Immunohistochemical markers and the clinical course of adenosarcoma: a series of seven cases

Adenosarcomas are tumors of low malignant potential, consisting of benign epithelial and malignant mesenchymal components. They are a rare subtype of uterine tumor, which represents less than 0.5% of uterine malignancies [1]. The median age at diagnosis is in the 50s, typically in postmenopausal women, but also occurs in adolescents to seniors, with age ranging from 13 to 94 years [2].

As they are rare, the pathology and immunohistochemical staining methods used for diagnosis and prognostic prediction are limited. Pathologically, some cases accompanied with sarcomatous overgrowth, deep myometrial invasion, extrauterine invasion, and/or heterogenous element, have poor prognoses [3‐6]. Similar to an endometrial stromal sarcoma, immunohistochemical staining of the sarcoma components are highly positive for CD10, WT1, estrogen receptor (ER), and progesterone receptor (PR). In cases of sarcomatous overgrowth, the expression of these markers generally decreases, reflecting the dedifferentiation of the mesenchymal component [7, 8]. TP53 pathway alterations are frequently found in high-grade adenosarcomas, resulting in nuclear atypia and severe pleomorphism identifiable at low-power magnification. Moreover, the p53 protein expression, detected by immunohistochemistry, is highly correlated with the mutation status. High-grade adenosarcomas with p53 protein overexpression harboring a TP53 missense mutation or complete absence of expression harboring a TP53 nonsense mutation are aggressive tumors with short-interval recurrences and metastases, regardless of sarcomatous overgrowth [9]. Genetic alterations in the Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex components, such as SMARCA4 [10] and BCOR [11, 12], are recently reported in young high-grade uterine sarcomas, but their relationship with adenosarcomas remains unknown. We reviewed the pathology and immunohistochemical features of seven adenosarcoma cases and investigated the relevance of the histomorphological features to the clinical course. In addition, we compared the immunohistochemical features of primary and recurrent tumors; to the best of our knowledge, our study is the first to make this comparison.

All seven patients aged 40 years-old at diagnosis and six of them were menopausal. All patients presented with polypoid tumors and abnormal bleeding, and had FIGO stage I disease with myometrium invasion. Four patients experienced recurrence and had sarcomatous overgrowth, with negative ER and PR; three patients had high MIB-1 proliferation ratio and p53overexpression. Three patients had recurrences in distant sites and biopsied tissues were pure sarcoma with the same immunohistochemical staining patterns as the primary tumor; in one case p53 expression became significantly stronger in the recurrent tumor compared with the primary. Two patients with recurrence were not adapted for surgery, progressed rapidly, and died 1–2 months after recurrence.

Adenosarcoma was initially described by Clement and Scully in 1974 [13], who described the tumor as an “admixture of a sarcomatous stromal element resembling endometrial stromal sarcomas of various types and grades and a benign, but often atypical, epithelial component.” The sarcomatous component is usually a low-grade uterine sarcoma, mostly endometrial stromal sarcoma, and the epithelium is often endometrium-like cells. Mixed tumors of epithelial and mesenchymal components are diagnosed as adenofibroma, adenosarcoma, and carcinosarcoma according to whether each component is benign or malignant. When the sarcomatous component occupies more than 25% of the tumor, it is defined as sarcomatous overgrowth.

Adenosarcomas arise mainly from endometrial lesions (85%), with others arising from the cervix, or being extrauterine (e.g., ovary, peritoneum, vagina) [1]. A mass protruding from the external os and occupying the uterine cavity and abnormal vaginal bleeding are the most common symptoms.

Only 3.1% and 2.5% of patients had nodal and/or distant metastases at diagnosis and stage 1 cancer without sarcomatous overgrowth have a good prognosis, which is defined as 5-year overall survival rate of 80% [1]. However, the following pathological findings are reported to be poor prognostic factors: sarcomatous overgrowth, myometrial invasion, lymphatic and/or vascular invasion, heterologous elements of the sarcomatous component (rhabdomyosarcomatous differentiation), extrauterine spread, and an extrauterine origin [3‐6]. Recurrence intervals were 0.5–9.5 years after primary surgery. Approximately half of the recurrent tumors were pure sarcomas while the others were adenosarcomas. Most of the recurrent tumors were typically less well-differentiated than the primary tumors, having non-specific spindle-cell sarcomas, with higher mitotic rates [2].

Our patients’ ages at diagnosis and presentation of polypoid tumor with abnormal bleeding were typical for the clinical course of adenosarcomas. Most recurrences of adenosarcomas occur locally, such as in the vagina and pelvis, and distant metastases are described in approximately 5% of cases [2]. Our patients had hematogenous recurrence in distant sites; nevertheless, they were all primarily in the early stage. Pathologically, all four patients with recurrent tumors showed high-grade sarcoma features, such as marked nuclear atypia, coarse chromatin, prominent nucleoli, pleomorphism, weak leaf-like structures, and sarcomatous overgrowth. Immunohistochemical staining showed negative results for ER and PR, high MIB-1 proliferation, and three patients p53 was overexpressed. Taken together, these findings suggested that the four patients with recurrent adenosarcomas had sarcoma components with high-grade malignant potential at the onset.

