—  SPECIALTY CONFERENCE  —

Gynecologic Pathology

Case 1 - Uterine Tumour Resembling Ovarian Sex Cord Tumour (UTROSCT)

Glenn McCluggage
Royal Hospitals
Belfast, Northern Ireland





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Case History
F60, postmenopausal bleeding, endometrial curettage


Case 1 - Figure 1
Case 1 - Figure 2
Case 1 - Figure 3


Histology
Histology shows tissue fragments composed of papillary arrangements of bland epithelial-like tissue. There is only mild nuclear pleomorphism and only occasional mitotic figures are present.

Key Words
endometrium, papillary lesion, uterine tumour resembling ovarian sex cord tumour.

Bullet Points
  1. papillary fragments of epithelium are not uncommonly encountered in endometrial biopsy specimens.

  2. when faced with epithelial elements with a papillary architecture in an endometrial biopsy, the differential diagnosis may range from artefactual papillary epithelium to non-neoplastic lesions to benign and malignant neoplasms.

  3. UTROSCT rarely presents in an endometrial biopsy specimen and may have a pronounced papillary architecture.

Papillary Lesions of Endometrium
Tissue with a papillary or micropapillary architecture is not uncommonly seen in endometrial biopsy specimens. A wide range of endometrial lesions may have a papillary architecture, ranging from artefactual papillary formations to benign epithelial lesions to various carcinomas. Some non-epithelial lesions may also have a papillary architecture. Table 1 lists endometrial and uterine lesions which potentially may be present in an endometrial biopsy and exhibit a papillary architecture. These are discussed in the next sections.

Artefactual Papillary Endometrium
In endometrial biopsies, especially but not exclusively outpatient endometrial pipelle biopsies, atrophic endometrium may exhibit a pseudopapillary architecture [1]. This change is common and, if widespread, may result in consideration of a papillary variant of adenocarcinoma. Awareness of the existence of this phenomenon together with careful high power examination which reveals atrophic epithelium without mitotic activity assists in establishing the diagnosis.

Papillary Syncytial Metaplasia
The term papillary syncytial metaplasia is a misnomer since this does not actually represent a metaplasia but rather a degenerative or reparative phenomenon associated with surface breakdown, either menstrual or non-menstrual in type. However, the term papillary syncytial metaplasia is in widespread use. Synonymous terms include eosinophilic syncytial change and surface syncytial change. It has been suggested that papillary syncytial metaplasia is a degenerative or regressive phenomenon based on a low proliferation and mitotic index [2]. Papillary syncytial metaplasia is common and is characterised by small syncytia or micropapillary proliferations of endometrial epithelial cells which may contain small glandular lumina and which are devoid of stromal support, lacking fibrovascular stromal cores. The cells usually have eosinophilic cytoplasm and there is often a neutrophilic infiltrate. There may be mild nuclear atypia and in a minority of cases, mitoses are present. In florid cases, papillary syncytial metaplasia may be confused with an endometrioid or serous adenocarcinoma or with serous endometrial intraepithelial carcinoma (serous EIC). Another important consideration is that foci similar to papillary syncytial metaplasia may occur on the surface of some endometrioid adenocarcinomas (discussed later). The distinction between papillary syncytial metaplasia and papillary adenocarcinomas of endometrioid or serous type is facilitated by recognition that papillary syncytial metaplasia is limited to the endometrial surface and is associated with other morphological features of breakdown such as apoptotic debris, neutrophils and adjacent glandular and stromal breakdown.

