Resident Short Review

Undifferentiated Endometrial CarcinomaA Diagnosis Frequently Overlooked

Shaymaa Al-Loh, MD; Maysa Al-Hussaini, MD, FRCPath

� Undifferentiated endometrial carcinoma (UEC) is arelatively uncommon neoplasm with only few studiespublished thus far. It has always been a diagnosticchallenge because of the lack of proper definition citedin most of the standard textbooks. Recently however, a fewstudies have highlighted the clinicopathologic features ofUEC. The distinctive morphology of UEC was noted by thegroup from MD Anderson Cancer Center, which enabled

them to establish the defining criteria. It appears to bemore aggressive than endometrial endometrioid adenocar-cinoma, FIGO (International Federation of Gynecologyand Obstetrics) grade 3, its main differential diagnosis.Proper recognition of this entity is important owing to itsaggressive behavior.

(Arch Pathol Lab Med. 2013;137:438–442; doi:10.5858/arpa.2011-0461-RS)

Undifferentiated endometrial carcinoma (UEC) has beenconcisely referred to only in the most traditional

anatomic pathology textbooks.1 The World Health Organi-zation (WHO) classification in Tumours of the Breast andFemale Genital Organs2 mentions UEC with only few linesappended, defining it as carcinoma lacking any evidence ofdifferentiation. Recently, a few studies3–5 have beenpublished in the literature, describing histologic findingsof UEC. Its prevalence is believed to be higher than hadbeen previously thought, as many cases of UEC were eitherreported as endometrioid adenocarcinoma FIGO (Interna-tional Federation of Gynecology and Obstetrics) grade 3,6–8

or as high-grade sarcomas and carcinosarcomas. Undiffer-entiated endometrial carcinoma, as compared to endome-trioid adenocarcinoma FIGO grade 3, carries a much worseprognosis, and presents in a more advanced stage.Moreover, it has been suggested that UEC may be linkedto the group of tumors belonging to hereditary nonpolyp-osis colorectal carcinoma or Lynch syndrome, since asignificant percentage of cases display loss of 1 or more ofthe DNA mismatch repair genes.5

CLINICAL PRESENTATION

Always thought of as a rare tumor; UEC has accounted forup to 9% of endometrial carcinomas in some reports.3,9 Themedian age at presentation ranges between 50 and 59 years

in various studies. However, UEC can affect young-agegroups and accounts for 7% of endometrial carcinomas inpatients younger than 40 years.10 In another study,5 40% ofthe patients with UEC were younger than 50 years, with theyoungest reported at 21 years of age. The most commonmodes of presentation are postmenopausal bleeding,vaginal discharge, and abdominal pain. Risk factors reportedin some cases are similar to endometrioid carcinoma andinclude hypertension, diabetes, and obesity.3

GROSS PATHOLOGY AND HISTOPATHOLOGY

Undifferentiated endometrial carcinoma may present aslarge polypoid masses with evident necrosis. Involvement ofand origin from the lower uterine segment is a frequentfinding, as well as gross involvement of the cervix.5

Microscopically, it is defined as a tumor composed ofmedium or large-sized cells with complete absence ofglandular differentiation and with absent or minimal(,10%) neuroendocrine differentiation.3,4,9 It usually dis-plays a patternless solid, sheetlike growth, with totalabsence of nests, papillae, glands, or trabeculae.3,5 Occa-sional delicate fibrovascular septae that segregate tumorcells focally into an alveolar pattern (Figure 1) are described,as well as vague cords and trabeculae. Large areas ofnecrosis with viable perivascular tumor cells are seen. Thecells are dyshesive, mostly monomorphic and relativelyuniform. The nuclei are vesicular with prominent eosino-philic nucleoli, although they can sometimes be hyperchro-matic. Variation of cellular size from small cells with scantybasophilic cytoplasm to large cells with clear or vacuolatedcytoplasm is also described (Figure 2), as well as variablepercentage of tumor cells demonstrating rhabdoid cellmorphology, often in a myxoid background (Figure 3).Numerous mitoses and also apoptosis are usually seen.Lymphovascular invasion is seen in more than half of cases.5

