In 2011, the Australasian and United Kingdom Royal Colleges of Pathologists, the College of American Pathologists and the Canadian Association of Pathologists, in association with the Canadian Partnership Against Cancer, formed the International Collaboration on Cancer Reporting (ICCR). The goal of the ICCR was to reduce the global replication of cancer data set development by different international institutions that commission, publish and maintain standardized cancer reporting data sets. Although the classification of cancers has been internationally standardized through the publication of the World Health Organization (WHO) Tumor Classification series, such standardization was not previously undertaken for international harmonization of cancer pathology reporting. Some countries lack sufficient pathologist workforce and resources to develop or implement standardized cancer reporting protocols and benefit from the availability of internationally accredited data sets. For countries which lack the resources to develop their own cancer reporting data sets, ICCR reporting standards provide a means of accomplishing international benchmarks for pathology reporting with minimal investment.
The ICCR now includes sponsor organizations from 18 pathology organizations across 6 continents. The ICCR has partnered with the International Agency for Research on Cancer (IARC) to develop coordinated international data sets synchrony with the WHO Blue Books. The ICCR has also formed strategic partnerships with the organizations responsible for tumor staging [the Union for International Cancer Control (UICC), American Joint Committee on Cancer (AJCC), the International Federation of Obstetricians and Gynecologists (FIGO], as well as the International Society of Gynecological Pathologists (ISGyP), the European Society of Pathology (ESP), and the European Organization for Research and Treatment of Cancer (EORTC).
To date, the ICCR has published 56 cancer data sets, including those related to other gynecological neoplasms, namely cervical, ovarian/fallopian tube/primary peritoneal, vaginal and vulval carcinomas, uterine mesenchymal neoplasms and trophoblastic neoplasms. ICCR data sets are evidence-based and have been produced by a panel of internationally recognized expert pathologists and at least one clinician in each specific field. The data sets have been subjected to international open consultation, and all ICCR data sets are freely available for worldwide noncommercial use at the following website: http://www.iccr-cancer.org/datasets. The data set development procedures have been previously outlined in peer-reviewed journals 1–3.
Endometrial cancer is one of the most common gynecological cancers worldwide and the endometrial cancer data set was 1 of 4 original ICCR data sets produced in 2011. Since then, there have been significant advances in the field of endometrial cancer, including an updated WHO Classification of Female Genital Tumors published in 2020 and the Cancer Genome Atlas (TCGA) molecular classification of endometrial cancers published in 2013 4. This necessitated a major revision of the ICCR Endometrial cancer data set which is the subject of this review.
The revision of the ICCR Endometrial cancer data set was to update the essential pathologic data required for cancer diagnosis, staging, prognosis and patient management. The updated data set ensures that histopathology reports include all contemporary and relevant information presented in a consistent, concise format in accordance with current international standards. Unified content and terminology allow for meaningful international comparison, benchmarking and epidemiological analysis.
The ICCR has developed and ratified a set of standard operating procedures outlining data set development (described in earlier publications) 1–3, as well as the selection process, roles and responsibilities of the chair, expert panel members, the ICCR Dataset Steering Committee (DSC) representative/s on the panel, and the project manager. The DSC appointed a chair to develop the updated data set for reporting endometrial cancer, and they identified 11 other expert gynecological pathologists who, together with a gynecological oncologist, the ICCR Series Champion and project manager, formed the Endometrial Cancer Dataset Authoring Committee (DAC). The Series Champion provided guidance and support to the chair of the DAC regarding ICCR standards and ensured harmonization across data sets, while the project manager coordinated the development process.
Publication of the 5th edition of the WHO Classification of Female Genital Tumors in 2020 5 prompted the ICCR to identify four gynecological data sets that were required for development and three for updating. A collaboration between the ICCR and the ISGyP was formed to develop the suite of gynecological cancer data sets. All data sets were subjected to an 8-wk period of international open consultation. The open consultation process consists of providing international stakeholders, which comprise pathology societies and various cancer organizations, with draft data sets for review and comment.
As discussed, the ICCR Endometrial cancer data set was one of the original data sets developed in 2011 and it was decided that a major rewrite was timely. A number of online meetings and email discussions were held, and DAC members were tasked with reviewing and updating all sections of the data set. This was then consolidated and reviewed by the expert panel via a number of online meetings and email discussions. The elements under discussion by the expert panel comprised core and noncore elements. Core elements are defined as those which are unanimously agreed by the panel to be essential for the histological diagnosis, clinical management, staging or prognosis of endometrial cancer. Noncore elements are defined as non-essential but clinically important and recommended as good practice and should ideally be included in the data set but which are not yet validated or regularly used in patient management. Evidentiary support at Level III-2 or above (based on prognostic factors in the National Health and Medical Research Council (NHMRC) levels of evidence document and defined as “Analysis of prognostic factors among persons in a single arm of a randomized controlled trial”) 6 is required to support core elements. Rarely, where Level III-2 evidence is not available, an element can be categorized as core with unanimous agreement of the expert panel. The summation of the core elements is the minimum information which should be included in the pathology report. In many jurisdictions around the world, most of the noncore elements will also be included in the pathology report.
Each data set element has an accompanying commentary which comprises explanatory text, diagrams or tables to: (i) clarify core and noncore elements, (ii) provide relevant evidence, and explain why each element is necessary (eg, how does it assist with diagnosis, clinical management or prognosis of the specific cancer); and (iii) define the way each element should be reported. The core elements and associated commentaries are presented below, followed by the noncore elements and commentaries. Where data set items include an admixture of core and noncore elements, these are included in the core data elements section of this article.
Scope of the Data Set
The data set has been developed for the pathology reporting of resection specimens of endometrial cancers, including carcinosarcomas. It is not applicable for small endometrial biopsy specimens. Hematopoietic neoplasms, mesenchymal neoplasms, adenosarcomas, malignant melanomas, other nonepithelial malignancies, and metastatic tumors are excluded from this data set. Adenosarcoma and other mesenchymal neoplasms are included in the ICCR Uterine malignant and potentially malignant mesenchymal tumors data set 7.
The updated edition of the ICCR Endometrial cancer data set includes changes to align the data set with the 2020 WHO Classification 5. The ICCR data set includes 5th edition Corrigenda, June 2021 8.
Core Data Elements
A list of the core elements for the reporting of endometrial carcinomas is presented in Table 1 and described below.
TABLE 1 -
Core data elements for pathological reporting of carcinoma of the endometrium
||Histologic tumor type*
||Histologic tumor grade
|| Mismatch repair testing
|| Extent of lymphovascular invasion
|| Site(s) of involvement
|| Site(s) of involvement
|| Margin status for paracervical soft tissue margin
|| Margin status for ectocervical/vaginal cuff margin
||Lymph node status
|| Maximum dimension of largest deposit in regional node
|| Sentinel, pelvic and para-aortic regional node(s)
|| Number of nodes examined
|| Number of positive nodes
|| Degree of involvement
||Pathologically confirmed distant metastasis
||Provisional pathologic staging
|| FIGO or TNM staging (UICC/AJCC 8th edition)
*Histologic tumor type is core; neuroendocrine carcinoma subtype, epithelial and sarcomatous percentage, homologous or heterologous is considered noncore.
Reporting of whether ancillary studies were performed, and any mismatch repair testing undertaken is a core element; reporting of other immunohistochemistry, molecular findings, the Cancer Genome Atlas (TCGA)-based molecular classification, other tests and representative blocks for ancillary studies are considered noncore (Table 2
Specification of presence or absence of myometrial invasion and whether <50% or ≥50% is core; pattern of myometrial invasion, absolute percentage of myometrial wall thickness invaded by carcinoma and distance of myoinvasive tumor to serosa are considered noncore (Table 2
Cervical stromal involvement is core; depth of cervical stromal invasion and percentage of cervical stromal invasion are considered noncore (Table 2
Involvement of paracervical soft tissue margin and ectocervical/vaginal cuff margin is core; the distance of tumor to the closest margin is considered noncore (Table 2
AJCC indicates American Joint Committee on Cancer; FIGO, International Federation of Obstetricians and Gynecologists; UICC, Union for International Cancer Control.
Depending on the presumed extent of spread of the carcinoma as assessed clinically or radiologically, either a simple or radical hysterectomy is performed, which may or may not be part of a staging procedure. A simple hysterectomy is defined as the removal of the total uterus (including the cervix). Radical hysterectomy entails en bloc resection of the uterus and cervix along with the surrounding parametria, upper vagina and uterosacral ligaments 9,10. These procedures can either be performed through laparoscopy, robot-assisted laparoscopy or laparotomy 11. Finally, a debulking procedure can be performed, if the tumor is macroscopically disseminated, to remove all visible tumor. Pelvic exenteration is not a frequent procedure, but is occasionally used in advanced and recurrent endometrial cancer 12,13, and is recognized in the European Society of Gynecological Oncology (ESGO)-European Society for Radiotherapy and Oncology (ESTRO)-European Society of Pathology (ESP) guidelines 14. In some instances, malignancy can be found in a morcellated hysterectomy specimen 15. Morcellation should be avoided whenever there is a suspicion of endometrial carcinoma.
Attached anatomical structures may include vaginal cuff, ovaries, fallopian tubes or parametria 16. Further specimens may be submitted for pathologic review including omentum, sentinel lymph nodes 17, pelvic and periaortic lymph nodes, peritoneal washings, and peritoneal biopsies from various sites 16.
Inking of peritoneal and/or nonperitoneal surfaces is recommended in hysterectomy specimens and is essential in radical hysterectomy specimens in which a vaginal cuff is present. In addition, inking the peritoneal and nonperitoneal surfaces and extending the ink all the way to the vaginal cuff is useful to provide the status of the vaginal cuff margin 16.
Histological Tumor Type
All endometrial carcinomas should be classified according to the 2020 WHO Classification of Tumours Editorial Board 5. It is beyond the scope of this data set to provide detailed information about the microscopic features of each histologic type. However, some points are highlighted for clarification, particularly regarding the main modifications introduced in the 2020 WHO Classification 5.
