Endometrial cancer is a common cancer of the female genital tract and its most common histological type is endometrioid adenocarcinoma, followed by plasmacytoma and undifferentiated carcinoma. Undifferentiated carcinoma can be combined with low-grade endometrioid adenocarcinoma, which suggests a process of tumor dedifferentiation; therefore, Silva et al. classified this type of tumor as endometrial dedifferentiated carcinoma in 2006.
The low-grade component of dedifferentiated carcinoma is typically endometrioid adenocarcinoma grade I or II. Undifferentiated carcinomas are malignant tumors of epithelial origin that lack any evidence of differentiation and cannot be classified as other tumor types. The number of reported cases of dedifferentiated carcinoma is limited so far, and the percentage of endometrial carcinoma is only 9%, so its histological features are not widely recognized by pathologists. Yan et al. reported a case of endometrial dedifferentiated carcinoma in an Asian patient in China.
The histologic grading of endometrioid adenocarcinoma in the International Federation of Gynecology and Obstetrics (FIGO) system is based on structural features and focuses only on the percentage of non-squamous solid areas in the carcinoma, without providing details of the histologic features of the solid areas of the tumor. Therefore the undifferentiated carcinoma component of dedifferentiated carcinoma is often not recognized or incorrectly classified as endometrioid adenocarcinoma grade III according to FIGO criteria. Correct diagnosis of these tumors is essential because their aggressiveness is consistent with that of plasmacytoma, and their prognosis is worse than that of clear cell carcinoma, requiring different treatment modalities.
I. Clinical manifestations and histological features
The most common symptoms are vaginal bleeding and pelvic pain. Microscopically, all dedifferentiated carcinomas consist of low-grade endometrioid adenocarcinoma and undifferentiated carcinoma components, which are two completely different tumor forms combined, with each component accounting for at least 10% of the tumor volume. Low-grade endometrioid adenocarcinoma is located superficially in the endometrium, adjacent to the uterine cavity, whereas undifferentiated carcinoma is located deep in the endometrium and myometrium and is well defined from low-grade carcinoma.
Undifferentiated carcinoma consists of small to moderately large, single epithelial cells that are arranged in solid sheets without specific structures or glandular differentiation. Sometimes the cells consist of patches of large round and polygonal cells. The nuclei were enlarged and the chromatin was thickened, sometimes with prominent basophilic nucleoli. Focal eosinophilic, rhabdoid cells with frequent necrosis may be seen. Undifferentiated carcinoma may be accompanied by small foci of neuroendocrine differentiation. Individual cases may show mucus-like interstitium, and tumor-infiltrating lymphocytes may be seen in the interstitium.
Immunohistochemical features
Undifferentiated carcinoma diffusely expresses wave proteins. Only 5% to 10% of the cells in about 80% to 90% of cases weakly express broad-spectrum cytokeratin (Ckpan). About 25% of the cells in almost all cases expressed epithelial membrane antigen (EMA) and cytokeratin 18 (CK18) with strong coloration. Almost all cases of undifferentiated carcinoma were negative for ER/PR. One or more neuroendocrine markers such as synaptophysin, chromogranin A, and CD56 could be expressed in 10% of tumor cells in more than 1/3 of cases.
Different proportions of dedifferentiated carcinomas often express DNA mismatch repair gene proteins, mostly showing MLH1 and PMS2 deletion, sometimes MSH2/MSH6 deletion, and thus associated with Lynch syndrome. Although rhabdoid cells may be present, the rhabdoid marker myostatin is negative and therefore does not support skeletal muscle differentiation.
III. Molecular features
Mutations in the TP53 gene frequently occur in cases of uterine dedifferentiated carcinoma, and a monoclonal relationship between low-grade endometrioid carcinoma and undifferentiated carcinoma was found in most patients with dedifferentiated carcinoma. Loss of heterozygosity (LOH) can contribute to the development of dedifferentiated carcinoma. giordano et al. observed 2 cases of dedifferentiated carcinoma, both with LOH and microsatellite instability (MSI). Their experimental results support the possibility that MSI may be associated with undifferentiated carcinoma morphology and also confirm the new hypothesis of Shia et al. that dedifferentiated carcinomas are structurally heterozygous and exhibit high MSI. undifferentiated carcinomas were previously thought to be associated with MLH1 promethylation, but in the study of Garg et al. 5 of 7 dedifferentiated carcinomas paradoxically expressed MLH1/PMS2 and 2 had MSH2/MSH6 expression deficiency.
