Dedifferentiated endometrioid carcinoma of the uterus : report of four cases and review of literature

Background: Dedifferentiated endometrioid adenocarcinoma (DEAC) is rare and is known to be more aggressive than high-grade endometrioid carcinoma. Differentiating between the two is important to provide appropriate treatment for patients. Case presentation: This is a retrospective study including four cases of DEAC of the uterus, which was diagnosed and treated in our Obstetrics and Gynecology department between January 2013 and December 2015. Clinical, pathological, and immunohistochemical staining features are discussed. Each tumor was composed of undifferentiated carcinoma (UC) and low-grade endometrioid carcinoma with abrupt transition between them. Two patients showed recurrence or progression within one month postoperatively and died at the last follow-up. An immunohistochemical study showed PAX-8, ER, PR, and E-cadherin expression in UC component.

DEAC should not be underdiagnosed as conventional endometrioid adenocarcinoma due to its fulminant clinical course. Therefore, UC, including DEAC, should be further categorized to provide intensive treatment to improve patient survival.

Dedifferentiated endometrioid carcinoma, Undifferentiated carcinoma, Endometrioid carcinoma

Endometrial carcinoma is the most common gynecologic malignancy in developed countries [1]. It comprises several pathological subtypes, such as endometrioid, mucinous, clear cell, mixed cell, undifferentiated, and dedifferentiated carcinoma[2]. The last two entities are recently defined to distinguish them from other less aggressive tumors, there- fore, providing proper treatment for patients. Undifferentiated carcinoma (UC) of the endometrium is defined as a malignant neoplasm with no differentiation. It displays solid patternless growth and has worse clinical outcome than high-grade endometrioid adenocarcinoma. It is often observed admixed with differentiated endome- trioid carcinoma (grade 1/2), which is referred to as dedif- ferentiated endometrioid adenocarcinoma (DEAC). The biologic features of DEAC are known to be determined by UC component even when this component represents 20% of the entire neoplasms, thus, with aggressive outcome [3]. In the current International Federation of Obstetrics and Gynecology (FIGO) grading system of endometrioid adenocarcinoma, tumors are graded by the proportion of solid components within a tumor, without further details on the histologic features of solid areas, resulting in misdiagnosis of DEAC as FIGO grade 2 or 3 endome- trioid carcinoma. However, differentiating between the two is important in providing appropriate treatment options for patients. The present study reports four cases diagnosed with DEAC and reviews the literatures updated on the clinical, radiological, and pathological DEAC characteristics of the uterus. Case presentation This is a retrospective study including four cases of DEAC of the uterus, which was diagnosed and treated in our Obstetrics and Gynecology department between January 2013 and December 2015. During this period, * Correspondence: [email protected] 1Department of Hospital Pathology, Seoul St. Mary ’s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Han et al. World Journal of Surgical Oncology (2017) 15:17 DOI 10.1186/s12957-016-1093-0 155 cases of endometrial carcinoma were initially diag- nosed and of which four patients (2.6%) were diagnosed with DEAC in our hospital. Clinical, pathological, and immunohistochemical staining features are outlined below and in Table 1, Table 2, and Table 3. Case 1 A 77-year-old woman (body mass index [BMI], 19.6 kg/m 2) presented with 1 week postmenopausal bleeding, which was preceded by vaginal spotting for 1 year and concomitant genital itching that had continued for 2 weeks. Transvaginal ultrasound re- vealed abnormally thickened endometrium (1.47 cm) and biopsy was recommended, but she refused. After 2 weeks, follow-up ultrasonography showed remark- ably increased endometrium thickness (2.36 cm) with a 7 cm mixed-echoic lesion within the endometrial cavity. Endometrial curettage revealed poorly differen- tiated carcinoma. Magnetic resonance imaging (MRI) showed 8.6 × 3.7 cm heterogeneously enhanced mass on contrast-enhanced T1-weighted images (CET1WI) (Fig. 1a). In addition, tumor involvement of the cer- vical stroma was observed on CET1WI. The patient subsequently underwent total hysterectomy (TH) with bilateral salpingo-oophorectomy (BSO) and pelvic lymphadenectomy. The surgical specimen of the uterus showed white gray polypoid mass filling the endometrial cavity (Fig. 1b). Upon microscopic exam- ination, the tumor with high cellularity and pattern- less growth without glandular differentiation invaded the full thickness of the lower uterine segment (Fig. 1c) extending to the cervical stroma. The tumor consisted of medium –sized monotonous cells with