Endocr Pathol DOI 10.1007/s12022-013-9285-4
Endocrine Pathology of the Ovary In Tribute to Robert E Scully, MD Esther Oliva & Robert H. Young
# Springer Science+Business Media New York 2014
Keywords Ovary . Function . Endocrine . Pathology
It is a pleasure and honor to be asked to contribute to this anniversary issue of the journal. Although tinged with sadness, it is fortuitous we were asked to write on the endocrine pathology of the ovary. This is the very same title as the wonderful book on the ovary written by our mentor, Dr. Robert E. Scully, with a gynecologist Dr. J.M Morris, in the mid 1950s and published in 1958 [1]. We began to work on this issue on Dr. Scully’s birthday, August 31, the first since his death in late October 2012, and the day, and time since working on this essay, has produced much reflection. We dedicate these pages to Dr. Scully knowing he would be happy we are focusing on an area of ovarian pathology of great interest to him. As is usually the case, it is hard, if not impossible, to improve on Dr. Scully’s approach; accordingly, we follow the outline of his book except that space constraints will not allow for a coverage of anatomic and embryological aspects or indeed all aspects of the topic overall. However, Dr. Scully devotes a chapter to this topic in his fascicle [2]. We highlight areas we find of greatest interest, expand to a degree on aspects such as immunohistochemistry, and update the literature review. We discuss the following categories in turn: non-neoplastic lesions, sex cord-stromal tumors, other neoplasms with E. Oliva : R. H. Young James Homer Wright Pathology Laboratories, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA E. Oliva (*) Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Warren 219, Boston, MA 02114, USA e-mail: [email protected]
endocrine manifestations, the fascinating phenomenon of ovarian tumors with functioning stroma (Table 1), a concept Dr. Morris and Dr. Scully had introduced in a review article a year before their book was published [3], and finally, and briefly, paraendocrine disorders. Dr. Scully’s interest in endocrine manifestations of ovarian lesions was shown in many ways, such as making a reference to it in his seminal paper on gonadoblastoma in 1953 [4] and considering it in even more detail in his 1970 magnum opus (Fig. 1) [5], and co-authoring a major contribution on metastatic tumors to the ovary with functioning stroma in 1961 [6]. He continued to explore endocrine function by non-neoplastic and neoplastic lesions over the years [7–15] and wrote one of the last comprehensive reviews on functioning stroma in 1987 [16]. Dr. Scully emphasized traditional pathology, but his curious mind was always interested in new techniques in a balanced way. Indeed, as soon as immunohistochemistry became available, he explored its use and was one of the first to write about it regarding ovarian tumors in both peer-reviewed articles [17–20] and in a review [21].
Non-neoplastic Lesions This category (Table 2) includes processes in which the ovary is not grossly abnormal or, if so, is to a limited degree as well as those that are typically associated with a mass and may be misconstrued as neoplasms, at least in some instances. The first group includes stromal hyperplasia/hyperthecosis (Fig. 2) and hilus cell hyperplasia. Pure stromal hyperplasia is rare as in most cases careful scrutiny shows at a least a minor component of lutein cells placing the process in the category of stromal hyperthecosis. Before the advent of immunohistochemistry, Dr. Scully reported oxidative enzyme activity by histochemistry in both luteinized and non-luteinized stromal cells in about 60 % of normal ovaries leading to the
Endocr Pathol Table 1 Outline—categories of functioning ovarian lesions 1. Non-neoplastic lesions 2. Thecoma 3. Other stromal lesions 4. Granulosa cell tumors 5. Sertoli and Sertoli–Leydig cell tumors 6. Sex cord tumor with annular tubules 7. Miscellaneous other neoplasms with endocrine function 8. Ovarian tumors with functioning stroma
introduction of the term “enzymatically active stromal cells” [15]. It was surmised that this was evidence of a spectrum from normal to histochemically abnormal to both histologically and histochemically abnormal cells. These findings parallel those observed today with inhibin or calretinin (Fig. 2c, d) [19, 22]. This spectrum may explain the occasional case in which there is some but usually not striking evidence of hormonal production (most often in the form of endometrial hyperplasia) in postmenopausal patients whose only ovarian pathology is stromal hyperplasia. These cells also express calretinin [23, 24]. When lutein cells are present, especially in significant numbers (stromal hyperthecosis) (Fig. 2a), the frequency of endocrine manifestations, most often estrogenic but occasionally androgenic, increases [25–27]. In some instances, the combined proliferation of stroma and lutein cells results in a grossly evident fibroma-like mass, but one that rarely exceeds 7 cm and in contrast to most fibromas is typically bilateral. When lutein cells are exuberant and form nodular aggregates up to 0.5 cm, the descriptive designation “nodular hyperthecosis” may be used (Fig. 2b). A greater size by convention would be considered a so-called stromal luteoma”, although this term is falling out of favor, as in the new World Health Organization (WHO) classification, they
