Selection of endometrial carcinomas for p53 immunohistochemistry based on nuclear features

Introduction

The discovery of good prognostic POLE mutations in endometrial endometrioid carcinomas (EECs) and the improvement of the surrogate immunohistochemical assay for poor prognostic p53 have great potential to refine the risk stratification of patients with endometrial carcinomas [1-4]. There is, however, considerable controversy on how this can be achieved. While some promote reflex testing for the molecular surrogates (POLE, mismatch repair [MMR] status, and p53), others argue for testing of selected cases [5, 6].

Endometrial carcinomas generally have a favorable prognosis with a 5-year relative survival rate of 81% compared to tubo-ovarian high-grade serous carcinomas with approximately 40% [7, 8]. Roughly half of all patients diagnosed with endometrial carcinomas are cured with surgery alone [9]. In contrast, high risk histotypes such as endometrial serous carcinoma (ESC), endometrial clear cell carcinoma (ECCC), and carcinosarcoma (CS) are associated with an aggressive disease course [10, 11]. A newly molecularly defined aggressive histotype derived from endometrioid carcinomas, SWI/SNF-deficient dedifferentiated/undifferentiated endometrial carcinomas (DDEC), shows the most aggressive course among all endometrial carcinomas [12]. The group with the most potential for molecular stratification is the grade 3 EEC (EEC3); several groups have shown that POLE mutations and p53 status further stratify this group with respect to survival [13-16].

Additionally, the recent European Society of Gynaecological Oncology (ESGO), European Society for Radiotherapy and Oncology (ESTRO), and European Society of Pathology (ESP) guidelines recommend integration of certain molecular information into the risk assessment [17]. While molecular classification is encouraged in all endometrial carcinomas, the authors acknowledge that this may not be cost-effective or feasible for all laboratories [17]. However, this also begs the question of whether cases can be selected for p53 status testing without missing abnormal cases that are at risk of progression.

We hypothesized that a substantial proportion of endometrial carcinomas (low grade and low stage) identified based on morphological features do not require additional molecular testing. Our aim was to assess the sensitivity of morphological review to select for cases that require assessment of p53 status. A secondary aim was to model the impact of abnormal p53 (p53abn) status on the ESGO/ESTRO/ESP molecular classification.

Materials and methods Study cohort

We identified and retrieved 306 consecutive endometrial carcinoma hysterectomy specimens from the pathology archives at the Foothills Medical Centre/Tom Baker Cancer Centre in Calgary, Alberta, Canada, received between November 2019 and February 2021. Gynecologic oncology surgery is centralized at the Foothills Medical Centre/Tom Baker Cancer Centre and serves southern Alberta with an overall population of approximately 2 million people. Fourteen cases were excluded due to post-neoadjuvant chemotherapy status (N = 3) or minimal (N = 8) or no residual tumor (N = 3) in the specimen, resulting in a final cohort of 292 cases. Original histotype and grade diagnoses were used, 94% of which were made by a group of seven pathologists with a subspecialty interest in gynecological pathology. Ethics approval was obtained from the Health Research Ethics Board of Alberta (HREBA.CC-20-0400).

p53 immunohistochemistry

p53 immunohistochemistry (IHC) status was clinically reported for 29.5% of cases. For cases not clinically reported, we performed the same p53 IHC on whole formalin-fixed and paraffin-embedded (FFPE) tissue sections of 4 μm thickness at the Department of Pathology and Laboratory Medicine, University of Calgary, Alberta, Canada, using a previously validated protocol [4]. After 30 min of heat-induced pretreatment using the high pH retrieval buffer, the DAKO Omnis protocol H30-10M-30 with the ready-to-use clone DO-7 (catalog # GA61661-2; Agilent Technologies, Santa Clara, CA, USA) was utilized. p53 was interpreted as abnormal/mutation-type when one of the three following patterns were observed: overexpression, complete absence, or cytoplasmic; and as normal/wild-type according to the recommended criteria [3]. Subclonal p53 was defined as the combination of normal with one or more abnormal patterns. The minimal threshold for subclonality was a cluster of at least 12 contiguous cells staining abnormally [18]. The number of subclonally abnormal patterns and their estimated extent as a percentage of the tumor were recorded.

