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Address for correspondence: Dr Karen L. Talia, Department of Anatomical Pathology, The Royal Women's Hospital (a division of Laboratory Services, Royal Children's Hospital), Level 5, 20 Flemington Road, Parkville, Vic 3052, Australia.
Endometrioid carcinoma (EC) accounts for approximately 10–12% of ovarian epithelial malignancies but compared to its relative frequency, results in a disproportionate number of diagnostically difficult cases with potential for misdiagnosis. In this review the protean and diverse morphologies of ovarian EC are discussed, including ‘metaplastic’ changes, EC with spindle cell differentiation/corded and hyalinised features and EC with sex cord-like formations. The propensity for ‘transdifferentiation’ in ovarian ECs is also discussed, one example being the association with a somatically derived yolk sac tumour. Although immunohistochemistry may be extremely useful in diagnosing EC and in distinguishing between EC and other ovarian epithelial malignancies, metastatic neoplasms and sex cord-stromal tumours, this review also discusses the propensity for ovarian EC to exhibit an aberrant immunophenotype which may compound diagnostic uncertainty. The genomic characteristics of these tumours and the recent ‘incorporation’ of seromucinous carcinoma into the EC category are also discussed.
When the morphology is classical, diagnosis is straightforward. However, compared to its relative prevalence, ovarian EC accounts for a disproportionately high number of cases which are difficult to diagnose and, like mucinous carcinoma, is over represented in referral practice compared to other ovarian epithelial malignancies. Ovarian ECs have a broadly similar morphological spectrum to the corresponding tumours within the uterine corpus but present different issues in diagnosis and differential diagnosis, with some of the ‘variants’ which result in diagnostic problems encountered more commonly in the ovary than the uterine corpus and vice versa. The wide range of morphological appearances sometimes results in consideration of a variety of other neoplasms including other primary ovarian carcinomas, other types of ovarian neoplasia (for example sex cord-stromal tumours) and metastatic adenocarcinomas (especially but not exclusively colorectal). With all the morphological variants, the presence of foci of typical EC and supportive endometrioid features such as endometriosis, adenofibromatous areas (which may be borderline or malignant) and squamous or mucinous elements may assist in diagnosis, as can immunohistochemistry, although there are many pitfalls which are discussed below.
Twenty years ago, Clement and Young published a seminal review article discussing the propensity for ECs of the uterine corpus to exhibit a very diverse morphology,
but as far as we are aware there has been no major review discussing the varied morphology of ovarian ECs. Herein we cover the diverse and protean morphology of ovarian EC, discuss the differential diagnosis and highlight the propensity of these neoplasms to exhibit an ‘aberrant’ immunophenotype which may compound diagnostic difficulty. We also cover recent developments characterising the genomic profile of these tumours. We will not provide detailed illustrations of the classical morphological features of ovarian ECs but will illustrate the unusual morphological features and immunophenotypes.
General issues and historical comments regarding ovarian endometrioid carcinomas
The 2020 World Health Organization (WHO) Classification of ovarian epithelial malignancies includes five major categories, namely high grade serous carcinoma (HGSC), low grade serous carcinoma (LGSC), EC, clear cell carcinoma and mucinous carcinoma.
These tumours differ with respect to their risk factors, underlying molecular events, morphology, immunophenotype, behaviour and sensitivity to classical platinum based chemotherapy and newer targeted therapies. Their diagnosis also signifies differences in risk for hereditary cancer syndromes; for example, any patient with a diagnosis of HGSC should be offered BRCA1/2 germline mutation testing, while a diagnosis of EC or clear cell carcinoma should prompt assessment for mismatch repair (MMR) protein abnormalities and possible Lynch syndrome.
Up until about 20 years ago, some pathologists tended to diagnose many high grade ovarian carcinomas as serous in type while others classified them as endometrioid or mixed serous and endometrioid. It is now well established that a large majority of these neoplasms represent HGSC. In the distinction between HGSC and high grade EC, WT1 immunohistochemistry may be of value.
Mixed ovarian epithelial carcinomas with clear cell and serous components are variants of high-grade serous carcinoma: an interobserver correlative and immunohistochemical study of 32 cases.
About 95% of primary tubo-ovarian HGSCs exhibit nuclear positivity with WT1 which is usually but not always diffuse, while most ECs are negative, although this is not invariable (see section 16 below).
Similarly, it was previously considered that the various types of ovarian carcinoma were part of a spectrum with the same origin (considered most likely to be ovarian surface epithelium) and with potential for multidirectional differentiation resulting in the common occurrence of mixed carcinomas.
Mixed ovarian epithelial carcinomas with clear cell and serous components are variants of high-grade serous carcinoma: an interobserver correlative and immunohistochemical study of 32 cases.
Indeed, up until the last 20 years, mixed carcinomas, such as mixed serous and endometrioid, mixed serous and clear cell, mixed serous and transitional and combinations of all these types were diagnosed not uncommonly. However, recent studies using current ‘modern’ diagnostic criteria, supplemented by immunohistochemistry (especially WT1), have shown that mixed carcinomas are very uncommon, accounting for less than 1% of ovarian carcinomas.
A population based study published in 2010, which included central pathology review using ‘modern’ diagnostic criteria, provides contemporary information regarding the relative frequency of the major types of ovarian carcinoma. In that study, HGSC accounted for 68.1% of cases, clear cell carcinoma 12.2%, EC 11.3% and LGSC and mucinous carcinoma 3.4% each.
This study revealed an increase and decrease in the frequency of serous and EC respectively; this likely reflects the fact that, as discussed, the distinction between HGSC and high grade EC was previously poorly reproducible and many neoplasms diagnosed as high grade EC were, in fact, HGSC. Use of ‘modern’ diagnostic criteria has also resulted in markedly improved interobserver variability in the diagnosis of ovarian carcinomas.
Histological features of ‘conventional’ endometrioid carcinoma and tumour grading
Ovarian ECs exhibit a broad morphological spectrum which mirrors that of their uterine corpus counterparts. The most common pattern is a confluent proliferation of variably sized glands forming closely crowded back-to-back and cribriform arrangements and anastomosing labyrinthine structures. The glands typically display smooth luminal borders and are lined by columnar cells with round to oval nuclei and moderate amounts of apical cytoplasm. The nuclei generally exhibit mild to moderate cytological atypia and variable but often modest mitotic activity. Papillary arrangements of cells with similar cytological features are often present and may be conspicuous. Variable proportions of solid tumour growth may also be seen. While the conventional morphology just described is common, ovarian ECs are notable for their tendency to display an array of epithelial metaplasias, most often squamous or mucinous (discussed in detail in the section ‘metaplastic’ changes in ovarian endometrioid carcinomas).