Histologic tumor type has consistently been demonstrated as an important biological predictor in endometrial carcinoma. Accurate histologic typing is important both in biopsy and resection specimens. Moreover, the assessment of histologic type determines the extent of the initial surgical procedure and subsequent use of adjuvant therapy 18.
Bokhman first described in 1983, 2 main pathogenetic types based on epidemiological studies and this concept was further expanded 19–21. Type I carcinomas are predominantly low-grade, estrogen-related, often clinically indolent, and histologically mostly of endometrioid type. In contrast, type II carcinomas are clinically aggressive carcinomas and unrelated to estrogen stimulation and histologically nonendometrioid, particularly of serous and clear cell type. Although the type I versus type II classification is interesting for educational and epidemiological purposes, it is not useful for tumor stratification from the pathologic viewpoint because there are significant overlapping features at the clinical, pathologic, and molecular levels 22–24.
Low-grade (grade 1 and 2) endometrioid carcinomas are the most common tumors and are usually associated with a favorable outcome. The prognosis for serous carcinoma is worse with recurrence occurring in about 50% of serous carcinomas compared with 20% recurrence in endometrioid carcinomas. Tumors that show combined or mixed features are rare but do occur. Although there is moderate to excellent (κ=0.62–0.87) reproducibility in histologic typing, the interobserver agreement is worse in high-grade carcinomas 25–27.
Low-grade endometrioid carcinoma is usually composed of cells arranged in a branching, maze-like glandular or complex papillary growth pattern, while high-grade endometrioid carcinoma has a predominant solid architecture 28, and serous carcinoma has a complex architectural pattern with papillae and cellular budding 29. However, serous carcinomas with a prominent glandular pattern can frequently be mistaken as low-grade endometrioid carcinoma 30,31; and endometrioid carcinoma with a papillary pattern can sometimes be misinterpreted as serous carcinoma 32.
Low-grade endometrioid carcinoma exhibits some specific types of terminal differentiation such as squamous and mucinous differentiation or specific patterns of growth such as villoglandular, small nonvillous papillae, microglandular, sex cord-like formations, corded and hyalinized patterns and sertoliform structures. The 2020 WHO Classification 5 incorporates mucinous carcinoma as a variant of low-grade endometrioid carcinoma due to its shared molecular features and natural history. Predominant mucinous features do not significantly affect survival when compared with nonmucinous endometrial carcinomas, although, in some series, the mucinous type has a higher tendency to develop lymph node metastasis 33, and distinction from proliferative, but not malignant, mucinous lesions may be challenging 34. The 2020 WHO Classification clearly distinguishes the mucinous variant of endometrioid carcinoma from gastrointestinal type mucinous endometrial carcinoma 5,35, a rare type of tumor with different features and a worse prognosis.
High-grade endometrioid carcinoma is characterized by a solid growth pattern associated with mostly moderate to severe nuclear atypia and an increased number of mitoses. Application of TCGA-molecular surrogate has demonstrated that this is a heterogeneous group of tumors 36. This is one of the scenarios that shows the importance of integrating histologic typing with molecular classification.
Serous carcinoma is distinguished from endometrioid carcinoma by its marked nuclear pleomorphism and prominent nucleoli in the background of mostly “well differentiated” architecture, which is typically papillary, but can also be glandular or even solid. In contrast to the typical round, smooth and regular glandular lumens in endometrioid carcinoma, the luminal surface in serous carcinoma is irregular, and the glandular structure often slit-like. Mitoses are prominent. The noninvasive type (formerly called serous endometrial intraepithelial carcinoma) is part of the spectrum of serous carcinoma, which is no longer included as a precursor lesion and can give rise to extrauterine metastasis 37.
Clear cell carcinoma is infrequent and strict adherence to architectural and cytological diagnostic criteria is necessary, since clear cells are commonly present in endometrioid and serous carcinomas 38–41. The major architectural patterns are tubulocystic, papillary and solid, and frequently these patterns are admixed. Tumor cells show cuboidal, polygonal, hobnail, or flat appearances, with clear or eosinophilic cytoplasm.
Undifferentiated carcinoma is usually composed of small to intermediate-sized, noncohesive cells of relatively uniform size arranged in sheets. If a second component of differentiated carcinoma is present, which is most frequently a low-grade endometrioid carcinoma occurring in ~40% of cases, the term dedifferentiated carcinoma is used 42,43. The differentiated component can be a low or high grade 44. A significant number of un/dedifferentiated carcinomas are characterized by an inactivating mutation resulting in loss of SMARCA4 or SMARCB1 protein 45.
Mixed carcinomas are composed of 2 or more discrete histologic types of endometrial carcinoma, of which at least 1 component is either serous or clear cell 46–49. Rigorous criteria should be applied to distinguish them from heterogeneous endometrioid carcinomas (eg, with a mixture of villoglandular, squamous and mucinous areas), which are frequently associated with mismatch repair (MMR) deficiency (MMRd) or POLE mutations 50. Any percentage of high-grade carcinoma is sufficient to classify the tumor as a mixed endometrial carcinoma. A diagnosis of mixed carcinoma should only be used when both components exhibit a characteristic morphology and immunophenotype 49.
Carcinosarcoma, formerly included in the group of mixed epithelial and stromal tumors, is now classified as a distinct type of endometrial carcinoma and shows the typical biphasic pattern morphologically 49. The carcinomatous component shows high grade morphology (serous, endometrioid, mixed or ambiguous), and shows a sharp demarcation from the sarcomatous component. The sarcomatous component can be homologous (no specific mesenchymal differentiation or differentiation toward smooth muscle or endometrial stroma phenotype) or heterologous (mesenchymal differentiation toward mesenchymal lineages not seen primarily in the uterus such as cartilaginous, osseous, skeletal muscle, and adipocytic).
Several studies have shown that the presence of heterologous elements in carcinosarcomas is an important adverse prognostic feature particularly in stage I tumors 51,52. Reporting of the percentage of epithelial and sarcomatous elements and whether the sarcomatous component is homologous or heterologous is a noncore element. The rare instance of carcinoma arising in an adenosarcoma appears to be a distinct biologic process and should not be diagnosed as carcinosarcoma 53.
The 2020 WHO Classification 5 includes novel tumor types, such as squamous cell carcinoma, mesonephric and mesonephric-like adenocarcinoma 54,55, as well as gastrointestinal-type mucinous carcinoma 35.
Neuroendocrine carcinomas of the endometrium are included in the section on neuroendocrine tumors of the female genital tract in the 2020 WHO Classification 5,56. Reporting of the neuroendocrine carcinoma subtype is a noncore feature.
Endometrial carcinomas should be adequately sampled. The ISGyP 2019 guidelines recommend 1 section per 10 mm, considering the largest tumor dimension 16. An alternative, when dealing with large tumors, is to submit at least 4 blocks of tumor. However, the entire endometrium and underlying inner myometrium should be submitted for microscopic examination in the setting of a preoperative endometrial specimen demonstrating malignancy, when no gross lesion is seen in the hysterectomy specimen 16.
Histologic Tumor Grade
Evaluation of histopathologic grade in endometrioid carcinoma is very important in both the initial biopsy/curettage and the final hysterectomy specimen, as risk stratification and decisions on the extent of surgical treatment and administration of adjuvant therapy take into account information on grading 18.
Serous, clear cell, undifferentiated and neuroendocrine carcinomas and carcinosarcomas are considered high grade by definition. Entities that are high grade by definition should be recorded as “not applicable” in the reporting guide. However, grading for endometrioid carcinoma is prognostically important 18,57. The value of the FIGO grading system was shown in a univariate analysis of >600 patients with clinical stage I or occult stage II endometrioid carcinoma 58. The 5-yr relative survival was 94% for patients with grade 1 tumors, 84% for those with grade 2 tumors, and 72% for those with grade 3 tumors 59.
The 2009 FIGO grading criteria for endometrioid carcinoma is primarily based on architectural features 59. Grade 1, 2, and 3 tumors exhibit ≤5%, 6% to 50%, and >50% solid nonglandular growth, respectively 59. In endometrioid carcinomas with squamous differentiation, the grade of the tumor should be assessed in the nonsquamous areas. The presence of severe cytological atypia in the majority of cells (>50%) increases the grade by 1 level.
Overall, the κ statistic for interobserver variability has been shown to be fair to good for the FIGO grading system, with κ values ranging from 0.41 to 0.65 60. In those studies that have looked at the individual components of the grading system, the interobserver agreement for architecture has ranged from 0.49 to 0.71 60.
ISGyP guidelines and the 2020 WHO Classification, highlight the benefits of binary grading, whereby grade 1 and 2 tumors are categorized as low grade and grade 3 tumors as high grade 5,61. This recommendation is based on the benefits of the binary grading system for easier clinical decision-making and improved reproducibility. Classification and regression tree statistical analysis shows that the distinction between low and high-grade tumors was the second most informative predictor of survival after the stage 62,63. However, some reports show a small but statistically significant survival difference of around 5% between low-stage, grade 1 and 2 tumors 61, and the distinction between grade 1 and 2 carcinomas may be still important in some institutions for patients desiring fertility-sparing treatments 64–67.
Agreement in histopathologic grade between biopsy and hysterectomy specimens varies, with a concordance of only 35% reported in some series 68,69. Tumor heterogeneity may explain this discrepancy since biopsies may not be necessarily representative of the whole tumor 70. When there is discrepancy between the reported histopathologic grade in the biopsy and the hysterectomy specimen, it is recommended to review the initial biopsy and to take this into account when assigning the final histologic grade, particularly in cases in which the amount of tumor in the hysterectomy specimen is very limited.