POLE sequencing

Because we hypothesized that finding subclonality on IHC in the context of MMR proficiency may indicate a POLE mutation, selected cases were subjected to POLE sequencing. Twelve cases fulfilled the following criteria: ESGO intermediate or high-intermediate risk group, endometrioid histotype, and subclonal p53 in the context of MMR proficiency or subclonal MMR loss. DNA was extracted from FFPE tumor tissue sections or punches using the QIAamp FFPE DNA Extraction Kit (QIAGEN, Hilden, Germany). A previously described set of three redundant primers covering common hot-spot mutations in exons 9,13, and 14 were used for Sanger sequencing in a tailed-amplicon sequencing strategy [19]. Only mutations previously classified as pathogenic [20] were called POLE mutated (POLEmut).

Expert review

One representative hematoxylin and eosin (H&E)-stained slide per case was reviewed by three faculty gynecologic pathologists blinded to case characteristics. Without prior instructions or training, they were asked to categorize cases into the following five groups: 1, p53 normal/wild-type – no IHC needed; 2, p53 abnormal/mutation-type – no IHC needed; 3, order IHC, favor normal/wild-type p53, rule out abnormal; 4, order IHC, possible subclonal p53; or 5, order IHC, to confirm p53 abnormal/mutant. In addition, they were asked to record the histotype (and grade if applicable) with the option to defer histotyping to after ancillary testing if the tumor showed ambiguous morphology.

Nuclear features review

A subset of study cases (N = 70) was selected for a detailed review of nuclear features, focusing only on EEC or ESC cases representing different patterns of p53 staining (22 p53abn, 10 p53 subclonal, 19 p53 normal/wild-type but with IHC ordered, and 19 p53 normal/wild-type but without IHC ordered by study pathologists). One reviewer blinded to the p53 status recorded the following features: tumor giant cells (absent, focal, conspicuous), pleomorphism (monomorphic, pleomorphic), predominant chromatin pattern (fine, open/pale, vesicular, coarse, hyperchromatic), smudged chromatin (absent, focal, conspicuous), atypical mitoses (absent, focal, conspicuous), and nucleoli (inconspicuous, prominent, cherry red, macronucleoli, macronucleoli with inclusions). The mitotic count per 10 high-power fields was assessed in a hot-spot area. Counts were performed using a Nikon Eclipse Ci-L microscope (×10 eye piece, ×40 objective; Nikon Instruments, Melville, NY, USA) with a field diameter of 0.53 mm and a field area of 0.221 mm2.

Molecular risk groups based on ESGO/ESTRO/ESP

Basic clinicopathological data were abstracted, including age, % of myometrial invasion, stage, lymph-vascular invasion (absent, focal, substantial), squamous differentiation, and clinically performed MMR protein testing. Five prognostic risk groups were defined according to the recent 2020 ESGO/ESTRO/ESP guidelines [17]: low risk (EEC1/2/stage IA), intermediate risk (EEC1/2/stage IB, EEC3/stage IA, non-endometrioid without myometrial invasion), high-intermediate risk (substantial lymph-vascular invasion, EEC3, stage IB, stage II), high risk (stage III–IVA, non-endometrioid with myometrial invasion), and advanced (residual disease, stage IVB). Dedifferentiated carcinomas were included in the non-endometrioid group, although they are derived from endometrioid carcinomas [21].

The Alberta Cancer Registry

For outcome analyses, an independent cohort of 4,546 endometrial carcinomas diagnosed in the province of Alberta, Canada, from 2008 to 2016 was extracted from the Alberta Cancer Registry. Follow-up status was updated up to 21 April 2021. Endometrial cancer-specific death was defined as death from endometrial cancer as coded by the Alberta Cancer Registry. Deaths due to non-cancer causes or other cancers were censored for endometrial cancer-specific death but included in the overall survival. Grade was available for 1751/3518 (49.8%) EECs.

Statistical analyses

Pearson's chi-squared test and analysis of variance were used for categorical and continuous data, respectively. The paired interobserver reproducibility was calculated using Cohen's kappa, and agreement was also expressed in percentages and reported as averages from the three pairs. Nominal logistic regression modeling was used to determine the predictive value of nuclear features considering their interactions. Kaplan–Meier and Cox proportional hazards survival analyses were performed. JMP14.0 software (SAS Institute, Cary, NC, USA) was used for all statistical analyses.

