Corded and hyalinized endometrioid carcinoma: a rare case and review of the literature

Corded and hyalinized endometrioid carcinoma(CHEC) is a rare morphological variation of endometrioid carcinoma(EC) in the endometrium. Reports of CHEC were very limited. We represent the clinical and pathological ndings of this rare endometrioid carcinoma in a 26-year-old woman and reviews the literatures updated on CHEC.

Conclusions CHEC is not uncommonly mistaken for a wide variety of diseases. It's of great signi cance to raise the awareness of CHEC to avoid over-treatment caused by over-diagnosis, especially in young patients and in curettage. We report one case of CHEC in a 26-year-old woman which was misdiagnosed as a mullerian mixed tumor in the initial curettage specimen. The clinicopathologic, light microscopic, immunohistochemical features of this tumor are described and the differential diagnosis is discussed.

Background
Endometrioid carcinoma (EC) accounts for 70 ~ 80% of newly diagnosed uterine corpus cancer worldwide in recent years [1]. The recognition of its typical morphology and clinical signi cance are usually straightforward; however, EC may have a variety of unusual appearances that can pose a diagnostic challenge and be associated with unique clinicopathological ndings [2]. EC with sex cord-like formations and hyalinization is a rare morphological variation of EC in the endometrium which was rst described in a review article in 2002 [3]. In 2005, Murray et al. described the clinical and pathologic features of this distinct variant and referred to this subtype as "corded and hyalinized endometrioid carcinoma(CHEC)" [4].
Histologically, CHEC is characterized by the presence of cords, nests, or clusters of bland epithelioid and spindled cells, which merge with a conventional component of low-grade typical EC. Typically in between the cords and clusters, there is abundant hyalinized to myxoid stroma which compresses the neoplastic cells and imparts a sex-cord like appearance. Clinically, CHECs tend to arise in younger patients compared with typical ECs and are usually low stage with a generally favorable prognosis, so it is important to distinguish CHECs from other endometrial tumors [5]. However, CHEC is not uncommonly mistaken for a wide variety of diseases, in particular carcinosarcoma, which is often high grade and clinically aggressive. Therefore, increased awareness of this rare morphological variation is essential for both clinicians and pathologists to avoid misdiagnosis and over-treatment.
To our knowledge, reports of CHEC were very limited [4,6]. In this study, we represent the clinical and pathological ndings of this rare endometrioid carcinoma in a 26-year-old woman and reviews the literatures updated on the clinical, morphologic and immunohistochemical features of CHEC.

Materials And Methods
The tissue obtained via hysterectomy was processed using routine histological methods: 10% formalin xed, para n embedded and haematoxylin-eosin stained. Immunohistochemical studies were carried out on formalin-xed para n-embedded tissue. Appropriate positive and negative controls were applied simultaneously. The primary antibodies used for the immunohistochemical studies are listed in Table 1.

Case Presentation
Clinical history A 26-year-old woman visited another clinic because of abnormal vaginal bleeding for 3 months. The initial cervical biopsy revealed a mullerian mixed tumor, following which she was referred to our hospital for evaluation and treatment. Her familial history and past history was uneventful. Her body mass index was 28.6 kg/m 2 . Abdominopelvic computed tomography revealed a mass in the uterine cavity and cervix, suggesting a malignant tumor ( Fig. 1a-1b). Serum levels of the tumor markers carcinoembryonic antigen, cancer antigen 125 and carbohydrate antigen 19 − 9 were 0.66 ug/L, 10.6 U/mL, and 3.85 U/mL respectively. The patient received total hysterectomy with bilateral salpingo-oophorectomy, omentectomy, intra-pelvic, para-aortic and presacral lymphadenectomy.

Pathological ndings
Gross examination in the hysterectomy specimen revealed a 60 × 33 × 10 mm papillary mass with a greywhitish cut surface in the uterine cavity that appeared to invade into the super cial myometrium and the surface of cervix (Fig. 1c).
Histologically, low-power magni cation revealed the tumor invaded the super cial layer of myometrium and extended to the surface of cevix but did not invade the cervical stroma (FIGO stage IA), showing a biphasic pattern characterized by an appearance of 2 components, the conventional endometrioid carcinoma component and sex cord-like component with hyalinization (Fig. 2a). Sections of the tumor showed typical low-grade endometrioid carcinoma (FIGO grade 1) in a background of endometrial hyperplasia (Fig. 2b). In 60% of areas of the tumor, sex cord-like elements were found to blend with the conventional endometrioid carcinoma. This distinct component of sex cord-like formations was restricted to the super cial aspects (Fig. 2c). In the areas of sex cord-like elements, the epithelioid and spindle cells were usually seen around the glands, and mostly arranged in cords or trabeculaes (Fig. 2d). In some areas, the epithelioid and spindle cells were embedded within a richly hyalinized collagenous or sometimes myxoid matrix, and the cells may formed small clusters or were individually disposed (Fig. 2e); but in some areas, a hyalinized matrix was absent and the cells were arranged in solid sheets   Fig. 3).
Based on histological and immunochemical examinations, the patient was diagnosed with CHEC.

Follow up
The patient had a disease-free follow-up 8 months after the surgery.

