Case 4 -

Low-grade mesodermal adenosarcoma with sarcomatous overgrowth arising in the colon Esther Oliva, M.D. Massachusetts General Hospital Boston, MA, USA

Clinical history: A 50-year-old woman presented with blood in stool. On colonoscopy a 9 x 5 cm polypoid mass was found to protrude into the lumen showing focal ulceration. Relevant prior clinical history included previous hysterectomy and bilateral salpingo-oophorectomy for leiomyomas and resection of extensive pelvic endometriosis 5 years ago. The initial colon biopsy only showed benign colonic mucosa. The patient underwent segmental resection of the rectosigmoid colon. Case 4 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Diagnosis : Low-grade mesodermal adenosarcoma with sarcomatous overgrowth arising in the colon. Müllerian adenosarcoma (AS) belongs to the category of mixed mullerian tumors and represents approximately 8% of all uterine sarcomas. Outside the uterus these tumors are rare and they are designated mesodermal adenosarcomas. Clement and Scully first described the features of 10 ASs arising in the uterus in 1974. Soon after, Roth and colleagues described a similar tumor in the cervix (1976) and two years later Clement and Scully first reported 5 histologically identical tumors arising at extrauterine sites. Among all extrauterine sites, mesodermal adenosarcomas are more often seen in the ovary, followed by peritoneum, intestine, cervix, vagina, liver, bladder and fallopian tube. Clinical Features: Uterine tumors typically occur in postmenopausal women (median 60 years), but in contrast to malignant mixed müllerian tumors, approximately 30% are found in-patients below 50 years of age. However, extrauterine ASs typically occur at a younger age (median 44 years) when compared to their uterine counterpart. An occasional association with hyperestrinism, prior pelvic radiation or tamoxifen therapy with both, uterine and extrauterine ASs, may suggest their possible etiologic role in some cases. Patients with uterine tumors present most commonly with abnormal vaginal bleeding, often accompanied by lower abdominal or pelvic pain whereas patients with extrauterine ASs present with a wide variety of symptoms and signs depending on tumor location, vaginal bleeding being by far much less common. Patients with tumors originating in the gastrointestinal tract often present with chronic abdominal pain, obstructive symptoms or even bleeding as described in the current case. Pelvic examination typically reveals an enlarged uterus, and in about half the cases, tumor protruding through the external os; a palpable pelvic or abdominal mass in ovarian tumors while tumors in other locations may be more difficult to evaluate. Patients with typical uterine ASs are almost always stage I at presentation and the presence of extrauterine tumor in this setting suggests multicentricity or metastases from an adenosarcoma with sarcomatous overgrowth. In contrast, in the ovary, 75% of the tumors where stage IC or higher at the time of diagnosis in the largest series reported up to date while outside the ovary these tumors are infrequently well circumscribed and exhibit more than one tumor nodule. IN THE UTERUS: Occasional patients have presented on two or more occasions with lesions misinterpreted microscopically as benign polyps. Recurrent endocervical or endometrial polyps are uncommon, particularly in young women, and their occurrence should therefore suggest the possibility of adenosarcoma. OUTSIDE THE UTERUS: If the lesion is only biopsied, it may be misinterpreted as endometriosis. Persistent or worsening symptomatology should raise the possibility of malignancy and the patient should undergo thorough evaluation. Gross features : Adenosarcomas typically form polypoid or villous broad-based masses; frequently with secondary prolapse through the external os when they arise from the endometrium (90%). Approximately 10% of the tumors originate in the endocervix. Uterine tumors have a mean size of 5 cm (range from 1 to 17 cm), which contrast with ovarian ASs, typically larger with a mean size of 14 cm (range 5.5 to 50 cm). This difference in size is probably related to the fact that ovarian ASs have more space to grow before they are associated with clinical manifestations. Tumors at other sites vary much more in size depending on their location. In the gastrointestinal tract they are frequently centered in the serosa but they may infiltrate the muscularis wall and even appear as ulcerated polyps. Their cut surface is frequently spongy, with cystic spaces filled with watery or mucoid fluid, surrounded by white to tan tissue. At extrauterine locations ASs may be mostly solid, predominantly cystic, or may also rarely show polypoid projections on their external surfaces. IN THE UTERUS, myometrial invasion, which is present in approximately one-sixth of adenosarcomas, may be grossly appreciable IN THE OVARY it is not infrequent that the tumor is ruptured during or before surgery IN OTHER EXTAUTERINE SITES, poorly defined tumors may be difficult to resect Microscopic features : The epithelial component has frequently cystically dilated glands scattered throughout the mesenchymal component. Occasionally a villous pattern, with the neoplastic epithelium lining thin papillae or broad polypoid fronds, and only a minor component of glands may be