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Home , Adenosarcoma, Uterine adenosarcoma

Uterine

Andre Pinto, MD; Brooke Howitt, MD

M¨ullerian adenosarcoma is an uncommon biphasic clinically with abnormal and/or pelvic pain tumor composed of malignant stromal and benign epithe- or, in a large percentage of cases, with no symptoms. lial components. Morphologically, adenosarcoma is char- Although the uterine corpus is by far the most common acterized by a broad leaflike architecture, reminiscent of primary site, adenosarcoma may also arise in the , phyllodes tumors of the breast. Periglandular cuffing of the , , or .4 Adenosarcoma occurring stromal cells around the compressed or cystically dilated outside the female genital tract likely represents tumors glands is characteristic. The mesenchymal component is arising from preexisting .5–7 Some studies typically a low-grade spindle cell , whereas the suggest that the use of may have a role in the epithelial counterpart is commonly endometrioid with pathogenesis of adenosarcoma.8–11 frequent squamous or mucinous metaplasia and may, in The prognosis of adenosarcoma greatly depends on stage some circumstances, show mild to moderate atypia. In all and the presence of sarcomatous overgrowth.12 A small cases, it is important to assess for the presence of series of cases13 found that the 2-year progression-free and sarcomatous overgrowth and myometrial invasion, which overall survival rates for tumors with sarcomatous over- are the prognostic factors. In this brief review, we present growth were 20% compared with 100% for adenosarcoma the clinical, histopathologic, and immunohistochemical lacking sarcomatous overgrowth. Another study14 demon- features of adenosarcoma, as well as updates on the strated that 36% of adenosarcoma with myometrial invasion molecular biology of this neoplasm. recurred, and the risk of recurrence in the absence of (Arch Pathol Lab Med. 2016;140:286–290; doi: 10.5858/ myoinvasion was only 7%. Overall survival is around 60% arpa.2014-0523-RS) for tumors with myoinvasion and less than 50% for tumors with associated .15 Tumors that arise in the ovary or extrauterine sites tend to have a higher recurrence rate n 1974, Clement and Scully1 reported a series of tumors of secondary to lack of a physical barrier to spread within the I the female genital tract that were described as ‘‘... mixed pelvis and abdomen. A new FIGO (International Federation tumors of the , in which the stromal component has of Gynecology and Obstetrics) staging system for adeno- been malignant, but the epithelial elements, benign,’’ and sarcoma, identical to that for endometrial stromal sarcoma proposed naming these tumors adenosarcoma. A subsequent (ESS), has been devised recently16 (Table 1). study,2 in 1979, added a few cases to the original series, and the term Mullerian¨ adenosarcoma has since become univer- MACROSCOPIC FEATURES sally recognized. The uterine cavity is typically filled with an exophytic and Mullerian¨ adenosarcoma is an uncommon biphasic polypoid mass, which may project through the cervix. The malignant mesenchymal tumor composed of a benign average size is 5 cm, although tumors up to 50 cm have been glandular component and a malignant, but generally low- reported.17 The cut surface shows variably cystic and solid grade, stromal component. With a growing number of cases areas, and papillary or polypoid projections into cystic reported (now considerably more than 200) in the literature, spaces can often be appreciated macroscopically (Figure 1). the spectrum of morphologies and clinical behavior is fairly Focal hemorrhage and necrosis may also be present. When well understood. The molecular pathogenesis of these sarcomatous overgrowth is present, the mass may acquire a tumors, however, remains to be elucidated. more fleshy appearance commonly seen in other types of Although uncommon, adenosarcoma affects women of a sarcoma.18,19 broad age range. The incidence is highest in perimenopausal or postmenopausal women, but cases have been reported in MICROSCOPIC FEATURES 3 children as young as 10 years. Patients may present Histologically, adenosarcoma is composed of benign- appearing and malignant stroma. Many of the Accepted for publication January 15, 2015. diagnostic features are best appreciated at low-power From the Division of Women’s and Perinatal Pathology, Brigham magnification and may reflect the gross appearance of this and Women’s Hospital, Boston, Massachusetts (Drs Pinto and tumor (Figure 