Fig. 1 Gonadoblastoma (right). Note large aggregate of lutein cells which may account for endocrine manifestations beneath typical nests containing sex cord and germ cells and the common calcification of this entity. At left are portions of the title pages of Dr. Scully’s original description and his later study of 74 cases
are considered a small steroid cell tumor without further subcategorization (see below) [28]. Hilus cell hyperplasia, if strictly defined, is a much less common phenomenon and typically androgenic [29]. Small aggregates of hilar (Leydig) cells are common and hilus cell hyperplasia should only be diagnosed when one or more confluent nodules are present. As with the spectrum of stromal hyperthecosis/stromal luteoma, a cutoff of 0.5 cm is a reasonable arbitrary criterion for the distinction between hilus cell hyperplasia versus hilar cell tumor. It should be noted that as with hilar cell tumors, hilus cell hyperplasia may exhibit degenerative-type atypia. Rarely, these lesions may be associated with androgenic manifestations [30]. These hyperplastic hilar cells are typically inhibin and calretinin positive [19, 23, 31] and they also express relaxin-like factor also known as Leydig cell insulin-like factor which also shows weak to moderate staining in theca and granulosa cell tumors [32]. Non-neoplastic lesions that are grossly visible include massive edema and fibromatosis, both rare. They are sometimes associated with menstrual irregularities presumptively due to estrogen production and more strikingly have been associated with androgenic manifestations, both explained by the presence of lutein cells in the background. Some have occurred during pregnancy; however, there is no specific relation to it [33]. Non-neoplastic lesions that are cystic include polycystic ovarian disease (PCOD). It has been historically considered an important disorder in the realm of endocrine pathology but is now considered primarily a clinical diagnosis, and ovaries are rarely sent for pathologic examination. Furthermore, the histologic findings in isolation are not diagnostic. Of interest, the granulosa cells lining follicles in PCOD are negative for αinhibin and positive for β-subunits. In contrast, the hyperplastic theca cells exhibit distinct positivity for all inhibin subunits [34]. They also produce excess activin or insufficient
Endocr Pathol Table 2 Non-neoplastic lesions potentially associated with function 1. Stromal hyperplasia 2. Stromal hyperthecosis 3. Hilus cell hyperplasia 4. Polycystic ovarian disease 5. Massive edema 6. Fibromatosis 7. Follicle cyst 8. Hyperreactio luteinalis 9. Pregnancy luteoma
follistatin which may contribute to theca cell hyperplasia [35]. Much more common are follicle cysts, a frequent cause of ovarian enlargement and symptomatology, the latter including endocrine manifestations. In the reproductive age group, the not infrequent menstrual irregularities are likely due to estrogen production but it is in the premenarchal years that a more dramatic presentation, isosexual pseudoprecocity, may be seen [36, 37]. Immunostaining of the cyst fluid with inhibin may be of value in confirming the presence of granulosa cells, thus establishing this diagnosis [38]. Theca and granulosa cells of follicle cysts are also typically positive for calretinin [23, 24]. Occasionally, follicle cysts, often multiple and bilateral, are a component of the McCune–Albright syndrome, characterized by the triad of polyostotic fibrous dysplasia, café-au-lait skin pigmentation, and precocious puberty [39] due to post-zygotic activating mutations of arginine 201 in the guanine–nucleotide-binding protein (G protein) α-subunit [40]. Ovarian cyst formation and regression in these patients is often described as a sign of ovarian follicle hyperactivation; however, there is heterogeneity of the clinical manifestations Fig. 2 Stromal hyperthecosis (a). Steroid-type cells with eosinophilic cytoplasm are scattered within the ovarian stroma. A large nodule of such cells, but not forming a gross mass, is descriptively considered “nodular hyperthecosis” (b). In some cases, cortical stroma without evident lutein cells shows immunoreactivity for inhibin (c) and luxuriant staining for inhibin, or calretinin (d), is typical of overt hyperthecosis
