Uterine papillary serous carcinoma (UPSC) is an uncommon form of endometrial cancer that typically arises in postmenopausal women. UPSC is staged like other forms of endometrial carcinoma at time of surgery using the FIGO cancer staging system. In case of infiltration of serosa or adnexa and / or tumor cells into ascites or peritoneal lavage, the carcinoma is classified as stage 3A. The tumor spread in the vagina and/or parametrium (direct extension or metastases) is staged as stage 3B according to the modified FIGO classification on 1/1/2010 and “Pathologic TNM staging of carcinoma and carcinosarcoma of the corpus uteri, AJCC 8th edition and FIGO 2018 update“[4,5]. For patients who undergo surgical staging—consisting of open abdominal exploration, hysterectomy, bilateral adnexal removal, and pelvic and para-aortic lymphadenectomy in the modified FIGO classification, peritoneal lavage cytology is no longer considered in tumor staging. In the presented clinical case, despite the metastases in the ovaries, the tumor is stage 3B.

Pathohistological characteristics of serous carcinoma adenocarcinoma: Complex papillary, solid or glandular architecture; The architecture is papillary with or without appreciable fibrovascular cores; slit-like spaces; gland-like spaces may be observed (but luminal borders are not sharp as seen in endometrioid carcinoma); solid growth. Psammoma bodies may be present in up to 33% of cases. Cytoplasm is usually scant but can be abundant with eosinophilia or clearing. Nuclei are typically high grade with pleomorphism, hyperchromasia, prominent nucleoli and frequent mitotic figures (including atypical mitotic figures) [6-8]. Most type II endometrial carcinomas, especially UPSC, have a complex papillary or glandular architecture, which is similar to serous papillary ovarian carcinomas. In general, densely fibrotic papillae fronds and slit-like spaces are common [1] [Figure 2,3]. Huge, round, undifferentiated tumor cells with a high number of mitotic figures, increased nuclear-to-cytoplasmic ratios, and prominent nuclear atypia are detached and present in the blank spaces. Hobnail cells, clear cells, and polygonal cells are frequently observed. Cilia are also observed in some cases, as in papillary serous ovarian carcinomas [9,10]. Serous carcinoma cells are arranged in true papillae lined with many cells with overlapping nuclei; cells are large, better preserved and with indistinct cell borders; nuclear chromatin is coarse with large prominent nucleoli [11] (Figure 2, Figure 3).

Immunohistochemical stains in papillary serous endometrial carcinoma show that the tumor is positive for p53 (strong and diffuse expression, mutated) and p16 (strong and diffuse expression) (Figure 4), focally positive for ER (Figure 5C) and negative for PR [6]. In the presented case all tumors (in the different parts of the genital tract) demonstrated diffuse/moderate-strong p16 expression (Figure 4), with percentage of positive tumor cells ranging from 90% to 100%. In contrast, endometrial endometrioid carcinomas exhibit less diffuse and less intense expression, with percentage of positive tumor cells ranging from 10% to 90% [12]. In endometrial endometrioid carcinoma, ER and PR are strongly positive; p53 and p16 are weak and patchy [6]. Highly expressed EMA by most adenocarcinomas is associated with poor prognosis [13,14].