2). The architecture often demonstrates a Howitt); and Harvard Medical School, Boston (Dr Howitt). broad leaflike appearance, formed by the malignant stroma The authors have no relevant financial interest in the products or compressing the benign epithelium, somewhat resembling a companies described in this article. Reprints: Brooke Howitt, MD, Division of Women’s and Perinatal phyllodes tumor of the breast (Figure 3). ‘‘Rigid cyst’’ Pathology, Brigham and Women’s Hospital, 75 Francis St, Amory 3, formation is another architectural pattern in which large, Boston, MA 02115 (e-mail: [email protected]). dilated, cystic structures, lined by benign epithelium, are 286 Arch Pathol Lab Med—Vol 140, March 2016 —Pinto & Howitt Table 1. The FIGO (International Federation of surrounded tightly by malignant stroma (Figure 4). Peri- Gynecology and Obstetrics) Staging System for glandular cuffing of the stromal cells condensing under the Uterine Adenosarcoma epithelium is characteristic and can also be appreciated from low-power microscopic examination. The epithelial or Stage Definition glandular component is usually endometrioid and frequent- I Tumor limited to uterus IA Tumor limited to endometrium/endocervix with no ly demonstrates metaplasia (squamous and mucinous are 12 myometrial invasion most common) and may show mild to moderate atypia. IB 50% myometrial invasion The malignant stroma can have a varied appearance but is IC .50% myometrial invasion II Tumor extends beyond the uterus, within the pelvis classically a low-grade spindle cell sarcoma, frequently with IIA Adnexal involvement myxoid foci, with no specific line of differentiation, although IIB Involvement of other pelvic tissues some consider it to resemble ESS. Mitoses are essentially III Tumor invades abdominal tissues (not just required for the diagnosis (at least 2 per 10 high-power protruding into the abdomen) IIIA One site fields). The mitoses are usually most pronounced in areas of IIIB .1 site periglandular cuffing. Atypical mitotic figures are generally IIIC Metastasis to pelvic and/or para-aortic lymph nodes absent except in the presence of sarcomatous overgrowth.17 IV IVA Tumor invades bladder and/or rectum Sex cord-like differentiation can be seen, which has no effect IVB Distant metastasis on prognosis.4

Figure 1. Gross image of Mullerian¨ adenosarcoma of the uterus. The mass has a yellow-tan, exophytic appearance, which fills the entire endometrial cavity and extends to the cervix. In this case, sarcomatous overgrowth was present. Figure 2. Section of endomyometrium showing a large, polypoid mass replacing the endometrium. Note the phyllodes architecture and cleftlike spaces at scanning magnification (hematoxylin-eosin; original magnification 310). Figure 3. The resemblance with phyllodes tumor of the breast is evident in a section of adenosarcoma at low power. The leaflike appearance with compressed epithelium is characteristic of these tumors (hematoxylin-eosin; original magnification 3200). Figure 4. Rigid cyst formation is an architectural pattern also frequently seen in adenosarcoma. Large cystic spaces lined by benign epithelium are surrounded by low-grade malignant stroma (hematoxylin-eosin; original magnification 3200). Arch Pathol Lab Med—Vol 140, March 2016 Uterine Adenosarcoma—Pinto & Howitt 287 The presence or absence of sarcomatous overgrowth is an important prognostic factor and should be assessed in all tumors.20 Sarcomatous overgrowth is defined as the presence of pure sarcoma (without any epithelial compo- nent) comprising at least 25% of the tumor. Morphologic features of sarcomatous overgrowth are typically high grade (Figure 5) and include severe cytologic atypia, brisk mitotic activity, and necrosis; however, high-grade stroma is not a requisite for the diagnosis of sarcomatous overgrowth. When high-grade stroma is present but comprises less than 25% of the tumor, it should be mentioned but no definitive data exist on the prognostic significance. Of course, additional tumor should be sampled and examined histo- logically if possible. Not uncommonly, adenosarcoma with sarcomatous overgrowth may demonstrate low- to inter- mediate-grade atypia with a myxoid appearance (Figure 6). Sarcomatous overgrowth is associated with deeper myo- metrial involvement and lymphovascular invasion.4 Heterologous elements, most notably rhabdomyoblastic differentiation, have no prognostic significance alone, although they occur most commonly in the presence of sarcomatous overgrowth.