[41]. A variant of follicle cyst, so-called large follicle cyst of pregnancy and the puerperium is, enigmatically, not associated with endocrine function. Although the pathogenesis of these cysts is unknown, high levels of human chorionic gonadotropin stimulation probably play an important role in their development [42–44]. A characteristic feature of these cysts that also differs from conventional follicle cyst is the presence focally of bizarre nuclei in 10 to 50 % of the lining cells [42]. Two important non-neoplastic lesions that may be functioning are pregnancy luteoma (Fig. 3) and hyperreactio luteinalis (Fig. 4), both of which may be associated with androgenic manifestations in about 25 and 15 %, respectively, but only the former is associated with virilization of female offspring, seen in 60 to 70 % of the cases [45–50]. These two lesions differ dramatically grossly, as pregnancy luteoma is composed of multiple solid nodules (∼50 %) and shows a brown, reddish cut surface, whereas hyperreactio luteinalis is composed of multiple thin-walled cysts and it is almost invariably bilateral in contrast to pregnancy luteoma (bilateral only in up to 40 %) [51, 52]. The morphology of pregnancy luteoma has recently been reviewed in detail [53]. The cysts of hyperreactio are in isolation similar to typical follicle cysts, differing only in their number and additionally stromal edema and luteinization are common.
Sex Cord-Stromal Tumors Thecoma This is one of the two ovarian tumors classically associated with estrogen production. The frequency of estrogenic
Endocr Pathol
Fig. 3 Pregnancy luteoma. Follicle-like spaces containing colloid-like material are relatively common in this entity
manifestations is hard to ascertain with certainty, but in one series as many as 21 % of patients had endometrial carcinoma, presumptively due to estrogen production [54]. These tumors are less common than granulosa cell tumors and differ from them from the clinical, gross, and microscopic viewpoints. They occur about 10 years later (63 versus 53 years) and are less often associated with pelvic symptomatology due to their smaller size (average 7 cm). They are typically solid, lobulated, and yellow to white. Microscopic examination shows sheets and nodules of pale “gray” cells with ill-defined cytoplasmic borders (Fig. 5) [55]. In our opinion, the lipid rich quality of the cells has been often overemphasized in the literature. Another well-known feature, hyaline plaques, are indeed common but may be seen in other tumors including fibromas, microcystic stromal tumors [56, 57], and even endometrioid stromal sarcoma [57, 58]. Thecomas are typically positive for inhibin [19], a 32-kDa heterodimeric glycoprotein hormone composed of an α- and a β-subunits that in normal conditions is secreted by ovarian granulosa cells. Inhibin is also produced by testicular Sertoli cells, and extragonadal expression has been demonstrated in the placenta, pituitary gland, and adrenal gland. Inhibin has autocrine and paracrine effects in addition to its role in suppressing folliclestimulating hormone secretion by the pituitary gland. Thus,
Fig. 4 Hyperreactio luteinalis. Part of four cysts separated by ovarian stroma are seen. Individually, the cysts are identical to follicle cysts of the non-pregnant ovary
Fig. 5 Thecoma. Typical pale cytoplasm which is less lipid-rich than often stated in the literature. Calcification, focally seen here, may be striking, particularly in tumors of younger patients
inhibin acts as a modulator of folliculogenesis [9]. These tumors are also typically positive for calretinin, a more sensitive but less specific marker than inhibin in the diagnosis of sex cord-stromal tumors in general [59]. As calretinin is a calcium-binding protein, and these proteins as well as calcium ions are involved in endocrine secretion by theca interna cells and corpus luteum in the normal ovary, calretinin positivity in theca interna cells, and some luteinized granulosa cells of the corpus luteum may suggest its expression is related to steroid secretion [60, 61]. Although melan-A has not been reported in ovarian thecomas, Zhang and colleagues have reported fibrothecomas of the testis to be positive for this marker [62]. The FOXL2 gene encodes a transcription factor that is required for granulosa cell function and ovarian follicle development and it is typically expressed in adult and juvenile granulosa cell tumors. This is a sensitive marker of sex cordstromal tumors and it can also be positive in thecomas [63]. FOXL-2 mis-sense mutations have been reported in ∼20 % of thecomas [64]. However, it has to be noted that some tumors diagnosed as thecomas and having this mutation have been reclassified as granulosa cell tumors, highlighting the
