- Discuss individual clinician’s preferences for moving to a binary grading scheme, while emphasizing its potential benefits.
- As a bridge toward uniform adoption of the binary FIGO grading scheme, it is acceptable to report both the binary grade and the FIGO grade [i.e. low-grade EEC (FIGO grade 2)].
- Going forward, we recommend the adoption of the binary FIGO grading system, when appropriate. Existing reporting data sets/synoptic templates/checklists for reporting endometrial carcinoma will need to be revised and updated.
Anticipating the future incorporation of The Cancer Genome Atlas (TCGA) classification system into endometrial cancer diagnosis and prognostication, it remains uncertain whether grading will remain an important clinical discriminator for tumors, especially in the polymerase E (POLE) category.
TOPIC 2: HOW TO SYNTHESIZE GENOMICALLY DEFINED TYPES OF ENDOMETRIAL CARCINOMA WITH THEIR MORPHOLOGIC, IMMUNOPHENOTYPIC, AND CLINICAL CHARACTERISTICS
For the purposes of this review, FIGO grade 3 endometrioid, serous, and clear cell carcinomas will be considered “high-grade endometrial carcinomas” (HGECs). Undifferentiated and dedifferentiated carcinomas and carcinosarcomas are dealt with elsewhere in this review series.
Various studies have shown that an HGEC diagnosis is not highly reproducible 21,22. This implies that: (1) diagnostic criteria are insufficiently detailed for practical use; (2) and/or diagnostic criteria were developed empirically and may not be evidence based; (3) and/or uniform diagnostic criteria are not utilized in practice. This lack of reproducibility is significant in that the reported clinicopathologic and molecular data concerning HGEC may not be readily interpreted because of differences in case series based on inconsistent diagnoses. Examples of the latter problem are the lack of consensus regarding whether grade 3 endometrioid carcinomas are “type II endometrial carcinomas” and whether they are as aggressive as serous carcinomas.
There have been a number of attempts to refine diagnostic criteria using evidence-based approaches. Among other groups, the MSK group used immunohistochemical and clinical evidence to describe gland-forming serous carcinomas that are distinct from FIGO grades 1 and 2 endometrioid carcinomas 4,23 (Fig. 2); the MD Anderson group used supporting clinical evidence to separate undifferentiated carcinomas from grade 3 endometrioid carcinomas; 24,25 the Massachusetts General Hospital group used supporting clinical evidence to separate corded and hyalinized endometrioid carcinomas from carcinosarcomas; 26 and the Vancouver group used a genomically based classifier to refine diagnostic criteria that more precisely separate grade 3 endometrioid carcinoma with a papillary/villoglandular or solid architectural pattern from serous carcinomas with similar architecture 27. These latter criteria also have clinical relevance.
Publication of the TCGA endometrial carcinoma data set has provided pathologists a unique opportunity to further refine diagnostic criteria for serous and grade 3 endometrioid carcinomas 28. These data do not include information about clear cell carcinoma, undifferentiated/dedifferentiated carcinoma, or carcinosarcoma.
Unlike the Bokhman “type I versus type II” classification of endometrial carcinoma, TCGA data indicated 4 genomic types of endometrial carcinoma. These subcategories of endometrial carcinoma were identified based on their genomic architecture. They include the following: POLE mutated/ultramutated; microsatellite instability-high (MSI-H)/hypermutated; copy number low (conceptually similar to “type I” endometrial carcinoma); and copy number high (presence of many genomic amplifications and/or deletions), also known as “the serous-like group,” which is similar to “type II” endometrial carcinoma. The copy number low group has the lowest mutation burden, whereas the hypermutated and ultramutated groups have, on average, 10-fold and 100-fold more mutations, respectively; the higher mutation burdens in these latter 2 groups are secondary to defects in mismatch repair (MMR) and POLE-mediated DNA repair, respectively. Note that mutations in TP53 were a distinguishing feature, when comparing copy number high versus copy number low groups (Fig. 3), once POLE and MSI tumors were excluded.
The overwhelming majority of low-grade (FIGO grades 1 and 2) endometrioid carcinomas map to the copy number low and MSI-H categories. Grade 3 endometrioid carcinomas are highly heterogenous, as they are found in every genomic category, and are least represented in the copy number low group. Endometrioid carcinomas mostly have an endometrioid genomic profile, with or without TP53 mutation/high copy number alterations, whereas serous carcinomas have TP53 mutations/high copy number alterations without additional mutations characteristic of endometrioid carcinomas.