IMMUNOHISTOCHEMISTRY Diffuse or multifocal expression of CD10 in the stromal compartment is seen in most adenosarcomas and often highlights the periglandular cuffing (Figure 7). Immunore- activity for estrogen and progesterone receptors is also seen in most cases, both in the glandular and stromal compo- nents. However, expression of these markers is significantly decreased in adenosarcoma with sarcomatous over- growth.14,21 Mesenchymal markers, such as smooth muscle actin (SMA), desmin, and CD34 can have variable positivity in the stromal component. More than one-half of tumors exhibit expression of SMA and/or desmin, whereas the percentage of CD34þ tumors is smaller.14,21 Cytokeratins may rarely be focally positive in the sarcomatous compo- nent.21,22 For an expanded summary of the immunohisto- chemical profile of adenosarcoma, refer to Table 2.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of adenosarcoma is broad and consists predominantly of tumors that also have a biphasic (epithelial and mesenchymal) appearance. The particular entities considered in the differential diagnosis vary with the type of adenosarcoma. At the very low end of the spectrum, the differential diagnosis includes primarily benign entities, such as the so-called adenofibroma, adenomyoma (benign), endometrial polyps with unusual features, and atypical polypoid adenomyoma. In the presence of high-grade sarcoma and/or sarcomatous overgrowth, the main diagno- sis to rule out is , although undifferentiated uterine sarcoma, ESS, and leiomyosarcoma should also be considered in the differential diagnosis. Figure 5. An example of sarcomatous overgrowth, in which the Differential Diagnosis of Adenosarcoma Without mesenchymal component comprises at least 25% of tumor with no Sarcomatous Overgrowth associated epithelium. This example demonstrates high-grade stroma with cytologic atypia and frequent mitoses (hematoxylin-eosin, original Endometrial polyps, adenofibroma, and adenomyoma are magnification 3400). tumors in which both the epithelial and stromal compo- Figure 6. Sarcomatous overgrowth with low-grade stroma. Mild nents are morphologically benign. So-called adenofibroma cytologic atypia is present. Myxoid stroma, as shown here, can be has the architectural features of adenosarcoma, but the seen in cases of sarcomatous overgrowth (hematoxylin-eosin, original stroma is typically hypocellular and fibrotic. Mitoses should magnification 3200). be absent or rare. Indeed, adenofibroma may represent the Figure 7. Immunohistochemistry for CD10 highlighting the perigland- far ‘‘low-grade’’ end of the spectrum of adenosarcoma, and ular ‘‘cuffing’’ of malignant stromal cells (original magnification 3200). 288 Arch Pathol Lab Med—Vol 140, March 2016 Uterine Adenosarcoma—Pinto & Howitt Table 2. Immunohistochemical Staining Patterns in Because CD10 immunostain is positive in both adenosarco- Uterine Adenosarcomaa ma and ESS, it is not helpful in distinguishing between these tumors. Many ESSs have a t(7;17) translocation Stroma (No Stroma (With resulting in JAZF1-SUZ12 gene fusion, and cytogenetic Sarcomatous Sarcomatous Stain Epithelium Overgrowth) Overgrowth) studies may be used in difficult cases. A high-grade ESS has also been described,24 which is AE1/AE3 þþ/ characterized by malignant cells with uniform atypia and Estrogen þþ receptor high mitotic index. The immunohistochemical profile varies, Progesterone þþ but these tumors are generally nonreactive for CD10, receptor estrogen receptor, and progesterone receptor, in contrast Androgen þ to adenosarcoma. High-grade ESSs are positive for cyclin receptor D1, which indirectly reflects the presence of a YWHAE- CD10 þ/þ þ/ p53 þ/ FAM22 gene fusion product created by the characteristic translocation t(10;17).24 a Key: þ, positive; , negative; þ/, either positive or negative. Given its