Rarely a sarcomatous component is present in association with an ovarian EC, this constituting a carcinosarcoma. The EC component may be either low grade or high grade, the former being extremely rare. In these rare ovarian carcinosarcomas with a low grade EC component, the mesenchymal component may be morphologically low grade or high grade and contain heterologous elements. Given the rarity of carcinosarcomas with a low grade EC component there are no recommendations regarding tumour grading and, as with more typical carcinosarcomas, we recommend automatically calling these grade 3.
Grading of ovarian ECs is performed using the FIGO grading system applied to ECs of the uterine corpus, although one study found the Silverberg grading system may offer better prediction of patient survival in ovarian EC.
Most ovarian ECs contain only a minor solid component and are typically low grade (grade 1 or 2) although a minority are high grade (grade 3), sometimes with a low grade component only identified after wide sampling.
ER staining is more common and generally more widespread than PR and both markers are more commonly positive in low grade (grade 1 or 2) EC. Grade 3 ECs are usually ER and PR positive but sometimes with weaker and more limited staining than in grade 1 and 2 neoplasms. ECs are usually also positive with CK7, PAX8 and CA125 and are typically negative with CK20 and CEA. Rates of vimentin positivity vary considerably in the literature with 3–84% of ovarian ECs reported to show vimentin expression.
Differential vimentin expression in ovarian and uterine corpus endometrioid adenocarcinomas: diagnostic utility in distinguishing double primaries from metastatic tumors.
In our experience while vimentin is often positive in ovarian ECs, staining is often focal rather than widespread. WT1 is usually but not always negative in ovarian ECs (see section 16 below).
Some ECs exhibit quite diffuse immunoreactivity with p16 but this is typically still patchy with alternating positive and negative areas (mosaic pattern).
Utility of p16 expression for distinction of uterine serous carcinomas from endometrial endometrioid and endocervical adenocarcinomas: immunohistochemical analysis of 201 cases.
Sometimes the high grade areas exhibit mutation-type staining while the low grade areas exhibit wild-type immunoreactivity and this may be diagnostically useful in the distinction between a high grade EC and a HGSC. Napsin A is usually negative in ovarian ECs. Aberrant MMR protein expression/microsatellite instability is present in 8–19% of ovarian ECs with loss of MLH1 and PMS2, usually due to MLH1 promoter methylation, most frequent
Accurate distinction of ovarian clear cell from endometrioid carcinoma requires integration of phenotype, immunohistochemical predictions, and genotype: implications for lynch syndrome screening.
and some cases are associated with Lynch syndrome. While confirmatory immunohistochemistry is not required in classical cases of ovarian EC, routine MMR immunohistochemistry is recommended in all cases of newly diagnosed ovarian EC (and clear cell carcinoma) as both tumour types occur in this syndrome, with EC representing the most common Lynch syndrome-associated ovarian cancer.
Accurate distinction of ovarian clear cell from endometrioid carcinoma requires integration of phenotype, immunohistochemical predictions, and genotype: implications for lynch syndrome screening.
So-called squamous morules exhibit an unusual immunophenotype (Fig. 1). Morules typically exhibit diffuse nuclear CDX2, SATB2 and β-catenin immunoreactivity (secondary to underlying CTNNB1 mutation) and stain positively with p16 and CD10.
SATB2 is consistently expressed in squamous morules associated with endometrioid proliferative lesions and in the stroma of atypical polypoid adenomyoma.
They are usually ER, PR, p63 and p40 negative. Given the negative staining with the squamous markers p63 and p40, morules may not actually represent a form of squamous differentiation and consequently the alternative term morular metaplasia has been proposed.
SATB2 is consistently expressed in squamous morules associated with endometrioid proliferative lesions and in the stroma of atypical polypoid adenomyoma.
Recently Niu et al. investigated the relationship between morules and non-morular squamous elements and CTNNB1 mutation in 270 cases of endometrial EC and atypical endometrial hyperplasia using immunohistochemistry and next generation sequencing. They confirmed a distinct immunophenotype for both forms of metaplasia and demonstrated a near perfect correlation between morules and glandular β-catenin nuclear expression in EC and atypical hyperplasia. All 20 morule containing cases selected for targeted sequencing showed CTNNB1 mutation. The authors concluded that morules and squamous differentiation are distinct biological phenomena, a conclusion also supported by their distinct immunophenotypes.
Distinction between endometrioid borderline tumour and grade 1 endometrioid carcinoma
In some cases it is difficult to distinguish between a grade 1 EC and a borderline endometrioid tumour. Borderline endometrioid tumours most commonly exhibit an adenofibromatous growth pattern with morphologically bland crowded endometrioid-type glands, often with morular or squamous metaplasia, within a fibromatous stroma. Such tumours usually retain a somewhat lobular architecture with significant stroma between the glands. In making the distinction between a grade 1 EC and a borderline endometrioid tumour with an adenofibromatous morphology, the diagnostic approach we broadly recommend is analogous to that applied in the uterus when distinguishing atypical hyperplasia from grade 1 EC. The diagnosis of malignancy is based on a confluent pattern of glandular proliferation, with fused and cribriform glands resulting in complete or near complete exclusion of intervening stroma; significant papillary growth is also suggestive of malignancy (Fig. 2).
Fig. 2This endometrioid carcinoma shows a somewhat lobular architecture reminiscent of a borderline endometrioid tumour but exhibits confluent glandular growth with gland fusion, cribriform architecture and stromal exclusion (A,B). Complex labyrinthine glands (C) or complex papillary growth (D) may also occur.
A more uncommon morphological variant of borderline endometrioid tumour is an intracystic lesion characterised by a papillary proliferation of endometrioid-type glands projecting into the lumen of a cyst, usually an endometriotic cyst. In such cases the differential diagnosis may include endometriosis with ‘proliferative’ changes, borderline endometrioid tumour and grade 1 intracystic EC and there are no firm criteria for the distinction between these. As with non-cystic ECs, when the intracystic proliferation is florid with stromal exclusion, we recommend a diagnosis of grade 1 intracystic EC. A case of an EC with intracystic growth is illustrated in Fig. 3.
Fig. 3Predominantly intracystic endometrioid proliferation (A) displaying an admixture of borderline endometrioid tumour and endometrioid carcinoma with malignant areas characterised by confluent epithelial proliferation and stromal exclusion (B).
‘Metaplastic’ changes in ovarian endometrioid carcinomas
A variety of ‘metaplastic’ changes (also referred to as cytoplasmic alterations) may be seen in ovarian ECs. These are variably common and of no clinical significance but may result in diagnostic confusion and consideration of other entities. They are discussed in the next sections.
Squamous and morular metaplasia
Squamous metaplasia is very common, occurring in approximately half of ovarian ECs and may be of morular or non-morular type or uncommonly a combination of both.
Morules comprise round aggregates or syncytial sheets of cells with evenly spaced, bland ovoid to spindled nuclei, sometimes with optically clear nuclear inclusions and abundant eosinophilic cytoplasm; they are so named because of their resemblance to mulberries.