Arias- Stella Reaction
Arias-Stella reaction (Arias-Stella effect or change) is almost always associated with pregnancy, either intrauterine or ectopic, or with trophoblastic disease. It rarely occurs secondary to hormone therapy, especially progestogens; occasionally there is no obvious cause [3]. Histologically, the Arias-Stella reaction is characterised by cellular stratification, secretory activity, vacuolated cytoplasm and enlargement of the epithelial cell nuclei and cytoplasm. The nuclei may be enlarged up to three times normal and can exhibit considerable atypia and a hobnail appearance with bulging into the glandular lumina. There may be micropapillary formations. Mitotic figures may be present, although these are rarely prominent and there is a low MIB1 proliferation index. Atypical mitoses have rarely been described [4]. The Arias-Stella reaction may be extensive, involving many glands, or focal with involvement of only a few glands or even part of a gland. The most important differential diagnosis is clear cell carcinoma but the diagnosis of Arias-Stella reaction is usually straightforward if the patient is known to be pregnant and if other morphological features of pregnancy are present, such as decidualisation of the stroma. Arias-Stella reaction involves pre-existing endometrial glands without evidence of stromal infiltration and there is no mass lesion. Although there is nuclear enlargement and atypia, a low nuclear to cytoplasmic ratio is maintained.

Hyperplastic Papillary Proliferation of Endometrium
The term hyperplastic papillary proliferation of the endometrium has been used for a lesion, usually occurring in postmenopausal women, characterised by the presence of papillae with fibrovascular stromal cores and variable degrees of branching and cellular tufting [5]. The papillae are lined by epithelial cells with bland nuclei. Epithelial metaplasias, most commonly mucinous, eosinophilic or ciliated in type, are often also present. Sometimes the papillae are entirely intracystic (projecting into cystically dilated endometrial glands) while in other instances they involve the endometrial surface. Papillary proliferation is most commonly seen on the surface of an endometrial polyp and, in some instances, the features are florid. There may be an association with hormonal preparations. A misdiagnosis of an adenocarcinoma of endometrioid or serous type is possible, especially if an underlying polyp is not present or not obvious. Awareness of this phenomenon and the realisation that it often occurs in a polyp are clues to the diagnosis, although both endometrioid and serous adenocarcinomas may arise in and be confined to a polyp. An absence of nuclear atypia helps to exclude an adenocarcinoma. It has been considered that these papillary proliferations are a form of hyperplasia that is closely associated with epithelial metaplasia. However, given the uneventful outcome in those cases with follow up, the term hyperplasia may not be appropriate.

Effects of Intrauterine Device
Intrauterine devices (IUDs) are in widespread use, mainly for contraceptive purposes. The histological features in the endometrium in association with an IUD are largely due to local mechanical effects. The surface endometrium may take on the configuration of the IUD due to a direct pressure effect. There may be surface micropapillary formations and focal reactive changes with nuclear enlargement, mild nuclear atypia, small nucleoli and cytoplasmic vacuolation. When micropapillary fragments of epithelium exhibiting these features are present in an endometrial biopsy, this may result in diagnostic difficulty. The glandular epithelium may also exhibit epithelial cytoplasmic change, including squamous metaplasia, and there may be surface ulceration. Although the features may be subtle, a focal inflammatory infiltrate is commonly present consisting of polymorphs, lymphocytes, histiocytes and plasma cells. Foreign body type giant cells and granulomas may be a component of the inflammatory infiltrate, the severity of which may be related to the type of IUD and the duration of use.