frequency among mesenchymal tumors of the gynecologic tract, leiomyosarcoma may also be considered. thus, a diagnosis of adenofibroma should be rendered with Leiomyosarcoma may uncommonly entrap benign endo- extreme caution, if at all.14,19 Occasionally, benign uterine metrial glands but does not demonstrate features charac- polyps may display features suggestive of adenosarcoma; teristic for adenosarcoma. The presence of typical fascicular however, those features are subdiagnostic, typically subtle, architecture and immunohistochemical positivity for smooth and only partially involve the polyp.23 Endometrial polyps muscle markers, particularly caldesmon, is diagnostic of with myomatous stroma can resemble adenosarcoma, but leiomyosarcoma. the stromal component is made of smooth muscle cells that form fascicles. Fascicular growth of the stromal component MOLECULAR DIAGNOSTICS in adenosarcoma is unusual. Atypical polypoid adenomyo- The precise molecular mechanism of tumorigenesis in ma is characterized by endometrial glands frequently adenosarcoma remains unclear. One reported karyotype of displaying mild cytologic and architectural atypia and often adenosarcoma with sarcomatous overgrowth revealed a diffuse or focal squamous morular metaplasia. The myofi- hyperdiploid karyotype with multiple structural and numerical bromatous stroma is cellular but lacks the leaflike architec- abnormalities involving chromosomes 2, 8, 10, 13, 19, and ture of adenosarcoma. 21.25 Some studies have found low rates of TP53 muta- tions,26–28 and others have described low-level amplification of Differential Diagnosis of Adenosarcoma With Sarcomatous MDM2 and other genes on band 12q14-15.26,27 Recently Overgrowth described alterations in adenosarcoma include MYBL1 Perhaps the most challenging differential diagnosis is amplification and ATRX mutation, which are each present carcinosarcoma. As the name implies, both elements of in 50% of adenosarcomas with sarcomatous overgrowth.27 these neoplasms are malignant, but adenosarcoma can MYBL1 is a transcription factor that regulates cell proliferation demonstrate cytologic atypia in the epithelial component; and is amplified in subsets of other types of tumors, including thus, the distinction from a small carcinoma can be difficult. 10% of uterine carcinosarcoma (http://www.cbioportal.org; To further complicate this differential diagnosis, epithelial accessed January 14, 2015). ATRX regulates DNA methylation malignancies may arise in the setting of adenosarcoma, and and chromatin remodeling; loss-of-function mutations in 29 can focally demonstrate areas mimicking ATRX have prognostic significance in other tumor types. adenosarcoma.4 In most carcinosarcomas, the sarcomatous component is not predominant; nevertheless, extensive TREATMENT sampling may be required to distinguish adenosarcoma Total abdominal or laparoscopic-assisted vaginal hyster- with sarcomatous overgrowth from carcinosarcomas com- ectomy is the treatment of choice for uterine adenosarcoma, posed predominantly of sarcoma. with or without bilateral salpingo-oophorectomy. One When the tumor cells are markedly high grade and do not study13 did not identify any ovarian metastases in patients recapitulate normal endometrial stroma, undifferentiated who underwent bilateral salpingo-oophorectomy for uterine uterine sarcoma should be considered. If entrapped glands adenosarcoma. However, given the frequent positivity of are present, it can mimic adenosarcoma. These tumors are estrogen and progesterone receptors in adenosarcoma, composed of pleomorphic, undifferentiated, malignant cells removal of the could potentially benefit patients, with high mitotic index. In the absence of classic features of even in the absence of metastatic disease—but that benefit adenosarcoma, undifferentiated uterine sarcoma should be needs to be weighed