The morules may fill gland lumina and/or coalesce to form syncytial sheets of cells which obliterate underlying glands; larger morules may also show central necrosis and produce an alarming appearance. When extensive, morules may create difficulty in discriminating between borderline and malignant neoplasia and in tumour grading, as confluent morules may be mistaken for solid growth of EC. Morules exhibit an unusual immunophenotype (discussed in the section typical immunophenotype of endometrioid carcinoma). Morular metaplasia is depicted in Fig. 1.
By comparison non-morular squamous elements exhibit overt squamous differentiation with keratinisation and/or intercellular bridges, features which are absent in morular metaplasia. These elements show a range of differentiation and cytological atypia and uncommonly exhibit obvious malignant cytological features. Occasionally associated keratin granulomas (without tumour cells) may be seen within the tumour or on the peritoneal surface; in the absence of neoplastic cells this should not result in tumour upstaging.
Peritoneal keratin granulomas with carcinomas of endometrium and ovary and atypical polypoid adenomyoma of endometrium. A clinicopathological analysis of 22 cases.
The same comment pertains to assessment of lymph nodes, where acellular keratin may result in an erroneous diagnosis of isolated tumour cells due to immunoreactivity with anti-cytokeratin antibodies. Peritoneal keratin granulomas are illustrated in Fig. 4. In some cases, the squamous elements are so extensive that they largely obscure the EC tumour component. Rarely a squamous cell carcinoma, a rare ovarian tumour usually arising in association with a teratoma
Fig. 4Keratin granulomas, composed of eosinophilic keratin with an associated histiocytic and giant cell reaction, in peritoneal sites in the absence of an epithelial component should not result in tumour upstaging (A,B) (keratinous material arrowed).
Clear cell change is not uncommon in ovarian EC and is typically confined to the glandular component although it may also involve the squamous elements; it may be due to cytoplasmic accumulation of lipid, mucin, glycogen or hydropic change.
When cytoplasmic clearing is sub or supranuclear, resulting in a morphology which somewhat resembles secretory endometrium, the designation ‘secretory variant’ of EC is used.
Clear cell change can be striking in EC and form solid sheets, have a foamy appearance or be in the form of cytoplasmic vacuoles. The cytoplasmic clearing may result in diagnostic uncertainty and, depending on the extent of the change, may prompt consideration of clear cell carcinoma or mixed endometrioid and clear cell carcinoma. The presence of a component of typical EC should assist in accurate classification. When contemplating a diagnosis of a mixed ovarian carcinoma it is reiterated that advances in ancillary markers and the emergence of more histotype specific stains have demonstrated that mixed tumours of the ovary are far less frequent than previously thought, comprising <1% of epithelial ovarian malignancies.
Consequently, if an obvious endometrioid component is present, a high threshold should be set before diagnosing a clear cell carcinoma component, as this is more likely to represent morphological mimicry in an EC, although true mixed endometrioid and clear cell carcinoma do rarely occur.
Fig. 5Clear cell change in ovarian endometrioid carcinoma. The cytoplasmic clearing usually involves the glandular epithelium and may resemble the subnuclear or supranuclear clearing seen in secretory-type endometrium (A–C).
Immunohistochemistry is of value in distinguishing between clear cell change within an EC and a component of clear cell carcinoma. Most but not all clear cell carcinomas are completely negative with hormone receptors (ER, PR) while most ECs are positive, at least focally. Hepatocyte nuclear factor 1-beta (HNF1-β) is usually diffusely and strongly positive in clear cell carcinomas; however, this marker lacks specificity and may be positive in other types of ovarian carcinoma.
Comparative analysis of Napsin A, alpha-methylacyl-coenzyme A racemase (AMACR, P504S), and hepatocyte nuclear factor 1 beta as diagnostic markers of ovarian clear cell carcinoma: an immunohistochemical study of 279 ovarian tumours.
Napsin A has much greater specificity for clear cell carcinoma than HNF1-β although it is limited by lower sensitivity, with negative staining reported in 8–25% of clear cell carcinomas. Some studies reporting lower sensitivity for Napsin A used tissue microarrays rather than whole tumour sections which is important given that Napsin A positivity in clear cell carcinomas is often focal.
Comparative analysis of Napsin A, alpha-methylacyl-coenzyme A racemase (AMACR, P504S), and hepatocyte nuclear factor 1 beta as diagnostic markers of ovarian clear cell carcinoma: an immunohistochemical study of 279 ovarian tumours.
In this context Napsin A can be supplemented by the addition of alpha-methylacyl-coA racemase (AMACR), although the utility of this stain for a diagnosis of clear cell carcinoma is limited by its suboptimal sensitivity.
Comparative analysis of Napsin A, alpha-methylacyl-coenzyme A racemase (AMACR, P504S), and hepatocyte nuclear factor 1 beta as diagnostic markers of ovarian clear cell carcinoma: an immunohistochemical study of 279 ovarian tumours.
negative Napsin A and positive PR expression is expected in EC and the opposite in clear cell carcinoma. Recently Rodriguez et al. applied a first line immunohistochemical panel combining Napsin A, HNF1-β and PR to distinguish ovarian EC and clear cell carcinomas. They found the two prototypical combinations (clear cell carcinoma: Napsin A+/HNF1-β diffusely+/PR–; EC: Napsin A-/HNF1-β non-diffuse/PR+) occurred in 75% of cases with 100% specificity.
Accurate distinction of ovarian clear cell from endometrioid carcinoma requires integration of phenotype, immunohistochemical predictions, and genotype: implications for lynch syndrome screening.
Small numbers of ciliated cells may be seen in ovarian endometrioid tumours. These have been described in benign and borderline endometrioid tumours and ECs.
Their presence in an EC does not warrant a diagnosis of ‘ciliated EC’ as it represents part of the morphological spectrum of usual ovarian ECs. Ciliated cell change is depicted in Fig. 6.
When such cells are a minor finding they do not result in diagnostic problems but when they predominate or are exclusive, this may result in consideration of other neoplasms such as an oxyphilic variant of clear cell carcinoma or sex cord-stromal tumour. The presence of oxyphilic cells is of no clinical significance since the behaviour is identical to conventional ECs of similar grade and stage.
Mucinous differentiation in ovarian endometrioid carcinoma
As with their endometrial counterpart it is not uncommon for ovarian ECs to exhibit mucinous differentiation and this may help to confirm an EC diagnosis in problematic cases. Mucinous differentiation is usually focal and results in no diagnostic problems. However, when there is extensive intracytoplasmic mucin involving most or even the entire tumour there is a significant potential for misdiagnosis as a mucinous carcinoma.