brisk mitosis (5 per high-power field (HPF)) and atyp- ical mitotic figures (Fig. 1d). Moderately differentiated endometrioid adenocarcinoma component with squa- mous differentiation comprised the major proportion of the tumor mass of the uterine body and fundus, which invaded more than one half of the myometrial thickness. No lymph node (LN) metastasis was found. Cytokeratin 8/18 (CK8/18) and pancytokeratin (CK AE1/AE3) expressed both components but in different patterns. In the UC component, they were expressed as dot-like patterns, whereas they showed cytoplasmic ex- pression in differentiated component (Figs. 1e, f ). Epithe- lial membrane antigen (EMA), estrogen receptor (ER), progesterone receptor (PR), E-cadherin, and PAX-8 were expressed in the differentiated component alone (T able 2). Based on the FIGO system, the patient had stage II. She was recommended adjuvant external beam pelvic RT (EBRT), but she refused. A month after the surgery, she presented with difficulty in urination. Abdominal pelvic computed tomography (CT) revealed multiple, large, peritoneal seeding masses, and multiple lymph node metastases in the external and internal iliac chains with large amount of ascites which was positive for malignant cells on cytologic examination. She died 7 weeks later after surgery due to tumor lysis syndrome. Case 2 A 54-year-old postmenopausal woman (BMI: 22.5 kg/m 2) was referred to our hospital after being diagnosed with endometrioid carcinoma FIGO grade 3 on biopsy at a local hospital. She experienced vaginal bleeding for 3 months. She had menopause at 51 year old hypertension history. MRI showed a 5.0 × 3.6 cm lobulated mass filling the endometrial cavity, which showed slightly high signal intensity (SI) on T2-weighted imaging (T2WI) and showed poor enhancement compared with the adjacent myometrium (Fig. 2a). Mildly enlarged pelvic LNs were noted in both external iliac areas. TH with BSO, pelvic lymphadenectomy, and para-aortic lymphadenectomy were performed. The mass was bulky and filled the entire endometrial cavity on gross examination (Fig. 2b). Micro- scopically, well-differentiated endometrioid adenocarcin- oma and UC with abrupt transition were found between them (Fig. 2c). The UC component showed a solid mono- morphic discohesive cell growth, showing no differenti- ation except for the presence of some rhabdoid cells (Fig. 2d). The invasion depth was less than one half of the myometrium, and LN metastasis was not observed. CK8/ 18, CK AE1/AE3, and EMA showed diffuse cytoplasmic expression in both components, and perinuclear cytokera- tin dots were also observed in the UC component. The ER, PR, E-cadherin, and PAX-8 expressions were recog- nized in the differentiated component alone (T able 2). The final FIGO stage was IA, and adjuvant treatment was not performed. The patient has been disease-free for 19 months after the initial diagnosis. Case 3 A 60-year-old postmenopausal woman (BMI: 25.3 kg/m 2) with a chief complaint of vaginal spotting for 1 year visited a local gynecologic clinic. She had menopause at 52 years old. Colposcopy showed necrotic tissue with bleeding at the right vaginal wall, and she was referred to our hospital for further evaluation. Ultrasonography showed an echo- genic mass in the endometrial cavity. The MRI revealed a 7.2 × 3.5 cm lobulated mass extending to the right above the endocervix (Fig 3a). The mass showed high SI on T2WI and low SI on T1WI with heterogeneous enhance- ment. Another 5 cm, elongated mass involving the lower vagina was also found. Vaginal biopsy revealed poorly dif- ferentiated carcinoma, and cytologic test of the endocervix revealed adenocarcinoma. The patient underwent wide cuff TH with BSO, and the separated additional vaginal mass was not removed. The surgical specimen showed a polypoid mass with necrosis and hemorrhage, which Han et al. World Journal of Surgical Oncology (2017) 15:17 Page 2 of 9 invaded more than one half of the myometrium of the uterus (Fig. 3b), extending to the cervix. Most of the tumor comprised discohesive cell growth with a solid sheet pattern on microscopic examination, suggesting a UC component. They were occasionally segregated by delicate fibrovascular septa forming a vague alveolar pat- tern (Fig. 3c). The UC component showed small amount of myxochondroid stroma, reminiscent of cartilage (Fig. 3d). A small proportion (10%) of tumor consisted of low-grade endometrioid adenocarcinoma juxtaposed with UC component. The histological finding of the UC com- ponent was similar to that of the lesion in the vaginal wall, suggesting vaginal metastasis (drop metastasis). ER and PR were not expressed in both UC and differentiated Table 1 Clinical and pathologic features of four patients with dedifferentiated endometrioid adenocarcinoma (DEAC) of uterus Case 1 Case 2 Case 3 Case 4 Clinical features Age at diagnosis, years 77 54 60 52 Age at menopause, years 60 