Assigning a tumor to the serous category requires the presence of a TP53 mutation/abnormal “mutation pattern” p53 immunostaining, the absence of endometrioid-type mutations (although this point is debatable, as some low-grade endometrioid carcinomas with PTEN mutations acquire TP53 mutations during tumor progression, along with “serous” morphology), and the presence of high copy number alterations. All serous carcinomas map to the copy number high, “serous-like” category, as do approximately one quarter of grade 3 endometrioid carcinomas. Although TCGA data are incomplete, they were sufficient to generate a Kaplan-Meier survival curve showing that POLE carcinomas have outstanding clinical outcomes irrespective of grade and perhaps stage. MSI-H and copy number low tumors have intermediate clinical risk, and the serous-like group, unsurprisingly, has the worst outcomes.
The first approach to extracting this information for practical diagnostic use was to describe the morphology of endometrioid carcinomas in each group. Although there are many characteristic features of tumors from the POLE 29,30 (peritumoral lymphocytes, tumor infiltrating lymphocytes, and intratumoral heterogeneity, tumor giant cells), MSI-H 31,32 (peritumoral lymphocytes, tumor infiltrating lymphocytes, and intratumoral heterogeneity), and serous-like groups (diffuse high nuclear grade), there is a general feeling that these features are incomplete, partly overlapping, and may not be able to be applied reproducibly. A particular problem that is not adequately addressed with a morphology-only approach is the existence of morphologically ambiguous tumors that reside in the POLE, MSI-H, and serous-like categories (but not the copy number low category) 33, and many POLE endometrioid carcinomas have components or subclones that are histologically similar to serous carcinomas. Given the particular heterogeneity of grade 3 endometrioid carcinomas, we were faced with the following questions and answers:
- Are serous-like grade 3 endometrioid carcinomas, as genetically defined, really endometrioid based on morphologic features/light microscopic examination?
- In some cases, they can show unequivocally endometrioid morphologic features, for example, squamous differentiation 34. Many are histologically ambiguous, as mentioned above, making the distinction between serous-like grade 3 endometrioid and serous carcinomas difficult or impossible; this also raises the question of whether there is a justification for attempting to separate these tumors.
- Are serous-like grade 3 endometrioid carcinomas clinically interchangeable with serous carcinomas?
- TP53-mutated grade 3 endometrioid carcinomas, compared with those lacking TP53 mutation, recur more frequently (T. Bosse et al., Am J Surg Pathol 2018, in press) 35. Detailed analyses indicate that TP53-mutated grade 3 endometrioid carcinomas (i.e. serous-like grade 3 endometrioid carcinomas) have a high-risk profile, with only rare exceptions. Although there are few such cases, it appears that TP53-mutated grade 3 endometrioid carcinomas from the POLE category retain the clinically low-risk profile of POLE endometrioid carcinomas that lack a TP53 mutation. There are sparse data suggesting that serous-like grade 3 endometrioid carcinomas metastasize to the peritoneum less frequently than serous carcinomas, but this requires validation. Currently, there is no compelling evidence to support that serous-like grade 3 endometrioid carcinomas are significantly clinically different than serous carcinomas, and unless there is improvement in diagnostic reproducibility for these 2 categories, it is difficult to envision such a distinction being a variable that can be used to guide patient treatment decisions.
- Can p53 immunohistochemistry alone be used to identify those grade 3 endometrioid carcinomas that belong to the copy number high group?
- No. As aberrant p53 staining is not confined to tumors in the serous-like category, additional ancillary tests would be necessary to exclude a TP53-mutated POLE or MSI-H grade 3 endometrioid carcinoma. Of interest, many TP53 mutations found in the POLE and MSI-H categories involve portions of the TP53 gene that are not mutated in serous carcinomas 36, leading to imperfect correlation between TP53 mutation and aberrant p53 staining in these groups of tumors.
- Is there a better assay than p53 immunohistochemistry to determine which grade 3 endometrioid carcinomas are serous-like?
- p53 immunohistochemistry was compared with TP53 mutational analysis and fluorescent in situ hybridization for copy number analysis and found to be equivalent in identifying the copy number high serous/serous-like group 36 (see below). Since aberrant p53 immunostaining is not synonymous with a copy number high tumor, other methods may prove to be superior surrogate markers of this genomic subtype. Aneuploidy, which is intuitively a good candidate marker of copy number high tumor, frequently was found to be present within the MSI-H and POLE categories, so testing to exclude MSI-H and POLE is, at this time, necessary before separation of copy number high and low tumors 37.
We used TCGA data to extract surrogate markers for the genome-wide analyses used to classify endometrial cancers into 1 of the 4 genomic categories, and then validated the classifier in an independent set of cases; this classifier, referred to as the ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer) classifier, includes MMR immunostaining (rather than MSI analysis, as was used in TCGA), sequencing of POLE exonuclease domains (rather than quantification of mutations genome wide) and p53 immunohistochemistry (rather than quantification of copy number alterations genome wide or TP53 mutational analysis), and was able to recreate the 4 prognostically significant genomic subsets of endometrial carcinoma 36,38 (Table 3). An identical strategy independently used by the group from Leiden was applied to clinical trial cases and also demonstrated that the 4 molecular subtypes are of prognostic significance 39.