Such neoplasms were previously referred to as Müllerian/endocervical type mucinous carcinomas but in the current WHO Classification the designation of ovarian mucinous carcinoma is reserved for tumours exhibiting intestinal/gastrointestinal differentiation.
Clues to recognising such carcinomas as being of endometrioid type include the presence of a component of typical EC, squamous differentiation and endometriosis. True mucinous carcinomas often have a component of typical mucinous borderline tumour and are composed of closely packed mucinous glands with an expansile or infiltrative pattern of invasion, sometimes containing goblet cells and associated with mucin extravasation and granulomas. Immunohistochemistry is extremely useful in such cases in diagnosing an EC (with mucinous differentiation) since these are usually diffusely positive with ER, PR, PAX8, vimentin or CA125, often in combination. In contrast true mucinous carcinomas are typically negative with ER, PR, vimentin and CA125.
Immunohistochemistry in the diagnosis of mucinous neoplasms involving the ovary: the added value of SATB2 and biomarker discovery through protein expression database mining.
this differs from the typical diffuse strong positivity of ECs for PAX8. However, as highlighted later, the propensity for some ovarian ECs to exhibit an aberrant immunophenotype should be appreciated. The occurrence of ovarian ECs with extensive mucinous differentiation is analogous to identical tumours within the endometrium, which are now classified as EC whereas previously these were termed mucinous carcinomas if more than half of the tumour cells contained abundant intracytoplasmic mucin.
An ovarian EC with mucinous differentiation is illustrated in Fig. 7.
Fig. 7Mucinous differentiation in endometrioid carcinoma. When extensive, this raises the differential diagnosis of mucinous carcinoma (A). The presence of diffuse ER (B) and PAX8 (C) expression is in keeping with EC with mucinous differentiation and essentially excludes mucinous carcinoma.
Endometrioid carcinoma with sex cord-like formations
It has been recognised for many years that the morphological appearance of some ovarian ECs may result in consideration of a sex cord-stromal tumour, especially an adult granulosa cell tumour or a Sertoli cell tumour.
If there is stromal luteinisation a Sertoli–Leydig cell tumour may also be considered. Such neoplasms have been referred to as EC with sex cord-like formations or Sertoliform variant of EC. These cases may have solid, nested, trabecular/corded or tubular (hollow or solid) growth patterns and the nuclear features are usually relatively bland. Often there is an appreciable amount of fibrous stroma between the individual nests, cords and tubules resulting in an ‘adenofibroma-like’ morphology. Sometimes, but not always, there is a component of conventional EC which is usually low grade. However, the sex cord-like formations may predominate or be exclusive.
The presence of areas of typical EC, endometriosis and squamous or mucinous elements assist in confirming an EC in problematic cases. Immunohistochemistry is also very helpful. Epithelial membrane antigen (EMA) is particularly useful since positivity is rare in sex cord-stromal tumours although focal immunoreactivity has been reported in occasional cases of juvenile granulosa cell tumour.
A panel of markers should always be used and EMA (and other ‘epithelial’ markers such as PAX8, CK7 and BerEP4, all of which are usually positive in the sex cord-like areas) can be combined with sex cord-stromal markers such as inhibin, steroidogenic factor 1 (SF1) and calretinin, which are usually negative. Broad spectrum cytokeratins are of little value since many sex cord-stromal tumours exhibit positive staining which can be diffuse. Grading of such neoplasms is often problematic given that the sex cord-like formations may have a non-glandular architecture and we recommend that grading be performed on the component of conventional EC, if present. A sex cord-like appearance in EC is illustrated in Fig. 8.
Fig. 8Sex cord-like morphology in ovarian endometrioid carcinomas. Such cases may have solid, nested, trabecular/corded or tubular (hollow or solid) growth patterns (A,B) and the nuclear features are usually bland. Often there is prominent fibrous stroma between the individual nests, cords and tubules resulting in an ‘adenofibroma-like’ morphology (C,D).
A less well-known and converse pitfall is that some ovarian Sertoli–Leydig cell tumours, especially well-differentiated or Sertoli cell tumours, have a Sertoli cell component which exhibits a ‘pseudo-endometrioid’ morphology with hollow, sometimes dilated, tubules which resemble endometrioid glands.
Such tumours can potentially be misdiagnosed as a borderline endometrioid tumour or EC. The presence of areas of typical Sertoli or Sertoli–Leydig cell tumour will assist in correct classification as will immunohistochemistry using a similar panel of markers to that just discussed.
A recent study reported five cases of uterine corpus EC with an admixture of typical low grade areas and high grade areas with a striking morphological and immunophenotypic resemblance to cutaneous pilomatrix carcinoma.
and we have seen several such cases in this location. In the reported endometrial tumours the high grade component exhibited a solid, basaloid morphology with conspicuous necrosis and the presence of ‘shadow cells’. There was diffuse nuclear and cytoplasmic β-catenin expression as well as variable CDX2 positivity. The high grade component in all cases showed loss of ER and PAX8 staining, retained MMR protein expression, wild-type p53, patchy p16 and diffuse positive cytokeratin (AE1/3 and CK7) expression. There was at least focal neuroendocrine marker expression in all cases. Two of the cases had molecular studies performed and both harboured mutations in exon 3 of CTNNB1; both cases lacked polymerase epsilon (POLE) and TP53 mutations and showed no microsatellite instability. The tumours were clinically aggressive with three of four patients with follow-up dead of disease within 14 months of diagnosis and the fourth who had distant metastatic disease at presentation alive with disease. The patient without follow-up information also had distant metastatic disease at presentation. The tumours were concluded to represent a highly aggressive CTNNB1-mutated subset of the ‘no specific molecular profile (NSMP)’ category of uterine ECs with divergent differentiation resembling cutaneous pilomatrix carcinoma.
Fig. 9 shows an ovarian EC resembling pilomatrix carcinoma.
Fig. 9Ovarian endometrioid carcinoma (EC) resembling pilomatrix carcinoma. The tumour is predominantly solid with high grade basaloid morphology, conspicuous abrupt necrosis and prominent keratinisation (A,B). A small component of admixed typical low grade EC is also present (C). Higher power view of the high grade EC component with extensive necrosis (D) and so called ‘shadow cells’ (E). Diffuse nuclear and cytoplasmic β-catenin expression (F).
Endometrioid carcinoma with spindle cells and corded and hyalinised endometrioid carcinoma (CHEC)
An uncommon morphological variant of EC, which based on our experience appears more common in the ovary than the uterine corpus, is EC with spindle cells.