Uterine Adenocarcinomas
A papillary architecture is very common in various uterine adenocarcinomas, most commonly of endometrioid and serous type. A papillary architecture is especially common in uterine serous adenocarcinoma (also known as papillary serous adenocarcinoma). However, some serous adenocarcinomas have a purely glandular architecture without papillary formations and for this reason the term papillary serous adenocarcinoma is not recommended. Many otherwise typical endometrioid adenocarcinomas also have a focal papillary architecture and in some cases the entire tumour or much of this exhibits papillary formations. In addition to typical endometrioid adenocarcinomas, some variants exhibit a papillary architecture, including villoglandular endometrioid adenocarcinoma [6] and endometrioid adenocarcinoma with small non-villous papillae [7]. In the distinction between an endometrioid and a serous adenocarcinoma, close attention to the cytological features usually allows a confident distinction. Serous adenocarcinomas are characterised by markedly atypical nuclei, often with prominent macronucleoli and smudged chromatin. Secondary budding from the papillary formations is common. The nuclear features are usually much blander and lower grade in endometrioid adenocarcinomas with a well differentiated glandular or papillary architecture. Squamoid elements are also commonly present in endometrioid adenocarcinomas. In the distinction between an endometrioid and a serous adenocarcinoma, immunohistochemical staining with p53, p16 and ER may assist [8, 9]. Most, although not all, serous adenocarcinomas exhibit diffuse nuclear immunoreactivity with p53 and diffuse staining with p16. ER is variable but may be negative, focally positive or sometimes diffusely positive. Most endometrioid adenocarcinomas are diffusely positive with ER and negative or only focally positive with p53 and p16. Occasional clear cell carcinomas of the endometrium have a papillary architecture, usually in combination with the other architectural patterns characteristic of clear cell carcinoma. Primary mucinous adenocarcinomas of the ovary may also occasionally have a papillary architecture. Rare transitional cell carcinomas occur as primary neoplasms within the endometrium, usually in association with a component of endometrioid adenocarcinoma [10]. These are morphologically similar to transitional carcinomas of the urological tract with a papillary architecture. Immunohistochemically, they exhibit a Mullerian rather than a transitional immunophenotype ie they are CK7 positive and CK20 negative [10]. Rare primary squamous carcinomas of the endometrium have a papillary architecture.

It is stressed that the term papillary adenocarcinoma should not be used as a diagnostic label since this denotes an architectural growth pattern rather than a tumour type. Rather when using the descriptive terminology of papillary, the tumour type should be stated. For example, the tumour comprises an endometrioid or serous adenocarcinoma with a papillary architecture. This is important since surgical and adjuvant therapies may differ between an endometrioid and a serous adenocarcinoma, as does the prognosis.

Progestogen Treatment of Endometrial Hyperplasia or Endometrioid Adenocarcinoma
The morphological effects of progestogenic compounds on the normal endometrium are well known. Progestogen therapy, either oral or delived via an IUD such as the Mirena coil, may be employed in the management of endometrial atypical hyperplasia or well differentiated endometrioid adenocarcinoma in a woman who wishes to preserve her fertility or who is a poor operative risk due to comorbid features. In such cases, radiological investigations are necessary to exclude myoinvasive disease. In patients treated in this manner, a significant response rate can be expected [11]. Patients are maintained on progestogen for a prolonged period and are monitored by regular endometrial sampling. Pathologists need to be aware of the effects of progestogen on endometrial hyperplasia and adenocarcinoma as histology is pivotal in assessing response and determining further management. The effects of progestogens on endometrial hyperplasia and well differentiated endometrioid adenocarcinoma have recently been described [11]. Histological changes associated with progestogens included a decreased gland to stroma ratio, decreased glandular cellularity, decreased mitotic activity, reduction in cytologic atypia and a variety of epithelial cytoplasmic changes, including mucinous, secretory, squamous and eosinophilic metaplasia. Architectural changes, specifically cribriform and papillary patterns, were induced by progestogens. In their study, 67% of women with atypical hyperplasia and 42% with well differentiated endometrioid adenocarcinoma had a complete resolution while 22% with atypical hyperplasia and 58% with adenocarcinoma had persistent disease [11].