Further morphologic characterization was provided by acomprehensive study with equal contribution by 2 groups,one from Memorial Sloan-Kettering Cancer Center (NewYork, NY) and the other from Stony Brook University

Accepted for publication May 1, 2012.From the Department of Pathology and Laboratory Medicine, King

Hussein Cancer Center, Amman, Jordan.The authors have no relevant financial interest in the products or

companies described in this article.Presented in part at the 4th International Congress of the Jordanian

Society of Pathology and Laboratory Medicine; April 15, 2011;Amman, Jordan.

Reprints: Maysa Al-Hussaini, MD, FRCPath, Department ofPathology and Laboratory Medicine, King Hussein Cancer Center,Queen Rania St, PO Box 1269, Al-Jubeiha, 11941, Amman, Jordan(e-mail: mhussaini@khcc.jo).

438 Arch Pathol Lab Med—Vol 137, March 2013 Undifferentiated Endometrial Carcinoma––Al-Loh & Al-Hussaini

Medical Center (New York, NY).5 They have concluded thatUEC can present in either pure or mixed forms, a findingthat also applies to similar cases from the ovary. Associationwith differentiated components, more commonly of low-grade (FIGO grade 1 or 2) endometrioid carcinoma, butoccasionally with endometrioid carcinoma FIGO grade 3, isthe defining feature for the mixed forms. Defined as such,pure forms appear to be more common in some reports,5

while the mixed forms are more common in others.3 In themixed forms, which are sometimes referred to as combinedcarcinoma5,9 or more appropriately, dedifferentiated carcino-ma,4,11,12 the percentage of the undifferentiated componentranged between 20% and 90%,4 and the interface betweenthe differentiated and the undifferentiated components wasdescribed as abrupt and sharply demarcated, with a moresuperficial location for the differentiated component and adeep location for the undifferentiated carcinoma.5 Occa-sionally, UEC may be detected asynchronously in therecurrences or metastasis of an otherwise previouslyconfirmed and treated endometrial endometrioid adenocar-cinoma.4 Other specific histologic details displayed by someUECs were marked nuclear pleomorphism and multi-nucleation, and prominent tumor-infiltrating lymphocytes.As originally described, this entity should not showsquamous differentiation, mucinous differentiation, orspindled growth pattern.3 Later reports, however, allowedfor foci of vague spindling, and abrupt keratinization.4,5

ANCILLARY STUDIES

Immunohistochemical characteristics of UEC include focalstaining (,10%) for keratin AE1/AE35,7, CAM 5.2, andepithelial membrane antigen (EMA). Others3 have reportedfocal (5%–10%) keratin staining (Figure 4) and focal (10%–20%) EMA staining in most cases. Special emphasis wasgiven to cytokeratin 18 as being the most helpful stain toshow epithelial differentiation,5 even if more than 1 tumorblock needed to be stained to pick up the very focaldiagnostic staining areas. Of note is the marked intensity oftumor cells staining for keratins and EMA, regardless of thepercentage of positive cells.3 In addition, UEC showedreactivity for vimentin (Figure 5) and retained nuclearstaining for BAF-47 (INI-1). One or more neuroendocrinemarkers including chromogranin, synaptophysin, and/orCD56 can be expressed focally in less than 10% to 20% oftumor cells.4,5 Focal staining for S100 protein, CD10,estrogen receptor, and progesterone receptor was alsonoticed.3,5,7 Completely negative staining for smooth muscleactin, desmin, and HMB-45 was reported.