seen. The glands are lined more commonly by proliferative-endometrial type epithelium, although endocervical (mucinous), tubal (ciliated), secretory-endometrial (with subnuclear vacuoles), hobnail, clear or indifferent epithelia may also be seen. Metaplastic squamous epithelium, typically nonkeratinizing, is often present. In approximately one-third of adenosarcomas, the glandular epithelium exhibits focal architectural or cytological atypia, and small foci of endometrial adenocarcinoma may be rarely encountered. The frequent mitotic activity of the epithelial component, the variety of epithelial cell types, the extensive distribution of glands throughout the stromal component and the occasional presence of glands within recurrent adenosarcoma are evidence of the neoplastic nature of the epithelial component of the tumor. The stromal component typically has the appearance of a low-grade sarcoma, usually an endometrial stromal sarcoma, fibrosarcoma, or combinations thereof. The stroma is more cellular around the glands, creating a cuff-like appearance which may be more prominent in uterine tumors than in extrauterine ASs. Intraluminal polypoid or papillary stromal projections of cellular stroma are a common finding. The stroma at a distance from the glands is often less cellular, and in some tumors, the stroma is predominantly hypocellular, myxoid or extensively hyalinized, imparting a deceptively benign appearance. The stromal cells exhibit mild or moderate nuclear atypia, but occasionally may be highly atypical. Mitotic activity is an almost constant finding, and >80% of tumors exhibit a mitotic rate of ³4 MFs/10HPFs, however, some uterine and extrauterine ASs may show less than 2 MFs/10HPFs. Foci of smooth muscle differentiation have been described and multinucleated giant cells, xanthoma cells and inflammatory cells may be seen. . In the ovary stromal luteinization or ectopic decidua have been reported. In the uterus, approximately 1/6 of ASs invade the myometrium; although in only 20% of such cases the invasion extends beyond the inner half of the myometrium Other microscopic features Heterologous elements are seen in approximately 20% of ASs, varying from minor foci of fat, cartilage, or rhabdomyoblasts to embryonal rhabdomyosarcoma occupying most or all of the stroma. Some of the cases with the latter type of stroma have also contained nodules of fetal-type cartilage similar to those occurring in some cases of embryonal rhabdomyosarcoma of the vagina and cervix. Foci of sex cord-like elements (SCLEs) within the stromal component. The SCLEs, which account for 5-50% of the tumors, are composed of benign-appearing epithelial type cells arranged in solid nests, trabeculae, and solid or hollow tubules. The cells may contain abundant eosinophilic or foamy, lipid-rich cytoplasm. The appearance of the SCLEs is similar to that of those encountered in some endometrial stromal tumors and in the rare uterine tumors resembling ovarian sex cord tumors. Sarcomatous overgrowth of the stromal component occurs more frequently in extrauterine ASs ("müllerian/mesodermal adenosarcoma with sarcomatous overgrowth") (MASO). To establish the diagnosis of MASO, the area of pure sarcoma should occupy at least 25% of the tumor volume or one low-power field in one slide. The sarcoma in most cases is high-grade with a destructive growth, but it can have a similar appearance to the low-grade sarcoma of the conventional AS. Useful criteria in diagnosing müllerian/mesodermal AS include in general: Two or more stromal mitotic figures/10 HPFs Marked stromal cellularity Significant stromal cell atypia Modified criteria for ovarian ASs include Conspicuous non-invasive müllerian-type glands within predominant malignant stromal component, either homologous or heterologous Periglandular cuffs or intraglandular protrusions of cellular stroma, or both Usually at least mild stromal atypia Stromal mitotic count variable, but may be very low Immunohistochemical profile : The stromal component is typically positive for vimentin, WT1, CD10, estrogen, and progesterone receptors (ER and PR) with variable expression of cytokeratin, muscle actin and androgen receptor, an immunohistologic profile that overlaps with that of endometrial stromal neoplasms. Areas of MASO are typically CD10, ER and PR negative. Differential Diagnosis : Adenofibroma. Although it may have a similar gross appearance in the uterus or at extrauterine sites, on microscopic examination the stromal component of the tumor is cytologically benign, with cells resembling fibroblasts or endometrial stromal cells exhibiting no or minimal nuclear atypia and no mitotic activity. Zaloudek and Norris reported stromal mitotic rate as the most reliable criterion in this differential diagnosis in uterine tumors, and concluded that only tumors with stromal mitotic counts ³ 4 MFs/10 HPFs should be diagnosed as AS. However, almost half of their clinically malignant ASs, had mitotic rates of only 4 or 5/10HPFs; while a "benign" count was that of 3MFs/10 HPFs, this subtle difference is within interobserver variation and also related to variations in cellularity. In contrast, Clement and Scully encountered a number of ASs with 2 or 3 MFs/10HPF that either had extrauterine disease at the time of presentation or recurred after hysterectomy, while Eichhorn and colleagues found that