Issues relevant only to the diagnosis of endometrial carcinoma on biopsy specimens will be considered. In 1983, Bokhman68
first proposed that there were two major variants of endometrial cancer—namely type 1 (the prototype of which is endometrioid carcinoma) and type 2 (the prototype of which is serous carcinoma). It is imperative that an endometrial cancer is both typed and graded, if appropriate, on an endometrial biopsy (the term endometrial adenocarcinoma does not suffice, as endometrial adenocarcinomas may be of several different morphological subtypes). This is especially so in countries with a well‐developed gynaecological oncology service, such as the UK, where different referral patterns exist for cancers of type 1 and type 2. For example, many endometrioid adenocarcinomas (grade 1 and grade 2) are dealt with in a cancer unit, whereas type‐2 cancers, including serous and clear‐cell carcinoma, are usually managed at a cancer centre. More extensive surgical staging may be undertaken with a type‐2 cancer—for example, omentectomy and lymphadenectomy may be carried out. Similarly, in many regions, grade‐3 endometrioid carcinomas are managed in a gynaecological oncology cancer centre. It is controversial whether serous carcinoma (and other type‐2 carcinomas such as clear cell) should be graded, and most take the view that these are by definition grade‐3 tumours. I believe that it is useful to state this on the pathology report, especially if dealing with general gynaecologists who are not routinely occupied with the management of gynaecological neoplasms. All endometrioid carcinomas (and other type‐1 carcinomas such as mucinous carcinoma) should be graded by using the revised 1988 International Federation of Gynecology and Obstetrics grading system.69
In this system, for an architectural grade‐1 or grade‐2 tumour to be upgraded to a grade‐2 or grade‐3 neoplasm, respectively, high‐grade (grade 3) nuclei should be present.69,70
Grade‐3 nuclei are defined as enlarged and pleomorphic, with abnormal coarsely clumped chromatin and large irregular nucleoli.69
In assessing the proportion of solid and non‐solid elements, squamous foci should be ignored. Assessing whether solid areas are squamous or non‐squamous is often difficult, as squamous foci may exhibit a variety of patterns, including a clear cell and spindle cell morphology.71
- In the evaluation of an endometrial biopsy specimen, an adequate clinical history is important, including details regarding the use of exogenous hormones.
- In a postmenopausal woman with an atrophic endometrium and no focal lesion on ultrasound scan, the presence of scant endometrial tissue in an outpatient biopsy is the norm.
- When an endometrial biopsy is carried out for abnormal uterine bleeding, the pathologist should always consider the possibility of a polyp.
- Serous proliferations, either serous carcinoma or endometrial intraepithelial carcinoma, have a propensity to arise in endometrial polyps.
- All endometrial cancers should be typed and, if appropriate, graded, even for small biopsy specimens.
Differentiating between an endometrioid and a serous carcinoma may be problematic on occasion. An endometrioid carcinoma with a papillary growth pattern may be misdiagnosed as a serous carcinoma and, conversely, serous carcinoma with a glandular growth pattern and little or no papillary formation may be mistaken for an endometrioid carcinoma. A diagnosis of a papillary adenocarcinoma should not be made without specification of the morphological type. Architecturally well‐differentiated endometrioid carcinomas usually have low‐grade nuclei; and in an architecturally well‐differentiated neoplasm with grade‐3 nuclei and without papillary formation, a glandular variant of serous carcinoma should be considered (fig 15). In the distinction between an endometrioid and a serous carcinoma, immunohistochemical analysis may be of value.72
Endometrioid adenocarcinomas, especially when grade 1 or grade 2, are usually oestrogen receptor positive and p53 negative. Conversely, serous carcinomas usually show diffuse nuclear p53 reactivity and are oestrogen receptor negative.73,74,75
Many exceptions exist, however, with occasional serous carcinomas being p53 negative and a considerable proportion exhibiting oestrogen receptor positivity, albeit often focal. Conversely, some endometrioid adenocarcinomas are p53 positive, although grade‐1 and grade‐2 neoplasms only rarely exhibit the diffuse strong nuclear reactivity that is characteristic of serous carcinoma. Mixed endometrioid and serous carcinomas are not uncommon. Staining with oestrogen receptor and p53 may also be of value in identifying small foci of EIC in a polypoid or non‐polypoid endometrium (fig 16) or in suggesting a diagnosis of serous neoplasia when only small fragments of tissue are present in an endometrial biopsy specimen.72
Figure 15Glandular variant of serous carcinoma without papillary formation. The glands are lined by markedly atypical nuclei, characteristic of serous neoplasia.
Figure 16Endometrial intraepithelial carcinoma exhibiting diffuse intense p53 positivity. The residual atrophic glands are negative.
As referred to previously, serous carcinoma and its presumed precursor lesion EIC (also variously termed endometrial carcinoma in situ or surface serous carcinoma) have a marked propensity to arise in or to be associated with otherwise benign endometrial polyps.18,19,76,77
I use the term “presumed precursor lesion”, as it is possible that EIC, defined as the replacement of residual atrophic glands by cells with markedly atypical nuclei that are characteristic of serous neoplasia without endometrial stromal, myometrial or vascular invasion,76,78,79
actually represents a growth pattern of serous carcinoma and not a precursor lesion. Endometrial polyps, especially when large and occurring in elderly patients, should be carefully scrutinised for small serous proliferations.
A commonly encountered problem in endometrial carcinoma is in determining the nature of clear‐cell areas. This may indicate a pure clear‐cell carcinoma or a component of clear‐cell carcinoma, a variant of type‐2 endometrial cancer usually with markedly atypical nuclei, sometimes with a hobnail pattern. Occasional clear‐cell carcinomas, however, have relatively bland nuclei. Negative staining for oestrogen receptor and diffuse p53 reactivity favour a clear‐cell carcinoma, although a significant proportion of clear‐cell carcinomas do not show this immunophenotype.80
Clear cells are not uncommon in endometrioid adenocarcinomas. This may represent a non‐specific change in clear cells, a secretory variant of endometrioid carcinoma or clear‐cell squamous areas (fig 17).71
Clearing of the cytoplasm in an endometrioid adenocarcinoma may also be a result of prior progestogen treatment.
Figure 17Endometrioid adenocarcinoma of the endometrium with clear‐cell squamous areas.