51 52 Not applicable Presentation Postmenopausal bleeding Postmenopausal bleeding Postmenopausal spotting Perimenopausal bleeding Initial diagnosis Poorly differentiated carcinoma Endometrioid adenocarcinoma, FIGO grade 3 Pap smear: adenocarcinoma vaginal biopsy: poorly differentiated carcinoma Leiomyoma Imaging findings MRI: 8.6 × 3.7 cm sized heterogeneously enhanced mass on CET1WI with involvement of the cervical stroma MRI: 5.0 × 3.6 cm sized lobulated mass filling endometrial cavity with slightly high SI in T2WI and poor enhancement than adjacent myometrium MRI: 7.2 × 3.5 cm sized lobulated mass which showed high SI on T2WI and low SI on T1WI with heterogeneous enhancement CT: 10 cm sized low density mass in the endometrial cavity and cervical canal Surgical management TH/BSO/PLND TH/BSO/PLND/PALND Wide cuff TH/BSO TH/BSO/PLND/PALND Operative findings Cancer extension to cervix Invasion to superficial myometrium Cancer extension to cervix and vaginal wall extension Necrotic mass filling endometrial cavity with protruding through cervical canal Postoperative management Refused Not needed Chemotherapy (CDDP + ADR + CTX) and EBRT(50 Gy) + ICR(20 Gy/4fx) EBRT(50 Gy) + ICR(20 Gy/4fx) First postoperative recurrence or progression 1 month None 1 month None FIGO surgical stage II IA IIIB II Clinical history Hypertension Hypertension Hypertension None Family history None None Gastric cancer (mother) None Status at last follow-up DOD (7 weeks) NED (19 months) DOD (10 months) NED (39 months) Pathologic features Tumor location Fundus, body, lower uterine segment, cervix Body Body, lower uterine segments Body, lower uterine segment Tumor grade G2 (80%) + UC (20%) G1 (70%) + UC (30%) G1 (10%) + UC (90%) G2 (40%) + UC (60%) Myometrial invasion Full thickness of myometrium <1/2 of myometrium 1/2 of myometrium Lymphovascular space invasion (LSI) Present Present Present Present Cervical stromal invasion Present Absent Present Present Ovaries and fallopian tubes Unremarkable Unremarkable Unremarkable Unremarkable CET1WI contrast-enhanced T1-weighted image; SI signal intensity; T2WI T2-weighted image; T1WI T1-weighted image; TH total hysterectomy; BSO bilateral salpingo-oophorectomy; PLND pelvic lymph node dissection; PALND para-aortic lymph node dissection; EBRT external beam radiation therapy; ICR intracavitary radiation; DOD die of disease; NED no evidence of disease; UC undifferentiated carcinoma; G1 FIGO grade 1 endometrioid adenocarcinoma; G2 FIGO grade 2 endometrioid adenocarcinoma; CDDP cisplatin; ADR adriamycin; PTX paclitaxel; CTX cyclophosphamide Han et al. World Journal of Surgical Oncology (2017) 15:17 Page 3 of 9 component on immunohistochemical staining (T able 2). One month after the surgery, postoperative positron emis- sion tomography-CT revealed multiple metastatic lymph- adenopathies in para-aortic, retrocaval, paracaval, both common and external iliac chains, and superficial inguinal areas with bone metastasis. The patients was treated with sequential chemoradiation therapy, which comprised of chemotherapy (cisplatin + Adriamycin + cyclophospha- mide) followed by EBRT, with a total dose of 50 Gy was administered for 5 weeks to the whole pelvis, vagina, and both inguinal lymph nodes, and high-dose intracavitary radiotherapy (ICR) (20 Gy in fractions). She presented with dyspnea 2 months after radiation therapy, and clinical examination revealed lung metastasis. She died 3 weeks later (10 months after surgery). Case 4 A 52-year-old nulligravid, perimenopausal woman (BMI 22.4 kg/m 2) was admitted to our hospital for treatment of leiomyoma, manifested as 10 cm low-density mass in the endometrial cavity and cervical canal on pelvic CT at a local clinic (Fig. 4a). She experienced intermittent vagi- nal bleeding 3 years prior. During surgery, the surgeon observed a 10 cm necrotic mass protruding through the cervical canal, which seemed to fill the entire endomet- rial cavity. Frozen section revealed malignancy. Surgical s t a g ew a sF I G Os t a g eI I ,d u et oc e r v i c a ls t r o m a li n v a s i o n . Any enlarged lymph node was not recognized. Hence, the patient was treated with bilateral salpingectomy with pelvic and para-aortic lymph node dissection. The fungating mass filling the entire endometrial cavity was recognized on gross examination (Fig. 4b). The tumor comprised of conven- tional endometrioid adenocarcinoma (FIGO grade 2) and UC with sharp border between them (Fig. 4c). CK8/18, CK AE1/AE3, and EMA were expressed focally as dot-like and c y t o p l a s m i cp a t t e r ni nU Cc o m p o n e n t( F i g .4 d ) .P A X - 8w a s diffusely expressed in both co mponents (T able 2). The pa- tient was treated with adjuvant EBRT in the whole pelvis with a total dose of 50 Gy in 28 fractions followed by vagi- nal cylinder ICR (20 Gy/4 fractions). No evidence of recur- rence or progression of disease was found after 39 months after surgery.

