—  SPECIALTY CONFERENCE  —

Gynecologic Pathology

Case 1 - Low-Grade Mullerian Adenosarcoma Arising in Hepatic Endometriosis

Charles V. Biscotti Cleveland Clinic Foundation
Cleveland, OH


Click on each slide thumbnail image for an enlarged view
Clinical History
A 51-year-old presented for resection of a hepatic endometrioma diagnosed by tissue biopsy three years prior. At that time, she had a significant response to leuprolide acetate: however, the mass recurred approximately 2.5 years after discontinuing monthly injections. Repeat tissue biopsy was again interpreted as endometriosis. This time, the patient had a poor response to leuprolide acetate. A 10x12x1.5 c.m. mass was excised.


Case 1 - Figure 1 - A variably thick capsule of soft tissue surrounds a central cavity containing blood clot and hemorrhagic soft tissue.
Case 1 - Figure 2 - Some of the periphery of the mass has endometrial tissue (left) a relatively hypocellular fibrous zone (center) and liver tissue (right).
Case 1 - Figure 3 - In this field, hypocellular fibrous stroma surrounds endometrial glands of varying size and shape.


Case 1 - Figure 4 - Some of the mass has more crowded and abnormally shaped endometrial glands surrounded by a more cellular stroma.
Case 1 - Figure 5 - This field represents an area of greatest stromal cellularity.

Diagnosis
Low-Grade Mullerian Adenosarcoma Arising in Hepatic Endometriosis

Gross and Microscopic Examination
The mass presented grossly as a partially collapsed 10 x 12 x 1.5 cm cyst with an indurated reddish gray capsule surrounding focally necrotic hemorrhagic soft tissue. Histologically, the capsule included variably cellular fibrosis tissue and portions of diaphragm, liver capsule and hepatic parenchyma. Centrally, the mass consisted of a variably cellular stroma, resembling a mixture of fibrous tissue and endometrial stroma surrounding endometrial glands. The endometrial glandular architecture varied including foci with crowded complex abnormally configured glands characteristic of complex endometrial hyperplasia. The glandular epithelium lacked cytologic atypia. Stromal cellularity varied with much of the tissue composed of relatively hypocellular fibrous stroma. A minor component had moderate and focally marked stromal hypercellularity. Scattered inconspicuous foci of periglandular stromal hypercellularity were identified along with intraglandular stromal protrusions imparting a phyllodes pattern, albeit it extremely focally. Most of the tumor lacked appreciable stromal mitotic activity; however, mitoses varied, up to 3 mitotic figures per 10 high magnification fields. Most of the tumor also lacked stromal nuclear atypia; however, focal stromal atypia was identified. The stroma lacked heterologous elements.

Differential Diagnosis
In addition to adenosarcoma, the differential diagnosis includes endometrioma or polypoid endometriosis and mullerian adenofibroma. The gross appearance favors adenofibroma/adenosarcoma rather than endometriosis. Endometriomas usually form cystic ovarian masses rather than solid and cystic hepatic masses as in the current case [17]. Endometriosis can form sizable polypoid masses simulating a neoplasm, so called polypoid endometriosis [17]; although this occurs extremely infrequently. In contrast, adenosarcomas characteristically form bulky solid and cystic masses. For example, in the gastrointestinal tract three cases of adenosarcoma, complicating endometriosis, were 6.5 cm, 10.5 cm, and 15 cm in greatest dimension, respectively [13]. In contrast, non-neoplastic endometriosis related masses ranged from 1.0 to 4.5 cm in greatest dimension, mean 2.6 [18]. Histologically, polypoid endometriosis lacks stromal nuclear atypia, periglandular hypercellularity, and a phyllodes pattern [6]. The current case has stromal nuclear atypia and a well-developed phyllodes pattern, albeit focal. Resolving this differential diagnosis requires extensive sampling and a high index of suspicion for any sizable mass of endometriotic tissue.

Distinguishing the low end of the spectrum of adenosarcoma from adenofibroma can be problematic. Adenofibromas have uniform stroma with infrequent mitoses and relatively low cellularity. Clement and Scully diagnose adenosarcoma in the presence of one or more of the following criteria: > 2 mitotic figures per 10 high magnification fields, more than mild stromal nuclear atypia, or marked stromal hypercellularity [2]. The mitotic count criterion uses an average count based on 40 high magnification fields in the most cellular zones [2]. Periglandular stromal hypercellularity and heterologous elements have also been cited as useful differential diagnostic criteria [20]. The current case has stromal nuclear atypia, periglandular stromal hypercellularity, marked stromal hypercellularity, and up to 3 mitotic figures per 10 high magnification fields.

Discussion
The clinicopathologic features of uterine mullerian adenosarcoma have been well-documented [1, 2, 21] . Clement and Scully described uterine mullerian adenosarcoma in a 10 case series in 1974 and a follow-up analysis of 100 cases [1, 2] . In these series, the patients' ages varied but most were postmenopausal (range 14 to 89 years, median 58) [2]. The Gynecologic Oncology Group reported a similar age distribution [3]. In the largest series, 78% of patients presented with vaginal bleeding [2]. Primary sites of involvement included the endometrium (83%), endocervix (7%), myometrium (4%), or multiple sites (7%) [2]. Grossly, uterine adenosarcomas present as polypoid or papillary masses, often containing small cysts [2, 3] . In the largest series, tumors ranged from 1-17 cm (mean 5 cm) in maximum dimension [2].