Pathological diagnosis of adenosarcomas is based on the histomorphological observation of the tissue specimens with hematoxylin and eosin staining. As the morphological analyses of adenosarcomas do not always meet typical findings, immunohistochemical tests have also been used. The most common immunohistochemical markers for the sarcomatous component of adenosarcomas are CD10 (71–100%), WT1 (79%), and vimentin (86%) [7, 8]. CD10 positivity has been found to be lower in patients with sarcomatous overgrowth [14]. Other markers for adenosarcomas are SMA (50–68%), desmin (32–62.5%), CD34 (35%), and cytokeratin (25–27%). In our study, the primary tumors positive for CD10, SMA, desmin, CD34, and cytokeratin were 60% (3/5), 33% (1/3), 40% (2/5), 50% (1/2), and 0% (0/3), respectively.

Adenosarcomas frequently expresses hormone receptors (ER, PR, and androgen receptors) similar to endometrial stromal cells or tumors. However, adenosarcomas with sarcomatous overgrowth lose expression of the hormone receptors, reflecting the nature of dedifferentiation [7, 8, 15]. Tasaka et al. [16] reported an adenosarcoma case arising from endometriosis. The primary tumors were positive for ER and PR, without sarcomatous overgrowth; however, the tumors’ regrowth revealed sarcomatous overgrowth with reduced expression levels of the hormone receptors. Estrogen stimulation by, for example, tamoxifen [17], pre-existing Stein-Leventhal syndrome [2], or ovarian thecoma [18], may play a role in the development of adenosarcoma. There are few cases reporting on hormone therapy [19, 20]; however, whether hormone receptors are prognostic factors for response to hormone therapy has not been determined yet.

TP53 is a well-known tumor suppressor gene, and the p53 protein expression measured by immunohistochemistry is highly correlated with the mutation status. In normal cells, p53 protein stains weakly in a heterogeneous fashion (wild-type). In constrast, in p53-mutated cells, p53 stains strongly in a homogenous fashion (overexpression) or is completely lost (null pattern). TP53 mutations have been reported only in a small fraction of adenosarcomas. Recently, Hodgson et al. [9], performed comprehensive genomic analysis targeting exons of 409 oncogenes and tumor suppressor genes of nine high-grade adenosarcomas. High-grade adenosarcomas are frequently associated with TP53 pathway alterations, identified in 7/9 (78%) cases. High-grade adenosarcoma with p53 protein overexpression might be aggressive with short-interval recurrences and metastases, regardless of sarcomatous overgrowth.

In our study, three recurrent patients showed p53overexpression in the primary tumors; One patient showed a wild-type expression pattern in the primary tumor, which became overexpressed at recurrence. Patients with recurrence had poor prognoses, consistent with previous reports. Whether expression of p53 changes at recurrence remains unclear.

We also performed SMARCA4 staining, for which none of our case showed a loss of expression. Loss of SMARCA4 by immunohistochemistry indicates biallelic inactivation of the SMARCA4 genes [21]. The SMARCA4 gene is one of the tumor suppressor genes that encode the BRG1 protein, a subunit of the SWI/SNF complex. SMARCA4 loss leads to extremely aggressive malignancy in young patients, such as ovarian small cell carcinomas of the hypercalcemic type [22] and thoracic sarcoma [23]. Recent genomic studies have identified loss of SMARCA4 in undifferentiated uterine sarcomas and dedifferentiated carcinomas of the endometrium or ovary [10, 24]. However, there have been no reports showing an association between adenosarcomas and SMARCA4 loss. In this research, the positive immunostaining results for SMARCA4 suggested that its inactivation was not associated with tumorigenesis of adenosarcoma.

BCOR is another SWI/SNF component gene that might affect high-grade sarcomas in young patients, such as clear cell sarcomas of kidney. Marino-Enriquez et al. [12] reported cases of patients aged 18–32 years with three high-grade sarcomas with BCOR, regarded as a unique subtype, possibly within the family of endometrial stromal neoplasia. Muthukumarana et al. [11] performed BCOR immunohistochemistry for 13 adenosarcomas and reported that nine cases expressed BCOR regardless of sarcomatous overgrowth. However, only one of these BCOR-positive cases harbored a BCOR gene rearrangement as determined by fluorescent in situ hybridization. In our research, one patient was positive for BCOR; however, further analysis of BCOR rearrangements should be performed in adenosarcomas that demonstrate BCOR expression.

The small study sample and the fact that it was obtained from only one institute was a limitation of this study. More multicenter cases and further molecular biology studies are awaited.