Alternative proposals to FIGO grading have been suggested, which take into account several different parameters, such as nuclear grade, architectural grade, combination of architectural and nuclear features, necrosis, and pattern of myometrial invasion 71–74. The alternate proposals have shown prognostic value but have not shown superiority to the FIGO scheme in terms of reproducibility or prediction, and some features, such as pattern of myometrial invasion, cannot be assessed on biopsies and curettage specimens 71–74.
Histologic grade may be difficult to apply for cases (especially hysterectomy specimens) in which the specimen was inappropriately fixed and/or the tumor is autolysed. The category of “cannot be assessed” should be used sparingly and only in cases where there is genuine doubt. In such cases, it may be useful to state the reason for a response of “cannot be assessed” in the report and correlation with the preoperative biopsy may be valuable. The “cannot be assessed” category may also be used in biopsy specimens containing extremely scant tissue.
The extent of myometrial invasion has long been recognized to be an important risk factor for regional lymph node metastasis, and in some studies, for overall survival in stage I endometrioid cancer patients 75,76. Accordingly, the extent of myometrial invasion is a central component of most contemporary systems for prognostication, staging, intraoperative and postoperative risk stratification, and decision-making models for adjuvant therapy 18,59,77.
Various methods of determining the extent of myometrial invasion have previously been evaluated. These have included the absolute depth of invasion (DOI) from the endomyometrial junction to the deepest focus of invasive carcinoma, the tumor free distance (TFD) to serosa, and the percentage of myometrium involved, expressed either as the percentage of the overall myometrial thickness that is infiltrated by carcinoma, or as 1 of 3 categories: none, <50%, or ≥50% 78–88.
The widely used TNM and FIGO Staging Systems take the latter approach, with tumors limited to endometrium or invading less than half of myometrium categorized as stage IA (pT1a), and tumors invading 50% or more categorized as stage IB (pT1b) 59,89,90.
For cancer reporting, the absence or presence and depth of myometrial invasion should be recorded as none, <50%, or ≥50%; this is a core element. In addition, the absolute percentage of myometrial wall thickness that is invaded by carcinoma can be recorded as a noncore element 91.
DOI as an individual variable has received less investigation. Nevertheless, higher depths of invasion have been associated with an increased risk of lymphovascular invasion (LVI), lymph node involvement, high stage, recurrence and death from disease in some studies 82,83,85,86, but not others 80,81,84,87,88.
TFD is the distance between the deepest point of myometrial invasion of the cancer and the nearest serosal surface 80–88. TFD theoretically eliminates some of the difficulties that are inherent to determining the depth of myometrial invasion 78,79, and is reportedly more reproducibly diagnosed by pathologists 92. However, much like DOI, the prognostic significance of TFD is unclear, since the reported findings have been conflicting 78,80–88. Most studies have found a statistically significant association, on univariate analyses, between shorter TFD and adverse clinicopathologic factors, including higher tumor grade, cervical involvement, LVI, and advanced patient age 81,82,85,86. An association between TFD and lymph node involvement, adnexal involvement and/or larger tumor size has also been reported in some studies 81,82,84,85 but not others 83,86,87. On multivariate analyses, TFD has been found to be an independent predictor of overall survival and recurrence-free survival in only 50% and 33% of the studies that have evaluated these questions, respectively 80–82,84,85,87. In 2 of the aforementioned studies, a TFD cut off of 10 mm was found to maximize sensitivity and specificity in predicting recurrences 81,82. Both DOI and TFD are noncore elements. Additional studies are needed to clarify the prognostic roles of DOI and TFD.
Assessment of tumor invasion from adenomyosis is a controversial issue without strong scientific evidence. ISGyP guidelines state that “it is preferable to use the standard method for determining DOI, based on the location of the deepest focus of invasive carcinoma in relation to the total myometrial thickness in this area, irrespective of its relationship to adenomyosis” 91. Thus, a tumor in which the only invasion arises from adenomyotic foci in the outer half of the myometrium, should be staged as FIGO stage IB and accompanied by a comment that the clinical significance is unknown, and that this may be an overestimate of true DOI 14,91.
Several patterns of myometrial invasion are recognized, and more than 1 pattern may be present within the same case 93–96. The conventional infiltrative pattern is the most commonly encountered pattern, and has no specific prognostic significance 93,94. This pattern is characterized by irregularly shaped glands that haphazardly infiltrate the myometrium, and are generally associated with a stromal response that may be granulation tissue-like, desmoplastic or inflammatory 93,94,96. The adenoma malignum-like pattern is characterized by typically round, isolated glands that are unequivocally myoinvasive but are not associated with any significant stromal response. The glandular epithelium is generally less columnar than the nonmyoinvasive component, and indeed may appear flattened 96. Eosinophilic luminal secretions may be prominent, especially when the tumor involves the lower uterine segment or burrows into the cervix, potentially leading an endometrial carcinoma to be mistaken for mesonephric remnants or mesonephric proliferations. The pushing or expansile pattern is present in 9.4% to 21% of endometrioid carcinomas, and shows a broad, noninfiltrative myoinvasive front, generally without a significant stromal reaction 93,94. The adenomyosis-like pattern is reminiscent of adenomyosis involved by cancer at scanning magnification, but tumor nests are smaller, overtly infiltrative and lack true endometrial stromal cells at the peripheries of myoinvasive nests 93,94. The adenomyosis-like, adenoma-malignum, and expansile myoinvasive patterns are devoid of any specific prognostic significance 93,94. The microcystic, elongated and fragmented (MELF) pattern is characterized by discrete foci of single cell clusters, cellular cords, or microcystic glands that are lined by variably flattened epithelium with eosinophilic or squamoid cytoplasm, and which are typically associated with a surrounding fibromyxoid stromal change with an interspersed, neutrophil-rich mixed inflammatory infiltrate 95. In one meta-analysis comprising 14 studies and 588 patients, the MELF pattern was associated with larger tumor size, higher grade, lymph node metastasis, LVI and >50% myometrial invasion, but was not significantly associated with disease-free survival, disease-specific survival, or vaginal recurrence rates 97. Nonetheless, the diagnostic significance of the MELF pattern of invasion is multifold: (1) the depth of myoinvasion may be underestimated if subtle epithelial cells within foci of MELF-associated fibromyxoid stroma in the myometrium are not recognized as such; (2) foci of MELF myoinvasion may be mistaken for LVI, or vice versa; and (3) lymph node metastases associated with the MELF pattern may be difficult to recognize, as they are frequently of small volume and a small subset of metastases may acquire a distinct histiocyte-like morphology 98–101. Among the other potentially encountered myoinvasive patterns, single cell infiltration has been associated with an increased likelihood of extrauterine extension on multivariate analyses 102. Tumor budding, which is probably a different iteration of the same biologic phenomenon, has also been associated with adverse clinicopathologic features and patient outcomes 93,101,103,104. The pattern of myometrial invasion may be documented in the pathology report to facilitate future study, but is not a core item.
In most cases, determining the depth of myometrial invasion does not pose a challenge. However, a variety of circumstances may be encountered that may potentially render making this determination problematic 105. The DAC endorses the ISGyP recommendations for handling these diagnostic scenarios as summarized below 91:
- Exophytic tumors and endometrial polyps: Exophytic carcinomas not uncommonly have an “incorporated” myomatous stroma that should not be mistaken for true myometrium for the purposes of measuring the depth of myometrial invasion. Tumor thickness, which encompasses the exophytic component of a myoinvasive tumor, is not synonymous with the depth of myometrial invasion, where measurement begins at the endomyometrial junction. The location of the true endomyometrial junction may be inferred by comparing the area in question with an adjacent section that is uninvolved by myoinvasive carcinoma. For tumors that infiltrate an endometrial polyp, the same approaches are applicable. In endometrial carcinomas in general, every attempt should be made to submit at least one section that depicts any exophytic component, the most myoinvasive component, and an adjacent noninvolved endomyometrial junction.
- Uterine cornu and lower uterine segment: given that the uterine wall thickness is thinnest at the cornu, the ISGyP recommendations are that the depth of myometrial invasion should not be measured at this focus, unless the tumor is entirely localized to the cornu, and/or extends to the serosa at that point. In contrast, for tumors whose maximal depth of myometrial invasion is in the lower uterine segment, measurements should be taken as they would be at other non-cornual areas of the uterine corpus.
- Leiomyoma: for tumors that infiltrate a leiomyoma, measurements should be taken as if the leiomyoma represents nonleiomyomatous myometrium. Specifically, the thickness of the myometrial wall at the focus of myoinvasion should include the thickness of the leiomyoma, and the measurements of the depth of myometrial invasion should include the portion of the tumor that is invasive of the leiomyoma.
- LVI: consistent with staging principles at other anatomic sites, LVI is not used, in and of itself, to upstage. Accordingly, in endometrial carcinoma, foci of LVI should not be used to determine the depth of myometrial invasion. For example, a stage I tumor with <50% invasion of the myometrial wall but which shows LVI in the outer myometrium should be classified as stage IA, rather than IB.
LVI is an important prognostic indicator in endometrial carcinoma and documenting the presence or absence of this is a core element. LVI can be confidently diagnosed at the invasive front of a carcinoma when there is a tumor embolus within an endothelial-lined channel 91,106–108. The embolus frequently takes the shape of the vessel lumen and may be attached to the endothelium. The tumor embolus usually resembles the endometrial carcinoma, but LVI associated with MELF invasion may contain single or clustered histiocytoid or metaplastic-appearing cells that resemble the myometrial invasive cells of MELF 106,109.