Because DEAC has been recently recognized, the inci- dence rate is not established. The incidence of undiffer- entiated carcinoma is known to be 1 to 9% [4, 5]. In several retrospective studies, 37 to 87% of UC were admixed with endometrioid adenocarcinoma [3, 5, 6]. In our institution, 2.6% of patients (four out of 155 pa- tients) with endometrial carcinoma were diagnosed with DEAC between 2013 and 2015. A dualistic model, proposed by Bokhman [7] based on clinical and epidemiological observations, has been known to be correlated with endometrial carcinoma classification based on histopathological subtypes. Pre- dominant form of type 1 endometrial carcinoma is low- grade endometrioid adenocarcinoma, whereas type II encompasses high-grade endometrioid adenocarcinoma, and most non-endometrioid histologic subtypes. How- ever, increasing evidence supports that the binary classi- fication is imperfect [8], and DEAC may be one of the representative entities. Type I tumors are known to be associated with unopposed estrogen stimulation, whereas type II tumors are commonly described as es- trogen independent. The established risk factors for type Table 2 Results of immunohistochemical stains of the four cases IHC stain Case 1 Case 2 Case 3 Case 4 UC DC UC DC UC DC UC DC CK 8/18 Diffuse, perinuclear dot-like Diffuse, cytoplasmic Diffuse, perinuclear dot-like, and cytoplasmic Diffuse, cytoplasmic Negative Diffuse, cytoplasmic Focal, perinuclear dot-like, and cytoplasmic Diffuse, cytoplasmic Pancytokeratin Diffuse, perinuclear dot-like Diffuse, cytoplasmic Diffuse, perinuclear dot-like < cytoplasmic Diffuse, cytoplasmic Focal, perinuclear dot-like < cytoplasmic Diffuse, cytoplasmic Focal, perinuclear dot-like < cytoplasmic Diffuse, cytoplasmic EMA Negative Diffuse, cytoplasmic Diffuse, perinuclear dot-like, and cytoplasmic Diffuse, cytoplasmic Focal, perinuclear dot-like, and cytoplasmic Diffuse, cytoplasmic Focal, perinuclear dot-like, and cytoplasmic Diffuse, cytoplasmic Vimentin Focal Negative Diffuse Diffuse Diffuse Diffuse Diffuse Focal ER Negative Positive Negative Positive Negative Negative Negative Positive PR Negative Positive Negative Positive Negative Negative Negative Positive E-cadherin Negative Diffuse Negative Focal Negative Diffuse, weakly Negative Diffuse PAX-8 Negative Diffuse Negative Diffuse Negative Diffuse Diffuse Diffuse Proportion of tumor cells are >50%, diffuse; 10 ~ 50%, focal; <10%, negative; EMA epithelial membrane antigen; ER estrogen receptor; PR progesterone receptor Han et al. World Journal of Surgical Oncology (2017) 15:17 Page 4 of 9 Table 3 Cases of dedifferentiated endometrioid adenocarcinoma (DEAC) with clinical and pathologic features Author Number of cases Age, years Surgical operation (cases) Stage (cases) Component of tumor Marker expression of UC component Adjuvant treatment (cases) Survival outcome (cases) Silva, EG (2006) [ 3] 25 51 (median) (range: 30–82) TH+ BSO (24) I (14) II (1) III (6) IV (4) Low grade (10 –80%) + UC(20-90%) Keratin (13 out of 15, focal or diffuse) EMA (all) Neuroendocrine marker (4 out of 15) Chemotherapy (18) radiation (4) DOD (15) (median: 7 months) AWPD (6) (6 ~ 8 months) NA(3) Shen, Y (2012) [ 18] 1 51 TH + BSO + PLND II Low grade (80%) + UC(20%) Negative for EMA focally positive for CK7, CK18 Vaginal radiation + chemotherapy (CDDP+ DTX + Taxanes) NA Vita, G (2011) [ 19] 1 45 TH + BSO IIIA Low grade (60%) + UC(40%) Positive for cytokeratins and EMA Chemotherapy (CDDP + ATC + Taxanes) NA Wu, ES (2013) [ 20] 1 62 NA NA NA NA Radiation + hormone therapy (Megace alternating with Tamoxifen) AWPD (3 months) Berretta, R (2013) [ 21] 1 67 NA IV NA Positive for keratin and negative for neuronal markers Chemotherapy (CBDCA + Taxol) NA Park, SY (2014) [ 22] 1 55 TH + USO + PLND IB Low grade (40%) + UC(60%) Focally positive for CK and EMA Chemotherapy (PTX + CDDP+DOXO) DOD (7 months) Li, Z (2016) [ 15] 13 61 (median) NA III/IV (12) NA Pancytokeratin (10 out of 13) Cam5.2 (8 out of 13) EMA (8 out of 13, weak and patchy) PAX-8 (1 out of 13) Chemotherapy and radiation (13) Recurrence or metastasis within 3 years of diagnosis (12) Disease-free after 3 years of diagnosis (1) Soyama, H (2016) [ 23] 1 41 Supravaginal hysterectomy + USO+partial resection of ileum IVB NA NA Chemotherapy alone DOD (7 months) Rabban (2016) [ 24] 1 50 TH + BSO+PLND IA G1(60%) + UC(40%) Negative for EMA, keratin, PAX-8 