PATHOGENESIS

Relation to Lynch syndrome has been suggested aftertesting of UEC for DNA mismatch repair (MMR) genes.5,13

Loss of 1 or more of these genes has been reported in 47%of the tested cases, most frequently, MLH1 and PMS2. Theloss was demonstrated in both differentiated and undiffer-entiated components in tested combined cases, supportingthe common origin of both components and thus thedesignation as dedifferentiated carcinoma. These resultsconferred the property of microsatellite instability to UEC,linking it to hereditary nonpolyposis colorectal carcinoma orLynch syndrome. MLH1 promoter hypermethylation hasbeen described in a subset of what appeared to be sporadiccases. The young age of presentation, presence of previoushistory of colorectal carcinoma, positive family history for

Figure 1. Delicate fibrovascular septae separating groups of tumorcells into alveolar pattern. Note the marked dyshesion of tumor cellsand the scattered mitotic figures (hematoxylin-eosin, original magnifi-cation 340).

Figure 2. Tumor cells show clear and vacuolated cytoplasm (hema-toxylin-eosin, original magnification 340).

Figure 3. Tumor cells with prominent dyshesion and rhabdoidmorphology in myxoid background (hematoxylin-eosin, original mag-nification 340).

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Lynch syndrome–associated tumors, localization to loweruterine segment, presence of tumor-infiltrating lympho-cytes, and synchronous ovarian carcinomas10,14 should allmandate testing of UEC for DNA MMR genes.

DIFFERENTIAL DIAGNOSIS

UEC Versus Endometrioid Adenocarcinoma FIGO Grade 3

Undifferentiated endometrial carcinoma is most frequent-ly misdiagnosed as endometrial endometrioid adenocarci-noma, FIGO grade 3. However, the latter is defined by theWHO as composed of 1% to 49% glandular areas. Althoughthe presence of focal glandular differentiation can help inseparating endometrial endometrioid adenocarcinoma,FIGO grade 3, from pure forms of UEC, this feature losesits power in cases of mixed forms of UEC or dedifferentiatedcarcinoma, where the UEC component is mostly seenadmixed with lower-grade endometrioid carcinoma. Thepresence of cohesive sheets of neoplastic cells in solid areas

(Figure 6), the comparable cytologic features in theglandular and solid components, the absence of rhabdoidfeatures, and the diffuse immunoreactivity for keratins(Figure 7) and EMA can help to support the diagnosis ofpoorly differentiated endometrioid adenocarcinoma.3 Thecytologic features of UEC and differentiated components inthe dedifferentiated carcinoma are distinct.5 The Tablesummarizes the main differences between UEC andendometrioid adenocarcinoma FIGO grade 3.

UEC Versus Neuroendocrine Carcinoma

Neuroendocrine carcinoma is another important differ-ential diagnosis. Tumors that usually had been referred to inthe literature as small and large cell carcinomas should beregarded as neuroendocrine carcinomas rather than variantsof UEC, as they do display a form of differentiation, whichgoes against the definition of undifferentiated carcinoma.Expression of 1 or more neuroendocrine markers, including

Figure 4. Cytokeratin MNF immunostain showing focal intense reactivity (original magnification 320).

Figure 5. The tumor is focally positive for vimentin immunostain (original magnification 340).

Figure 6. Cohesive growth of the solid component of the poorly differentiated endometrioid adenocarcinoma, FIGO (International Federation ofGynecology and Obstetrics) grade 3 (hematoxylin-eosin, original magnification 320).

Figure 7. Cytokeratin MNF immunostain showing diffuse and strong reactivity in poorly differentiated endometrial adenocarcinoma, FIGO(International Federation of Gynecology and Obstetrics) grade 3 (original magnification 320).

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synaptophysin, chromogranin, and/or CD56 in more than20% of tumor cells, should support this diagnosis.5,9

UEC Versus Serous Carcinoma

Serous carcinoma with solid growth pattern tends toshow distinctive high-grade cytologic findings, in additionto the papillary and/or slitlike spaces. Frequent lymphovas-cular invasion with papillary formations is seen frequently inthe advancing edge of the tumor. In addition; psammomabodies are indentified in one-third of cases of serouscarcinoma.15

UEC Versus Carcinosarcoma

Carcinosarcoma affects elderly females and would evi-dently display a biphasic pattern, associated usually withhigh-grade carcinomatous component, most frequentlyserous carcinoma, and a pleomorphic, typically spindle-cellsarcomatous component.