There are several types of artifact that simulate LVI: these include artifacts secondary to tumor disruption; MELF pattern myometrial invasion; and retraction artifacts 106,107,110,111. The first situation is predominantly encountered in the setting of laparoscopic and/or robotic surgery followed by dissection of the uterus before adequate fixation 110–114. Clues to the presence of this type of artifact include fragments of tumor and, sometimes, normal constituents around the cut surfaces of the section, in tissue “cracks,” in large, medium-sized and small vessels, both adjacent to the tumor’s invasive front and in distant locations 106,107. Often the amount of tumor within vessel appears disproportionate, for example, in a tumor which is low grade and low stage. Rarely it may be impossible to distinguish “real” LVI from artifacts; this should be expressed in the surgical pathology report. Adequate fixation before prosection, generally lessens the degree of artifact. The second artifact type results from the morphologic similarity between MELF myometrial invasion and LVI 115. Adding to the complexity is that MELF myometrial invasion is, indeed, associated with LVI 97. The distinction between the 2 can usually be resolved by knowing about this type of artifact and careful examination to differentiate between endothelium on one hand (LVI) and tumor cells floating in a microcyst lined by flattened and attenuated epithelium (MELF myometrial invasion). Immunohistochemical endothelial markers can sometimes be used to confirm a suspicion of LVI, especially when there is extensive retraction artifact. Epithelial markers, in addition, may be added to the panel when MELF myometrial invasion is present, although the literature is not consistent on the added value of immunohistochemistry (IHC) after hematoxylin and eosin (H&E) evaluation 91,116.
The absence of LVI is defined as no tumor cells within vessels 61. There is controversial data regarding the cut off for “extensive” or “substantial” LVI. “Extensive” is defined as the presence of 3 or more vessels containing tumor, according to ISGyP recommendations 61, but 5 or more vessels in the 2020 WHO Classification 5 and in the ESGO-ESTRO-ESP guidelines 14.
Recent data indicate that “substantial” or “extensive” LVI is associated with adverse outcomes when compared with carcinomas with “focal” or “no” LVI 117–119. Although there have been different proposals for what constitutes extensive LVI, it is a good rule of thumb to diagnose extensive LVI when it is easily recognisable at scanning magnification (and artifact is excluded) and when present in 3 or more vessels on closer inspection. Recording the degree of LVI (focal or substantial/extensive) is regarded as a core element instead as is regarded as a non-core element. LVI should not be included in the assessment of depth of myometrial invasion, or indeed, in determining any element of pathologic staging 91. LVI features in many (but not all) multivariate clinical outcomes analyses and is associated with lymph node metastasis, local and distant recurrence and poor survival 117,118,120. Thus, the presence of substantial LVI may highlight the need for adjuvant treatment, such as recommended in the 2020 ESGO-ESTRO-ESP consensus guidelines 14. A value of “indeterminate” should be used sparingly and only in cases where there is genuine doubt. In such cases, it may be useful to report the reason for a response of “indeterminate.”
Cervical stromal invasion indicates stage II endometrial carcinoma according to the current FIGO Staging System and is a core element for reporting 59. Cervical stromal invasion is associated with a significant risk of recurrence and is a predictor of pelvic lymph node metastases 121,122. However, the role of cervical stromal involvement as an independent prognosticator per se has been questioned 18. Cervical stromal invasion often occurs in the presence of other adverse features such as high histologic grade, deep myometrial invasion, and LVI 123. In one study, the presence of these factors conferred worse disease-free survival in patients with stage II endometrial cancer 124
Cervical stromal invasion is defined as infiltrative or expansile (pushing) tumor growth into the cervical stroma. Characteristics of infiltrative invasion include irregular glands, single cells or tumor cell clusters, and desmoplastic stromal reaction. In the absence of infiltrative features, assessment of stromal invasion is facilitated by comparing the architecture of the carcinoma with the normal endocervical crypts: expansile (pushing) invasion is favored if there is altered architecture with complex cribriform or microacinar growth (exceeding what would normally be accepted as just intraglandular growth) 91
Determination of cervical stromal invasion can be complicated by difficulties in demarcating the cervix from the lower uterine segment. By convention, the boundary is defined by the most proximal benign endocervical crypt 106,125. Consequently, any invasion identified at the level of, or distal to, a benign endocervical crypt should be considered cervical stromal invasion.
Significant interobserver variation in the assessment of cervical involvement by endometrial carcinoma has been documented. McCluggage et al. 125 showed fair to good agreement among 6 experienced gynecologic pathologists in this exercise. While Zaino et al. 126 showed high agreement in determining whether the cervix is involved or not, but only slight agreement in the distinction between glandular and stromal involvement. Problematic scenarios include: determination of the junction between the lower uterine segment and upper endocervix; the distinction between “floaters” and true cervical glandular involvement; the distinction between cervical glandular involvement and stromal involvement; and the distinction between cervical glandular involvement and reactive non-neoplastic glandular lesions such as tuboendometrial metaplasia or changes secondary to recent biopsy 125. Strict definitions as to what constitutes cervical stromal invasion and the boundary between cervix and lower uterine segment, as provided above, are likely to improve reproducibility. In addition, consensus diagnosis via intra- or inter-departmental consultation is encouraged.
A value of “indeterminate” should be used sparingly and only in cases where there is genuine doubt; in such cases, it may be useful to state the reason for a response of indeterminate in the report.
Most hysterectomies for endometrial cancer are simple hysterectomies and do not have parametrial resections, although occasionally parametrial resection is undertaken when cervical stromal invasion is suspected preoperatively (radical or modified radical hysterectomy). Endometrial carcinomas with parametrial invasion are staged as FIGO stage IIIB 59. Although not an independent prognostic indicator, parametrial involvement by direct extension is a poor prognostic factor 127–129. It is associated not only with cervical stromal invasion but also with outer half myometrial invasion, pelvic and/or para-aortic lymph node metastasis, ovarian metastasis, positive peritoneal cytology, and LVI 127–129. Reporting of the presence or absence of parametrial involvement in hysterectomy specimens containing parametrial tissue is a core element.
In endometrial carcinoma, vaginal involvement may occur in 2 different scenarios:
- Vaginal involvement at diagnosis (uncommon scenario).
- Vaginal recurrence of endometrial carcinoma (common scenario).
Vaginal involvement at the time of diagnosis is uncommon, and places the disease in FIGO Stage IIIB (pT3b) 90. Vaginal involvement occurs either via direct extension from the corpus to the cervix and vagina or metastasis through lymphatic pathways. It is essential to report vaginal involvement for staging of disease and prognosis. Vaginal involvement at diagnosis is rare (<1% of cases) and it is very unusual that patients present with vaginal extension without lymph node metastasis or spread to other distant sites. The 5-yr survival rate for these patients is ~25%, with a median survival of 1 to 2 yr 130. Vaginal metastasis may be identified in a vaginal nodule submitted separately by the surgeon or from sampling the vaginal cuff tissue from a radical hysterectomy specimen.
The vagina represents the most common site of recurrence of endometrial carcinoma 131,132. In the majority of cases, recurrence involves the upper vagina, while recurrence in the middle third or distal vagina is less common 133. In a study by Moschiano et al. 133, there were no disease-related deaths in patients with vaginal recurrence only, suggesting that vaginal recurrence is not a marker of aggressive tumor biology. Vaginal recurrences are also associated with cervical tumor involvement 133. Endometrial carcinoma with vaginal recurrence show different features compared with tumors that recur at other sites, in particular: older age, superficial myometrial invasion, low nuclear grade, no greater than 1 focus of LVI, LVI not deeper than the invasive front, <5% MELF pattern at the invasive tumor front, and no lymph node metastasis at presentation 134. Stolnicu et al. 135 suggests that vaginal recurrence in patients with endometrial carcinoma might be caused by distal migration of tumor cells in the vagina as a result of tumor cells dropping off from polypoid tumors, tumors involving the cervix, or tumor bleeding during surgical treatment.
Omentectomy is part of the surgical staging procedure for some high-grade endometrial cancers. Omental spread by endometrial carcinoma is associated with decreased overall survival 136,137. Omental metastases are associated with other adverse prognostic features such as high tumor grade, serous histology, deep myometrial invasion, LVI, and adnexal involvement 136,138.
Spread of endometrial carcinoma to the omentum, either supracolic or infracolic, is regarded as a distant metastasis and places the disease in FIGO Stage IVB (pM1) 91,139. The previous version of the ICCR Endometrial cancer data set did not make recommendations on this staging component 140.
Omental metastases by endometrial carcinomas are uncommon. One study documented that 92.7% of omentectomy specimens for staging of endometrial adenocarcinoma showed no tumor.
Reporting of peritoneal involvement is core when biopsy specimens are submitted as part of staging of endometrial carcinoma. The site of the peritoneal biopsies and the presence or absence of tumor involvement should be documented. Taking of blind peritoneal biopsies is routine in some institutions 141.
It is important to distinguish between abdominal and pelvic peritoneal involvement since this denotes a different Stage (IIIA for pelvic peritoneal involvement and IVB for upper abdominal peritoneal involvement).
Documentation of the presence or absence of serosal involvement is a core element. According to ESGO/ESTRO/ESP 14 and ISGyP guidelines 91, tumor infiltrating the full myometrial thickness and reaching submesothelial fibroconnective tissue or the mesothelial layer should be reported as serosal involvement. Tumor may or may not be present on the surface of the uterus and a desmoplastic response may or may not be present. It should be noted that, when present, a desmoplastic stromal reaction can obscure evaluation of the serosa. Locating the serosal plane flanking the area in question and extending the plane through the area of desmoplasia can be helpful. Serosal involvement is considered present if there is disruption of that plane or carcinoma extends beyond the plane. Involvement of the serosa (FIGO Stage IIIA) carries a higher risk of locoregional recurrence than does adnexal involvement (also FIGO Stage IIIA) 142.
The presence or absence of adnexal involvement is a core element. Adnexal involvement has an impact on overall survival rate 59,89,90. The presence of adnexal involvement categorizes a tumor as Stage IIIA in FIGO and pT3a in TNM Staging Systems, respectively 59,89,90. Prognosis is worse when ovarian metastases are associated with metastases at other sites 143. The involved adnexa should also be documented, particularly specifying which ovary and which fallopian tube is involved as well as the location of tubal involvement.