Untreated Progression after 10 months of surgery TH total hysterectomy; BSO bilateral salpingo-oophorectomy; PLND pelvic lymph node dissection; DOD die of disease; AWPD alive with progressive disease; USO unilateral salpingo-oophorectomy; NA not available; CDDP cisplatin; DTX docetaxel; ATC anthracycline; CBDCA Carboplatin; PTX paclitaxel; DOXO doxorubicin Han et al. World Journal of Surgical Oncology (2017) 15:17 Page 5 of 9 I endometrial carcinomas are obesity, unopposed estro- gen therapy use, nulliparity, early menarche, late meno- pause, oral contraceptive use, and smoking, whereas little is known regarding the risk factors for type II tu- mors. A recent study [9] showed that most classical endometrial cancer risk factors were also associated with type II tumors, suggesting that the etiology of type II tu- mors may not be completely estrogen independent. In the same context, three of four patients of our cases were postmenopausal, older ( ≥54 year old) women, and the other perimenopausal woman was nulliparous. Three patients of our cases had hypertension as underlying dis- ease. Giordano et al. [10] showed that the majority of patients with malignant endometrial polyps had risk fac- tors, such as hypertension, obesity, and unopposed es- trogen therapy, for the development of endometrial carcinoma. Fig. 1 Case 1. (A1) Sagittal contrast-enhanced T1-weighted MRI shows heterogeneously enhanced mass filling the endometrial cavity with cervical stromal invasion. (A2) The tumor shows white infiltrative lesion with necrosis involving lower uterine segment and uterine body, extending to cervix. The UC component (A3, ×2.5) infiltrates the full thickness of the lower uterine segment and arranged in patternless with extensive necrosis and hemorrhage. The tumor (A4,× 4 0 0 ) comprises monotonous cells with moderate pleomorphism, prominent nucleoli, and high mitotic rates. Cytokeratin 8/18 (CK8/18) expressed as perinuclear dots in the UC component (A5, ×400) and showed diffuse cytoplasmic expression in differentiated component (A6,× 2 0 0 ) Fig. 2 Case 2. (B1) Sagittal T2-weighted MRI shows a large polypoid endometrial mass with superficial infiltration of myometrium. (B2)G r o s s photograph shows a polypoid mass compacting the endometrial cavity. Well-circumscribed round mass, submural leiomyoma is seen (arrow). (B3, ×100) The tumor comprises moderately differentiated endometrioid adenocarcinoma and UC with abrupt transition (arrows) between them. (B4, ×400) The UC cell component shows discohesive rhabdoid feature Fig. 3 Case 3. ( C1) Sagittal contrast-enhanced T1-weighted MRI shows a large polypoid mass lesion filling the endometrial cavity. (C2) The tan polypoid mass involving more than one half of the myometrium. (C3, ×200) A delicate fibrovascular septa separating discohesive cells into vague alveolar nests are found. ( C4, ×200) Focal areas of UC component shows myxochondroid stroma with embedded tumor cells, resembling the cartilage Han et al. World Journal of Surgical Oncology (2017) 15:17 Page 6 of 9 In all our cases, DEAC could not be diagnosed on bi- opsy or curettage and imaging studies, but could only be correctly diagnosed by pathological examination of the surgical specimen. Two cases were initially diagnosed as poorly differentiated carcinoma, and one case was diag- nosed as FIGO grade 3 endometrioid adenocarcinoma by endometrial biopsy or curettage. A recent study [11] showed that preoperative endometrial biopsy or curet- tage is sensitive overall for detecting endometrial cancer, but sensitivity decreases with high-risk histology endo- metrial cancer. In addition, interobserver reproducibility in diagnosing high-grade endometrial carcinomas has been known to be worse than that of low-grade tumors [12]. Therefore, if preoperative examination suggests high-grade endometrial carcinomas, the surgeon should proceed to a more thorough surgical staging. To correctly diagnose DEAC, recognizing the UC component is important. Recent studies [5, 13] empha- sized that there is reproducible, distinctive histological features of UC, which are confirmed in all present cases. Although histological findings of UC can overlap with that of high-grade endometrioid adenocarcinoma, differ- ences were found between them. In UC, tumor cells lack intercellular cohesion and arranged in patternless solid sheets without gland formation, which were