Differential diagnosis (DD): Non-endometrioid carcinomas, which account for about 10% of endometrial carcinomas, may pose a great array of problems in differential diagnosis, including their distinction not only from benign lesions but also from endometrioid carcinoma and various tumors that may secondarily involve the uterine corpus [15]. The complex papillary architecture of serous uterine carcinoma causes a number of diagnostic difficulties. The differential diagnosis includes Villoglandular Variant Of Endometrial Carcinoma.   Papillary endometrioid or villoglandular adenocarcinoma (VGAC) is a relatively common type of well-differentiated endometrial adenocarcinoma [16,17]. VGAC is characterized by a papillary architecture with delicate fibrovascular stalks lined by cuboidal to columnar cells with minimal cellular stratification and mild nuclear pleomorphism [16]. VGAC only superficially invades the myometrium, being diagnosed at an early stage and thereby having a better prognosis than typical endometrioid carcinoma. To avoid confusion with papillary serous carcinoma, some authors refer to this entity as endometrioid adenocarcinoma with papillary architecture(16). In mixed endometrial adenocarcinomas the tumor has microscopic features intermediate between serous and endometrioid; for example, papillary architecture typical of serous but without classical cytologic features or glandular architecture with epithelial features suggestive of serous (11). Villoglandular Cervical Adenocarcinoma (VGCA) is a rare well-differentiated subtype of endocervical mucinous adenocarcinoma that usually occurs in young women in early clinical stage I-II [18-24]. VGCA is associated with a better prognosis than other adenocarcinomas [18-20,23,25-27] аnd accounts for 5% of cervical adenocarcinomas [28,29]. It is characterized as superficially infiltrative and shows infrequent lymph node invasion and lymphovascular space invasion [30,31]. Serous Carcinoma of the Uterine Cervix (SCUC) is a very rare malignant tumor, while this histological subtype is common in the ovary, fallopian tube, uterine corpus and peritoneum. Because of its rarity, details of the clinicopathological features of SCUC are largely unknown [32]. SCUC has a complex papillary pattern with epithelial stratification. The tumor is characterized by >10 mitotic figures per 10 high-power fields. An intense acute and chronic inflammatory infiltrate is typically present within the cores of the papillae and in areas of stromal invasion [33]. Pleomorphic and macronucleated atypical cells are observed [32]. Occasional psammoma bodies are present, like in the presented clinical case (Figure 1). The tumor cells in SCUC are positive for p16, focally positive for p53 and ER, and negative for progesteron receptor. Age <65 years, stage >I, tumor size >2 cm, tumor invasion >10 mm, the presence of lymph node metastases, and elevation of serum CA-125 were associated with a poor prognosis [33].