Fig. 6 Sclerosing stromal tumor. This example from a pregnant patient shows lutein cells in greater number and with a more robust appearance than is typical, likely due to the HCG stimulation of pregnancy. Note a striking ectatic vessel, a typical feature of this neoplasm, although it may be seen in other stromal tumors
Endocr Pathol Fig. 7 Luteinized thecoma of type associated with sclerosing peritonitis. In some cases, the ovaries are not enlarged but have a striking cerebriform contour, something also seen microscopically (a). Lutein cells are seen in this lesion (b). Another common feature is stromal edema sometimes imparting a “microcystic” appearance (c). A representative example of the sclerosing peritonitis of this entity is seen in d
difficulty of the differential diagnosis of thecoma versus granulosa cell tumor in some cases. Of note, and although unrelated to endocrine manifestations, consistent numerical chromosomal aberrations have been described in 21 of 29 ovarian tumors in the thecoma–fibroma group, trisomy or tetrasomy 12 being most common [65]. Other Stromal Tumors Although fibromas are conventionally considered nonfunctioning, and usually are, they may be associated with endocrine manifestations if they contain lutein cells. Such tumors, until recently, were placed in the “luteinized thecoma” category [66, 67], but the upcoming WHO classification ignores the lutein cells with regard to nomenclature, although they should be mentioned in a note if they help explain hormone function [28, 68]. A similar comment pertains to cases in which lutein-like cells in stromal neoplasms contain crystals of Reinke, enabling them to be designated as Leydig cells. These rare neoplasms have been reported as “stromal– Leydig cell tumor” [69], but the current WHO classification does not include this tumor as a specific entity [28]. Some fibromas containing lutein cells have been associated with androgenic manifestations [67, 68]. Finally, even when lutein cells are not seen, some fibromas may express inhibin as well as calretinin, indicative of limited endocrine activity [19, 24, 59]. These tumors although positive for FOXL-2 lack the FOXL-2 mutation, and this finding may be a helpful diagnostic adjunct in the differential diagnosis with diffuse type adult granulosa cell tumor [70]. They also express SF-1 (adrenal 4binding protein), a nuclear transcription factor that regulates genes that are involved in steroidogenesis, development of the
gonads and adrenal glands, sexual differentiation, reproduction, and metabolism. Of interest, this gene is thought to regulate the inhibin gene, thus is expressed in cells that are also inhibin positive, but this marker has been reported to be more sensitive than inhibin in the diagnosis of sex cordstromal tumors and it is more frequently positive in this category of tumors than inhibin [71]. Sclerosing stromal tumor is a morphologically distinctive neoplasm with interesting clinical and pathological features but it is only briefly mentioned here as it is rarely functioning [72]. At first glance, this is surprising as a definitional feature of the tumor is a component of lutein cells but they usually have a degenerative appearance presumably explaining the lack of function. When “robust” lutein cells with abundant
Fig. 8 Adult granulosa cell tumor. One of many gross appearances is a solid mass which may be characterized by multiple discrete yellow nodules separated by firm white areas representative of the common background stroma of this neoplasm
Endocr Pathol Fig. 9 Adult granulosa cell tumor with bizarre nuclei. Characteristic features are seen (a), but a significant component of this tumor is characterized by bizarre nuclear atypia (b), a finding not of adverse prognostic significance
eosinophilic cytoplasm (in contrast to the more common pale vacuolated appearance) are present in abundance, as seen for example during pregnancy (Fig. 6), hormone production may be striking including even virilization [73–75]. These tumors, although usually not clinically functioning, express inhibin and calretinin [19, 24, 59]. They are also FOXL-2 positive but lack FOXL -2 mutations [63]. The so-called luteinized thecoma associated with sclerosing peritonitis (Fig. 7), although it has lutein cells, rarely is associated with estrogenic or androgenic manifestations. However, the lutein cells are typically inhibin positive in contrast to the spindle cells which show negative or only rarely show focal positive expression of this marker [76]. These tumors are also positive for FOXL2 and SF-1 [70]. Parenthetically, although sclerosing peritonitis is typically associated with this distinctive stromal neoplasm, it has been described with one granulosa cell tumor [77]. As with sclerosing stromal tumor, the rarity of function is likely related to the weak nature of the luteinization (Fig. 7b). Other rare entities in the stromal tumor category such as microcystic stromal tumor and signet ring cell stromal tumor have not