Results Study cohort

We assembled 292 consecutive cases of endometrial carcinoma specimens from November 2019 to February 2021. The cohort consisted of 178 EEC, grade 1 (EEC1, 61.0%), 40 EEC, grade 2 (EEC2, 13.7%), 26 EEC, grade 3 (EEC3, 8.9%), 15 ESC (5.1%), 12 CS (4.1%), 9 ECCC (3.1%), 9 DDEC (3.1%; 8/9 were SWI/SNF-deficient, all with ARID1B/ARID1A co-loss), and one each of mesonephric-like adenocarcinoma, large cell neuroendocrine carcinoma, and squamous cell carcinoma.

The clinicopathological parameters by main histotypes are shown in Table 1. As promoted by the 2020 World Health Organization Classification of Tumours, EEC1 and EEC2 were combined as low-grade EECs, grades 1 and 2 (EEC1/2). Notably, 152 EEC1/2 (52.1% of all cases; 69.7% of EEC1/2) were stage IA and accordingly 147 of EEC1/2 (50.3% of all cases) were low risk by ESGO.

Table 1. Clinicopathological characteristics. EEC1/2 EEC3 ESC CS ECCC) DDEC Total P value N (%) N (%) N (%) N (%) N (%) N (%) Mean age, years (range) 63.8 (35–90) 64.8 (45–83) 71.7 (61–84) 70.8 (62–83) 71.2 (64–84) 68.4 (62–74) 64.9 (35–90) 0.011 Mean myometrial invasion, % (standard deviation) 28.64 (31.6) 41.48 (32.4) 32.2 (39.4) 53.22 (40.3) 19.5 (34.4) 72.88 (34.9) 32.28 (33.8) 0.001 Stage IA 152 (69.7) 12 (46.2) 9 (60.0) 3 (25.0) 4 (44.4) 2 (22.2) 182 (63.0) 0.009 IB 38 (17.4) 9 (34.6) 3 (20.0) 3 (25.0) 0 (0) 2 (22.2) 55 (19.0) II 5 (2.3) 0 (0) 0 (0) 1 (8.3) 3 (33.3) 0 (0) 9 (3.1) IIIA 6 (2.8) 1 (3.9) 1 (6.7) 1 (8.3) 0 (0) 0 (0) 9 (3.1) IIIC1 12 (5.5) 2 (7.7) 0 (0) 4 (33.3) 1 (11.1) 3 (33.3) 22 (7.6) IIIC2 4 (1.8) 1 (3.9) 1 (6.7) 0 (0) 0 (0) 1 (11.1) 7 (2.4) IVB 1 (0.5) 1 (3.9) 1 (6.7) 0 (0) 1 (11.1) 1 (11.1) 5 (1.7) Lymph-vascular invasion Absent 162 (74.3) 11 (42.3) 11 (73.3) 2 (16.7) 9 (100) 0 (0) 195 (67.5) <0.0001 Focal 30 (13.8) 7 (26.9) 1 (6.7) 3 (25.0) 0 (0) 4 (44.4) 45 (15.6) Substantial 25 (11.5) 8 (30.8) 2 (13.3) 7 (58.3) 0 (0) 5 (55.6) 47 (16.3) Unknown 1 0 1 0 0 0 2 Squamous differentiation Absent 165 (75.7) 20 (76.9) 15 (100) 11 (91.7) 9 (100) 8 (88.9) 228 (78.9) 0.04 Present 53 (24.3) 6 (23.1) 0 (0) 1 (8.3) 0 (0) 1 (11.1) 61 (21.1) MMR status Proficient 150 (72.5) 19 (73.1) 7 (100) 4 (100) 4 (100) 3 (33.3) 187 (72.2) <0.0001 Subclonal 7 (3.4) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 7 (2.7) Deficient 50 (24.2) 7 (26.9) 0 (0) 0 (0) 0 (0) 6 (66.7) 63 (24.3) Unknown 11 0 8 8 5 0 32 ESGO/ESTRO/ESP risk groups LR 147 (67.4) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 147 (50.3) <0.0001 IR 30 (13.8) 10 (38.5) 4 (26.7) 2 (16.7) 3 (33.3) 0 (0) 49 (16.8) HIR 18 (8.3) 11 (42.3) 0 (0) 0 (0) 0 (0) 0 (0) 29 (9.9) HR 22 (10.1) 4 (15.4) 10 (66.7) 10 (83.3) 5 (55.6) 8 (88.9) 62 (21.2) Advanced metastatic 1 (0.5) 1 (3.8) 1 (6.7) 0 (0) 1 (11.1) 1 (11.1) 5 (1.7) Total 218 (100) 26 (100) 15 (100) 12 (100) 9 (100) 9 (100) 289 (100)