These neoplasms often contain a component of typical EC which is usually low grade, but this may be sparse and only revealed by extensive sampling. There is also a component of bland spindle-shaped cells and sometimes within the spindle cell component there is eosinophilic material resembling osteoid or even mature bone or cartilage. These neoplasms are often misdiagnosed as a carcinosarcoma or less commonly a sex cord-stromal tumour, an endometrial stromal sarcoma or a female adnexal tumour of Wolffian origin. In most carcinosarcomas both the epithelial and stromal components are morphologically high grade and sharply demarcated from each other. In most but not all ECs with spindle cells, there is gradual ‘merging’ of the obvious epithelial and spindle cell components although sometimes the two components are sharply demarcated. Immunohistochemically the spindle cell component is usually positive with epithelial markers such as broad spectrum cytokeratins and EMA, and with PAX8 and ER; however, there is usually ‘attenuated’ expression of these markers in the spindle cells with positive staining being much more focal and often weaker than in the component of typical EC.
It is our opinion that EC with spindle cells exhibits significant morphological overlap with corded and hyalinised EC (CHEC) and these are probably related and form a spectrum. CHEC is more common within the uterine corpus than the ovary, although it occurs in the latter, and is characterised by nests and cords of morphologically bland epithelioid cells within a hyalinised stroma that sometimes contains osteoid and/or bone or cartilage.
Endometrioid carcinomas of the uterine corpus with sex cord-like formations, hyalinization, and other unusual morphologic features: a report of 31 cases of a neoplasm that may be confused with carcinosarcoma and other uterine neoplasms.
Almost always there is a component of typical EC which is usually but not always low grade, although this may be sparse and sometimes even absent. As with EC with spindle cells, carcinosarcoma, and sometimes other neoplasms, are often considered in the differential diagnosis. Immunohistochemically, as with EC with spindle cells, the corded and hyalinised component usually exhibits ‘attenuated’ expression of epithelial markers (broad spectrum cytokeratins and EMA), hormone receptors and PAX8. In some cases the glandular or corded components exhibit positive nuclear staining with β-catenin;
Corded and hyalinized and spindled endometrioid endometrial carcinoma: a clinicopathologic and molecular analysis of 9 tumors based on the TCGA classifier.
Aberrant nuclear beta-catenin expression in the spindle or corded cells in so-called corded and hyalinized endometrioid carcinomas. Another critical role of the unique morphological feature.
nuclear expression of CDX2 and neuroendocrine markers may also occur in the corded component. Fig. 10 illustrates some of the morphological and immunohistochemical features of EC with spindle cells and CHEC.
Fig. 10Endometrioid carcinoma (EC) with spindle cells and corded and hyalinised EC (CHEC). There is often a component of typical EC, which is usually low grade, admixed with the spindle cell component which may form discrete sheets and mimic solid tumour growth (A) or merge with the endometrioid glands (B,C). The spindled cells show uniform nuclear morphology and are usually positive with epithelial markers, PAX8 and ER although there may be ‘attenuated’ expression in spindle cell areas (D, reduced ER expression in spindled component). There may be aberrant expression of neuroendocrine makers (E, chromogranin; F, synaptophysin). CHEC (G,H) with attenuated cytokeratin expression in the corded and hyalinised component (I).
In the International Society of Gynecological Pathologists' recommendations on endometrial carcinomas, it is suggested to grade CHEC on the basis of the component of typical EC.
Issues in the differential diagnosis of uterine low-grade endometrioid carcinoma, including mixed endometrial carcinomas: recommendations from the International Society of Gynecological Pathologists.
Given the similarities to EC with spindle cell differentiation, we recommend a similar approach to grading these neoplasms in the ovary. In those uncommon cases with minimal or no component of typical EC this may not be possible and sometimes by default these are categorised as ungradable or grade 3 given the solid nature of the proliferation.
One study reported a series of ovarian ECs with a morphology resembling serous borderline tumour; most of these neoplasms were originally diagnosed as or were suspected to represent serous borderline tumour with or without a component of LGSC.
A diagnosis of serous borderline tumour was suspected because of the low power architecture with papillary and glandular formations of rather bland epithelial cells covering stromal cores which projected into cystic spaces. In all cases there were areas of typical EC, although these foci represented a minor component of the neoplasm. Features helpful in confirming an endometrioid neoplasm were a monomorphic cell population (rather than the often heterogeneous admixture of cell types found in typical serous borderline tumours), areas of cytoplasmic clearing, foci of more pronounced nuclear atypia and mitotic activity than is typical of low grade serous neoplasms, squamous elements, endometriosis and absent or only focal WT1 staining. Not all of these features were present in every case. In such cases extensive sampling may be of value in revealing more typical areas of endometrioid neoplasia. Fig. 11 illustrates EC resembling serous borderline tumour.
Fig. 11Ovarian endometrioid carcinoma mimicking serous borderline tumour. The low power exophytic papillary architecture with hierarchical branching mirrors that of serous borderline tumour (A). On higher power, the monomorphous endometrioid-type columnar epithelium is apparent (B, C). Squamous differentiation is a helpful clue to the endometrioid nature of the tumour (D). The tumour lacks WT1 expression (E) and shows wild-type staining with p53 (F).
Ovarian endometrioid carcinoma with malignant squamous transformation
As discussed earlier, squamous differentiation is common in ovarian ECs. In most cases the squamous elements are morphologically bland, and although they can be widespread, they are admixed with endometrioid glands. Rarely the squamous elements ‘overgrow’ the endometrioid component and are overtly malignant.
Essentially this represents a squamous cell carcinoma arising out of an EC. The terminology in these rare cases is controversial but we recommend diagnosing squamous cell carcinoma arising out of an EC rather than EC with squamous differentiation or adenosquamous carcinoma. Fig. 12 illustrates this phenomenon. When dealing with a primary ovarian squamous cell carcinoma the most common scenario is that this has arisen within a teratoma, and if no teratomatous elements are present, origin in an EC should be considered. Judicious sampling in such cases may assist in identifying an EC component or endometriosis. Rarely a squamous cell carcinoma arises in ovarian endometriosis without an identifiable component of EC and in such cases a pre-existing EC component may have been present and is overgrown.
Fig. 12Ovarian endometrioid carcinoma with associated squamous cell carcinoma. The malignant squamous component dominates and overgrows the endometrioid tumour component (A, endometrioid component arrowed). Discrete endometrioid (B) and squamous cell carcinoma components (C) are represented elsewhere within the tumour.
‘Transdifferentiation’ in ovarian endometrioid carcinomas
ECs appear more likely than other ovarian carcinomas to exhibit so called ‘transdifferentiation,’ a term used for a poorly understood process whereby several ‘lines of differentiation’ arise from an epithelial neoplasm. These include trophoblastic elements (scattered syncytiotrophoblastic giant cells or trophoblastic neoplasia), neuroectodermal elements, somatically derived yolk sac tumour (and more uncommonly other germ cell elements), hepatoid differentiation, dedifferentiation (admixed with component of undifferentiated carcinoma) and a neuroendocrine carcinoma component.
Ovarian neuroendocrine carcinomas of non-small-cell type associated with surface epithelial adenocarcinomas. A study of five cases and review of the literature.