UEC Versus Sarcoma

Endometrial stromal tumors, especially undifferentiatedendometrial sarcoma (UES), should be considered in thedifferential diagnosis. This is a high-grade tumor withmarked pleomorphism, brisk mitosis, and necrosis. Al-though UES might show some staining with CD10, it isnonreactive for other markers, including epithelial markers,5

and extensive sampling to rule out the presence of focalareas of differentiation should always be performed. High-grade endometrial stromal sarcoma is a recently ‘‘revisited’’entity, with intermediate features between low-gradeendometrial stromal sarcoma and UES. It exhibits uniformcells with evidence of endometrial stromal differentiation.16

Epithelioid leiomyosarcoma is ruled out through negativ-ity for muscle markers including desmin, smooth muscleactin, and h-caldesmon. Pancytokeratin staining should becautiously interpreted in epithelioid leiomyosarcoma as itcan show positivity.17

Others

The striking dyshesion of the UEC tumor cells makeslymphoma, plasmacytoma, and granulocytic sarcoma enter

the list of the differential diagnoses. Nonetheless, immu-nophenotyping makes the distinction quite easy.

CURRENT TREATMENT AND PROGNOSIS

Undifferentiated endometrial carcinoma appears to pur-sue an aggressive clinical course with advanced stage atpresentation and a median survival of 6 months. Disease-related death rate ranges from 41% to 75% of reportedcases, which occurs mostly in the first 5 years afterdiagnosis. According to Altrabulsi et al,3 54% of UECspresent as high-stage disease (stage III or IV), as comparedto 30% of endometrioid adenocarcinomas FIGO grade 3.Pelvic and paraaortic lymph nodes are the most commonsites of metastasis. Silva et al4 and Tafe et al5 noted that incases of combined histologic appearance, the presence ofeven a small undifferentiated component appears to carry apoor clinical outcome, while the presence of a better-differentiated component, irrespective of its extent, does notappear to confer improved clinical outcome. No associationwas found between age, stage, presence and number oftumor-infiltrating lymphocytes, rhabdoid cell morphology,and clinical outcome.5

Treatment modalities include total abdominal hysterecto-my and bilateral salpingo-oopherectomy, as well aschemotherapy and radiotherapy, with regimens similar tothose for endometrioid carcinoma FIGO grade 3. Hayashi etal18 reported a successful experience with a case of UEC thatwas treated by surgery in conjunction with a combinationchemotherapy regimen consisting of tetrahydropryanyl-adriamycin, taxane (paclitaxel), and JM-8 (carboplatin), theTTJ regimen. The patient was treated with 6 cycles of TTJand achieved complete response. She continued to becarefully followed up by clinical examination, magneticresonance imaging, and bone scan. She was followed up for41 months and remained alive without metastasis. Anotherexample of long survival is that of a patient with advanced-stage disease who was treated exclusively with radiotherapyand showed no evidence of disease after a follow-up of 104months.3

Clinicopathologic Features of Undifferentiated Endometrial Carcinoma/Dedifferentiated Carcinomaand Endometrial Endometrioid Adenocarcinoma, FIGO Grade 3

Undifferentiated/DedifferentiatedEndometrial Carcinoma

Endometrial Adenocarcinoma,FIGO Grade 3

Clinical features3

Mean age at presentation, y 55 68High stage (stage III/IV), % 45 30

MorphologyGrowth pattern Diffuse patternless sheetsa Solid and glandularGlands Absenta Present (1%–49% of tumor area)Cords and trabeculae Vaguea Well demarcatedCohesive growth Dyshesive cells Cohesive squamoidlikeComponent demarcation Sharp demarcation Intermingled componentsRhabdoid cells May be present AbsentMyxoid matrix May be present Absent