Changes on Surface of Endometrial Adenocarcinoma
Not uncommonly on the surface of an endometrial adenocarcinoma of endometrioid or mucinous type, there is a micropapillary or microglandular architecture. These changes may very closely mimic papillary syncytial metaplasia or cervical microglandular hyperplasia [12]. Since these surface elements are likely to be sampled in preference to the underlying typical adenocarcinoma, this phenomenon is especially noticeable in biopsy material and may result in a misdiagnosis of papillary syncytial metaplasia or cervical microglandular hyperplasia. Usually there will be areas of obvious adenocarcinoma and this assists in establishing the diagnosis as does awareness that this phenomenon occurs on the surface of some endometrial adenocarcinomas. As stated, these foci may bear a very close resemblance to cervical microglandular hyperplasia and caution should be exercised before making this diagnosis in an endometrial biopsy in a postmenopausal woman, although cervical microglandular hyperplasia does occur in this age group, especially with the increasing use of hormonal preparations. Probably the most useful histologic feature in distinguishing between microglandular areas on the surface of an endometrial adenocarcinoma and cervical microglandular hyperplasia is subnuclear vacuolation since this is common in the latter but is uncommon in microglandular areas on the surface of an adenocarcinoma [13]. Immunohistochemistry can assist in the distinction, although there may be significant immunophenotypic overlap. Probably the most useful marker is vimentin since this is negative in cervical microglandular hyperplasia but is positive in most uterine endometrioid adenocarcinomas. However, some endometrial adenocarcinomas are negative, including some mucinous adenocarcinomas. Occasionally much of a uterine adenocarcinoma will be composed of microglandular formations resembling cervical microglandular hyperplasia; this is referred to as microglandular adenocarcinoma [13].

Miscellaneous Uterine Neoplasms with a Papillary or Pseudopapillary Architecture
A few cases of endometrial stromal sarcoma with a pseudopapillary architecture have been reported [14]. Usually this is a focal phenomenon but occasionally it is widespread, involving much of the neoplasm.

Diagnosis
Uterine Tumour Resembling Ovarian Sex Cord Tumour (UTROSCT)

UTROSCTs are rare primary uterine neoplasms which morphologically resemble ovarian sex cord- stromal tumours. They were originally described by Clement and Scully in 1976 [15]. In this seminal publication, these neoplasms were classified into two groups: - type I were typical endometrial stromal neoplasms with focal areas with a sex cord-like pattern and in type II tumours the sex cord-like elements were exclusive or predominated. Now type I neoplasms are generally referred to as endometrial stromal tumours with sex cord-like elements while type II tumours are designated UTROSCT, the latter term being reserved for those uterine neoplasms composed exclusively of sex cord-like elements. In the latest World Health Organization classification of tumours of the female genital organs, UTROSCT is classified separately to endometrial stromal neoplasms [16]. However, there is ongoing debate as to the exact histogenesis ie whether they represent variants of endometrial stromal neoplasm with overgrowth of the sex cord-like elements or are separate unrelated tumours. This is discussed later.

These neoplasms usually occur in women in the reproductive and postmenopausal age groups [17, 18, 19, 20]. Most are relatively well circumscribed intramural myometrial masses, although submucosal polypoid lesions occur and may be sampled on endometrial biopsy, as do lesions projecting from the serosal surface of the uterus. Rare tumours have been described within the cervix [21]. Some neoplasms have a yellow cut surface, a characteristic, but not specific, feature of UTROSCT, and a point of similarity to ovarian sex cord-stromal tumours. The morphology of UTROSCT is variable with corded, trabecular, insular, nested, solid and glandular or tubular growth patterns described, often in combination. Other growth patterns include papillary (as in the present case), retiform and glomeruloid arrangements. Often, the tumour cells have an epithelioid appearance and sometimes there is a rhabdoid phenotype with eccentric nuclei and abundant eosinophilic cytoplasm. There is generally only mild nuclear pleomorphism and little in the way of mitotic activity. Foam cells may occur, as may smooth muscle cells. It is controversial whether this represents entrapped smooth muscle or an integral component of the neoplasm.