It is important to distinguish between endometrial carcinoma with ovarian metastasis and synchronous primary tumors of the endometrium and the ovary 144. For high grade tumors, including serous carcinoma, ovarian involvement is almost always categorized as metastatic. However, there is always the possibility of coincidental independent primary serous carcinomas in the endometrium and the tube/ovary, although this situation is exceedingly unusual. Furthermore, metastasis from the adnexa to the endometrium rarely occurs. Ancillary techniques (such as WT1 and p53 staining) and evaluation of the fallopian tube by Sectioning and Extensively Examining the Fimbria (SEE-FIM) protocol may be helpful 16.
Five percent of endometrioid adenocarcinomas are associated with an endometrioid carcinoma of the ovary. Cases with simultaneous involvement of endometrium and ovary by low-grade endometrioid carcinomas are often associated with indolent outcome.
Clinicopathologic criteria can help to distinguish patients with good prognosis (such as those with two independent primary tumors/“low-risk”) and patients with bad prognosis (such as those with an endometrial carcinoma with ovarian metastasis/“high-risk”). Distinction between these 2 prognostic types is based on several criteria including: (1) size of the tumor, (2) histologic type and grade, (3) extent/depth of myometrial invasion, (4) presence of LVI, (5) tubal invasion, (6) presence of endometrial hyperplasia, (7) presence of ovarian endometriosis, (8) pattern of ovarian invasion, including bilaterality, and (9) presence of additional metastases.
Recent molecular studies have shown that for low-grade endometrioid carcinomas, there is a clonal relationship between the endometrial and ovarian tumor in the vast majority of cases, suggesting that the tumor arises in the endometrium, and secondarily extends to the ovary 145–148. However, this clonal relationship should not be equated with the clinical outcomes expected of metastatic endometrial carcinoma.
In the 2020 edition of the WHO Classification 5, it is suggested that patients with clonally related low-risk tumors be managed conservatively (as if they were 2 independent primaries) when the following criteria are met: (1) low-grade endometrioid morphology, (2) no more than superficial myometrial invasion, (3) absence of LVI, and (4) absence of additional metastases 5,149. This is an evolving field, and it is not clear at this time why a subset of metastatic tumors are associated with good prognosis. This phenomenon is also seen in endocervical adenocarcinomas metastatic to the ovaries 150,151. Potential explanations are: (1) that clonal ovarian metastasis occurs early in the process of endometrial tumor development, thereby allowing tumors in each site to acquire additional, sometimes distinct genetic abnormalities; and (2) tumor cells follow retrograde uterine/transtubal spread, possibly with ovarian implantation, rather than destructive invasion. It is recommended to discuss these cases in multidisciplinary tumor boards.
Although true independent simultaneous endometrial and ovarian carcinomas do exist, they are relatively infrequent, and share characteristics of tumors arising in the setting of Lynch syndrome 148. In this scenario, endometrioid carcinomas of the endometrium may coexist with ovarian clear cell carcinoma 152,153.
It is important to remember that the presence of LVI in ovarian hilar or parenchymal vessels or tubal vessels without stromal invasion does not affect stage.
Tumor involvement of the fallopian tube should also be recorded 143. It is important to stress that the presence of detached aggregates of tumor cells in the tubal lumen, without the involvement of the fallopian wall, should not be considered tubal involvement 112, since this is thought to be an artifact related to the type of surgery performed and/or specimen fixation. However, it has been reported that the presence of serous carcinoma cells in the lumen of the fallopian tube is often associated with peritoneal metastasis 154. Floating tumor cells in the fallopian tube lumen should not lead to upstaging of the tumor, although this should prompt a careful review of the peritoneal/pelvic washings.
Tubal involvement by endometrial carcinoma in the form of intramucosal spread has controversial prognostic significance. Tubal tumor is generally considered metastatic from the endometrium, but it is sometimes considered to represent a coincidental low-risk “synchronous” endometrioid carcinoma of the fallopian tube. The approach to distinguishing between low-risk and high-risk carcinomas could theoretically follow the same paradigm used for tumors involving endometrium and ovary. The prognostic significance of tubal mucosal involvement by endometrioid carcinoma (either low-risk or high-risk) is unknown 91.
Tubal involvement by serous carcinoma, with or without stromal invasion is usually a manifestation of metastatic serous carcinoma. Recent studies have shown that endometrial serous carcinoma frequently extends to the fallopian tube, giving rise to a lesion that may be indistinguishable from serous tubal intraepithelial carcinoma (STIC)/STIC-like lesion 155. There is also the possibility that a bona fide STIC can be the nidus from which serous carcinoma cells detach and implant in the endometrium, simulating a primary endometrial serous carcinoma 156. Furthermore, there is also the possibility of the coincidental presence of an endometrial serous carcinoma and a primary STIC, but in these cases ancillary techniques are required. Assessment of WT1 expression may be helpful in these scenarios. WT1 immunoreactivity is negative in the majority of primary endometrial carcinomas but positive in almost all carcinomas arising from the ovaries or the fallopian tube 157.
Endometrial carcinomas metastatic to the fallopian tube wall or its serosa should be interpreted as metastatic unless there is evidence of an origin in endometriosis.
It is important to record the status of paracervical soft tissue and ectocervical/vaginal cuff margins, and this is a core reporting element. The term paracervical soft tissue refers to the small part of the parametrium that is included in simple hysterectomy specimens, which is the common surgical procedure for endometrial carcinoma.
Vaginal (direct extension or metastasis) or parametrial involvement by endometrial carcinoma is currently staged as IIIB 59,90. Positive margin status has been identified as a risk factor for local recurrence and mortality, and patients with positive margins are more likely to receive a vaginal vault brachytherapy boost 158,159. Vascular invasion at the cervical/parametrial/vaginal resection margin is not considered a positive margin.
Close cervical/parametrial/vaginal margins may indicate an increased risk of recurrence and may be taken into consideration for adjuvant radiotherapy 160. However, there are no criteria regarding the distance to margins that would be considered “close.” The distance to the margins is a noncore reporting element; when reported, the distance to margins should be stated in millimeters.
Lymph Node Status
Lymph node status is an important prognostic factor for endometrial carcinoma and its assessment is crucial for determining both stage and appropriate adjuvant therapy. According to the FIGO Staging System, metastatic involvement of lymph nodes increases tumor stage (IIIC1 and IIIC2 for pelvic and para-aortic nodes, respectively) 59. In contrast, a therapeutic benefit from lymph node resection has not been shown yet in randomized trials 161–163, although a large retrospective study has shown benefit from extensive nodal dissection especially in serous tumors 163.
Intraoperative frozen section analysis can be useful to assess lymph node metastases 164. The technique has its limitations for the detection of micrometastasis and isolated tumor cells 165. Notably, intraoperative frozen section is only justified if the results have immediate therapeutic consequences. Serial sections from different levels are not recommended to avoid tissue depletion. The tissue block used for frozen section needs to be fixed in formalin and embedded in paraffin and, if negative for metastasis, submitted for ultrastaging.
Resected lymph nodes are categorized as regional (paracervical, parametrial, various pelvic lymph node groups, including obturator, internal, common or external iliac, presacral and lateral sacral, and para-aortic) or nonregional nodes (inguinal and other nodes). It should be noted that nonregional lymph nodes (including inguinal nodes) are considered to be distant metastases.
Core data regarding lymph node status includes the number of lymph nodes identified from the various sites, the number of lymph nodes involved by metastatic tumor and the size of largest metastasis (maximum diameter in millimeter). Some other parameters which may be useful for future research may be recorded, such as extranodal spread. Extranodal spread is a noncore element. Occasionally, metastatic tumor is present in the specimen removed, but no lymph node tissue is identified.
The FIGO Staging System includes lymph node status, and its structure is similar to that of the TNM system 59,89,90. Pelvic lymph node involvement is Stage IIIC1 and para-aortic nodal involvement Stage IIIC2. For TNM stage, regional lymph node metastases contribute to the N category, whereas metastases in non-regional nodes are regarded as distant metastasis and belong to the M category 89,90. According to TNM8 89, macrometastases are >2 mm, micrometastases are >0.2 to 2 mm and/or >200 cells, and isolated tumor cells are up to 0.2 mm and ≤200 cells. Macrometastases are regarded as pN1 or pN2 depending on location (pelvic for pN1, para-aortic for pN2), micrometastases as pN1mi or pN2mi (depending again on location of the involved lymph nodes) and isolated tumor cells are pN0(i+); isolated tumor cells do not upstage a carcinoma 89,90,166,167.
Grossing of the lymph nodes is an important step for a thorough histologic evaluation. Lymph nodes up to 2 mm are embedded whole. If lymph nodes are larger than 2 mm, they should be sliced perpendicular to the long axis at 2 to 3 mm intervals and entirely submitted.
Traditionally, lymph node status has been assessed either by removal of enlarged and grossly suspicious lymph nodes or systematic lymphadenectomy. More recently, the technique of sentinel node biopsy has been developed and established for endometrial carcinoma as an alternative to systematic and selective lymphadenectomy. Multiple studies confirm the high sensitivity of the sentinel lymph node approach for determining the lymph node status in early-stage endometrial carcinoma and underscore the value of sentinel node biopsy in selecting therapeutic approaches 168–171. Currently, indocyanine green is considered the most reliable tracer and the highest detection rate can be achieved when the substance is injected into the cervix 172,173.
One of the strengths of sentinel lymph node biopsy is the detection of a high percentage of lymph node positive cases by accurate analysis of one or a few lymph nodes. Isolated tumor cells, micrometastases, and small macrometastases are detected by ultra-staging of the lymph nodes in combination with IHC. In addition, sentinel lymph node biopsy is associated with a substantially lower risk of post-operative morbidity, especially lower leg lymphoedema when the dissection of other pelvic lymph nodes is avoided 174,175.