against the age of the patient and cost diagnosed, with the understanding that a subset of these of surgical . heterogenous tumors may represent extensive sarcomatous There is no standardized , hormonal overgrowth of an adenosarcoma. therapy, or in adenosarcoma, but standard Low-grade ESS may resemble adenosarcoma with sarco- sarcoma chemotherapy regimens, such as doxorubicin, matous overgrowth, particularly if glandular elements and/ ifosfamide, or gemcitabine/docetaxel, and newer drugs, or entrapped benign endometrial glands are present. In ESS, such as trabectedin, appear to have some efficacy in the tumor cells are monomorphic and have fusiform, round adenosarcoma with sarcomatous overgrowth.13,30,31 to ovoid nuclei and fine chromatin. The cell borders are indistinct, and cytoplasm is scant. Delicate vasculature is CONCLUSION characteristic of these tumors, which is composed of thin- Mullerian¨ adenosarcoma is a relatively uncommon entity walled blood vessels surrounded by whorling of tumor cells. in gynecologic pathology that has distinctive clinical and Arch Pathol Lab Med—Vol 140, March 2016 Uterine Adenosarcoma—Pinto & Howitt 289 histologic characteristics. It is important for pathologists to 14. Gallardo A, Prat J. Mullerian adenosarcoma: a clinicopathologic and immunohistochemical study of 55 cases challenging the existence of adenofi- be aware of the morphologic features of these neoplasms to broma. Am J Surg Pathol. 2009;33(2):278–288. distinguish them from other biphasic (epithelial and 15. Arend R, Bagaria M, Lewin SN, et al. Long-term outcome and natural mesenchymal) tumors, both benign and malignant. Ad- history of uterine adenosarcomas. Gynecol Oncol. 2010;119(2):305–308. enosarcoma is of generally low malignant potential, except 16. Prat J. FIGO staging for uterine . Int J Gynaecol Obstet. 2009; 104(3):177–178. when accompanied by sarcomatous overgrowth and my- 17. Eichhorn JH, Young RH, Clement PB, Scully RE. Mesodermal (mullerian)¨ oinvasion. Patients with adenosarcoma lacking these 2 adenosarcoma of the ovary: a clinicopathologic analysis of 40 cases and a review histopathologic features have an excellent prognosis. of the literature. Am J Surg Pathol. 2002;26(10):1243–1258. 18. Oliva E. Mullerian Adenosarcoma, Corpus. Diagnostic Pathology: References Gynecological. Vol 1. 1st ed. Altona, Manitoba, Canada: Amirsys; 2014: 1. Clement PB, Scully RE. Mullerian¨ adenosarcoma of the uterus: a (3)224–229. clinicopathologic analysis of ten cases of a distinctive type of mullerian¨ mixed 19. Zaloudek CJ, Norris HJ. Adenofibroma and adenosarcoma of the uterus: a tumor. . 1974;34(4):1138–1149. clinicopathologic study of 35 cases. Cancer. 1981;48(2):354–366. 2. Valdez VA, Planas AT, Lopez VF, Goldberg M, Herrera NE. Adenosarcoma 20. Clarke BA, Mulligan AM, Irving JA, McCluggage WG, Oliva E. Mullerian¨ of uterus and ovary: a clinicopathologic study of two cases. Cancer. 1979;43(4): adenosarcomas with unusual growth patterns: staging issues. Int J Gynecol Pathol. 1439–1447. 2011;30(4):340–347. 3. Fleming NA, Hopkins L, de Nanassy J, Senterman M, Black AY. Mullerian 21. Soslow RA, Ali A, Oliva E. Mullerian adenosarcomas: an immunopheno- adenosarcoma of the cervix in a 10-year-old girl: case report and review of the typic analysis of 35 cases. Am J Surg Pathol. 2008;32(7):1013–1021. literature. J Pediatr Adolesc Gynecol. 2009;22(4):45–51. 22. Abeler VM, Nenodovic M. Diagnostic immunohistochemistry in uterine 4. McCluggage WG. Mullerian adenosarcoma of the female genital tract. Adv sarcomas: a study of 397 cases. Int J Gynecol Pathol. 2011;30(3):236–243. Anat Pathol. 2010;17(2):122–129. 23. Howitt BE, Quade BJ, Nucci MR. Uterine polyps with features overlapping 5. 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290 Arch Pathol Lab Med—Vol 140, March 2016 Uterine Adenosarcoma—Pinto & Howitt