occasionally admixed with rhabdoid cells. In contrast, high-grade endometrioid adenocarcinoma has at least a foci of gland formation of cohesive cells with rare or no rhab- doid cells. In addition, the tumor cells of UC in our cases also tended to have larger nuclei with more prom- inent nucleoli than conventional endometrioid adenocar- cinoma. When UC are juxtaposed with low-grade endometrioid adenocarcinoma, such as in DEAC, a sharp boundary is noted between them, whereas a seam- less transition from glandular component to solid area is observed in high-grade endometrioid adenocarcinoma. Immunochemical studies are also helpful in making a differential diagnosis. Among the epithelial markers, EMA and CK18 are known to be strongly and diffusely stained in the solid area of high-grade endometrioid car- cinoma, but are focal or weak in the UC component [6]. In the previous case reports, expression of EMA in the UC components showed relatively inconsistency (Table 3), and our cases also showed variable expression of EMA and CK18 (Table 2). However, we found that expression of EMA and CK18 were perinuclear dot-like pattern in UC component, whereas diffuse cytoplasmic pattern in differentiated component in all cases. Rama- lingam et al. [14] suggested PAX-8 to be the most effect- ive immunomarker to distinguish UC from the solid component of either endometrioid carcinoma or serous carcinoma. In the present study, three of 4 cases expressed PAX-8 in the differentiated component alone, whereas the other one also expressed PAX-8 in the UC component. ER, PR, and E-cadherin are known to be retained in conventional endometrioid adenocarcinoma [6, 15, 16], but not in the UC, which were consistent with our cases. Therefore, perinuclear dot-like staining of cyto- keratin and EMA, loss of expression of PAX-8, ER, PR, and E-cadherin would be helpful to distinguish UC from conventional endometrioid adenocarcinoma. Differentiating between them is important because DEACs have fulminant clinical outcomes and poorer prognosis than high-grade endometrioid carcinoma. Sev- eral reports of DEAC cases with clinical feature, are summarized in Table 3. In our cases, the proportion of UC component ranged from 20 to 90% (Table 1), which did not seem to be as- sociated with clinical outcomes. In addition, the involve- ment to the lower uterine segment and cervix occurred in the UC component in all cases. The morphologic appearance of DEACs suggest very broad differential diagnoses, including not only high- grade endometrioid adenocarcinoma, but also unclassi- fied sarcomas, malignant mixed Müllerian tumors (MMMT), and rhabdoid tumor. The UC component in DEAC may be negative or focal positive for keratin in immunohistochemical staining, and it can be misdiagnosed as sarcoma. Most sarcomas in the uterus comprise spindle cells with muscular dif- ferentiation and seldom comprise epithelioid cells only. Immunostaining with markers for muscular differenti- ation, such as desmin, caldesmon, and SMA may help to Fig. 4 Case 4. ( D1) Sagittal contrast-enhanced CT shows a bulky hypodense mass filling the endometrial cavity. (D2) The large outbulging mass with friable surface. (D3, ×2.5) A sharp border between differentiated and UC component and EMA ( D4, ×2.5 and ×400) shows strong cytoplasmic expression in the former and focal dot and cytoplasmic expression in the latter Han et al. World Journal of Surgical Oncology (2017) 15:17 Page 7 of 9 distinguish between them because DEACs are negative for these markers. MMMT is a biphasic tumor that usually contains car- cinoma and sarcomatous components. However, both components are high-grade in MMMT, whereas the gland-forming component is low-grade (grade 1/2), and no mesenchymal component is found in DEACs. Case 3 had focal areas with myxoid stroma mimicking heterol- ogous component of MMMT. MMMTs typically occur in older women, whereas DEACs may occur in young patients. Moreover, these two entities may have distinct biology; MMMT is usually not associated with microsat- ellite instability, however, a proportion of DEACs appear to be associated with microsatellite instability [17]. Our cases had various proportions of rhabdoid cells, and if these are prominent, DEACs need to be differenti- ated from extrarenal malignant rhabdoid tumor. Unlike DEACs, rhabdoid tumors are not associated with a well- differentiated endometrioid carcinoma.