MMR status was assessed in 259/292 (88.7%) cases from which 70/259 (27.0%) showed MMR deficiency (MMRd). This included 7/259 (2.7%) cases with subclonal MLH1 or PMS2 loss. Seven cases had loss of both MSH2 and MSH6 while six cases demonstrated loss of only MSH6. Hence, at least 13/259 (5.0%) cases were possible Lynch syndrome. The distribution of MMRd by histotype is shown in Table 1. Twelve cases based on IHC subclonality findings of p53 or MMR within the intermediate and high-intermediate risk groups were assessed for POLE mutation status and pathogenic POLE mutations (P286R, P436R, M444K; variant allelic frequency > 30%) were detected in 3/12 (25.0%) cases.

p53 status

p53 status assessed by surrogate IHC was normal/wild-type in 225/292 (77.1%), subclonal in 24/292 (8.2%), and abnormal/mutation-type in 43/292 (14.7%) cases. Among p53abn cases, the following patterns were observed: 34/43 (79.1%) overexpression, 8/43 (18.6%) complete absence, and 1/43 (2.3%) cytoplasmic. The distribution of p53 status by histotype is shown in Table 2. Notably, all 15 ESC and 12 CS were p53abn. p53abn was more common in endometrioid carcinomas with solid architecture (26.9%, 7/26) compared to only 2/218 (0.9%) EEC1/2. The relationship of p53 with MMR and POLE status is shown in supplementary material, Table S1.

Table 2. p53 status by histotype. EEC1/2 EEC3 ESC CS ECCC DDEC Total P value N (%) N (%) N (%) N (%) N (%) N (%) p53 status Normal/wild-type 198 (90.8) 14 (53.9) 0 (0) 0 (0) 5 (55.6) 6 (66.7) 223 (77.1) <0.0001 Subclonal 18 (8.3) 5 (19.2) 0 (0) 0 (0) 0 (0) 1 (11.1) 24 (8.3) Abnormal/mutation-type 2 (0.9) 7 (26.9) 15 (100) 12 (100) 4 (44.4) 2 (22.2) 42 (14.5) Total 218 (100) 26 (100) 15 (100) 12 (100) 9 (100) 9 (100) 289 (100)

Subclonal p53 patterns were exclusively seen in endometrioid carcinomas (EEC1/2, EEC3, DDEC; Figure 1 and Table 2). The average area of tumor demonstrating one or more abnormal subclonal patterns was 27% (range 1–95%). In 12/24 cases, subclonality was focal (<10%). Four out of 24 (16.7%) cases with subclonal patterns showed more than one abnormal pattern in combination with the normal wild-type pattern, and 3/3 tested and therefore informative cases harbored a POLE mutation. Fourteen of 19 (73.7%) informative cases with subclonal p53 were either MMRd or POLEmut (supplementary material, Table S2).

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Cases showing subclonal p53 staining patterns. (A, B) Low-power images of p53 IHC demonstrating geographic distribution of mutation-type overexpression and normal wild-type staining patterns. (C, D) High-power views of p53 IHC illustrating the transition between abnormal and normal p53. (E, F) High-power images of an H&E-stained slide demonstrating no obvious differences in nuclear features between areas with abnormal versus normal p53 patterns.

Prediction of p53 status by H&E morphology

We then asked three observers to predict the p53 status based on H&E morphology and indicate whether they would order p53 IHC. We considered H&E morphology as a screening test and focused on the sensitivity, i.e. probability of true positive, to predict subclonality first. The average sensitivity among the three observers to predict subclonal p53 was only 33.4% (supplementary material, Table S3). As it was so unlikely to predict subclonal p53 on H&E morphology, we focused our analysis on predicting p53abn occurring as a truncal event and grouped subclonal with normal/wild-type. The average sensitivity to predict abnormal p53 was 83.6%, meaning there would be a false negativity rate of 16.4% (supplementary material, Table S3).