Important for the DD between endometrial and endocervical carcinoma is the study which notes that p16 reactivity is mainly limited to areas with endometrioid or nonspecific cell type differentiation and does not occur in areas with normal endocervical mucinous morphology [34]. It is important to recognize special variants such as uterine serous carcinoma and clear cell carcinoma, as these can show extensive staining for p16 [34].  Univariate analysis on the training set identified 6 markers—p16, ProExC, ER, PR, vimentin, and HPV ISH—as performing well in distinguishing between endocervical and endometrial origin. Positive results for vimentin, ER, and PR support endometrial origin whereas p16, ProExC, and HPV ISH support endocervical origin [34,35]. Primary endocervical adenocarcinomas are characterized by CEA positivity, which is usually, but not always diffuse, negativity for vimentin, and negativity or focal weak positivity for ER [35]. Similar to serous carcinomas, all endocervical adenocarcinomas exhibited diffuse/moderate-strong p16 expression, with percentage of positive tumor cells ranging from 90% to 100% [12]. In the distinction between a high-risk HPV-related (usual type) endocervical adenocarcinoma and a low-grade endometrial endometrioid adenocarcinoma, the most useful immunohistochemical markers are p16 and ER and PR hormone receptors [36]. Given the limits of immunohistochemical stains in distinguishing between endocervical and endometrial origin, individual cases should be evaluated in the context of standard clinical, radiographic, gross, and morphologic findings [34]. In the presented clinical case, DD is required between synchronous serous adenocarcinomas, i.e. primary endometrial with infiltration in the uterine cervix and primary tubo-ovarian carcinoma, or serous endometrial carcinoma with metastases in both ovaries. Multifocal tumor distribution is relatively common in carcinomas arising in the female genital tract. Accurate designation of tumor origin is not always straightforward but is important for staging, prognosis and management [36]. In the context of endometrial carcinoma, the most common dilemmas occur in the setting of concurrent endometrial and adnexal/peritoneal high-grade serous adenocarcinoma [3]. High grade serous tubo-ovarian adenocarcinomas are characterized by complex papillary, solid or glandular architecture [6]; Significant nuclear atypia; significant nuclear pleomorphism (>3 x variation in size) with large, bizarre and multinucleated forms [37]. Prominent nucleoli, often large and eosinophilic; High mitotic index: ≥ 12 mitotic figures per 10 high power fields, often atypical; Necrosis is frequent [13]. Positive stains: p16 (~60%), ER (80%), PR (30%), high Ki67 proliferation index (> 75%) [38]. Usually they present as unilateral tubo-ovarian tumor in 80-90% of cases, no tumor infiltration on the surface of the ovary; without invasion into the lumen of the tube; without vascular invasion - 71.4%; without or presence of ovarian endometriosis [39,40]. IHC analysis of ER and PR of endometrioid endometrial and ovarian tumors distinguishes primary tumor synchronicity from hematogenous metastasis. The same levels of ER and PR are found in metastatic endometrial or ovarian cancer (Figure 5C,5D) and different in synchronous primary endometrial and ovarian neoplasms [41,42]. One general principle used in determining tumor origin in pathology is the identification of  intraepithelial carcinoma because the presence of such a lesion is considered a strong evidence of tumor development at a particular anatomic site. Occasionally metastases can colonize preexisting mucosal structures and replace the native epithelium, for example, endometrial serous adenocarcinoma may involve the mucosa of the fallopian tube and closely mimic serous tubal intraepithelial carcinoma [3]. Simultaneous endometrioid carcinomas of the uterus and of the fallopian tube are unusual and occur primarily in obese perimenopausal women. These tumors are predominantly well or moderately differentiated with dissimilar endometrial and fallopian tube grades. The carcinoma of the fallopian tube  is usually unilateral and located at the distal end of the tube [36]. It is well established that high-grade endometrial carcinomas may present with metastases even when there is minimal myometrial invasion [3].

Conclusions from the IHC panel of the presented clinical case: 1/The positive expression of ER and PR receptors in the tumor cells of the tumor in the cervix proves the primary endometrial origin of the carcinoma with infiltration of the cervical canal (Figure 5A,5B,5D,5E). 2/ Diffuse positive expression of p16 in the tumor cells of the endometrial tumor mass and in the cervical tumor is typical for serous carcinomas (Figure 4). 3 / Positive expression for Vimentin in the tumor cells in the cervical and the ovarian tumors is typical for primary endometrial carcinoma, negative - is observed in primary viloglandular endocervical adenocarcinoma and primary endometrioid ovarian carcinomas. The positive expression of Vimentin in both tumors of the cervix and the ovary proves the local growth of serous endometrial carcinoma to the cervix with bilateral metastases in the ovaries (Figure 6). 4/ IHC analysis of ER and PR of the endometrial and the ovarian tumors distinguishes primary tumor synchronicity from hematogenous metastasis. The same levels of ER and PR in the endometrial and ovarian tumors report bilateral metastatic tumor spread in the ovaries (Figure 5). 5/ Positive EMA expression in cervical tumor cells determines a poor prognosis (Figure 7). 6/ Psammoma bodies are observed on histological examination of the tumors of the cervix, uterine body, fallopian tube (Figure 1,3A,3B,5A,5B). They are typical for malignancies such as serous carcinoma of the ovaries and serous carcinomas of the cervix, endometrium, fallopian tube, peritoneum [43].

By the above immunohistochemical characteristics primary locally advanced serous endometrial carcinoma/ III B class stage is evidenced. Despite the initial tumor infiltration in the myometrium, as well as the superficial invasion of the cervix in the presented clinical case, the typical tumor spread of locally advanced serous carcinoma with unilateral infiltration into the right fallopian tube and left parametrium and bilateral ovarian metastases are observed.