clement and Scully employ a threshold of 2 MF/10 HPF, whereas Zaloudek and Norris present evidence to support a threshold of 4 MF/10 HPF. [11, 55] This controversy largely reflects the observation that these predictors are far from perfect and occasional adenofibromatous lesions, even with minimal or no mitotic activity, may demonstrate myoinvasion or local recurrence on clinical follow-up. [10, 12]

Distinction between adenofibroma and adenosarcoma in the ovary and other extra-genital sites can be more difficult, due to the exuberant stromal component that may accompany some of the epithelial neoplasms in these sites. To compound this problem, adenosarcoma may occasionally develop as a mural nodule in otherwise conventional serous or endometrioid cystadenoma. [49] Problems most often arise when the adenosarcoma exhibits predominantly fibromatous stromal overgrowth, inconspicuous periglandular cuffs or few, abortive intraglandular projections. To circumvent these problems, all cases with any ambiguous histologic features falling within the endometrioid adenofibroma-adenosarcoma spectrum should be thoroughly sampled when encountered in an extra-genital site. If the problematic lesion still defies classification after thorough sectioning, consultation should be obtained.

Endometrial Polyp vs Adenosarcoma
Endometrial polyps may contain atypical stromal cells with cytologic features similar to the atypical stromal cells observed in the vulva, vagina and cervix. [48] However, the characteristic intra-glandular polypoid projections and periglandular stromal cuffs of adenosarcoma are not present in benign polyps. Large endometrial polyps may harbor increased stromal mitotic figures (up to 5 MF/10 HPF), but these polyps do not have significant stromal atypia nor do they have a marked increase in stromal cellularity. Such polyps are distinguished from adenofibromas on the basis of the characteristic papillary or intraglandular polypoid projections in adenofibroma. [19]

Polypoid Adenomyoma/Atypical Polypoid Adenomyoma vs Adenosarcoma
Polypoid adenomyomas or adenomyofibromas (PA) are circumscribed aggregates of fibromuscular tissue containing small, architecturally simple glands without branching or budding. [18, 47] The constituent cells are cytologically bland. Morules may be present but they are usually not prominent and endometrial stroma may be present. They uncommonly present as an exophytic or endophytic polypoid growth and are thought to represent endometrial polyps or submucosal leiomyomas until they are examined histologically. These lesions are benign. They usually do not pose a significant diagnostic problem unless they feature an especially prominent fibromyomatous stroma or foci of alternate stromal differentiation.

Atypical polypoid adenomyomas or adenomyofibromas (APA)  are characterized by a localized, polypoid endometrial proliferation with features of complex atypical hyperplasia set in a stroma composed of smooth muscle or more commonly, smooth muscle and fibrous tissue. [30, 32, 54] Trichrome stain often confirms the impression of a mixture of spindled smooth muscle cells and collagen. In most cases, stromal mitotic figures do not exceed 2 MF/10 HPF; occasionally, focal increased stromal mitotic figures (3 to 5 MF/ 10 HPF) may be present, raising the differential diagnosis of adenosarcoma. [30] The problem may be compounded by foci of squamous epithelial differentiation, which are present in most cases. Unlike uterine adenosarcoma, most PA and APA occur in premenopausal or perimenopausal women. Many of the patients are nulliparous and a clinical history of infertility is not uncommon. Although tumors in the adenofibroma-adenosarcoma spectrum may feature stromal smooth muscle, the stroma elsewhere is usually also either highly cellular and resembles endometrial stroma or paucicellular and populated by spindled fibroblastic cells with abundant collagen. Rarely, we have encountered adenosarcomas with a predominant low-grade smooth muscle stroma, but even in these tumors, areas of classic periglandular stromal condensation and intraluminal polypoid projections are seen.

Polypoid Endometriosis vs Adenosarcoma
Polypoid endometriosis is a rare manifestation of endometriosis that may simulate a neoplasm on clinical, intraoperative, or pathologic assessment. [37] Some cases may be attributable to exogenous hormones or hyperestrinism and, like conventional endometriosis, some may represent a premalignant or neoplastic process. Unlike conventional endometriosis, polypoid endometriosis affects a slightly older age group with 60% of cases occurring in women >50 years of age. Clinical follow up in the largest series of cases reported to date indicates a benign course, although follow up is limited in that only seven of the reported patients had >5 years follow up and only four had > 7 years. [37]