On the basis of this information, we propose a multimodality classification system of HGECs that separates the 4 genomically defined groups of HGEC using only the following assays (Table 3 and Fig. 4): POLE mutational analysis and immunohistochemistry for p53 and the DNA MMR markers PMS2 and MSH6. As noted previously, this algorithm has been validated in 3 independent case series, including in Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) clinical trial cases 36,38,39.
This multimodality molecular classification system may not be feasible in many pathology laboratories, especially in resource-restricted areas of the world. In resource-rich regions of the world, the main impediment to making this proposal the standard of care is not only buy-in from our clinical colleagues and the availability of POLE mutational testing, but also the recognition by regulatory authorities that this is a crucial, medically valid, and necessary assay (and in the United States, this means being worthy of reimbursement by insurance companies).
For laboratories that do not have the means to perform POLE mutational analysis, it will still be possible to identify the MMR-deficient (MMR-D) and p53 abnormal groups using immunostaining with a 3-marker panel (PMS2, MSH6, and p53). The ∼8% of endometrial cancers in the POLE group will not be identified, and separating these frequently histologically high-grade and FIGO stage I carcinomas from serous carcinomas will remain a problem. At this time, we do not know if the favorable prognosis of the histologically high-grade POLE-mutant endometrial cancers reflects indolent biology, effective most immunity, or a good response to treatment, and until this is resolved through clinical trials, conventional therapy, based on current risk assessment (eg, European Society of Medical Oncology guidelines), will continue to be implemented for these tumors, and their prognosis will remain excellent.
There is also some resistance to performing universal DNA MMR protein immunohistochemistry. The clinical argument for universal MMR testing is compelling, and this approach is recommended in the NCCN guidelines (NCCN guideline version 1.2018) for Lynch syndrome triage and in another review in this issue. There are other benefits to universal testing, as it may be used as an ancillary diagnostic test (i.e. to help exclude a serous carcinoma or to help assign endometrial rather than cervical primary site) and, in the setting of recurrent endometrial carcinoma, it provides therapeutic prediction for the use of immunotherapy.
What about clear cell carcinomas? Work from the MSK group indicates that endometrial clear cell carcinomas are just as heterogenous as grade 3 endometrioid carcinomas. There are POLE hotspot mutated, MSI-H, copy number low, and copy number high (serous-like) clear cell carcinomas, and those in the copy number low and serous-like clusters have significantly worse clinical outcomes compared with the others 40. Once this work is confirmed by other groups, we would provisionally propose that clear cell carcinomas be classified based on the same multimodality system as that of grade 3 endometrioid carcinomas.
Related and Unresolved Issues
Current treatment paradigms rely on the classic parameters of tumor histotype, especially the distinction between endometrioid versus nonendometrioid histology, and grade (i.e. FIGO grade as applied to endometrioid-type tumors). Therefore, any recommended terminology using the genomic classifier must continue to clearly include these parameters for the foreseeable future, although unpublished data from MSK and recently published data from Vancouver 36,38 indicate that prognosis is independent of histotype (in a multivariate model), and instead depends on stage, grade, and genomic classification. We would therefore recommend that reporting the genomic classifier be clearly noted, as well as the analyses used to assign the classification. For example:
Endometrioid endometrial carcinoma, FIGO grade 3. Genomic classifier group: Copy number high (p53 abnormal by immunostaining)
Mixed endometrioid and serous carcinoma. Genomic classifier group: POLE (POLE exonuclease mutation identified by sequencing)
When to Utilize the ProMisE Algorithm
Universal MMR testing should be performed on biopsy/curettage material in patients desiring fertility-sparing conservative medical management, since the recognition of Lynch syndrome in such cases would encourage prophylactic hysterectomy and bilateral salpingo-oophorectomy at the appropriate age. These tests should also be considered in biopsy/curettage material when treatment planning depends on genomic classification. This is not yet a standard practice, although selected gynecologic pathology teams are currently using this approach. It should also be noted that antigen preservation may be superior in biopsies/curettages compared with hysterectomy specimens, and that molecular classification based on the biopsy does accurately reflect the findings in the subsequent hysterectomy specimen 41,42.