ovarian ASs with 2 or less mitoses/10HPFs also behaved in a malignant fashion. Thus, it appears that almost any measurable degree of stromal mitotic activity can be associated with a malignant behavior and that the diagnosis should rely upon other morphologic findings including absence of heterologous elements, periglandular condensation of the stromal cells and invasion in adenofibromas. We diagnose as adenosarcoma tumors with 2 or more MFs/10HPFs, a mitotic rate that will detect almost all tumors with a malignant potential. Because rare essentially amitotic tumors with marked stromal cellularity, stromal atypia or both have recurred, we also consider tumors with these features low-grade adenosarcomas. Extensive sampling is required to exclude foci exhibiting mitotic activity, marked cellularity, or stromal cell atypia. Benign endometrial polyp . The stroma typically resemble that of the adjacent endometrium or it is less cellular and often sclerotic, but even when cellular it is typically inactive. Bizarre stromal cells may be seen in an otherwise typical endometrial polyp and should not be misinterpreted as cytologic atypia, however, the same atypical ("bizarre") cells may be seen in ASs. If the stromal component is unusually cellular or mitotically active, if its glandular cells differ in appearance from those of the adjacent endometrium, or if periglandular cuffing or intraglandular stromal papillae are present, the diagnosis of AS should be considered. Atypical polypoid adenomyoma when the AS has a prominent smooth muscle component. The predominant stromal component is smooth muscle arranged in fascicles that may be cellular and mitotically active. The glandular component is less cystic and generally more atypical than that of an AS and usually contains prominent numbers of squamous morules that may contain central areas of necrosis. There is absence of intraglandular polypoid projections or periglandular cuffing. Endometrial/ioid stromal sarcoma (ESS). Both entities share a similar appearance of the stromal component, both tumors may have sex cord-like differentiation, and rarely, ESSs may show focal prominent glandular differentiation. However, ESS typically lacks the typical epithelium/stroma relationship seen in AS and unlike ASs, it typically has highly infiltrative borders with extensive invasion and vascular permeation. Polypoid endometriosis may enter in the differential diagnosis of extrauterine lesions. However, this lesion has an appearance similar to that of endometrial polyps or endometrial hyperplasia, but stromal atypia, periglandular cuffing and true intraluminal stromal protrusions are not seen. Embryonal rhabdomyosarcoma. Both tumors occur at a younger age than AS arising in the corpus and share the polypoid gross appearance and the presence of cartilage and rhabdomyoblasts. However, in contrast to embryonal rhabdomyosarcoma, cervical AS has more glands, they often show the characteristic intraluminal polypoid projections and there is a variety of müllerian-type epithelium. Fibrosarcoma, endometrial stromal sarcoma, diffuse adult granulosa cell tumor (in the ovary) or even gastrointestinal stromal tumor (in the peritoneum) when MASO is present. Thorough sampling is very important in these cases. Histogenesis: Uterine ASs arise from the malignant transformation of the endometrial stromal cells, however the histogenesis of ovarian and extrauterine non-ovarian ASs is unknown. It has been postulated that these tumors arise from preexisting endometriosis, as these tumors are more often encountered in regions where endometriosis is common, however, endometriosis is only found in a minority of cases. Possibly, most ovarian ASs arise directly from the surface epithelium and ovarian stroma, while extrauterine extraovarian ASs arise from pluripotential mesothelial and mesenchymal cells. Behavior: Uterine adenosarcomas present with vaginal or abdominopelvic recurrence in approximately 1/4 of cases, while hematogenous spread occurs in less than 5%. Even in clinically malignant cases, the recurrent tumor is commonly indolent. The tumors often recur 5 or more years after hysterectomy. In the ovary, extraovarian spread and high-grade of the tumor are associated with higher rates of recurrence, and even so, recurrence was seen in 63% of stage I low-grade tumors in the largest series of ovarian ASs. In that study it was concluded that age <53, tumor rupture and high-grade might appeared to be associated with recurrence, especially in stage I tumors and overall these tumors have a poorer prognosis than uterine ASs with early recurrences and a 5-, 10-, and 15-year survival of 64%, 46% and 30% respectively. Experience with extrauterine extraovarian ASs is limited, however, a 60% recurrence rate (early recurrence) and a 33% frequency of hematogenous spread have been reported, and patients die from their tumors despite adjuvant therapy. The recurrent tumor is a pure sarcoma in the majority of cases, an AS in almost 30% and rarely as carcinosarcoma and blood-borne metastases have been pure sarcomas. The risk of recurrence in UTERINE AS correlates with the presence of myometrial invasion. MASO correlates with an increased recurrence risk in UTERINE AND EXTRAUTERINE ASs, having a behavior similar to that of other high-grade sarcomas. 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