A rare feature of ovarian ECs is the presence of an undifferentiated carcinoma component, usually combined with a low grade EC component (dedifferentiated carcinoma); the undifferentiated carcinoma component may also occur in pure form.
Undifferentiated carcinoma comprises sheets of monotonous dyscohesive cells with medium to large nuclei, often exhibiting geographic necrosis and frequent mitoses. In some cases there are prominent tumour infiltrating lymphocytes; foci of overt nuclear pleomorphism, focal keratinisation, a component of rhabdoid cells or a myxoid matrix are also occasionally seen.
The immunophenotype has been more extensively investigated in the more common counterpart within the uterine corpus and the undifferentiated component typically shows only focal cytokeratin and EMA staining, often lacks ER, PR and PAX8 expression and exhibits loss of E-cadherin.
Loss of expression of switch sucrose non-fermentable (SWI/SNF) chromatin remodelling proteins SMARCA4 (BRG1), SMARCA2 (BRM), SMARCB1 (INI1), ARID1A or ARID1B and MMR proteins is common.
Undifferentiated carcinoma is illustrated in Fig. 13.
Fig. 13Undifferentiated carcinoma comprising a sheet-like proliferation of small, monotonous dyscohesive cells (A,B) which may be present in a myxoid stromal matrix (C). SMARCA4 (BRG1) immunohistochemistry demonstrating loss of expression in tumour cells with retained nuclear staining in stromal and endothelial cells which acts as a positive internal control (D).
An undifferentiated carcinoma component raises several differential diagnoses. Cellular dyshesion may result in consideration of lymphoma and other haematopoietic neoplasms while the solid sheet-like growth may prompt consideration of neuroendocrine carcinoma, high grade EC or small cell carcinoma of the ovary of hypercalcaemic type (SCCOHT). Many of these differentials are readily resolved with immunohistochemistry. Negative staining with lymphoid markers, focal positive staining with cytokeratins and EMA and, if present, loss of MMR or SWI/SNF protein expression favours undifferentiated carcinoma over haematopoetic neoplasms. The immunophenotype of undifferentiated carcinoma and neuroendocrine carcinoma exhibit significant overlap, both tumours typically being negative for PAX8 and hormone receptors and both potentially expressing neuroendocrine markers. Loss of expression of SWI/SNF proteins and only focal neuroendocrine marker expression favours undifferentiated carcinoma, with diffuse expression of the latter more typical of neuroendocrine carcinoma.
Distinction from high grade EC is facilitated by the more cohesive growth pattern of the latter, which in the solid areas typically contains scattered glandular structures. Diffuse expression of cytokeratins, EMA, PAX8, hormone receptors and E-cadherin is suggestive of high grade EC. SCCOHT, which in most cases exhibits loss of expression of SMARCA4 (BRG1) typically occurs at a younger age than undifferentiated carcinoma and is characterised by the presence of follicle-like spaces and often diffuse WT1 expression. Finally, carcinosarcoma may enter the differential diagnosis with dedifferentiated carcinoma. The presence of a high grade carcinoma component, spindled morphology and/or heterologous elements and mutation-type p53 expression favour carcinosarcoma over dedifferentiated carcinoma.
Endometrioid carcinoma with somatically derived yolk sac tumour
Ovarian yolk sac tumours (YSTs) generally occur in childhood, adolescence and early adulthood with a median age of 16–19 years; they are uncommon over age 40. Rarely ovarian YSTs occur in older adults, mostly associated with a somatic epithelial neoplasm and this accounts for the second peak of ovarian YSTs seen in older adults.
The somatic neoplasm may be any type of ovarian epithelial tumour but is most commonly an EC, sometimes with associated endometriosis; occasionally only endometriosis is present and it is likely in such cases that a component of EC (or clear cell carcinoma)
Germ cell tumour growth patterns originating from clear cell carcinomas of the ovary and endometrium: a comparative immunohistochemical study favouring their origin from somatic stem cells.
has been present and totally overgrown. It is speculated in such cases that the YST derives from the epithelial neoplasm through a poorly defined process which has been referred to as transdifferentiation, neometaplasia, aberrant differentiation or retrodifferentiation.
Germ cell tumour growth patterns originating from clear cell carcinomas of the ovary and endometrium: a comparative immunohistochemical study favouring their origin from somatic stem cells.
A recent study of tumours with a combination of epithelial and germ cell or trophoblastic components using next generation sequencing demonstrated that the mutational profile of the Müllerian and non-Müllerian components were almost identical and the driver mutations identified were those expected in the specific type of Müllerian component.
Malignant tumours of the uterus and ovaries with Mullerian and germ cell or trophoblastic components have a somatic origin and are characterised by genomic instability.
Variants expected in post-pubertal germ cell tumours and gestational trophoblastic tumours were not identified and FISH for i (12p) was negative in all cases tested. The results suggested that the YST and trophoblastic tumour components in these neoplasms have a somatic origin.
A high index of suspicion is needed by the pathologist to diagnose the YST component in such cases since the morphology is not typically that characteristic of a YST occurring in younger patients but often represents a glandular variant which may exhibit significant morphological overlap with various types of Müllerian carcinoma. There is also often significant immunophenotypical overlap with Müllerian carcinomas since the YST component may be positive with EMA, BerEP4, PAX8 and CK7, as well as YST markers such as SALL4, α-fetoprotein, glypican 3, CDX2 and villin; positivity with CDX2 and villin may result in an erroneous diagnosis of a metastatic colorectal adenocarcinoma. Combined somatic epithelial carcinomas and YSTs should be distinguished from glandular variants of pure YST where there is close morphological mimicry of an EC (sometimes with cytoplasmic vacuolation mimicking a secretory EC) or an intestinal adenocarcinoma.
Propensity for ovarian endometrioid carcinoma to exhibit an aberrant immunophenotype
As discussed above, ovarian ECs may exhibit a wide range of unusual morphologies (variant patterns) resulting in diagnostic difficulties and consideration of other tumours. The difficulties can be compounded by the presence of an unusual immunophenotype in some classical ECs and ECs with variant morphology. In this latter group of neoplasms, immunohistochemistry is often performed to support a diagnosis of EC. These ‘aberrant’ staining patterns have not been extensively discussed in the literature and in our experience, are more common in ECs than in other types of ovarian carcinoma. Some ECs are negative with ‘Müllerian’ markers CK7, PAX8, CA125, ER and PR, individually or in combination. While these markers are often assumed to be positive in virtually all ovarian ECs this is not the case. Furthermore, CK20, CDX2, SATB2, TTF1, Napsin A and WT1 may be positive in ovarian ECs.
WT1 is often assumed to be a relatively specific marker of tubo-ovarian serous carcinomas (low grade and high grade) but it is positive in a small but significant proportion of ovarian ECs (14% in one study).