A study by Kim et al. 176 on low risk endometrial carcinoma patients (myometrial invasion <50%, low histologic grade) has shown involvement of sentinel lymph nodes in 6% of patients, of which half were identified by pathological ultra-staging. Patients with carcinomas limited to the endometrium were not identified with positive sentinel lymph nodes and, therefore, sentinel node biopsy could be omitted in this patient population 177. However, this usually is confirmed after hysterectomy only.
The presence of nodal micrometastases is associated with worse prognosis, particularly in patients not receiving adjuvant treatment 178. There is no evidence that the presence of isolated tumor cells which would be classified as pN0(i+) has prognostic ramifications. Based on large randomized trials 161–163, lymph node staging does not show any impact on survival but provides information on extent of the disease and decisions about adjuvant treatment. According to recent European (ESGO-ESTRO-ESP 2020) guidelines 14, sentinel lymph node biopsy can be considered for staging purposes in patients with low/intermediate risk disease and can be omitted in cases without myometrial invasion. Systematic lymphadenectomy is not recommended for these carcinomas due to the morbidity associated with the procedure and low incidence of positive nodes. For high-intermediate/high-risk carcinomas in Stages I/II, surgical lymph node staging should be performed and sentinel lymph node biopsy is an acceptable alternative to systematic lymphadenectomy 179.
Ultrastaging is recommended for the analysis of sentinel nodes negative for metastasis by routine histopathologic analysis since it provides valuable clinical information 180,181. Notably, if sentinel nodes are negative by ultrastaging the occurrence of isolated nodal paraaortic metastasis is less likely 14,181. Several ultrastaging protocols have been published; however, there is no preferred standardized technique. Ultrastaging consists of additional sections cut at defined intervals and stained by H&E and pankeratin for improved detection of micrometastases and isolated tumor cells. There is some evidence that the results between different protocols do not reveal significant differences 180–183. Two different methods were compared without significant differences: 5 H&E levels at 250 μm intervals with two unstained slides at each level; pankeratin IHC performed on level 1 in cases with negative H&E levels; or 1 H&E level plus 2 unstained slides cut 250 μm into the tissue block and pankeratin IHC performed in cases with negative H&E 180. Another protocol uses H&E and pankeratin IHC at 50 μm into the tissue block with a total of 5 sections per block.
IHC for MMR Proteins and MLH1 Promoter methylation
IHC for MMR proteins is recommended in addition to analysis for MLH1 promoter methylation when there is immunohistochemical loss of MLH1 or PMS2 as a core reporting parameter 184.
Endometrial cancer is one of the most common tumors in patients with Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) 185,186. Around 3% of all endometrial carcinomas and ~10% of MMRd/microsatellite unstable endometrial carcinomas are causally related to germline mutations of one of the MMR genes MLH1, PMS2, MSH2, and MSH6 or a related gene, EPCAM 187. “Constitutive methylation” is also a rare cause of Lynch syndrome 188.
Testing for MMR status/microsatellite instability (MSI) in endometrial carcinoma patients has been shown to be important for 4 key reasons:
- Diagnostic, since MMRd/MSI is helpful to diagnose endometrioid carcinomas (as opposed to serous carcinoma or human papillomavirus (HPV)-associated cervical carcinoma).
- It is part of the screening algorithm to identify potential patients with Lynch syndrome 189.
- Prognostic, as part of the TCGA surrogate molecular classification 190.
- Therapeutically as a predictive biomarker for potential utility of immune checkpoint inhibitor therapy 191.
Systematic clinical screening of personal and family history misses a significant proportion of women with Lynch syndrome, since up to 75% of patients do not fulfill the revised Bethesda Guidelines criteria 192. ISGyP has recommended testing for MMR status/MSI in all endometrial carcinomas (preferably curettings or biopsy), irrespective of age 184. This has also been recommended whenever resources are available by other societies/groups, such as the Manchester International Consensus Group 193. The identification of Lynch syndrome in women with endometrial carcinoma can lead to the prevention of a second cancer in the patient and reduced incidence of cancers in family members through risk reducing strategies and heightened surveillance.
MSI can be detected by different methods, including polymerase chain reaction (PCR)-based approaches 192,194,195 and next-generation sequencing 196. Next-generation sequencing is in the process of being validated for this scenario. MSI can also be accurately predicted using IHC.
IHC is cost-effective and is implemented in most pathology departments. ISGyP guidelines recommend IHC as the best test for MMRd and, indirectly, for MSI 184. The IHC approach consists of an assessment of the expression of four DNA MMR proteins; MLH1, PMS2, MSH6, and MSH2. A simplified version includes only PMS2 and MSH6, with expanded analysis of MLH1 when PMS2 is lost, and of MSH2 when MSH6 is lost 197. Carcinomas showing loss of MLH1 and PMS2 expression should be investigated for MLH1 promoter hypermethylation 198, as its presence essentially excludes Lynch syndrome. Endometrial cancer patients whose tumors are MMRd, but not methylated at the MLH1 promoter, should undergo genetic counselling with consideration for germline testing.
IHC may be not informative when the specimen has been subjected to poor preanalytical conditions, such as inappropriate or delayed fixation. Furthermore, occasionally there are germline genetic abnormalities that do not result in abnormal expression of MMR proteins. In these cases, PCR-based techniques to assess MSI may be appropriate. This is particularly relevant in patients with normal MMR IHC and highly suspicious family history for Lynch syndrome. MSI detected by PCR-based methods usually requires testing both normal and tumor tissue, although there is a recently described method that only requires tumor tissue 199.
The cumulative incidences of colorectal, endometrial, ovarian, upper gastrointestinal, urinary and brain cancers in women aged 75 yr with Lynch syndrome, depend on the specific mutation. The cumulative incidences have been reported as: germline MLH1 mutation (46%, 43%, 10%, 21%, 8%, 1%); germline MSH2 mutation (43%, 57%, 17%, 10%, 25%, 5%); germline MSH6 mutation (15%, 46%, 13%, 7%, 11%, 1%), respectively 200. In contrast, PMS2 is mostly associated with a moderate increase in colon and endometrial cancer risk, with a cumulative incidence at age 80 yr of 12% and 13%, respectively 201.
TCGA-based Molecular Classification of Endometrial Carcinomas
Reporting of TCGA-based molecular classification of endometrial carcinomas is a non-core parameter. Diagnosis and classification of endometrial carcinoma has up until now largely been based on the microscopic appearance of the tumors 5. The different histologic types have different molecular features, microscopic appearances, precursor lesions, and natural history, although in multivariate analyses 22, FIGO stage and grade have more prognostic significance than histotype. Unfortunately, histologic typing engenders problems with interobserver reproducibility and prognostication. While diagnosis is quite reproducible in low-grade (FIGO grades 1 and 2) endometrioid carcinomas, which account for 70% of endometrial carcinomas, in typical serous and clear cell carcinomas, there is poor interobserver agreement in ~10% of tumors. This is particularly evident in a subset of endometrial carcinomas with high grade morphology 25–27 with microscopic and immunohistochemical features that are shared between high-grade endometrioid and serous carcinomas.
The TCGA performed an integrated genomic, transcriptomic and proteomic characterization of endometrial carcinoma 4. Exome sequence analysis revealed 4 groups of tumors. Group 1 carcinomas (7% of endometrial carcinomas) have somatic inactivating hotspot mutations in the POLE exonuclease domain and a very high mutational burden (ultramutated). FIGO grade 3 endometrioid carcinomas are highly represented in group 1, some of which resemble serous carcinomas. Irrespective of grade, group 1 tumors have an excellent prognosis, although this is not confirmed in all of the recent literature 4,202–204. Group 2 and group 3 show similar progression-free survival rates that are intermediate between groups 1 and 4. With additional research, it is becoming apparent that groups 2 and 3 are heterogeneous, each having genomically-defined subgroups of tumors, some of which are prognostically favorable and others that are unfavorable 4,205–207. Group 2 (28% of tumors) include endometrioid carcinomas with MSI (hypermutated), frequently with MLH1 promoter hypermethylation and high mutation rates. Group 3 tumors (39% of endometrial carcinomas) include endometrioid carcinoma with low copy number alterations, and low mutational burden, while lacking POLE mutations and MSI-high (MSI-H). Group 3 tumors have also been referred to as “no specific molecular profile (NSMP)”. Finally, Group 4 (serous-like or copy-number high; 26% of carcinomas) show a low mutation rate, nearly universal (95%) TP53 mutations, and a highly unfavorable prognosis. Most of these tumors are serous carcinomas, but up to 25% of endometrioid (mostly high grade) and clear cell carcinomas, along with carcinosarcomas, can be found in this group.
In an attempt to bring the TCGA molecular-based classification into clinical practice, different groups have proposed a surrogate (simplified) algorithm precluding comprehensive tumor profiling 190,206,207. The algorithm includes 3 immunohistochemical markers (p53, MSH6, and PMS2) and 1 molecular test (mutation analysis of POLE). Several studies have demonstrated the prognostic value of this TCGA-surrogate approach, and ISGyP has recommended this scheme 61,184,205.
According to this simplified algorithm, tumors with pathogenic POLE mutations correspond to ultramutated tumors. MSH6 or PMS2 abnormal expression defines tumors in the hypermutated group. Abnormal expression of p53 (mutated pattern), characterizes the high copy number group. Finally, NSMP is defined by the absence of POLE mutation, and a normal expression pattern for MSH6, PMS2, and p53 190,207.
The TCGA surrogate approach has been shown to be particularly helpful in the group of high-grade endometrioid carcinomas, including cases in the gray zone between endometrioid and serous carcinomas. High-grade endometrioid carcinoma had been regarded as an aggressive tumor type with some similarities to serous carcinoma. However, application of the TCGA surrogate shows that there is a group of high-grade endometrioid carcinomas with an improved prognosis (tumors with pathogenic POLE mutations), and a group with a very poor prognosis (p53-abnormal tumors). MSI-H and NSMP grade 3 endometrioid carcinomas have an intermediate prognosis 36. Application of this algorithm for clear cell carcinoma 208, undifferentiated carcinoma 42, neuroendocrine carcinoma 209, and carcinosarcoma 210 is possible, but this is currently considered investigational as these tumors were not included in the original TCGA paper 4. The vast majority of low-grade endometrioid carcinomas are NSMP or MSI, with POLE-mutated, or TP53-abnormal tumors accounting for <10%. Moreover, the vast majority (95%) of serous carcinoma are TP53 abnormal.