ImmunohistochemistryPancytokeratin Patchy/focal Diffuseb

EMA Patchy/focal Diffuseb

ER/PR Focal in 12% of cases Diffuseb in 60% of cases

Abbreviations: EMA, epithelial membrane antigen; ER, estrogen receptor; FIGO, International Federation of Gynecology and Obstetrics; PR,progesterone receptor.a This applies only to pure forms of undifferentiated endometrial carcinoma, as glandular component can be seen in the lower-grade component of

the dedifferentiated carcinoma.b Diffuse staining is defined as staining in more than 50% of tumor cells.

Arch Pathol Lab Med—Vol 137, March 2013 Undifferentiated Endometrial Carcinoma––Al-Loh & Al-Hussaini 441

POINTS OF CONTROVERSIES

Are UEC and Neuroendocrine Carcinomathe Same or Different?

The exact relation between neuroendocrine carcinoma andUEC needs further elaboration. Focal neuroendocrine differ-entiation, defined as less than 10% positivity of variousintensities with 1 or more neuroendocrine markers, wasreported in 41% of UECs by Taraif et al.19 Interestingly, therewas no difference in the prognosis and overall survivalbetween both groups.19 Within UEC, this focal neuroendocrinedifferentiation does not seem to affect the outcome either.4

What Is the Difference Between Pure Forms of UECand Mixed or Dedifferentiated Carcinoma Forms?

Microsatellite instability immunostaining performed insome cases is in support of a common origin of the betterdifferentiated and undifferentiated components in the mixedtumors; thus, the suggested term dedifferentiated carcino-ma.4,5 Treatment protocols are similar in both scenarios, aspure and mixed forms of UEC are treated as endometrioidcarcinoma FIGO grade 3. Prognosis is reported to be poorregardless of the amount of undifferentiated component,and the presence of a better-differentiated component,irrespective of its extent, does not appear to confer animproved clinical outcome. Total engulfment of the better-differentiated component by the undifferentiated one mightoffer a reasonable possible explanation.

The authors thank Dean Daya, MD, MHA, FRCPC, atHenderson General Hospital, Hamilton, Ontario, Canada, for theconstructive review of the manuscript.

References

1. Hedrick Ellenson L, Ronnett BM, Soslow RA, Zaino RJ, Kurman RJ.Endometrial carcinoma. In: Kurman RJ, Hedrick Ellenson L, Ronnett BM, eds.Blaustein’s Pathology of the Female Genital Tract. 6th ed. New York, NY: Springer;2011:394–452.

2. Silverberg SG, Nogales F. Tumours of the uterine corpus. In: Tavassoli FA,Devilee P, eds. Pathology and Genetics: Tumours of the Breast and FemaleGenital Organs. Lyon, France: IARC Press; 2003. World Health OrganizationClassification of Tumours; vol 4. 217–257.

3. Altrabulsi B, Malpica A, Deavers MT, Bodurka DC, Broaddus R, Silva EG.Undifferentiated carcinoma of the endometrium. Am J Surg Pathol. 2005;29(10):1316–1321.

4. Silva EG, Deavers MT, Bodurka DC, Malpica A. Association of low-gradeendometrioid carcinoma of the uterus and ovary with undifferentiatedcarcinoma: a new type of dedifferentiated carcinoma? Int J Gynecol Pathol.2006;25(1):52–58.

5. Tafe LJ, Garg K, Chew I, Tornos C, Soslow RA. Endometrial and ovariancarcinomas with undifferentiated components: clinically aggressive and fre-quently underrecognized neoplasms. Mod Pathol. 2010;23(6):781–789.

