Case 2 -

Endometrial Carcinoma, Mixed Adenocarcinoma C. Blake Gilks University of British Columbia Vancouver, BC, Canada

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Clinical History This 69 year-old woman presented with post menopausal bleeding and an endometrial biopsy showed "adenocarcinoma of endometrioid-type, Grade II/III". The submitted slide is from a subsequent hysterectomy and bilateral salpingo-oophorectomy specimen and is taken from the uterine corpus. In this TAHBSO specimen, the tumour was seen to invade into the inner half of the myometrium. There was invasion of myometrial lymphatics by tumour and there was extrauterine extension, with involvement of the sigmoid peritoneum and both left and right ovaries. Immunohistochemical staining of the tumour showed that there was focal ER and PR-positivity, the tumour cell nuclei were negative for p53 and there was weak positivity for PTEN. 78% of the tumour cell nuclei were positive for the proliferation marker MIB1. The patient was alive, without evidence of disease, at the time of last follow-up, 6.5 years after the hysterectomy was performed. Diagnosis: Endometrial carcinoma, mixed adenocarcinoma. The predominant component is serous carcinoma with a minor component of endometrioid type adenocarcinoma present. Case 2 - Figure 1 - Endometrial adenocarcinoma, mixed serous (left) and endometrioid (right) pattern. Case 2 - Figure 2 - Endometrial adenocarcinoma, mixed serous and endometrioid pattern.This focus exhibits endometrioid architecture; however, note the high nuclear grade. Case 2 - Figure 3 - Endometrial adenocarcinoma, mixed serous and endometrioid pattern. This focus exhibits classic serous morphology. Case 2 - Figure 4 - Endometrial adenocarcinoma, mixed serous and endometrioid pattern. This focus shows low-grade endometrioid morphology. Discussion: The differential diagnosis in this case is straightforward. This is an endometrial adenocarcinoma and the only diagnostic issues are whether or not there is a component of uterine serous carcinoma (USC) and, if so, what percentage of the tumour is serous versus endometrioid. To address these issues will require us to consider the following questions: What are the pathological criteria for a diagnosis of USC? How reproducible is the separation of serous carcinoma from endometrioid carcinoma, based on these criteria? What are the implications of the occurrence of mixed endometrial carcinomas (of serous and endometrioid types) on our understanding of the histogenesis of endometrial cancer? Can immunohistochemistry serve as a diagnostic adjunct in the differential diagnosis of serous versus endometrioid carcinoma? What are the clinical implications of the diagnosis of USC with respect to patient prognosis and management? 1. Although the initial recognition of USC as a distinct entity was based on both the architectural features (papillary architecture with broad, often hyalinized stalks) and high-grade cytological features [1], the emphasis more recently is on the cytological features and in recognition of this both the most recent edition of Blaustein [2] and the WHO Blue Book on Tumors of the Breast and Female Genital Organs [3] have dropped the word 'papillary' from the designation "uterine papillary serous carcinoma", shortening it to uterine serous carcinoma. To quote the former reference "What distinguishes serous carcinomas from these other types is the uniformly marked cytological atypia. Thus the designation serous carcinoma rather than papillary serous carcinoma is preferred so that cell-type rather than architecture is emphasised" [2]. There has been, then, a subtle change in diagnostic criteria since this entity was first recognised in 1982. Although it is now recognized that the architecture of USC is variable, it does remain a helpful feature in that the exophytic component of USC typically is papillary, while the invasive component shows ragged or slit-like glandular outlines. In this case, the tumour cells show high-grade nuclear features with prominent nucleoli, occasional macronucleoli, and cellular stratification and tufting, at least focally. As well there is papillary architecture. Other areas of the tumour show glandular architecture with sharply defined glandular lumens and lower grade cytological features. Thus there is a component of USC present, with other areas showing an endometrioid pattern. 2. Given the subtle changes in diagnostic criteria over the years it would be interesting to know how reproducibly pathologists distinguish USC from endometrioid carcinoma. We recently examined interobserver reproducibility in assignment of cell-type of endometrial carcinomas, based on three reviewers examining a single slide from fifty consecutive cases [4]. There was substantial but not perfect interobserver reproducibility in assignment of cell-type (kappa = 0.70). This would undoubtedly be lower if only high-grade tumours were considered, as in common, low-grade endometrial adenocarcinomas of endometrioid-type distinction from USC is not an issue. It is only within the smaller subset of higher grade tumours where this becomes problematic and although this group of tumours has not been examined specifically it is likely that the reproducibility in assignment of cell-type in endometrial cancer is suboptimal. For example, in ovarian cancer, there is very poor reproducibility in assignment of cell-type for high-grade tumours of serous and endometrioid type [5]. As patient management may vary depending on whether we diagnose USC or not, efforts to improve reproducibility are needed. 