In our experience WT1 is especially likely to be positive in ovarian low grade ECs and this may result in misdiagnosis as a serous carcinoma, either LGSC or HGSC.
The presence of positive staining with CK20, CDX2 and SATB2, alone or in combination, together with negative staining with some of the Müllerian markers listed above may result in an erroneous diagnosis of a metastatic colorectal carcinoma. Additionally, we and others have noted that ovarian (and uterine corpus) ECs, low grade and high grade, not uncommonly exhibit ‘aberrant’ immunohistochemical staining with neuroendocrine markers chromogranin and synaptophysin.
Chromogranin especially is often considered a specific neuroendocrine marker but in the context of ECs this is not the case; the explanation for neuroendocrine marker expression in such cases is not known. ECs exhibiting positivity with neuroendocrine markers should not be reported as neuroendocrine carcinomas or ECs exhibiting neuroendocrine differentiation. Fig. 15 illustrates aberrant unexpected staining in ovarian ECs.
Fig. 15Aberrant immunohistochemical staining in ovarian endometrioid carcinoma. Aberrant loss of PAX8 immunoreactivity (A) and expression of SATB2 (B), CDX2 (C) and neuroendocrine markers (D, chromogranin) may occur.
Molecular pathology of ovarian endometrioid carcinoma
The landmark The Cancer Genome Atlas (TCGA) study of endometrial cancers, published in 2013, demonstrated the heterogeneous nature of these tumours which stratify into four molecular groups, with important implications for prognosis and treatment.
These comprise tumours harbouring mutations in the POLE exonuclease domain (POLEmut) which demonstrate a favourable prognosis irrespective of tumour morphology, a ‘p53 abnormal (p53abn)’ or ‘serous-like’ group with adverse prognosis, and ‘microsatellite unstable/MMR deficient (MMRd)’ and ‘NSMP’ groups with intermediate clinical outcomes. Integration of this molecular classification into histological reporting, clinical risk stratification and treatment algorithms for endometrial cancer is now becoming routine.
By comparison, the genomic profile of ovarian ECs is less well defined, with older studies flawed by the inclusion of misclassified HGSCs and more recent data limited by small patient cohorts and varied inclusion criteria.
Targeted or whole genome sequencing approaches have demonstrated the heterogeneous nature of ovarian ECs, identifying frequent mutations in PTEN, ARID1A, PIK3CA, KRAS, CTNNB1 and genes encoding MMR proteins; these are similar to the molecular events in ECs of the uterine corpus. TP53 mutations are also present in some ovarian ECs but at far lower rates than in HGSC.
has shown that ovarian ECs stratify into the four molecular subtypes, with combined data demonstrating 3–10% harbour POLE mutations, 8–19% are MMRd, 11–24% p53abn and 58–66% NSMP.
These molecular events are broadly similar to those identified in endometrial EC, albeit with a lower frequency of POLEmut and MMRd tumours, with the lower rate of MMRd tumours likely associated with a lower rate of somatic methylation.
Significant frequency of MSH2/MSH6 abnormality in ovarian endometrioid carcinoma supports histotype-specific Lynch syndrome screening in ovarian carcinomas.
In one recent study, Hollis et al. performed whole exome sequencing on 112 rigorously selected ovarian ECs, identifying mutation in the following genes: CTNNB1 (43%), PIK3CA (43%), ARID1A (36%), PTEN (29%), KRAS (26%), TP53 (26%) and SOX8 (19%).
NSMP tumours, the most common molecular group, are usually low grade (grade 1 or 2) and have a higher frequency of morular metaplasia and β-catenin expression/CTNNB1 mutation.
Hollis et al. delineated the distinct biological behaviour of TP53 mutant versus CTNNB1 mutant ovarian ECs. TP53 mutant tumours demonstrated greater frequency of advanced stage at diagnosis (48% FIGO Stage III or IV), higher rates of incomplete tumour resection and inferior survival.
By comparison, CTNNB1 mutation, mutually exclusive with TP53 mutation, was associated with excellent clinical outcome with 89% stage I or II at diagnosis;
The authors suggest that translation into clinical practice, using immunohistochemistry for p53 and β-catenin, could provide risk stratification. Whether POLE mutation confers a survival benefit in ovarian EC remains unclear, possibly due to small case numbers limiting the power of statistical analysis.
stratified 72 patients with ovarian EC into prognostic groups and correlated with disease free survival in multivariate analysis, independent of tumour stage and grade.
In that series, POLEmut and MMRd tumours had excellent survival while p53abn tumours had adverse outcome. Another study of 19 cases found CTNNB1 and KRAS mutations and microsatellite instability to be strongly associated with low grade ovarian EC, whereas p53 overexpression characterised high grade EC.
Significant frequency of MSH2/MSH6 abnormality in ovarian endometrioid carcinoma supports histotype-specific Lynch syndrome screening in ovarian carcinomas.
The relationship between MMR deficiency, patient age and morphological features, such as tumour infiltrating lymphocytes and mucinous differentiation, appears inconsistent supporting reflex MMR immunohistochemistry in all cases of ovarian EC.
Significant frequency of MSH2/MSH6 abnormality in ovarian endometrioid carcinoma supports histotype-specific Lynch syndrome screening in ovarian carcinomas.
Ovarian endometrioid adenocarcinoma: incidence and clinical significance of the morphologic and immunohistochemical markers of mismatch repair protein defects and tumor microsatellite instability.
Undifferentiated carcinomas of the ovary, some of which are thought to derive from low grade EC (dedifferentiated carcinoma), are associated with inactivating mutations in SWI/SNF chromatin remodelling genes ARID1A/B and SMARCA4/A2/B in some cases, with MMR deficiency detected in about a third of cases.
These are characterised by aggressive clinical behaviour.
Differential diagnosis of ovarian endometrioid carcinoma not discussed elsewhere
Many of the differential diagnoses of ovarian EC have already been covered earlier in the context of unusual morphological variants of EC. Below we discuss some other common differentials which have not already been discussed.
Differential diagnosis of high grade endometrioid and high grade serous carcinoma
Convincing evidence supports the prevailing view that the vast majority of high grade ovarian carcinomas represent HGSC.
High grade ovarian EC is comparatively uncommon and shows genomic heterogeneity and overlapping morphological features with HGSC, with recognised suboptimal diagnostic reproducibility based on morphology alone for these tumour types.
One of the reasons behind this is that some HGSCs have focal or extensive areas of punched out glandular spaces resulting in a pseudoendometrioid appearance. Application of modern diagnostic criteria, including a targeted immunohistochemical panel, has demonstrated that the highest rate of misclassification of tubo-ovarian carcinomas occurs in high grade EC, which is often reclassified as HGSC.
Features in favour of a diagnosis of high grade EC rather than HGSC include the presence of a low grade gland-forming endometrioid component, confirmatory endometrioid features, wild-type staining with p53 and WT1 negativity.