Several studies have examined the immunophenotype of UTROSCT [17, 18, 19, 20, 22]. In a recent series we reported, we undertook a detailed immunohistochemical analysis and reviewed the results of previous studies in which immunohistochemistry was performed [19]. In general, UTROSCTs have a polyphenotypic immunophenotype, often with coexpression of epithelial, myoid and ovarian sex cord markers as well as hormone receptors. Three of our 4 neoplasms were diffusely positive with the broad spectrum cytokeratin AE1/3. Of the previously reported UTROSCTs, 22 of 26 had been positive with anti-cytokeratins, illustrating that these neoplasms commonly express epithelial markers. An interesting observation in our study was that all 4 tumours expressed EMA, albeit of weak or moderate intensity. This is perhaps slightly surprising since UTROSCT is thought by some to represent the uterine counterpart of an ovarian sex cord-stromal tumour and possibly to be derived from misplaced gonadal tissue. Cytokeratin immunoreactivity is not uncommon in ovarian sex cord-stromal tumours, but EMA positivity is unusual. EMA positivity argues against a true sex cord-stromal neoplasm, similar to those which arise in the ovary, although immunoreactivity with sex cord markers (discussed below) suggests that UTROSCT exhibits sex cord differentiation to some extent.

Our neoplasms were typically positive with smooth muscle markers with desmin and α SMA being positive in 3 and 4 cases respectively. Other studies have also revealed smooth muscle marker positivity in UTROSCT with altogether 8 of 25 and 13 of 18 cases respectively being positive with desmin and α SMA.

We stained our cases with a variety of markers which are commonly expressed in ovarian sex cord-stromal tumours. Calretinin and inhibin are the two best known and most widely utilised markers of an ovarian sex cord-stromal tumour [23, 24], the former being slightly more sensitive and the latter a more specific marker of this group of neoplasms. Two of the cases were positive with inhibin and all 4 with calretinin. Melan A and CD99 may also be positive in ovarian sex cord-stromal tumours and one and 2 of our neoplasms respectively were immunoreactive. Positivity with these markers has been demonstrated previously in UTROSCT. Fourteen of 26, 10 of 11, 7 of 15 and 22 of 24 cases examined have been positive with inhibin, calretinin, melan A and CD99 respectively, suggesting that UTROSCT may exhibit sex cord differentiation although, as discussed, EMA positivity is unusual in ovarian sex cord-stromal tumours and argues against a true sex cord-stromal neoplasm. Furthermore, although the overall morphological appearances are suggestive of a sex cord-stromal neoplasm, the histological picture in most cases is not characteristic of any particular type of ovarian sex cord-stromal tumour. For example, although the various patterns, such as solid, nested, trabecular, corded and glandular, would be compatible with an adult granulosa cell tumour, the nuclear features are not typical of this neoplasm. However, occasional cases have been considered to be indistinguishable from a Sertoli or Sertoli-Leydig cell tumour. All 4 neoplasms in our study were diffusely and strongly positive with CD56, a widely used neuroendocrine marker. It has been demonstrated recently that ovarian sex cord-stromal tumours are almost invariably positive with CD56 [25]; therefore CD56 positivity in UTROSCT may be a manifestation of sex cord differentiation.

All of our cases exhibited nuclear immunoreactivity with ER and PR which has been demonstrated in other studies of UTROSCT with 13 of 15 and 15 of 16 cases respectively being positive. Three of 4 cases were positive with androgen receptor.

The differential diagnosis of UTROSCT is potentially wide and may include an endometrial stromal and an epithelioid smooth muscle neoplasm, a metastatic ovarian sex cord-stromal tumour, a carcinosarcoma and primary and metastatic epithelial neoplasms, especially endometrioid adenocarcinoma with sex cord-like features and lobular breast carcinoma. A perivascular epithelioid cell tumour (PEComa) might also be considered. This would be positive with HMB45. Interpreted in isolation, immunoreactivity with any of the markers discussed may result in an erroneous diagnosis. A polyphenotypic immunophenotype is characteristic of UTROSCT and may be useful in differential diagnosis.