Like adenosarcoma, polypoid endometriosis often features various types of epithelial metaplasia (tubal, mucinous, squamous, papillary syncytial metaplasia), but unlike adenosarcoma, it usually does not exhibit the characteristic stromal cellularity or stromal atypia of adenosarcoma. Some cases may feature intraglandular stromal papillae and focal periglandular stromal hypercellularity and the point at which these lesions cease to be polypoid endometriosis and warrant classification as adenosarcoma is not always easy to define. [37] Because of this potential for histologic overlap, the distinction between these two processes can be very difficult on frozen section as well as on permanent sections in some cases. [3, 21, 24] Given the diagnostic difficulties and the limited data concerning the clinical behavior of polypoid endometriosis, the possibility of adenosarcoma should be mentioned during intraoperative consultation on any endometriotic lesion presenting as an unusual mass-like process. Whenever possible, complete conservative excision is probably warranted. In problematic cases, examination of multiple sections and consultation should be performed.

Conventional endometriosis can give rise to a number of malignant processes. Ovarian clear cell carcinoma and endometrioid adenocarcinoma are the most notable examples of tumors arising in association with endometriosis in the ovary. In extragenital sites, adenosarcoma and endometrial stromal sarcoma are also prominent. [43, 44, 52] A significant proportion of extragenital adenosarcomas that have been reported in the literature are diagnosed only after repeated biopsies and/or multiple clinical recurrences of endometriosis. While it is likely that some of these cases are histologically non-informative and possibly responsible for the historic designation of "aggressive endometriosis", it is also possible that at least some cases may contain more diagnostic foci that can only be identified when extensively sampled. Adenosarcoma should be given strong consideration in the differential diagnosis of any new pelvic or abdominal mass in a patient with a history of endometriosis and such masses should be subjected to extensive sectioning and histologic evaluation.

Carcinosarcoma vs Adenosarcoma
This distinction is based on the epithelial component. The malignant epithelial component in carcinosarcoma is typically high grade and is usually not confused with the atypical glands that may occur in adenosarcoma. Uncertainty in a curettage or biopsy specimen may occur due to inadequate sampling, and many of these ambiguous cases can be resolved on hysterectomy. However, foci of atypical glands and even well differentiated adenocarcinoma may rarely occur in tumors that are otherwise indistinguishable from adenosarcomas. Since the clinical behavior of virtually all biphasic mullerian tumors can be predicted on the basis of the most histologically malignant areas, the behavior of adenosarcomas with focal low grade adenocarcinoma is probably closer to that of an adenosarcoma than a carcinosarcoma, provided the foci are relatively small. Recent data suggests that the distinction between uterine carcinosarcoma and adenosarcoma with high-grade sarcomatous overgrowth may be moot, given the observed equivalent poor prognosis. [26]

Sarcoma Entrapping Benign Glands vs Adenosarcoma
In adenosarcoma, the glands are typically scattered throughout the tumor and they are large, irregular and cystic in contour with stromal cuffing. Often, they feature papillations and various types of metaplastic epithelium. In contrast, glands that are entrapped by a sarcomatous proliferation are typically small and inconspicuous or form focal aggregates of residual glands surrounded by sarcoma. Obviously, adenosarcomas with stromal overgrowth may also entrap benign glands in the areas of stromal overgrowth. The key to the diagnosis is the presence elsewhere of typical adenosarcoma.

Endometrial Stroma Sarcoma with Glandular Elements vs Adenosarcoma
Adenosarcoma and rarely, adenofibroma, may exhibit overlapping histologic features with that of endometrial stromal sarcoma with prominent glandular elements. Over a certain range of appearances there is no sharp distinction between the two, but features favoring adenosarcoma include dilated, irregularly shaped glands with intraluminal polypoid protrusions, a variety of mullerian epithelial types and the characteristic periglandular stromal condensation.

If epithelium is present in endometrial stromal sarcoma, it usually takes the form of poorly circumscribed, but regularly contoured small tubular glands or cords of epithelial-like cells. The epithelial type in stromal sarcoma is almost always endometrioid, while a variety of epithelial types with mucinous, squamous and syncytial metaplasia are often present in adenosarcoma. The stroma in endometrial stromal sarcoma is also more monomorphous and does not exhibit the periglandular condensation around glands that is so characteristic of adenosarcoma. Sex cord elements may be seen in both.

