Endometrial Carcinoma, Grossing and Processing Issues: Recommendations of the International Society of Gynecologic Pathologists.

The number of sections submitted should not be altered in the context of adenomyosis. However, in cases where the assessment of myometrial invasion is difficult because of tumor involving adenomyosis taking additional sections of the uterine wall may be useful. None of the manuals reviewed addresses the measurement of myometrial invasion in the context of adenomyosis 6 .

Omentectomy is part of the staging procedure of endometrial serous carcinoma, clear cell carcinoma and carcinosarcoma. The gross appearance and measurement of the omentum should be provided. Omental tissue should be sliced at 0.5 cm intervals to detect small abnormalities. There are no standard sampling recommendations, but in general the number of sections to be submitted will depend on the gross examination findings. If the omentum is grossly positive, one or 2 representative sections are enough for microscopic evaluation, but if it is grossly negative, one representative section per 2 or 3 cm of maximal omental dimension 85 or at least a total of 4 blocks of tissue should be submitted 28 . Currently, guidelines on omental tissue sampling in endometrial cancer are included in the Dataset for Histological Reporting of Endometrial Cancer by the Royal College of Pathologists 28 , but not included in the recommendations of either the CAP 11 or the International Collaboration on Cancer Reporting 86 The former recommends submission of a total of 4 blocks of tissue if grossly negative omentum. Others, advocate for submission of one representative section per 2 or 3 cm of maximal omental dimension if the omentum is grossly unremarkable 73 . One study found that submitting 5 blocks of grossly negative omentum has a sensitivity of 82% while examining 10 blocks raises the sensitivity to 95% 87 .

Uteri should be opened immediately upon receipt in the pathology laboratory and placed in formalin within an hour of opening whenever possible. The purpose of opening the uterus immediately is to prevent autolysis, which is very common in hysterectomy specimens, and to avoid potential preanalytical issues when ordering immunohistochemical or molecular studies 3 – 5 . Although most of the grossing manuals used in academic institutions in North America do not provide specific timelines, some include specific instructions such as opening and fixation within 1 h of receipt in the pathology laboratory, documentation of cold ischemic interval and interval in formalin, and prompt procurement of fresh tissue for banking and/or investigational protocol purposes 6 .

The cervix should be left attached to the corpus during the gross examination of a hysterectomy specimen obtained for endometrial carcinoma. No practice manual recommends amputation of the cervix 6 . Amputation could potentially interfere in the pathologic assessment of the tumor and the relationship with the upper endocervix, which can be problematic even at the microscopic level 64 .

The description of the SLN should include measurements, gross appearance, the presence of dye and the radioactive tracer reading provided by the surgeon, if any. The lymph node is sliced at 2.0 mm intervals perpendicular to its long axis (Fig. 8 ). A small rim of adipose tissue should be left around the lymph node. The entire lymph node is submitted for microscopic examination in properly identified cassettes. The SLN is usually ultrastaged [i.e. additional recuts and/or immunohistochemistry (IHC) for keratin], although some institutions do not routinely undertake ultrastaging. At the present time there is no universal ultrastaging protocol; however, all institutions undertaking SLN examination should have a standard procedure for SLNs in endometrial cancer. Sentinel lymph node, parallel slices are perpendicular to the long axis of the specimen. SLN removal has been introduced in the surgical staging of endometrial carcinoma to decrease the morbidity secondary to a lymphadenectomy but still obtain information about the lymph node status 95 . The 2018 NCCN Guidelines indicate that SLN mapping may be considered in patients with apparent uterine-confined endometrial cancer (clinical stage I disease) 57 . As delineated in the NCCN guidelines and the Society of Gynecologic Oncology recommendations, there are several key points when using this technique: (1) the expertise of the surgeon and attention to technical detail are critical to ensure mapping success; (2) superficial and deep cervical injection of dye has been validated as a useful mapping technique; (3) complete evaluation of the peritoneal cavity is mandatory; (4) SLN dissection starts with the evaluation of the retroperitoneal spaces and identification of the sentinel drainage pathways that emanate from the parametrial tissue, this is followed by excision of all mapped SLNs; (5) any suspicious non-SLN should be excised and frozen section may be required to determine if a para-aortic lymphadenectomy will be performed. Of note, routine frozen section of SLNs is not advisable as small foci of tumor may be lost when cutting the frozen section slides in addition to the relatively low sensitivity for detection of metastases in grossly unremarkable lymph nodes, (6) should mapping failure occur in a hemi-pelvis, a side-specific lymphadenectomy should be performed; (7) pathology ultrastaging is required to improve the detection of low-volume metastases 57 , 95 . The 2018 NCCN guidelines also state that recent evidence indicates that SLN mapping may be used in high-risk histologies (serous carcinoma, clear cell carcinoma, and carcinosarcoma) 57 . At the present time, it has been established that the use of indocyanine green, which requires use of a near infra-red camera for localization, has similar rates of mapping success to those of radiocolloid Tc-99 combined with blue dye 95 . The gross processing of SLNs is critical to ensure the success of this technique. It is of utmost importance to obtain serial perpendicular, thin (2.0 mm) sections as an initial step as this raises the odds of metastatic tumor detection independent of the ultrastaging process 84 . This method not only facilitates the examination of the lymph node subcapsular space and parenchymal surface, but is designed to detect all metastases >2.0 mm. A study comparing 2 different ultrastaging protocols (method #1, obtaining 5 H&E-stained levels at 250 μm with 2 unstained slides at each level—pankeratin IHC performed on level 1 in cases with negative H&E or method #2, 1 H&E level and 2 unstained slides cut at 250 μm into the tissue block, pankeratin IHC performed in cases with negative H&E) found no statistically significant differences between the methods with respect to number of positive SLNs detected, size of metastasis or false-negative rate 84 . There is no universal protocol for the ultrastaging of SLNs 95 . Protocols used at the 2 largest cancer centers in the United Stated are as follows: The University of Texas M.D. Anderson Cancer Center Protocol. If the H&E-stained slide is negative for tumor, 3 consecutive sections at 250 µm into the paraffin block are obtained (one for H&E and one of the remaining 2 to be used for keratin cocktail IHC if the additional H&E-stained slide is negative 96 (Fig. 9 A). Memorial Sloan Kettering Cancer Center Protocol. If the initial H&E-stained slide is negative for carcinoma and the endometrial cancer is myoinvasive or associated with vascular/lymphatic invasion, 2 additional levels 50 µm apart are examined, at each level 2 slides are obtained, one for H&E and the second for keratin cocktail IHC if the H&E-stained slide is negative 97 (Fig. 9 B). The University of Texas M.D. Anderson Cancer Center Protocol. If the H&E-stained slide is negative for tumor, 3 consecutive sections at 250 µm into the paraffin block are obtained (one for H&E and one of the remaining 2 to be used for keratin cocktail IHC if the additional H&E-stained slide is negative 96 (Fig. 9 A). Memorial Sloan Kettering Cancer Center Protocol. If the initial H&E-stained slide is negative for carcinoma and the endometrial cancer is myoinvasive or associated with vascular/lymphatic invasion, 2 additional levels 50 µm apart are examined, at each level 2 slides are obtained, one for H&E and the second for keratin cocktail IHC if the H&E-stained slide is negative 97 (Fig. 9 B). Ultrastaging protocols, MD Anderson Cancer Center (MDACC) (A) and Memorial Sloan Kettering Cancer Center (MSKCC), ultrastaging will be obtained if there is myometrial or vascular/lymphatic invasion (*) (B). H&E indicates hematoxylin and eosin; IHC, immunohistochemistry; SLN, sentinel lymph node.