We also asked the observers to select cases for which p53 status should be assessed. The three observers chose to order p53 IHC on average in 115/292 (39.4%, range 31.5–54.4%) cases (Figure 2). The average sensitivity to detect p53abn was 98.5%, and the average negative predictive value was 99.6%. Two observers missed the same p53 abnormal case (1/292, 0.3%). This particular case was diagnosed as EEC1 and is illustrated in supplementary material, Figure S1. All three observers ordered p53 for another p53abn case that was originally diagnosed as EEC2 (supplementary material, Figure S2).

image

Left vertical bar shows the p53 status: p53abn (red), subclonal (pink), or normal (dark blue), followed to the right by which cases of the three observers would have ordered p53 IHC (orange) or not ordered (light blue). Note the single p53 abnormal case where IHC was not ordered. The first column illustrates p53 abnormal cases for which p53 IHC was ordered. The cases show hyperchromatic nuclei, multinucleated tumor giant cells, atypical mitoses, macronucleoli, and smudged chromatin. The middle column represents normal p53 cases for which p53 IHC was ordered, where the cases showed similar cytologic features compared to the left column. The right column shows cases with normal p53 for which p53 IHC was not ordered. The nuclear features demonstrate fine, open, or vesicular chromatin. Squamous differentiation may be seen. Degenerative smudged chromatin is a common feature, particularly at the surface of the tumor (lower right image).

Morphological features of p53 abnormal cases

One reviewer blinded to the mutational data reviewed predefined nuclear features and mitotic activity of 70 selected cases. All features were significantly different across the p53 status but none of the individual features were perfectly sensitive in identifying p53abn (supplementary material, Table S4). However, using a nominal logistic regression model, the combination of features perfectly separated p53abn from normal cases (area under the curve of 1.000). While all features significantly contributed to the prediction, the extent of smudged chromatin, presence of pleomorphism, presence of atypical mitosis, and presence of tumor giant cells were the four most important features (Figure 2 and supplementary material, Figures S3 and S4).

In addition to the nuclear features, squamous differentiation was almost mutually exclusive to the presence of p53abn. Only two cases, one CS and one EEC3, showed both squamous differentiation and p53abn, and the EEC3 case is illustrated in supplementary material, Figure S5. However, the sensitivity of squamous differentiation appears to be limited because it only occurred in 21.1% of endometrial carcinomas (supplementary material, Table S5).

Interobserver agreement on histotype and tumor grade

The three observers were also asked to assess histotype information. When cases selected for requiring IHC for diagnosis were excluded, which on average represented 37/292 (12.7%) cases, the average interobserver agreement for histotype when grouped into ESGO groups (low-grade endometrioid, high-grade endometrioid, and non-endometrioid) was excellent with an average kappa coefficient of 0.818 (average interobserver agreement 95.3%, range 94.4–96.0%), where 91.2% (N = 31/34) of all disagreements were between low-grade and high-grade endometrioid carcinomas.

ESGO risk groups with known molecular p53 status

The distribution of ESGO risk groups by p53 status and histotype is shown in Figure 3. Changes due to known p53 status occurred in 7/292 (2.4%): 2 were upgraded to intermediate risk (IR) from low risk (LR), and 5 to high risk (HR) with 1 from IR and 4 from high-intermediate risk (HIR) (Figure 3C). However, adjuvant chemotherapy would only be added for the one case that was changed from IR to HR because the other four HIR cases, which were EEC3, would have been already offered adjuvant chemotherapy.

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(A) Relationship between histotype and p53 status. (B) Relationship between histotype (column designation same as for A; for color coding, see C) and the ESGO risk groups. Note that approximately half of all cases are EEC1/2 and LR; a disproportionally high number of EEC3 are in the HIR group; a high proportion of non-endometrioid and dedifferentiated carcinomas are in the HR group. (C) Sankey diagram to illustrate changes in risk groups based on p53 status: Two cases to IR and five cases to HR.

Model of ESGO risk groups with potential changes due to known POLE mutation status

POLE mutation status information has the potential to change the risk assignment for cases in the IR/HIR group (N = 78/292, 26.7%). By selecting cases from the IR/HIR group using subclonality in the absence of MMRd as the potential cause, we detected POLE mutations in 3/12 cases, downgrading 1 case from HIR to LR and 2 from IR to LR. However, not all IR/HIR cases were tested for POLE. Assuming an unbiased distribution and a POLE mutation prevalence of 10% in unselected endometrial carcinomas based on 12.2% reported in a large retrospective cohort, from which 82% are now considered pathogenic mutations [22, 23], we estimated that approximately 8/78 IR/HIR cases would harbor POLE mutations. Hence, an estimate of 8/292 (2.7%) cases could be potentially reclassified in terms of ESGO categories based on molecular information. However, as the IR group usually does not receive adjuvant therapy, we alternatively focused on the HIR group, which is more commonly offered adjuvant therapy. Within the HIR group, 15 EEC1/2 and 5 EEC3 were assigned to HIR based on substantial lymph-vascular invasion, 6 cases were stage IB EEC3, and 3 were stage II EEC1/2. While the EEC1/2 cases would receive some form of radiation, only the 11 EEC3 in this subgroup would be considered for chemotherapy with an estimated prevalence of 1 or 2 POLEmut tumors.