While application of WT1 and p53 are recommended in this context, as discussed earlier, positive WT1 staining and mutation-type p53 expression occur in a subset of ovarian ECs, with mutation-type p53 staining more likely in high grade EC; sometimes the associated low grade component exhibits wild-type immunoreactivity which may be diagnostically useful.
Mixed ovarian epithelial carcinomas with clear cell and serous components are variants of high-grade serous carcinoma: an interobserver correlative and immunohistochemical study of 32 cases.
In this setting, when there is contradictory morphology and immunohistochemistry, judicious application of additional markers including β-catenin, ARID1A, PTEN, vimentin, and MMR stains could be considered, as could molecular testing.
Differential diagnosis of ovarian endometrioid carcinoma and metastatic colorectal carcinoma
The morphology of ovarian EC, with predominant gland-forming architecture, may result in consideration of a metastatic colorectal carcinoma and this is a pitfall which has long been emphasised. In the absence of confirmatory endometrioid features immunohistochemistry is often undertaken in this context. In this setting a broad panel of markers including PAX8, ER, PR, CA125, CK7 (usually diffusely positive in EC) and CK20, CDX2 and SATB2 (usually diffusely positive in colorectal carcinoma) is recommended.
However as discussed, the propensity for ovarian ECs to exhibit aberrant loss of Müllerian markers and positive staining with CK20, CDX2 and SATB2, alone or in combination, may result in an erroneous diagnosis of a metastatic colorectal carcinoma.
Ovarian seromucinous carcinomas
Seromucinous neoplasms were introduced as a new category of ovarian epithelial tumour in the 2014 WHO Classification where benign, borderline and malignant categories were included.
Seromucinous neoplasms commonly arise within endometriosis, and borderline variants, previously referred to as Müllerian mucinous, endocervical-type mucinous or mixed borderline tumours, are the most common.
Mucinous ovarian tumors of Mullerian-type: an analysis of 17 cases including borderline tumors and intraepithelial, microinvasive, and invasive carcinomas.
In the WHO 2014 Classification, seromucinous carcinoma was defined as a carcinoma composed predominantly of serous and endocervical-type mucinous epithelium, often with foci containing clear cells and areas of endometrioid and squamous differentiation. The inclusion of the category of seromucinous carcinoma in WHO 2014 predated the description of a substantial series of these tumours and was largely to take account of the idea that if a seromucinous borderline tumour exists, a category of seromucinous carcinoma must also exist. In 2015, one of us (WGM) co-authored a study of 19 ovarian seromucinous carcinomas.
The morphology was highly variable both within and between individual tumours. Growth patterns included papillary, glandular, microglandular and solid. Characteristically there was an admixture of cell types including endocervical-like mucinous, endometrioid, hobnail, indifferent eosinophilic, squamous, clear and signet-ring. An infiltrate of neutrophils was a prominent feature in most cases and some had areas resembling cervical microglandular hyperplasia with a microglandular architecture and cytoplasmic clearing. Endometriosis was identified in the same ovary in 10 cases and in 10 there was a component of seromucinous borderline tumour. Most tumours were low grade (grade 1 or 2) using the FIGO grading system for ECs. Immunohistochemically, there was consistent positive staining with CK7, ER, PR, CA125 and PAX8. WT1 was usually negative and CK20 and CDX2 were negative in all cases tested. In that study, it was concluded that seromucinous carcinomas had many features in common with ECs and it was recommended to grade them as for ECs.
A follow-up study investigated whether seromucinous carcinoma was a distinct histotype by assessing its diagnostic reproducibility and comparing its immunohistochemical and molecular profile to the five major types of ovarian carcinoma (discussed previously).
Thirty-two tumours diagnosed as seromucinous carcinoma were included and there was low to moderate agreement between pathologists with the diagnosis of seromucinous carcinoma. The immunophenotype was not unique but overlapped predominantly with EC and to a lesser extent LGSC. Molecular alterations were detected in a number of genes, including KRAS (70%), PIK3CA (37%), PTEN (19%) and ARID1A (16%); no CTNNB1 mutations were identified. Nine cases (30%) harboured concurrent KRAS and PIK3CA mutations. By integrating morphology, immunophenotype and genotype, the authors reclassified the tumours as EC (23/32; 72%), LGSC (8/32; 25%) and mucinous carcinoma (1/32; 3%). The authors concluded that a diagnosis of seromucinous carcinoma is not reproducible and this neoplasm does not exhibit a distinct immunophenotype or genotype. It was suggested that the category of seromucinous carcinoma be discontinued as ancillary tests can assign neoplasms to one of the major types. For these reasons, seromucinous carcinoma was removed from the 2020 WHO Classification with the accompanying statement ‘immunohistochemical and molecular studies have also suggested that most cases represent unusual morphological patterns of EC; therefore, seromucinous carcinoma is now considered a subtype of EC’.
Mesonephric-like adenocarcinoma (MLA) was introduced as a new tumour type in the endometrium and the ovary in the 2020 WHO Classification following its initial description in 2016.
Hormone receptor-negative, thyroid transcription factor 1-positive uterine and ovarian adenocarcinomas: report of a series of mesonephric-like adenocarcinomas.
Mesonephric-like adenocarcinoma of the female genital tract: from morphologic observations to a well-characterized carcinoma with aggressive clinical behavior.
In the ovary these neoplasms often arise in endometriosis and they can be added to the list of endometriosis-associated ovarian neoplasms. These neoplasms will not be discussed further in this review but we mention that these would mostly have been diagnosed as low grade EC in the past.
Conflicts of interest and sources of funding
The authors state that there are no conflicts of interest to disclose. No special funding was received by the authors of this review.
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Germ cell tumour growth patterns originating from clear cell carcinomas of the ovary and endometrium: a comparative immunohistochemical study favouring their origin from somatic stem cells.
Malignant tumours of the uterus and ovaries with Mullerian and germ cell or trophoblastic components have a somatic origin and are characterised by genomic instability.
Significant frequency of MSH2/MSH6 abnormality in ovarian endometrioid carcinoma supports histotype-specific Lynch syndrome screening in ovarian carcinomas.
Ovarian endometrioid adenocarcinoma: incidence and clinical significance of the morphologic and immunohistochemical markers of mismatch repair protein defects and tumor microsatellite instability.
Mucinous ovarian tumors of Mullerian-type: an analysis of 17 cases including borderline tumors and intraepithelial, microinvasive, and invasive carcinomas.
Hormone receptor-negative, thyroid transcription factor 1-positive uterine and ovarian adenocarcinomas: report of a series of mesonephric-like adenocarcinomas.
Mesonephric-like adenocarcinoma of the female genital tract: from morphologic observations to a well-characterized carcinoma with aggressive clinical behavior.
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