Tumor grading in the context of molecular subtype is a complex issue. FIGO grading is presumably only appropriate for tumors that are within the MSI-H/MMR-D or copy number low (also referred to as tumors with no specific molecular profile, as they lack POLE mutation, MMR deficiency, or abnormal p53 immunostaining) groups, as these most clearly correspond to the “classic” endometrioid tumors. FIGO grading in these 2 groups may provide the prognostic information that one expects from older, histology-based clinical studies, and would allow them to be provisionally placed into low-risk and high-risk groups, although this remains to be studied. In contrast, tumors in the copy number high/p53 abnormal group (serous-like) clearly belong in the “high-risk” group, in which no histologic grading is appropriate. There is likely no value in assigning grade to tumors in the POLE group, for which studies indicate a survival rate approaching 100%. A significant proportion of these tumors morphologically would be considered high grade and could potentially be treated with unnecessary lymphadenectomy and chemotherapy. The intersection of genomic classification, surgical staging, and delivery of adjuvant therapy is not yet resolved.
Some researchers strongly believe that endometrial carcinomas are more heterogenous than their ovarian counterparts (i.e. more likely to contain true mixed tumors). Van Esterik et al. 43 demonstrated that this morphologic heterogeneity does not extend to the level of genomic abnormalities, that is, genomic subtype is uniform throughout.
Many tumors assigned to the MMR-D/MSI-H and POLE categories demonstrate significant intratumoral morphologic heterogeneity, whereas tumors in these groups and the p53 abnormal/copy number high cluster also typically show morphologic ambiguity 44,45 that gives rise to diagnostic problems 33. Hence, where does intratumoral heterogeneity stop and mixed epithelial carcinoma begin? Given emerging data 46 indicating that most mixed epithelial carcinomas represent different morphologic expressions of 1 clonal tumor, one is left with the impression that mixed epithelial carcinomas may not be diagnosed with any frequency in the future, apart from some exceptional situations, for example, grade 1 EEC giving rise to undifferentiated carcinoma. Also, what do we make of the assertion that any type II component of a mixed epithelial carcinoma places the tumor in a clinically high-risk category? It is probable that most “mixed epithelial carcinomas” with poor clinical outcomes represent heterogenous or morphologically ambiguous p53 abnormal/copy number high tumors. Other examples, however, likely represent heterogenous or ambiguous POLE or MSI-H tumors whose clinical behavior is baseline or favorable despite the histologically high-grade appearance of 1 portion of the tumor. These concepts need to be developed further and validated with good clinical, morphologic, and genomic data. For the time being, it is reasonable to continue to follow the ISGP recommendation that grading mixed epithelial carcinomas (such as mixed endometrioid and serous or clear cell carcinoma) be based on the highest grade component (discussed in another review in this issue). However, it also must be recognized this practice may not be clinically informative in MSI-H and POLE tumors.
- TCGA classification separates prognostically favorable from unfavorable types of FIGO grade 3 endometrioid carcinoma. Furthermore, it separates serous carcinoma from hitherto unknown types of clinically low-grade endometrial carcinomas that can morphologically mimic serous carcinoma to a substantial degree (eg, POLE, MMR-D). The classification is powerfully prognostically relevant and is independently associated with clinical outcomes, unlike histologic subtype assignment based on examination of hematoxylin and eosin slides alone.
- In laboratories undertaking genomic classification, this should be reported in conjunction with grade and histotype.
- Since the practical application of TCGA classification relies on universal POLE gene sequencing and universal immunohistochemistry for p53 and 2 or 4 of the DNA MMR markers, reimbursement and financial issues need to be considered. We do not expect significant problems with implementation once regulatory authorities understand the potentially enormous clinical impact of these assays.
- Once regulatory and financial issues are resolved, the most efficient workflow for accomplishing the ancillary tests, interpreting them and incorporating them into a diagnostic report that synthesizes morphology, POLE genotype and immunophenotype will need to be defined.
- As accumulating data already suggest modifications to the “high-intermediate risk category” of uterus-confined endometrial carcinoma based on ProMisE/TCGA cluster assignment, clinical trials to validate its usefulness for clinical applications will be needed.
- It is uncertain whether it will continue to be necessary to distinguish serous-like (p53 abnormal/copy number high) FIGO grade 3 endometrioid, serous, and clear cell carcinomas.
- Although there are data indicating that the ProMisE classifier reliably assigns matched tumors from preoperative and hysterectomy specimens to the same genomic group 40,41, it is uncertain whether preoperative ProMisE/TCGA classification (using biopsy or curettage material) can be used to triage patients to different types of staging surgery. For example, patients with POLE-mutant tumors might not need comprehensive surgical staging. Similarly, patients with serous and serous-like carcinomas may not benefit from comprehensive surgical staging, since nearly all will require adjuvant chemotherapy, and it is possible that comprehensive surgical staging may only be applicable to the remaining categories.
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Keywords:©2019International Society of Gynecological Pathologists
Endometrial cancer; FIGO grade; The Cancer Genome Atlas; TCGA; Genomic subtype