Given the polyphenotypic immunophenotype, I believe that UTROSCT is most likely derived from an uncommitted cell with the capacity to differentiate along several lines and express epithelial, myoid and sex cord markers. Some neoplasms express markers of all these lineages and others of 1 or two. An origin from displaced gonadal sex cord cells is also a possibility but EMA positivity is against this theory. As discussed, another major theory of histogenesis is that UTROSCT represents a variant of endometrial stromal neoplasm. Focal sex cord-like elements may be present in otherwise typical endometrial stromal neoplasms and it is possible that UTROSCT represents an endometrial stromal tumour in which these elements are exclusive or predominate. However, it is my opinion that the sex cord-like elements in endometrial stromal neoplasms differ morphologically in most cases from UTROSCT, the former being composed of typical endometrial stromal cells which form tubular, trabecular and other arrangements. Most UTROSCTs are relatively well circumscribed while most endometrial stromal neoplasms (endometrial stromal sarcomas) exhibit a widely infiltrative growth pattern and this is a further argument against an endometrial stromal origin. Moreover, judging by previous studies the sex cord-like elements in endometrial stromal neoplasms exhibit less of a polyphenotypic immunophenotype and it is my belief that these neoplasms are not related to UTROSCT. Greater than 60% of endometrial stromal neoplasms have been shown to exhibit rearrangements involving chromosomes 6, 7 and 17, most commonly a t(7;17)(p15;q21) translocation which results in a JAZF1-JJAZ1 gene fusion [26]. This translocation has also been demonstrated in endometrial stromal sarcomas with sex cord-like elements. In a recent study, using FISH and RT-PCR, we examined a series of 24 UTROSCTs to look for JAZF1-JJAZ1 gene fusion (manuscript in preparation). The translocation was not identified in any neoplasm, providing evidence that UTROSCT is not a variant of endometrial stromal neoplasm.

UTROSCTs usually exhibit a benign behaviour, especially when well circumscribed. However, since some of these neoplasms may exhibit a more infiltrative growth pattern and even vascular invasion, rare tumours have metastasised and only a few cases have been reported with long term follow-up, UTROSCT should be regarded as a neoplasm of uncertain but low malignant potential.

Table 1 – Endometrial and Uterine Lesions Which May Exhibit a Papillary Architecture
Non-neoplastic lesions:
  • Artefacts

  • Papillary syncytial metaplasia

  • Arias-Stella reaction

  • Hyperplastic papillary proliferation

  • Secondary to intrauterine device
Carcinomas:
  • Usual endometrioid

  • Villoglandular endometrioid

  • Endometrioid with small non-villous papillae

  • Surface changes in endometrioid

  • Serous

  • Clear cell

  • Mucinous

  • Transitional

  • Squamous
Miscellaneous:
  • Progestogen effect on hyperplasia or adenocarcinoma

  • Endometrial stromal sarcoma

  • Uterine tumour resembling ovarian sex cord tumour

References
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  2. Shah SS, Mazur MT. Endometrial eosinophilic syncytial change related to breakdown: immunohistochemical evidence suggests a regressive process. Int J Gynecol Pathol 2008;27;534-538.

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  13. Qui W, Mittal K. Comparison of morphologic and immunohistochemical features of cervical microglandular hyperplasia with low-grade mucinous adenocarcinoma of the endometrium. Int J Gynecol Pathol 2003;22;261-265.

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  24. McCluggage WG, Maxwell P, Sloan JM. Immunohistochemical staining of ovarian granulosa cell tumors with monoclonal antibody against inhibin. Hum Pathol 1997;28:1034-1038.

  25. McCluggage WG, McKenna M, McBride HA. CD56 is a sensitive and diagnostically useful immunohistochemical marker of ovarian sex cord-stromal tumors. Int J Gynecol Pathol 2007;26;322-327.

  26. Dal Cin P, Aly MS, De Wever I, et al. Endometrial stromal sarcoma t(7;17) (p15-21;q12-21) is a nonrandom chromosome change. Cancer Genet Cytogenet 1992;63;43-6.