IV. Differential diagnosis
Because the histological differences are not very obvious, dedifferentiated carcinoma may be confused with endometrioid adenocarcinoma and neuroendocrine tumors.
(1) Differentiation from high-grade endometrioid adenocarcinoma: The undifferentiated component of dedifferentiated carcinoma of the uterus is easily mistaken for the solid area of endometrioid adenocarcinoma, but the solid area of dedifferentiated carcinoma is non-adherent and non-glandular differentiated. Local foci frequently show mucinous stroma, multinucleated cells, or rhabdoid cells. In contrast, most solid areas of endometrioid adenocarcinoma show a well-differentiated glandular component; tend to show adhesive manifestations, often with striated, trabecular structures, and have the same cytologic features as areas of highly differentiated carcinoma. Immunohistochemistry can be used to identify. cK and EMA are diffusely positive in solid areas of grade III endometrioid carcinoma. In addition, ER/PR was expressed in approximately 60% of endometrioid carcinomas grade III, but was focally expressed or not expressed in only 12% of dedifferentiated carcinomas. In dedifferentiated carcinoma, we can clearly observe the difference in staining for CK, ER and PR between undifferentiated carcinoma and endometrioid adenocarcinoma due to their combined presence.
(2) Differentiation from neuroendocrine carcinoma: Neuroendocrine carcinoma of the endometrium often shows a solid growth pattern, which may be confused with dedifferentiated carcinoma. However, the latter shows relatively homogeneous tumor cells with active nuclear schizophrenia and necrosis, whereas these features are not common in neuroendocrine carcinoma. Most neuroendocrine carcinomas diffusely express 2 or more neuroendocrine differentiation markers. Since undifferentiated carcinomas can focally express neuroendocrine markers, it is recommended that at least 20% of tumor cells express 2 or more markers for a definitive diagnosis of neuroendocrine carcinoma. (b) Neuroendocrine carcinoma also diffusely expresses p16, p53 and thyroid transcription factor-1 (TTF-1), but dedifferentiated carcinoma does not express these markers.
(3) Differentiation from non-epithelial uterine tumors: undifferentiated sarcoma can be confused with dedifferentiated carcinoma, especially the medium to small cell type with focal spindle cell morphology and no loss of adhesion features. In addition, undifferentiated sarcoma does not express EMA, whereas uterine dedifferentiated carcinoma often does. The dedifferentiated carcinoma can be confused with endometrial mesenchymal sarcoma at low magnification, but lacks the latter’s tongue-like myxoid infiltrate and morphologic features of small spiral arteries. Because dedifferentiated carcinoma of the uterus can have a bidirectional character and in some cases may focally appear as rhabdoid cells in a mucinous mesenchymal background, dedifferentiated carcinoma can be misdiagnosed as carcinosarcoma. However, dedifferentiated carcinomas often occur in younger women (40% are under 50 years of age) and lack pleomorphic spindle cells with heterogeneous components. The sarcomatous component of malignant mesodermal mixed tumors is often spindle cells and the epithelial component is usually plasmacytotic.
V. Prognosis and treatment
The biological behavior of dedifferentiated carcinoma is determined by the undifferentiated component, and the prognosis is poor even if the undifferentiated component is small. More than 50% of patients with dedifferentiated carcinoma are at high stage at the time of diagnosis, and >60% of patients die from this disease within 5 years after diagnosis. In contrast, only 30% of high-grade endometrioid adenocarcinomas are high stage, and approximately 35% of patients die of this disease within 5 years.
Silva et al. found that only 1 of 25 cases of dedifferentiated carcinoma had a disease-free survival of 104 months. Currently, based on the paucity of extant case data, there is no strict definition of the surgical approach to dedifferentiated cancer or the significance of adjuvant therapy (radiation and chemotherapy).
Treatment of dedifferentiated carcinoma almost always involves total hysterectomy and bilateral adnexal resection, which may be supplemented by chemotherapy, radiotherapy and endocrine therapy; chemotherapy treatment routinely applied to endometrioid adenocarcinoma has not responded well. Endometrial dedifferentiated carcinoma is a newly recognized malignant tumor of the endometrium. Due to the limited number of reported cases, research on its histological features and molecular characteristics is still in its early stages, and more information is needed to confirm it.