In summary, DEAC is a rare and recently defined entity, which has distinct histological and immunohistochemi- cal features and should not be underdiagnosed as con- ventional endometrioid adenocarcinoma. Furthermore, among the endometrioid type 2 tumors, UC including DEAC should be further categorized because of their worse clinical and biological behavior. Abbreviations BMI: Body mass index; BSO: Bilateral salpingo-oophorectomy; CET1WI: Contrast-enhanced T1-weighted images; CK AE1/ AE3: Pancytokeratin; CK8/18: Cytokeratin 8/18; DEAC: Dedifferentiated endometrioid adenocarcinoma; EBRT: External-beam pelvic RT; EMA: Epithelial membrane antigen; ER: Estrogen receptor; FIGO: Federation of Obstetrics and Gynecology; HPF: High-power field; ICR: Intracavitary radiotherapy; LN: Lymph node; PR: Progesterone receptor; TH: Total hysterectomy; UC: Undifferentiated carcinoma

The authors declare that there are no acknowledgements. Availability of data and materials All the data on which the conclusions of this case report are based are included in this manuscript. Author’s contributions JH collected the data and authored the manuscript. EY and SE contributed to the data analysis and shaping of the manuscript. SY performed the surgical procedure and also contributed the data analysis. AW conceived the given instructions for acquisition of data, outlined, and contributed to the shaping of the manuscript. All authors have read and approved the final manuscript. Competing interests The authors declare that they have no competing interests. Consent for publication Written informed consent was obtained from the patient for the publication of this case report and any accompanying images. Ethics approval and consent to participate Ethical approval is obtained from the Institutional Review Boards of St. Mary ’s Hospital (Application number: KC16ZISE0659). Consents of the patients were obtained to participate to the presentation of this report. Author details 1Department of Hospital Pathology, Seoul St. Mary ’s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea. 2Department of Obstetrics and Gynecology, Seoul St. Mary ’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. 3Department of Radiology, Seoul St. Mary ’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Received: 23 September 2016 Accepted: 23 December 2016

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30. 2. Kurman RJ, Carcangiu ML, Herrington CS, Young RH. WHO classification of tumours of female reproductive organs. 4th ed. Lyon: International Agency for Research on Cancer; 2014. 3. Silva EG, Deavers MT, Bodurka DC, Malpica A. Association of low-grade endometrioid carcinoma of the uterus and ovary with undifferentiated carcinoma: a new type of dedifferentiated carcinoma? Int J Gynecol Pathol. 2006;25:52–8. 4. Ronnett BM, Zaino RJ, Ellenson LH, Kurman RJ. Endometrial carcinoma. In: Kurman RJ, editor. Blaustein ’s pathology of the female genital tract. 5th ed. New York: Springer-Verlag; 2002. p. 501 –59. 5. Altrabulsi B, Malpica A, Deavers MT, Bodurka DC, Broaddus R, Silva EG. Undifferentiated carcinoma of the endometrium. Am J Surg Pathol. 2005;29: 1316–21. 6. Tafe LJ, Garg K, Chew I, Tornos C, Soslow RA. Endometrial and ovarian carcinomas with undifferentiated components: clinically aggressive and frequently underrecognized neoplasms. Mod Pathol. 2010;23:781 –9. 7. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983;15:10–7. 8. Murali R, Soslow RA, Weigelt B. Classification of endometrial carcinoma: more than two types. Lancet Oncol. 2014;15:e268 –78. 9. Setiawan VW, Yang HP, Pike MC, McCann SE, Yu H, Xiang YB, et al. Type I and II endometrial cancers: have they different risk factors? J Clin Oncol. 