There is still discussion about whether to apply the molecular classifier to all endometrial carcinomas or just in diagnostically challenging high grade tumors. An important factor in the decision to base therapy selection on genomic subgrouping, includes that most evidence is still retrospective. Prospective studies are awaited and ongoing (eg, PORTEC 4a). The availability of resources, particularly for POLE mutation analysis, are not always accessible. However, perhaps the most important argument against generalized introduction of the molecular classifier is that studies so far have not shown that risk stratification using TCGA molecular data is superior to the European Society for Medical Oncology (ESMO) classification, which relies on clinicopathological data 190. Also, most evidence in support of the TCGA classification is based on 2 large but retrospective cohorts 190,207. There are 2 additional complexities to POLE testing: distinguishing between pathogenic and nonpathogenic mutations 211, and coexistence of ultramutation (ie, pathogenic POLE mutation) with secondary mutations in TP53 and/or one or more of the DNA MMR genes 212. These “multiple classifier” cases are currently thought to retain the favorable prognosis of POLE mutated tumors, regardless of the MMR or p53 status but this is still an evolving field.
IHC may be helpful for diagnosis. With a differential diagnosis involving endometrioid and serous carcinomas, loss of expression of DNA MMR proteins, PTEN and/or ARID1A expression would favor endometrioid carcinoma, whereas both serous and endometrioid carcinomas can show aberrant p53 staining and p16 overexpression (both more common in serous carcinoma) 213. Napsin A, HNF1-beta, and AMACR [together with negative estrogen receptor (ER)] 214,215 may be helpful in diagnosing clear cell carcinoma. A combination of cytokeratin staining, EMA, PAX8, and E-cadherin may also be useful in distinguishing between undifferentiated carcinomas and high-grade endometrioid carcinomas since the former generally shows markedly reduced staining with these markers compared with the latter. Neuroendocrine markers can help in recognition of neuroendocrine tumors 56 and GATA3, TTF1, CD10, and calretinin may help in recognizing mesonephric-like carcinoma 54,55. Finally, a panel including p16, ER, progesterone receptor (PR), and high risk HPV in situ hybridization may be useful in ruling out an HPV-associated endocervical adenocarcinoma 143.
There are also immunohistochemical markers of prognostic and predictive value. HER2 protein overexpression and/or HER2 gene amplification is encountered in ~25% to 30% of endometrial serous carcinomas 216–218, and 14% of endometrial carcinosarcomas 219. Intratumoral heterogeneity of HER2 expression and gene amplification are common in these tumors and should be taken into consideration when evaluating their HER2 status 216,220. HER2 positivity in endometrial serous carcinomas is associated with worse progression-free and overall survival 221, but they can be therapeutically targeted by adding trastuzumab to the standard chemotherapy regimen 222,223. It has been recently shown that HER2 amplification is characteristic of p53-abnormal endometrial carcinomas as defined in the molecular classification, and is not restricted to the serous carcinoma category 224. Although currently no official endometrial cancer-specific pathology HER2 scoring guidelines exist, a new set of criteria have been recently proposed based on the successful clinical trial experience 225.
L1CAM expression has been touted as a marker of aggressive behavior among the NSMP carcinomas and is associated with nonendometrioid histology, distant metastasis, and poor survival 226–228. Mutations in CTNNB1 (but not necessarily nuclear expression of beta-catenin with IHC) are considered by some to be associated with diminished survival in low-grade endometrioid carcinomas, but this is not universally accepted 207,229,230.
ER expression has been associated with tumor behavior and survival in endometrioid tumors 231,232. ER/PR may assist with tumor classification and may be important to some clinicians for treatment planning, although there is some controversy on whether the expression status of the initial hysterectomy specimen reflects the status of the recurrent disease. A recent systematic review confirmed improved response rates to endocrine therapy in tumors with positive ER and PR, especially when determined in the metastatic tissue 233.
WT1 expression may be helpful to distinguish between a primary endometrial serous carcinoma and a tubo-ovarian high-grade serous carcinoma since the latter is more likely to be positive. However, up to 30% to 40% of endometrial serous carcinomas may exhibit some degree of WT1 positivity 234.
Pathologically Confirmed Distant Metastases
Documentation of known metastatic disease is an important part of the pathology report. Such information, if available, should be recorded with as much detail as is available including the site, whether the specimen is a histopathology or cytopathology specimen and with reference to any relevant prior surgical pathology or cytopathology specimens.
Provisional Pathologic Staging
The pathologic staging must be provided on the pathology report and is therefore a core element. The term “provisional pathological staging” is used in this data set to indicate that the stage that is provided may not represent the final tumor stage which should be determined at the multidisciplinary tumor board meeting where all the pathologic, clinical and radiologic features are available 59,89,90,235.
The latest version of either FIGO or TNM staging, or both, can be used depending on local preferences 59,89,90,235. The FIGO system is in widespread use internationally and is the system used in most clinical trials and research studies. However, UICC or AJCC versions of TNM are used or mandated in many parts of the world 89,90. With regards to updating of staging systems, there is collaboration between FIGO and those agencies responsible for TNM with an agreement to adopt changes to FIGO staging. Following the introduction of a new FIGO Staging System, this is usually incorporated into TNM (both UICC and AJCC versions) at a later date. Apart from minor discrepancies in terminology, the UICC and AJCC 8th edition systems are broadly concurrent.
A tumor should be staged following diagnosis using various appropriate modalities (clinical, radiologic, pathologic). While the original tumor stage should not be altered following treatment, TNM systems allow staging to be performed on a resection specimen following nonsurgical treatment (eg, chemotherapy, radiotherapy); in such cases, if a stage is being provided on the pathology report (this is optional), it should be prefixed by “y” to indicate that this is a posttherapy stage.
McCluggage 106 suggests “there are several scenarios where tumor involves sites which are not specifically mentioned in the FIGO (or TNM) Staging Systems and it is useful for the pathologist to know the correct staging in these scenarios. Involvement of pelvic serosal structures (cul-de-sac, bladder, sigmoid serosa) are all Stage IIIA, whereas involvement of the omentum and the abdominal peritoneum is Stage IVB”.
The reference document TNM Supplement: A commentary on uniform use, 5th edition (C Wittekind et al. editors) may be of assistance when staging 236.
NONCORE DATA ELEMENTS
A list of the noncore elements for the reporting of endometrial carcinomas is presented in Table 2 and described below.
TABLE 2 -
Noncore data elements for pathological reporting of carcinoma of the endometrium
||Histologic tumor type*
| Family history of cancer or cancer-associated syndrome
||Maximum tumor dimension
|| Neuroendocrine carcinoma subtype
| Prior history of cancer
|| Carcinosarcoma NOS epithelial %
|| Molecular findings
| Prior therapy
||Block identification key
|| Carcinosarcoma NOS sarcomatous %; homologous/heterologous
|| TCGA-based molecular classification
|| Pattern of myometrial invasion
|| Absolute percentage of myometrial wall thickness invaded by carcinoma
|| Distance of myoinvasive tumor to serosa
||Cervical surface or crypt
||Lower uterine segment
|| Depth of cervical stromal invasion
|| Percentage of cervical stromal invasion
|| Specify site
|| Distance of tumor to closest margin for paracervical soft tissue margin
|| Distance of tumor to closest margin for ectocervical/vaginal cuff margin
||Lymph node status
|| Extracapsular spread
*Neuroendocrine carcinoma subtype, epithelial and sarcomatous percentage, homologous or heterologous is noncore; histologic tumor type is considered core.
Reporting of other immunohistochemistry, molecular findings, the Cancer Genome Atlas (TCGA)-based molecular classification, other tests and representative blocks for ancillary studies is noncore; reporting of whether ancillary studies were performed, and any mismatch repair testing is considered core (Table 1
Pattern of myometrial invasion, absolute percentage of myometrial wall thickness invaded by carcinoma and distance of myoinvasive tumor to serosa is noncore; specification of presence or absence of myometrial invasion and whether <50% or ≥50% is considered core (Table 1
Depth of cervical stromal invasion and percentage of cervical stromal invasion is noncore; cervical stromal involvement is considered core (Table 1
The distance of tumor to the closest margin is noncore; involvement of paracervical soft tissue margin and ectocervical/vaginal cuff margin is considered core (Table 1
NOS indicates not otherwise specified; TCGA, the Cancer Genome Atlas.
Clinical information regarding history of familial cancer (particularly for Lynch syndrome, but also for other hereditary cancer syndromes) is important. In addition, the history of previous cancer, prior neoadjuvant therapy (including hormonal therapy), or any other clinical data that can be relevant for pathologic interpretation is of benefit to report.
Anatomically, the lower uterine segment begins where the body funnels toward the cervix and ends at the internal os. The fundus is that part of the uterus above the origin of the fallopian tubes.
Endometrial carcinoma involving the lower uterine segment has several implications. Tumors originating in this location are more frequently associated with MMR protein deficiencies 153,237. Lower uterine segment involvement in early endometrial carcinoma is predictive of lymph node metastasis and is an independent poor prognostic factor for distant recurrence and death 140,238–240.
Endometrial carcinomas arising in the body of the uterus may extend to involve the lower uterine segment and this should also be recorded. Distinguishing lower uterine segment endometrial carcinoma from endocervical carcinoma is important for staging, prognosis, and management, but this is not always straightforward.