A variety of epithelia line the glands, usually proliferative endometrioid cells followed by, in decreasing order of infrequency, endocervical mucinous, squamous, serous, and secretory endometrioid cells [2]. Most cases have at least two epithelial cell types and some have three or four [2]. In the largest series 10% of cases had glandular crowding and architectural atypia. One third had mild to marked nuclear atypia, always focal [2]. One case had a small grade one endometrioid adenocarcinoma [2].

The sarcomatous component of uterine tumors has distinctive histologic features. The sarcomatous component usually resembles a low-grade homologous sarcoma, endometrial stromal sarcoma and/or fibrosarcoma. Pure homologous sarcoma has been described in 78% of cases including high-grade homologous sarcoma in 3 (4%) of 78 tumors without sarcomatous overgrowth and 2 (20%) of 10 tumors with sarcomatous overgrowth [2, 4] . The stromal cellularity commonly varies with hypocellular fibrous zones imparting a benign appearance [2]. This feature reinforces the importance of sampling to avoid misdiagnosis as benign endometrial polyp or mullerian adenofibroma. Smooth muscle differentiation has been reported in approximately six percent of cases [2]. Heterologous sarcomatous differentiation almost always rhabdomyosarcoma, occurs in approximately in 22% of uterine adenosarcomas [2]. Stromal mitotic rates vary. In the largest series, stromal mitotic counts, expressed as an average per 10 high magnification fields based on 40 fields, varied from less than 1 to 40 (mean 9) [2]. Other characteristic features of the sarcomatous component include periglandular hypercellularity (80% of cases), phyllodes pattern (60% of cases), moderate nuclear atypia (32% of cases), marked nuclear atypia (38% of cases), and sarcomatous overgrowth (8% of cases) [2, 4] . Pure sarcoma similar to or of higher grade than that of the underlying adenosarcoma, occupying at least 25% of a well-sampled tumor defines sarcomatous overgrowth [4]. In the seminal study of mullerian adenosarcomas with sarcomatous overgrowth, the pure sarcomatous component was of higher-grade in 7 of 10 cases [4].

Uterine mullerian adenosarcomas behave as low-grade malignancies except those tumors with sarcomatous overgrowth. Only about 25% of mullerian adenosarcomas without sarcomatous overgrowth invade the underlying myometrium (2,8) compared to 60% of those with sarcomatous overgrowth [4]. More importantly, recurrence affects approximately 26% [2] of patients without sarcomatous overgrowth compared to 76% of patients with sarcomatous overgrowth [4, 9] . In the series of Clement and Scully no tumor deaths occurred in 95 patients without sarcomatous overgrowth [2, 8] but tumor related deaths have been reported [5]. In contrast, 15 of 21 (71%) patients with sarcomatous overgrowth died of disease [4, 9] . Sarcomatous overgrowth occurs in approximately eight percent of cases [2, 4] . The pure sarcomatous component usually has a higher-grade [4]

Other pathologic prognostic variables for uterine adenosarcoma include stage and myoinvasion [2, 3] . In one study tumors with vascular invasion and tumors with rhabdomyoblastic differentiation recurred more often but the difference was not statistically significant [3].

The ovary is the second most common site for mullerian adenosarcoma accounting for 15% of cases in one series [5]. Ovarian mullerian adenosarcomas differ from their uterine counterparts with respect to some clinical and pathologic features. Clinically, ovarian tumors affect younger patients, present at higher stage and have a worse prognosis [6]. Approximately half of the patients with ovarian adenosarcomas have been less than 50 years of age [6, 7] . In contrast, most uterine tumors affect post-menopausal patients with a median age of 58 years in the largest series [2]. Ovarian tumors appear to rupture easily as evidenced by the fact that 75% of tumors were stage IC or greater [6]. Thirty-five percent were stage II or greater in the largest series [6]. In a separate study both tumors had ruptured and one of these also had peritoneal implants [7]. Unlike uterine mullerian adenosarcomas most ovarian tumors recur (62%), almost always within five years. Further, 38% of patients have died of disease, two thirds of these within five years [6, 7] . In contrast 31% of uterine tumors recur and six percent of patients die of disease [2, 4] . Compared to their uterine counterparts, ovarian mullerian adenosarcomas more often have sarcomatous overgrowth (30% versus 8%) and sex cord-like elements (15% versus 7%) [2, 4, 6, 8] . Interestingly, Eichhorn and colleagues observed some differences in pathologic prognostic variables. Specifically, high-grade and the presence of a high-grade sarcomatous overgrowth component were associated with recurrence in ovarian tumors [6]. The presence or amount of sarcomatous overgrowth was not associated with recurrence provided that the sarcomatous overgrowth component was low-grade [6].

Mullerian adenosarcomas complicate endometriosis, albeit infrequently. The prevalence of endometriosis has been estimated at 15% among pre-menopausal women and 2-5% among post-menopausal women [10]. Malignant transformation occurs rarely with estimates ranging from 0.3 to 0.8% for surgical series of ovarian endometriosis [11]. In one study 78.7% of endometriosis-associated malignancies arose in the ovary [10]. The histologic types of malignant neoplasms differ between ovarian and extraovarian sites. Carcinomas, almost always endometrioid or clear cell, predominate in both the ovary and extraovarian sites. However, sarcomas are relatively more common in extraovarian sites, accounting for 25% of malignancies compared to 11.6% of malignancies associated with all sites of endometriosis combined [10]. In one study, adenosarcoma accounted for three of 15 neoplasms involving extraovarian endometriosis compared to 0 of 27 neoplasms associated with ovarian endometriosis [12]. Mullerian adenosarcomas accounted for four of 17 [13] and one of six [14] neoplasms arising in gastrointestinal endometriosis. Mullerian adenosarcomas have been linked to endometriosis at other sites including the vagina [15, 16] and liver [19].

References

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