2013;31:2607–18. 10. Giordano G, Gnetti L, Merisio C, Melpignano M. Postmenopausal status, hypertension and obesity as risk factors for malignant transformation in endometrial polyps. Maturitas. 2007;56:190 –7. 11. Kanis MJ, Rahaman J, Moshier EL, Zakashansky K, Chuang L, Kolev V. Detection and correlation of pre-operative, frozen section, and final pathology in high- risk endometrial cancer. Eur J Gynaecol Oncol. 2016;37:338–41. 12. Thomas S, Hussein Y, Bandyopadhyay S, Cote M, Hassan O, Abdulfatah E, et al. Interobserver variability in the diagnosis of uterine high-grade endometrioid carcinoma. Arch Pathol Lab Med. 2016;140:836 –43. 13. Silva EG, Deavers MT, Malpica A. Undifferentiated carcinoma of the endometrium: a review. Pathology. 2007;39:134 –8. 14. Ramalingam P, Masand RP, Euscher ED, Malpica A. Undifferentiated carcinoma of the endometrium: an expanded immunohistochemical analysis including PAX-8 and basal-like carcinoma surrogate markers. Int J Gynecol Pathol. 2016;35:410 –8. 15. Li Z, Zhao C. Clinicopathologic and immunohistochemical characterization of dedifferentiated endometrioid adenocarcinoma. Appl Immunohistochem Mol Morphol. 2016;24:562 –8. 16. Romero-Pérez L, López-García MÁ, Díaz-Martín J, Biscuola M, Castilla MÁ, Tafe LJ, et al. ZEB1 overexpression associated with E-cadherin and microRNA-200 downregulation is characteristic of undifferentiated endometrial carcinoma. Mod Pathol. 2013;26:1514 –24. 17. Garg K, Leitao Jr MM, Kauff ND, Hansen J, Kosarin K, Shia J, et al. Selection of endometrial carcinomas for DNA mismatch repair protein immunohistochemistry using patient age and tumor morphology enhances detection of mismatch repair abnormalities. Am J Surg Pathol. 2009;33:925–33. 18. Shen Y, Wang Y, Shi Y, Liu J, Liu Y. Clinicopathologic study of endometrial dedifferentiated endometrioid adenocarcinoma: a case report. Int J Clin Exp Pathol. 2012;5:77–82. Han et al. World Journal of Surgical Oncology (2017) 15:17 Page 8 of 9 19. Vita G, Borgia L, Di Giovannantonio L, Bisceglia M. Dedifferentiated endometrioid adenocarcinoma of the uterus: a clinicopathologic study of a case. Int J Surg Pathol. 2011;19:649 –52. 20. Wu ES, Shih Ie M, Diaz-Montes TP. Dedifferentiated endometrioid adenocarcinoma: An under-recognized but aggressive tumor? Gynecol Oncol Case Rep. 2013;5:25 –7. 21. Berretta R, Patrelli TS, Faioli R, Mautone D, Gizzo S, Mezzogiorno A, et al. Dedifferentiated endometrial cancer: an atypical case diagnosed from cerebellar and adrenal metastasis: case presentation and review of literature. Int J Clin Exp Pathol. 2013;6:1652 –7. 22. Park SY, Park MH, Ko HS, Cha EJ, Sohn JS, Jung US, et al. Dedifferentiated endometrioid adenocarcinoma of the uterus: highly aggressive and poor prognostic tumor. Korean J Pathol. 2014;48:327 –30. 23. Soyama H, Takano M, Miyamoto M, Kato M, Goto T, Furuya K. Dedifferentiated endometrioid adenocarcinoma of the uterus: a case report. Eur J Gynaecol Oncol. 2016;37:426 –9. 24. Rabban JT. Dedifferentiated endometrial carcinoma: An aggressive tumor that may morphologically mimic lower-grade endometrioid adenocarcinoma. AJSP: Reviews & Reports. 2016;21:57 –72. • We accept pre-submission inquiries  Our selector tool helps you to find the most relevant journal  We provide round the clock customer support  Convenient online submission  Thorough peer review  Inclusion in PubMed and all major indexing services  Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit Submit your next manuscript to BioMed Central and we will help you at every step: Han et al. World Journal of Surgical Oncology (2017) 15:17 Page 9 of 9