Discussion And Conclusions
EC may have a variety of unusual appearances which can cause di culty in making correct diagnosis [2]. CHEC is a rare morphological variant of EC developing in the endometrium [4]. Lack of awareness of this entity may lead to misdiagnosis and unnecessary treatment.
Reports of CHEC are limited; updating to now, only 37 cases are described by two articles (written in English) retrieved from PubMed [4,6]. From these studies, patient age ranged from 25 to 83 years, with a mean of 51 years. Among 27 patients with clinical staging data, 20 patients (74%) were at FIGO stage .
Among 18 patients with follow-up information, 15 patients were alive with no evidence of disease, 1 patient was alive with disease, 1 patient died as a result of tumor, and 1 patient died of other causes. In the present case, the patient was only 26-year-old, at FIGO stage and was alive with no evidence of disease for 8 months. We can conclude that CHEC tends to arise in younger patients compared with conventional endometrial EC, and usually develops at a lower stage with more favorable prognosis than conventional endometrial EC [7,8]. However, CHEC is not uncommonly mistaken for a wide variety of diseases. In the present case, the patient was misdiagnosed as a mullerian mixed tumor in the curettage specimen. Accordingly, it's of great signi cance to raise the awareness of CHEC to avoid over-treatment caused by over-diagnosis, especially in young patients and in curettage.
Histologically, all cases that have been reported consist of a component of conventional grade or conventional EC that accounts for 10-90%. Endometrial hyperplasia can be identi ed in most cases. The de nition of CHEC is the presence of cords of epithelioid cells, spindled cells, or fusiform cells with or without hyalinized stroma. This component is generally restricted to the super cial aspects and often embedded within a striking hyalinized collagenous matrix which in some cases formed osteid. Increased squamous differentiation is often found.
CHEC tends to be easily misdiagnosed as carcinosarcoma, because of its striking biphasic appearance exhibiting both epithelioid and mesenchymal elements, especially in the setting of biopsy or curretage. Unlike CHEC, carcinosarcoma often occurs in elderly women and has a high-stage clinical presentation and more aggressive clinical behavior [9]. Moreover, pathologically carcinosarcoma is mostly composed of high-grade adenocarcinomatous and sarcomatous components with increased nuclear atypia and mitosis [10]. Also, p53 is diffusely and strongly expressed in adenocarcinoma while it is scattered positive in CHEC [11].
Dedifferentiated EC contains a component of either FIGO grade 1 or 2 EC and a second component of undifferentiated carcinoma. The undifferentiated carcinoma is composed of dyshesive cells of uniform size arranged in sheets without any corded or trabecular architecture which is seen in CHEC. The nuclear chromatin is usually condensed and most cases have > 25 mitotic gure per 10 HPF while the nuclei of the epithelioid and spindle cells showed less atypia and only rare mitotic gures in CHEC [12,13]. The undifferentiated component grows beneath the differentiated endometrioid component while the epithelioid and spindle cells are restricted to the super cial aspects in CHEC. The undifferentiated components display evidence of epithelial differentiation in only occasional tumor cells, with intense EMA and CK18 expression in the absence of staining with pan-cytokeratins [14]. Also, a proportion of dedifferentiated EC appear to be associated with microsatellite instability [15].
In sertoliform EC, tumor cells are arranged as small hollow tubules in the areas resembling Sertoli and Sertoli-Leydig cell tumors, but sometimes they can arranged as cord and trabeculaes, which can be confused with CHEC. However, prominent stromal hyalinization and spindle cells are not a feature of the sertoliform EC of the endometrium and the sertoliform elements are always positive for EMA and CK, which helps us distinguish sertoliform EC with CHEC [16,17].
LGESS can also show sex cord-like features and the tumor cells in this element are small and uniform without prominent nuclear atypia and mitotic activity [18]. However, typical EC is absent in LGESS. Immunohistochemically, the sex cord elements in LGESS show positive staining of endometrial stromal, smooth muscle markers. Sex cord markers including inhibin, CD99, calretinin and CD56 could also be positive [19,20]. PHF1 rearrangement has been found to be predominant in the sex cord variant of LGESS [21].
Corded and hyalinized mesonephric-like adenocarcinoma can also mimick CHEC. Differentiating the tumor from CHEC is its heterogeneous architecture resembling mesonephric growth patterns, segments of attenuated epithelium, lack of squamous differentiation, essentially negative hormone receptor expression, considerable positivity for TTF1 and GATA3 [22].
In summary, CHEC is not uncommonly mistaken for a wide variety of diseases. We report one case of CHEC in a 26-year-old woman. The clinicopathologic, light microscopic, immunohistochemical fetaures of this tumor are described and the differential diagnosis is discussed. We hope that this report help to raise the awareness of CHEC and avoid misdiagnosis and mistreatment.  Figure 1 Computed tomography imaging and macroscopic analysis a. Reconstructed sagittal pre-contrast CT image: the presence of endometrial thickening (arrow) and cervical mass (star) is obscured in the precontrast CT image. b. Reconstructed sagittal post-contrast CT image endometrial thickening (arrow), enhancing mass (less enhanced than the myometrium) in the uterus cervix (star). c. Gross examination in the hysterectomy specimen revealed a 60 x 33 x 10 mm papillary mass with a grey-whitish cut surface in the uterine cavity that appeared to invade into the super cial myometrium and the surface of cervix.

Figure 2
Histological ndings of the tumor. a. Low-power magni cation showed a biphasic pattern due to neoplastic endometrioid glands separated by a focally hyalinized stroma containing cords.
Haematoxylin-eosin staining, 20x magni cation. b. Typical endometrioid carcinoma (grade 1) in a background of endometrial hyperplasia. Haematoxylin-eosin staining, 40x magni cation. c. The sex cordlike elements blended with the conventional endometrioid carcinoma. Haematoxylin-eosin staining, 20x magni cation. d. In the areas of sex cord-like elements, the epithelioid and spindle cells were around the glands, and mostly arranged in cords or trabeculaes. Haematoxylin-eosin staining, 100x magni cation. e.
In some areas, the epithelioid and spindle cells were embedded within a richly hyalinized collagenous or sometimes myxoid matrix, and the cells may formed small clusters or were individually disposed.