The ectocervical margin of a hysterectomy specimen should be reported in an endometrial cancer with cervical involvement. The vaginal cuff and parametrial margins should be reported in endometrial carcinomas with cervical and/or parametrial involvement when a radical hysterectomy is undertaken. Otherwise, reporting of margins is optional 11 . In cases where it is required to report the above margins, including the distance between the tumor and the margin is also optional 11 . Involvement of the uterine serosa by tumor should be reported as this finding indicates FIGO stage III A disease 39 ; however, the uterine serosa is not a margin and should not be designated as such.

It is our hope that these ISGyP developed recommendations will help to standardize the processing of endometrial cancer specimens; this will facilitate accurate pathologic reporting and a better understanding of this disease which will be to the ultimate benefit of patients suffering from it.

Orient the specimen, that is identify the anterior and posterior walls of the uterus using anatomic landmarks such as the peritoneal reflection and the round ligament/ovaries (Figs. 1 A, B). Document all organs/structures received and record their measurements and gross appearance. Orientation of hysterectomy specimen using anatomical landmarks, peritoneal reflection is higher anteriorly (arrow) and the sequence of structures in the adnexal region is round ligament (*), fallopian tube (arrowhead) and ovary (**) (A), peritoneal reflection is lower posteriorly (arrow) and the sequence of structures in the adnexal region is ovary (**), fallopian tube (arrowhead) and round ligament (B), the latter is not visualized in this photograph.

In cases where intraoperative assessment is requested by the surgeon to determine whether staging will be obtained, examine the specimen carefully, including the uterine serosa, lower uterine segment, cervix and adnexal structures. Identify the lesion, measure it, cross-section the uterine wall, and evaluate the status of the myometrium. Submit at least one section of the lesion for frozen section including the adjacent uterine wall. Should myometrial invasion be suspected, submit the lesion and the full thickness of the uterine wall containing the deepest point of myometrial invasion for frozen section. Should cervical, uterine serosal or adnexal involvement be suspected, submit appropriate sections for frozen section examination. Intraoperative evaluation of hysterectomy and bilateral salpingo-oophorectomy specimens obtained for endometrial cancer to determine parameters that guide lymph nodes dissection, and in some cases omentectomy, which are needed for staging and prognosis, is commonly performed in the United States, and much less frequently, if at all, in other parts of the world 31 . Histotype, tumor grade if applicable, and depth of myometrial invasion are typically reported 31 . In addition, tumor size needs to be determined if the Mayo algorithm is being applied. Briefly, using this algorithm cases are stratified as low risk or high risk. Low risk is defined as FIGO grade 1 or 2 endometrioid carcinoma with myometrial invasion ≤50% and primary tumor diameter ≤2 cm while high risk is defined as FIGO grade 3 endometrioid carcinoma, nonendometrioid histotype, myometrial invasion >50% or primary tumor diameter >2 cm. Cases in the low risk category are spared a systematic pelvic and para-aortic lymphadenectomy while these procedures are performed in cases in the high risk category 21 . Lower uterine segment, cervical, and adnexal involvement and lymphovascular space invasion should be reported if these findings are identified during the intraoperative evaluation.

All pathology reports should include a detailed section code/block key on which the origin/designation of all tissue blocks should be recorded. This information is particularly important should there be a need for internal or external review as reviewers need to be clear about the origin of each tissue block in order to provide an informed specialist opinion. Recording the origin/designation of all tissue blocks also facilitates retrieval of blocks for immunohistochemical or molecular analysis, research studies or clinical trials.