Dedifferentiated Endometrioid Adenocarcinoma of the Uterus: Highly Aggressive and Poor Prognostic Tumor

Abstract

According to the International Federation of Gy- necology and Obstetrics (FIGO) system, this case was FIGO stage IB. The World Health Organization (WHO) classification defines endometrial undifferentiated carcinoma as a malignant tumor with an epithelial structure that is too poorly differentiated to be placed in any other category of carcinomas.4 The MD Anderson group reviewed 633 cases of endometrial ad- enocarcinomas and found that cases of undifferentiated carcino- ma of the endometrium represent 9% of endometrial carcino- mas.2,3 In their series, 71% of cases of undifferentiated carcinoma were admixed with low-grade endometrioid adenocarcinoma re- ferred to as DEAC.2,3 They suggested that the undifferentiated carcinoma originated secondary to the transformation or the de- differentiation of the low-grade endometrioid adenocarcinoma.2 A recent study suggests that undifferentiated carcinoma is asso- ciated with a defect in the DNA mismatch repair pathway, as in Lynch syndrome.5 Dedifferentiation refers to the progression of cells toward a less differentiated state in which the original line of differentia- tion is no longer evident.5 Dedifferentiation was first proposed by Dahlin and Beabout in 19716 when they described dediffer- entiated chondrosarcoma as a distinct clinicopathological entity characterized by a low-grade chondrosarcoma juxtaposed to a histologically different high-grade sarcoma.6 Lately, dedifferenti- ation has been recognized in a variety of epithelial malignancies, including those affecting salivary gland, kidneys, and thyroid.7 DEAC is part of the spectrum of undifferentiated carcinomas of the endometrium.

Dedifferentiated endometrioid adenocarcinoma (DEAC) is a recently described, rare uterine neoplasm containing both low- grade endometrioid adenocarcinoma and undifferentiated carci- noma.1 Undifferentiated carcinoma in DEAC may originate sec- ondary to transformation or dedifferentiation of low-grade endo- metrioid adenocarcinoma and appears to be more aggressive than endometrial endometrioid adenocarcinoma.2 The undiffer- entiated component in DEAC can be misdiagnosed as the solid component of grade 3 endometrioid adenocarcinoma.3 Therefore, accurate diagnosis of this neoplasm is important in treatment and prognosis. Here we report a case of DEAC of the uterus.

CASE REPORT

A 55-year-old Korean woman was admitted to our hospital because of vaginal bleeding that had lasted eight months. She was well except for a history of left salpingo-oophorectomy for benign ovarian cyst seven years ago. Ultrasonography revealed a thickened endometrium. An endometrial biopsy revealed well- differentiated endometrioid adenocarcinoma. She underwent total hysterectomy with right salpingo-oophorectomy and pel- vic lymphadenectomy.

The uterus measured 8× 6× 4 cm. Right adnexa was grossly unremarkable. A 7× 7× 1-cm-sized protruding mass was found in the endometrial cavity. The mass was infiltrating into the myometrium and there were leiomyomas beneath the tumor mass (Fig. 1A, B).

Microscopically, the tumor consisted of a low-grade endome- trioid adenocarcinoma (40% of the tumor volume) on the sur- face and underlying undifferentiated carcinoma (60%) with a sharp border between the two components (Fig. 2A, B). The un- differentiated component exhibited a solid growth of monomor- phic dyscohesive cells, lacking any differentiating features (Fig. 2C). The tumor cells were round with prominent nucleoli and frequent mitosis, and rhabdoid cells with eosinoophilic cyto- plasm and eccentric nuclei were noted in myxoid background (Fig. 2D). Numerous vascular and endolymphatic tumor emboli were present. Immunohistochemiscally, cytokeratin (CK), epi- thelial membrane antigen (EMA), estrogen receptor (ER), and progesterone receptor (PR) were diffusely expressed in the well- differentiated component. The undifferentiated cells were dif- fusely positive for vimentin and focally positive for CK and EMA (Fig. 2E, F). ER, PR, smooth muscle actin and neuroen- docrine markers including chromogranin, synaptophysin, and CD56 were all negative. No metastasis was present in 24 pelvic lymph nodes. According to the International Federation of Gy- necology and Obstetrics (FIGO) system, this case was FIGO stage IB.

After surgery, the patient received vaginal radiation. Two months later, she complained of hip pain. A follow-up positron emission tomography-computed tomography revealed multiple pulmonary, peritoneal, pelvic bone, and mediastinal lymph node metastases (Fig. 3). A brain computed tomography re- vealed multiple metastatic nodules. Although the patient un- derwent three cycles of chemotherapy, including pacitaxel, cis- platin, and doxorubicin, she died seven months after the diag- nosis of DEAC.