Population-based survival of patients with EEC1/2

The Alberta Cancer Registry recorded 4,546 endometrial carcinoma diagnoses during the period from 2008 to 2016. The annual numbers increased by 56% from 386 in 2008 to 603 in 2016, during which time there was a population growth of 17% [24]. Among all cases, 3,518/4,546 (77.4%) were diagnosed as endometrioid carcinomas (supplementary material, Figure S6). Among those, 273 were grade 3; however, grade was not available for 1,767/3,518 (50.2%) cases. Despite this limitation, we performed survival analyses for 3,245 endometrial carcinomas, predominantly grade 1 or 2 but containing approximately 270/3,245 (8.3%) potential grade 3 cases. We refer to this cohort as EEC1/2*. Of 3,245 EEC1/2* cases, 2,063 (63.6%) were diagnosed at stage IA. The 5- and 10-year overall survival of stage IA, EEC1/2* cases were 95.3% (SE 0.5) and 86.3% (SE 0.1), respectively (Figure 4). The endometrial cancer disease-specific 5- and 10-year survival of this group were 98.5% (SE 0.3) and 96.4% (SE 0.8), respectively, with 41 disease-specific deaths in 2,058 cases (Figure 4).

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(A) Overall survival of EEC1/2* by stage. EEC1/2* stage IA shows a 5-year overall survival of 95.3% (SE = 0.5) and a 10-year overall survival of 86.3% (SE = 0.1). (B) Disease-specific survival of EEC1/2* by stage. EEC1/2* stage IA demonstrates a 5-year endometrial cancer disease-specific survival of 98.5% (SE = 0.3) and a 10-year endometrial cancer disease-specific survival of 96.4% (SE = 0.8). *Grade information was not available for a subset of cases (please see main text).

Discussion

Our study shows that pathologists can reliably select endometrial carcinomas for ancillary p53 testing based on nuclear features with a negligible false negativity rate. With an acceptable interobserver variability regarding the rate of ordering, slightly more than half of all endometrial carcinomas do not require p53 testing. This group largely overlaps with the ESGO/ESTRO/ESP low risk group defined by EEC1/2 and stage IA disease. In our population-based outcome registry, we confirm the excellent 5-year disease-specific survival of 98.5% for this subset. This is consistent with the conventional wisdom that many endometrial cancer patients are cured by surgery alone. We believe that there is limited advantage of universal reflex testing for p53 in endometrial carcinomas when pathologists are aware of the expected nuclear features in cases with abnormal p53 and the importance of this diagnostic and prognostic marker [25].

The rate of ordering p53 varied among the observers roughly between 40 and 60%, which was slightly higher than the original clinical ordering rate of 29.5%, possibly due to increased awareness of the diagnostic and prognostic importance of p53. The differences among observers may be related to levels of experience or thresholds, e.g. a more generous ordering to detect more subclonal cases. Nevertheless, only one challenging p53abn EEC1/2 would have been ‘missed’. This prognostic oxymoron occurred only twice in our series. Of 42 p53abn cases, 40 were of congruent high-grade endometrioid or non-endometrioid histotype. The one ‘missed’ p53abn EEC1 occurred in a young woman, with overwhelmingly bland nuclear features and only scattered smudged chromatin. If this case had not been confined to an endometrial polyp but had shown myometrial invasion, it would pose a dilemma whether to administer chemotherapy based purely on p53abn status [26]. According to The Cancer Genome Atlas, there is a group of low copy number endometrial carcinomas that harbor TP53 mutations as single events, in the absence of high copy number status [1]. Perhaps, copy number analysis may be warranted in these cases. The second p53abn case represents the danger of underdiagnosing a p53abn case as EEC2 despite severe nuclear atypia: on histotype study review, this case was labelled as high-grade endometrioid carcinoma by the observers. Overall, our recent rate of p53abn EEC1/2 is much lower compared to the historical cohorts [27, 28]. This shows the impact of pathologists as rational decision-makers when adapting p53 IHC in their diagnostic approach [

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