Embryonal Rhabdomyosarcoma vs Adenosarcoma with Heterologous Rhabdomyosarcomatous Differentiation
Adenosarcomas tend to occur in the uterine cervix of reproductive aged women, as well as in postmenopausal women. The predilection for these tumors to occur in the cervix of postmenarchal teenagers often poses a clinical differential diagnosis of embryonal rhabdomyosarcoma (sarcoma botryoides). This differential diagnosis may continue at the macroscopic level, since a botryoides appearance has been reported in some cases of cervical adenosarcoma. Furthermore, when these cervical adenosarcomas feature microscopic rhabdomyosarcomatous differentiation, they can be especially difficult to distinguish from embryonal rhabdomyosarcoma. [7] Since the treatment and prognosis of cervical embryonal rhabdomyosarcomas may differ substantially from that of an adenosarcoma, the diagnosis of adenosarcoma in this setting should be made with caution and only after complete histologic evaluation and consultation. Embryonal rhabdomyosarcoma usually occurs in a younger premenarchal age group as opposed to the postmenarchal age group.

Miscellaneous Sarcomas
A variety of pure sarcomas have been reported in the female genital tract but they are all quite rare. These include osteosarcoma, chondrosarcoma, rhabdomyosarcoma, liposarcomas, malignant schwannoma, and angiosarcomas. [20] The chief differential diagnostic consideration in all of these tumors is a carcinosarcoma or adenosarcoma with stromal overgrowth and an inconspicuous epithelial component. Since each of these sarcomas is high grade and treated similarly the distinction may not be of great importance. This might change if it becomes apparent that carcinosarcomas respond more like carcinomas than sarcomas.

A Managerial Approach
Although authorities differ on the appropriate mitotic index conventions for distinguishing adenofibroma from adenosarcoma, uterine tumors with particularly cellular stroma, more than minimal stromal cell atypia and/or borderline mitotic counts should be considered as being of at least uncertain malignant potential, particularly if subepithelial condensation is present. When such tumors are encountered in the ovary and extra-genital sites, they should be classified as adenosarcomas due to the higher risk of recurrent disease at these sites. Other benign proliferations featuring a mixture of glands and stroma (endometrial polyps, polypoid adenomyoma - both typical and atypical - and polypoid endometriosis) typically lack the characteristic peri-glandular cuffing and the polypoid invaginations seen in adenosarcoma, but may require additional sectioning or sampling in order to exclude the latter diagnosis.

It can be especially difficult to distinguish adenofibroma from adenosarcoma on a limited endometrial sampling. The difficulty is heightened by the rare reported instances of lesions that otherwise resemble a typical adenofibroma, but have demonstrated myometrial invasion in the hysterectomy specimen. When this differential diagnosis occurs in the post-reproductive years, the distinction is mostly of prognostic significance. However, when it occurs in women during the reproductive years, the distinction may carry significant therapeutic implications, since an adenofibroma can be treated by polypectomy whereas adenosarcoma is treated by hysterectomy. In these latter cases, imaging studies and repeat hysteroscopic directed sampling with consultation should be sought.

The distinction between adenosarcoma with sarcomatous stromal overgrowth and pure uterine sarcoma or carcinosarcoma depends on identifying neoplastic glands in some part of the tumor – benign in adenosarcoma and malignant in the case of carcinosarcoma.

Most malignant mixed mullerian neoplasms (carcinosarcoma) are easily recognized as high-grade biphasic malignant neoplasms, whether the tumor is initially encountered in an endometrial sampling or a hysterectomy specimen. On occasion, adenosarcomas may contain foci of glandular atypia that meet criteria for carcinoma in situ or even focal adenocarcinoma, raising the differential diagnosis of carcinosarcoma. If the remaining glandular pattern is consistent with an adenosarcoma, the lesion should be diagnosed as such with a comment in the report that there are areas featuring carcinomatous epithelium. Such tumors are uncommon and so there is no outcome data (other than anecdotal) that supports this classification, but one would expect that such tumors would behave more like typical adenosarcoma unless there is associated high grade carcinoma, high grade sarcoma, or stromal overgrowth.

Differential Diagnosis of Adenosarcoma [20, 29]

Benign glands Malignant glands
Benign stroma Adenofibroma
Polypoid endometriosis
Adenomyoma
Atypical polypoid adenomyoma 		[Carcinofibroma] *
Malignant stroma Adenosarcoma
with sarcomatous stroma
with stromal overgrowth
Endometrial stromal sarcoma with glandular elements
Sarcoma entrapping benign glands 		Carcinosarcoma
Homologous
Heterologous

* Carcinofibroma, a term reported in the older literature to describe the presence of adenocarcinoma in an adenofibromatous process, is not currently considered to be a standard diagnostic entity.

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