Maximum Tumor Dimension
Some studies have found that a larger tumor size is significantly associated with increased invasion of the lymphovascular space, lymph node metastasis, and/or risk of recurrence in endometrioid endometrial carcinoma; however, the threshold defining a larger tumor size varies from ≥20 to ≥50 mm 241–248. Some studies have not found an association between a tumor size of ≥20 mm and prognosis 102,249.
It is recommended that the largest dimension of the tumor should be reported; other dimensions are not required. This may be determined by macroscopic or microscopic assessment or the combination of both 91.
Omentectomy is currently undertaken in many, but not all, institutions for all high-grade endometrial carcinomas 90, such as grade 3 endometrioid carcinoma, serous carcinoma, clear cell carcinoma, undifferentiated carcinoma, and carcinosarcoma 140. Grade 1 and 2 endometrioid carcinomas are subject to omentectomy in some centers 140.
Thorough macroscopic examination of the omentum is essential 138. The omentum should be cut at 5 mm intervals to detect small lesions 16. Obvious lesions can be sampled in 1 or 2 blocks but if no lesion is seen then at least 4 blocks are recommended 138. One study suggests improving the sensitivity for detection of microscopic disease in macroscopically normal omentum to 95% if at least 10 blocks are submitted 250.
Block Identification Key
The origin/designation of all tissue blocks should be recorded. This information should ideally be documented in the final pathology report and is particularly important should the need for internal or external review arise. The reviewer needs to be clear about the origin of each block in order to provide an informed specialist opinion. If this information is not included in the final pathology report, it should be available on the laboratory computer system and relayed to the reviewing pathologist. It may be useful to have a digital image of the specimen and record of the origin of the tumor blocks in some cases.
Recording the origin/designation of tissue blocks also facilitates retrieval of blocks for further immunohistochemical or molecular analysis, research studies or clinical trials.
Cervical Surface or Crypt
Cervical surface mucosal or crypt epithelial involvement (without cervical stromal invasion) does not affect tumor stage in the 2009 FIGO Staging System and is regarded as a noncore element 59. However, it is a potential adverse risk factor for locoregional recurrence and may be taken into consideration for adjuvant radiotherapy 91. In the Post Operative Radiation Therapy in Endometrial Carcinoma-2 (PORTEC-2) and Gynecology Oncology Group trial 99 (GOG #99) prospective randomized trials, patients with high-intermediate risk factors, including cervical surface or crypt involvement (FIGO 1988 Stage IIA), were found to have improved locoregional disease control (reduced recurrence rate) with postoperative radiation (vaginal brachytherapy or pelvic radiation) 132,251–253. While the above studies lacked an overall survival benefit, a recent large retrospective cohort (analyzing over 14,000 patients) demonstrated improved overall survival in FIGO 1988 Stage IIA patients receiving adjuvant radiation 254.
The current clinical practice guidelines of the American Society for Radiation Oncology and the Society of Gynecologic Oncology are based on the results of the PORTEC-2 and GOG #99 trials for adjuvant radiotherapy 255,256.
Lower Uterine Segment
As stated in the Tumor site section, similar to cervical surface or crypt involvement, although not affecting the FIGO tumor stage, lower uterine segment involvement is a potential adverse risk factor for locoregional and distant recurrence and may be taken into consideration for adjuvant radiotherapy 238. It is regarded as a noncore element for reporting. As tumors arising in the lower uterine segment also show frequent association with Lynch syndrome, documentation of lower uterine segment involvement has important risk implications 237.
Depth of Cervical Stromal Invasion
The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology Uterine Neoplasms lists deep cervical stromal invasion as an adverse risk factor in patients with Stage II endometrial carcinoma 257. While external beam radiation therapy is preferred in patients with surgically staged Stage II endometrial carcinoma, vaginal brachytherapy is listed as a valid option for those patients with low grade disease with minimal cervical stromal invasion and no tumor outside the corpus and cervix 257.
There is no clear definition of what constitutes “minimal cervical stromal invasion”. A retrospective, single-institution study by Orezzoli et al (2009) stratified cervical stromal invasion into 4 subcategories (≤1 mm; >1 and ≤3 mm; >3 and ≤5 mm; >5 mm), and found no statistical association with survival 258. Barnes et al. 259 reported on their retrospective, single-institution experience study on brachytherapy alone in patients with low-grade endometrial carcinoma and cervical stromal invasion confined to the inner half of the cervix, which showed good results. Absolute depth of cervical stromal invasion and percentage of cervical stromal invasion are noncore elements.
Positive peritoneal cytology is no longer part of the FIGO Staging System, but the results of the peritoneal cytology may provide risk-stratification. As a consequence, consideration for adjuvant therapy may be discussed in multidisciplinary tumor board meetings. Positive peritoneal cytology has been shown to be an independent prognostic factor for serous carcinoma regardless of stage and it will be important to report for other invasive carcinomas 59,257,260,261.
There is lack of consensus in the literature regarding the prognostic significance of positive peritoneal washings in the absence of other evidence of extrauterine spread, and it is also unclear whether the method of hysteroscopy or operative procedure may influence the likelihood of positive peritoneal washings 91. FIGO and the UICC recommend to record positive peritoneal washings but without altering the tumor stage 59,89.
The background endometrium may provide useful information regarding tumor pathogenesis and may have prognostic implications 140. The presence of stromal predecidual change and Arias-Stella reaction may serve as evidence of preoperative hormonal therapy 262. These should be reported under “other.”
Hyperplasia without atypia may occur due to prolonged exposure to unopposed estrogen, whereas atypical hyperplasia/endometrioid intraepithelial neoplasia is a manifestation of clonal expansion of neoplastic glands 263,264. These lesions predispose to endometrioid carcinoma 265–267. Serous carcinoma typically arises in a background of atrophic endometrium although it remains controversial as to what constitutes a precise precursor lesion. Serous endometrial intraepithelial carcinoma is regarded as a serous carcinoma which grows along pre-existing glands but still has the potential to metastasize to extrauterine sites. Therefore, it is considered a carcinoma rather than a precursor lesion 268,269. A precursor of clear cell carcinoma has not yet been defined 270,271.
Carcinomas arising in an endometrial polyp, may be endometrioid or serous in type, with the latter being more common 272. To prove that a carcinoma has arisen within an endometrial polyp rather than secondarily involving it, the tumor should be confined to the polyp. Usually this needs to be confirmed on a hysterectomy specimen.
Although metaplasias are common in benign endometrium, some subtypes, such as papillary proliferation and morular metaplasia, may be associated with concurrent or subsequent atypical endometrial hyperplasia and endometrial carcinoma 273,274. Papillary mucinous metaplasia and complex mucinous glandular proliferation predispose to endometrioid carcinoma with mucinous differentiation 34,275.
This new ICCR endometrial cancer data set is an update of the previous one developed in 2011 and includes significant changes in both the core and noncore elements. The update and changes were necessitated given the significant advances in endometrial cancer pathology reporting in the last 10 yr, including a new WHO Classification of Female Genital Tumors published in 2020 5 and TCGA molecular classification of endometrial cancers published in 2013 4. There has also been significant new information regarding other parameters, for example, the importance of LVI in prognosis in endometrial carcinomas with recent data indicating that “substantial” or “extensive” LVI is associated with adverse outcomes when compared with carcinomas with “focal” or “no” LVI.
For core elements, the most significant changes from the prior data set are:
- More detailed information is provided regarding the specimens submitted for pathologic examination.
- Update on histologic classification, according to the 2020 WHO classification with inclusion of “new” tumor types such as squamous cell carcinoma, mesonephric and mesonephric-like adenocarcinoma 54,55, and gastrointestinal-type mucinous carcinoma. Carcinosarcoma is now included as a type of epithelial malignancy and updated criteria for the diagnosis of mixed carcinomas are provided.
- Inclusion of the distinction between extensive/substantial versus focal LVI, because of the important prognostic value and relevance in tumor risk stratification in some clinical guidelines.
- More detailed information regarding location of adnexal involvement and the distinction between synchronous and metastatic adnexal involvement.
- More precise description of margin status, including paracervical soft tissue margin and ectocervical/vaginal cuff margin.
- More detailed description of lymph node status, including information regarding sentinel nodes, extent of involvement, and the maximum dimension of the largest tumor deposit.
- Update on core ancillary studies including assessment of MMRd, in addition to analysis for MLH1 promoter methylation when there is loss of MLH1 and PMS2 immunostaining. This is important from a diagnostic and prognostic viewpoint, as a predictive biomarker for immunotherapy and as part of the screening algorithm to identify Lynch syndrome patients.
For noncore elements, the most significant changes from the prior data set are:
- More detailed clinical information, including family history of cancer, prior history of cancer and previous therapies. This is of importance in pathologic interpretation and clinicopathologic correlation.
- Omentum dimensions, when omentectomy is performed.
- Incorporation of the pattern of myometrial invasion (conventional infiltrative, adenoma malignum-like, pushing or expansile, MELF).
- More precise definition of the depth of cervical stromal invasion, which may be important for clinical decision-making regarding adjuvant therapy.
- Update on some non-core ancillary studies, including IHC useful in diagnosis and prognosis and molecular findings. Data on TCGA-based molecular classification is also included as a non-core element. This is regarded as an evolving area, which will likely need to be updated following analysis and publication of additional scientific evidence, provided by ongoing prospective clinical trials.
The process of revising the ICCR data set for the reporting of endometrial carcinomas is described in this paper. The data set outlines the core elements which should be recorded in pathology reports of resection specimens of endometrial carcinoma, and non-core elements which may be included. These recommendations were developed by an international panel of expert gynecological pathologists and an expert clinician and detail the response values for each element and provide explanatory notes/commentary. Such internationally agreed, evidence-based, structured pathology data sets help to advance international standardization for best practice case reporting and patient care in addition to progressing future cancer research and benchmarking.
The authors acknowledge the support of ISGyP toward the production of this data set. The authors would like to acknowledge Meagan Judge from the ICCR for providing expert editorial and data set administration management.
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