6. Narita F, Sato A, Hamana S, Deguchi M, Otani T, Maruo T. Simultaneousimmunohistochemical localization of beta-catenin and cyclin D1 in differenti-ated but not in undifferentiated human endometrial carcinoma. Eur J GynaecolOncol. 2003;24(2):129–134.

7. Abeler VM, Kjorstad KE, Nesland JM. Undifferentiated carcinoma of theendometrium: a histopathologic and clinical study of 31 cases. Cancer. 1991;68(1):98–105.

8. Wilson TO, Podratz KC, Gaffey TA, Malkasian GD Jr, O’Brien PC,Naessens JM. Evaluation of unfavorable histologic subtypes in endometrialadenocarcinoma. Am J Obstet Gynecol. 1990;162(2):418–426.

9. Silva EG, Deavers MT, Malpica A. Undifferentiated carcinoma of theendometrium: a review. Pathology. 2007;39(1):134–138.

10. Garg K, Shih K, Barakat R, Zhou Q, Iasonos A, Soslow RA. Endometrialcarcinomas in women aged 40 years and younger: tumors associated with loss ofDNA mismatch repair proteins comprise a distinct clinicopathologic subset. Am JSurg Pathol. 2009;33(12):1869–1877.

11. Vita G, Borgia L, Di Giovannantonio L, Bisceglia M. Dedifferentiatedendometrioid adenocarcinoma of the uterus: a clinicopathologic study of a case.Int J Surg Pathol. 2011;19(5):649–652.

12. Giordano G, D’Adda T, Bottarelli L, et al. Two cases of low-gradeendometriod carcinoma associated with undifferentiated carcinoma of the uterus(dedifferentiated carcinoma): a molecular study. Pathol Oncol Res. 2012;18(2):523–528.

13. Broaddus RR, Lynch HT, Chen LM, et al. Pathologic features of endometrialcarcinoma associated with HNPCC: a comparison with sporadic endometrialcarcinoma. Cancer. 2006;106(1):87–94.

14. Garg K, Soslow RA. Lynch syndrome (hereditary non-polyposis colorectalcancer) and endometrial carcinoma. J Clin Pathol. 2009;62(8):679–684.

15. Bartosch C, Manuel Lopes J, Oliva E. Endometrial carcinomas: a reviewemphasizing overlapping and distinctive morphological and immunohistochem-ical features. Adv Anat Pathol. 2011;18(6):415–437.

16. Xue WC, Cheung AN. Endometrial stromal sarcoma of uterus. Best PractRes Clin Obstet Gynaecol. 2011;25(6):719–732.

17. Oliva E, Young RH, Amin MB, Clement PB. An immunohistochemicalanalysis of endometrial stromal and smooth muscle tumors of the uterus: a studyof 54 cases emphasizing the importance of using a panel because of overlap inimmunoreactivity for individual antibodies. Am J Surg Pathol. 2002;26(4):403–412.

18. Hayashi M, Ueda Y, Takimoto T, Ohkura T. Undifferentiated endometrialcarcinoma of the uterus: marked effect of chemotherapy with tetrahydropyranyl-adriamycin, paclitaxel, and carboplatin. Int J Gynecol Cancer. 2004;14(2):388–394.

19. Taraif SH, Deavers MT, Malpica A, Silva EG. The significance ofneuroendocrine expression in undifferentiated carcinoma of the endometrium.Int J Gynecol Pathol. 2009;28(2):142–147.

CAP ’13 Abstract Program Accepting Submissions

Abstract and case study submissions will be accepted beginning Monday, February 4,2013 for the College of American Pathologists (CAP) 2013 meeting. CAP ’13 will be heldOctober 13 through the 16th in Orlando, Florida. Submissions for the CAP ’13 AbstractProgram will be accepted through Monday, April 1, 2013.

Accepted submissions will appear in the October 2013 issue of the Archives of Pathology& Laboratory Medicine. Visit the CAP ’13 Website at www.cap.org/cap13 for a link to theabstract submission site and additional abstract program information as it becomesavailable.

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