DISCUSSION

Undifferentiated carcinoma of the endometrium is a poorly defined neoplasm. The World Health Organization (WHO) classification defines endometrial undifferentiated carcinoma as a malignant tumor with an epithelial structure that is too poorly differentiated to be placed in any other category of carcinomas.4 The MD Anderson group reviewed 633 cases of endometrial ad- enocarcinomas and found that cases of undifferentiated carcino- ma of the endometrium represent 9% of endometrial carcino- mas.2,3 In their series, 71% of cases of undifferentiated carcinoma were admixed with low-grade endometrioid adenocarcinoma re- ferred to as DEAC.2,3 They suggested that the undifferentiated carcinoma originated secondary to the transformation or the de- differentiation of the low-grade endometrioid adenocarcinoma.2 A recent study suggests that undifferentiated carcinoma is asso- ciated with a defect in the DNA mismatch repair pathway, as in Lynch syndrome.5

Dedifferentiation refers to the progression of cells toward a less differentiated state in which the original line of differentia- tion is no longer evident.5 Dedifferentiation was first proposed by Dahlin and Beabout in 19716 when they described dediffer- entiated chondrosarcoma as a distinct clinicopathological entity characterized by a low-grade chondrosarcoma juxtaposed to a histologically different high-grade sarcoma.6 Lately, dedifferenti- ation has been recognized in a variety of epithelial malignancies, including those affecting salivary gland, kidneys, and thyroid.7

DEAC is part of the spectrum of undifferentiated carcinomas of the endometrium. The biological behavior of DEAC is deter- mined by the undifferentiated component. The presence of even a small undifferentiated component appears to be associated with poor clinical outcomes.2

Patients with undifferentiated carcinoma often present with advanced stage disease, and more than 60% of these patients die from the disease within five years of being diagnosed.8

Taraif et al.9 reported that 80% of patients died within 12 months of diagnosis. In our case, the pathological stage was low at the time of the surgery. However, despite postoperative chemoradiation therapy, the patient died seven months after the diagnosis due to extensive tumor metastasis.

The undifferentiated component of DEAC can be misdiag- nosed as the solid component of a FIGO grade 3 endometrioid adenocarcinoma. FIGO grade 3 endometrioid adenocarcinoma always exhibits a solid growth pattern, with focal glandular dif- ferentiation.3 The nuclear features of tumor cells in both the glandular and the solid areas tend to be cytologically similar.1 In contrast, the solid areas in DEAC are characterized by dyshe- sive cells which grow in a sheet-like sarcomatoid pattern. The cytological features of the undifferentiated and differentiated components are distinct. Usually, the differentiated components tend to be superficial, whereas the undifferentiated components are deep and invade the myometrium.10 These two components often display an abrupt transition which resembles a collision tumor. As in this case, the immunohistochemical expression of CK and EMA are diffusely positive in FIGO grade 3 endometrioid adenocarcinoma, whereas the expression of CK and EMA is focal (< 10%) in the solid area of DEAC.

The undifferentiated component of DEAC can be confused with other tumors, including carcinosarcoma, undifferentiated endometrial sarcoma, poorly differentiated neuroendocrine car- cinoma, and lymphoma. DEAC can be misdiagnosed as carci- nosarcoma due to its biphasic appearance. The sarcomatous component of a carcinosarcoma is usually composed of spindle cells, and the epithelial component usually consists of high grade tumor cells.10 Undifferentiated endometrial sarcomas are frequently much more pleomorphic and at least focally spin- dled.10 Neuroendocrine carcinomas and lymphomas can be dif- ferentiated on the basis of their immunohistochemistry.

In summary, DEAC is an uncommon, highly aggressive, and frequently misdiagnosed tumor. The recognition of the undiffer- entiated component associated with low-grade endometrioid ad- enocarcinoma is very important. A range of differentials needs to be considered and ruled out on the basis of the clinical profile, morphology, and immunohistochemical features of this tumor.

Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

References

REFERENCES

1. Shen Y, Wang Y, Shi Y, Liu J, Liu Y. Clinicopathologic study of en- dometrial dedifferentiated endometrioid adenocarcinoma: a case report. Int J Clin Exp Pathol 2012; 5: 77-82.

2. Silva EG, Deavers MT, Bodurka DC, Malpica A. Association of low- grade endometrioid carcinoma of the uterus and ovary with undif- ferentiated carcinoma: a new type of dedifferentiated carcinoma? Int J Gynecol Pathol 2006; 25: 52-8.

3. 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.

4. Silverberg SG, Mutter GL, Kurman RJ, Kubik-Huch RA, Nogales FF, Tavassoli FA. Tumours of the uterine corpus. Epithelial tumours and related lesions. In: Tavassoli FA. Debelee P eds. World Health Organization classification of tumors. Pathology and genetics. Tu- mors of the breast and female genital organs. Tumors of the uterine corpus. Lyon: IARC Press, 2003; 277.

5. Katoh M, Shaw C, Xu Q, et al. An orderly retreat: Dedifferentiation is a regulated process. Proc Natl Acad Sci U S A 2004; 101: 7005-10.

6. Dahlin DC, Beabout JW. Dedifferentiation of low-grade chondro- sarcomas. Cancer 1971; 28: 461-6.

7. Vita G, Borgia L, Di Giovannantonio L, Bisceglia M. Dedifferentiat- ed endometrioid adenocarcinoma of the uterus: a clinicopathologic study of a case. Int J Surg Pathol 2011; 19: 649-52.

8. Silva EG, Deavers MT, Malpica A. Undifferentiated carcinoma of the endometrium: a review. Pathology 2007; 39: 134-8.

9. Taraif SH, Deavers MT, Malpica A, Silva EG. The significance of neuroendocrine expression in undifferentiated carcinoma of the endometrium. Int J Gynecol Pathol 2009; 28: 142-7.

10. 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.