3. One definition of mixed adenocarcinoma of the endometrium is "a tumour composed of an admixture of a type-1……and a type-2 carcinoma" [3]. As type-1 and type-2 tumours arise by separate pathways this obviously creates problems in understanding the histogenesis of a tumour such as this. The following table highlights some differences between type-1 and type-2 cancers. (It is important to remember that these designations describe "two loose clinicopathologic Table 1. Type-1 versus Type-2 Endometrial Carcinomas   Type-1 Type-2 Hyperestrinism + - Complex atypical hyperplasia + - p53 mutation/loss - + PTEN mutation/loss + - clusters or syndromes" [6] rather than a robust diagnostic terminology that is easily applicable to individual cases.) In data represented at last year's USCAP, we showed that with a panel of immunohistochemical markers, using unsupervised hierarchical clustering analysis, three subsets of endometrial cancer emerge [7]. There is a large group composed of predominantly low grade endometrioid adenocarcinomas that are characterized by ER +ve, p53 –ve immunophenotype. Another smaller group of tumours, consisting predominantly of USC, shows an ER -ve, p53 +ve immunophenotype. The case being presented is typical of a third group that is characterised by positivity for ER but also positivity for p53 and/or other oncogenes not typically seen in low-grade endometrioid carcinoma. It is likely that these tumours start off as lower grade, hormonally sensitive tumours, and through accumulation of new mutations become higher grade. This is in contrast to the classic pathway for type-2 tumours, that arise from endometrial intraepithelial carcinoma, without going through a hormonally dependent phase. In this case, ER and PR immunostaining highlight the lower grade endometrioid component, which stands in contrast to the majority of this tumour, which is ER and PR–ve. 4. There has been increasing attention on the use of immunohistochemical staining to aid in the differential diagnosis of USC versus endometrioid carcinoma. The following table shows the immunophenotype of different subsets of endometrial adenocarcinoma stained in our centre. Table 2. Immunomarkers in Endometrial Carcinoma Marker Total Grade 1&2 endometrioid Grade 3 endometrioid USC & Clear cell p-value p53 16% (25/155) 2.8% (3/107) 38% (13/34) 64% (9/14) <0.0001 ER 89% (139/156) 97% (106/109) 79% (27/34) 46% (6/13) <0.0001 Her2Neu 4.5% (7/155) 0% (0/107) 3% (1/34) 43% (6/14) <0.0001 E2F-1 24% (37/153) 18% (19/106) 32% (11/34) 54% (7/13) 0.008 It is clear that there are highly significant differences in immunophenotype, especially between architecturally differentiated endometrioid carcinomas and USC, but no single marker that provides adequate discrimination. Darvishan et al. found that by discriminant analysis the combination of p53, PR and PTEN were the most useful in distinguishing between USC and endometrioid carcinoma [8]. Only a minority of this tumour is ER and PR+ve, with the majority being ER –ve, PR –ve, and PTEN +ve, supporting the interpretation that this tumour is predominantly USC with a minor component of endometrioid carcinoma. 5. The clinical significance of a diagnosis of USC is surprisingly hard to present concisely. A recent editorial in Cancer summarised the important clinical questions as follows: Is there a significant difference with regard to prognosis between USC and other high-grade uterine lesions? What is the best treatment strategy for women with USC? Are there specific prognostic factors that impact the risk inside of USC disease recurrence? [9] It is beyond the scope of this presentation to focus on the latter two questions, beyond acknowledging that there is no consensus with regards to treatment for patients with USC, and there are no validated prognostic factors other than tumour stage. With regards to the prognostic significance of USC, there is ample evidence documenting that it is a high-grade tumour. It is not clear, however, whether, stage for stage, it is associated with a worse prognosis than grade 3 endometrioid carcinoma. Boruta et al did find that for low-stage tumours, USC is associated with a significantly worse outcome than high-grade endometrioid carcinoma [10]. Creasman et al, in a review of cases reported to FIGO, found no difference between grade 3 endometrioid versus USC for stage I tumours [11]. These two large recent studies continue the trend for conflicting data to emerge related to this important question, suggesting that if there are prognostic differences between USC and endometrioid carcinoma, they are small. The available evidence suggests that for mixed tumours, the prognosis is similar to that of pure USC unless the USC component is a small minority of the tumour. The exact fraction of USC that is required to convey a poor prognosis is uncertain as most studies looking at this issue have lacked sufficient cases to adequately define a cut-off. Boruta et al speculated that with an adequately powered study, even <10% USC component may prove to be prognostically significant [10]. The usual cut-offs currently in use would be to consider tumours with >10% or >25% component of USC to be prognostically equivalent to pure USC. References Hendrickson M, Ross J, Eifel P, et al. Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma. Am J Surg Pathol 1982;6:93-108. Ronnett BM, Zaino RJ, Ellenson Lh, et al. Endometrial carcinoma. In: Kurman RJ, ed. Blaustein's Pathology of the Female Genital Tract. New York: Springer-Verlag, 2002:501-559. Silverberg SG, Kurman RJ, Nogales F, et al. Epithelial tumours and related lesions. In: Tavassoli FA, Deville P. eds. World Health Organization Classification of Tumours: Pathology and Genetics. Tumours of the Breast and Female Genital Organs. Lyon, France: IARC Press, 2003:221-232. Alkushi A, Abdul-Rahman ZH, Lim P, et al. Description of novel system for grading of endometrial carcinoma, and comparison with existing grading systems. Am J Surg Pathol, in press. Cramer SF, Roth LM, Ulbright TM, et al. 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