Fig. 10 Adult granulosa cell tumor. A tumor that has a background resembling a cellular fibroma is punctuated by aggregates of cells with an epithelial-like arrangement (a) and their granulosa cell nature is highlighted by strong staining for inhibin (b). A reticulin stain from another case (c) shows large areas devoid of reticulin, a finding that helps substantiate granulosa cell differentiation in a tumor with a prominent stroma
been reported to be endocrinologically active, although the possibility exists [57, 78]. However, the former often shows positivity for CD10, vimentin, and WT-1 and also has βcatenin mutations [79] but is negative for inhibin [57]. Granulosa Cell Tumors For approximately the last two decades, granulosa cell tumors have been subdivided into two categories following Dr. Scully’s appreciation circa the late 1960s that in young females these tumors often had distinctive microscopic features, leading him to designate them “juvenile granulosa cell tumor” [80]. This, of necessity, resulted in the need for a companion name for the well-known tumors that peak in the perimenopausal age group and the term “adult granulosa cell tumor” was introduced. It should be emphasized, however, that these designations are terms of convenience to capture a constellation of findings, and there is overlap between the two tumor types, some neoplasms having microscopic features of both subtypes. Furthermore, it must be noted that the classic adult
Endocr Pathol Fig. 11 Adult granulosa cell tumor. This neoplasm, in part, had a very typical pattern of regular anastomosing cords (a), but in other areas had a peculiar clear cell morphology (b), potentially leading to a broad differential diagnosis in the absence of typical granulosa cell foci
granulosa cell tumor may occur in children and young women [81] and conversely but less often the juvenile form can occur in older women [80]. Adult granulosa cell tumors (AGCT) are often associated with estrogenic manifestations with a frequency that varies but can broadly be considered seen in half to two thirds of the patients. They include postmenopausal bleeding or menstrual irregularities in younger women. In children, they, like the juvenile form, may cause isosexual pseudoprecocity. If the endometrium is evaluated pathologically, it may show endometrial hyperplasia or even low-grade endometrioid adenocarcinoma. Rarely, AGCT may be androgenic, a finding for unknown reasons disproportionally seen with cystic neoplasms. Sometimes, estrogenic and androgenic manifestations can coexist. Cystic AGCTs are also notable grossly as they may have smooth cyst linings and suggest other more Fig. 12 Juvenile granulosa cell tumor. Marked nuclear pleomorphism (a) is more common in this tumor than in the adult neoplasm. Note the helpful finding of focal follicular differentiation. Some juvenile granulosa cell tumors grow only in the form of large nodular aggregates (b)
common cystic tumors. The gross spectrum of the AGCT is wide, ranging from cystic, to solid and cystic, to solid (Fig. 8.). They may be unilocular or multilocular and not uncommonly large, 20 cm or more [82]. Inhibin, mentioned earlier as an immunohistochemical adjunct in the identification of lutein or endocrine active ovarian stromal cells, can also be used as a serum marker to monitor disease course [83]. Only a few comments will be made on the microscopic appearance of the AGCT which is remarkably varied (Figs. 9, 10, and 11). The most common is a diffuse growth of round, oval, or, less often, spindle-shaped cells that almost always is associated with minor foci of obvious epithelial patterns, most often in the form of delicate cords. In these tumors, the stroma is usually minimal to absent. Tumors in which spindled cells dominate have been referred to as “sarcomatoid” but that designation is discouraged as it may cause confusion from
Endocr Pathol Fig. 13 Juvenile granulosa cell tumor, cystic forms. One neoplasm (a) shows a cyst with a thick lining of neoplastic granulosa cells underlain by theca cells whereas another cyst has a much less conspicuous component of lining cells. In cystic juvenile granulosa cell tumors, as in the adult counterpart, degenerative changes may result in a striking pseudopapillary appearance (b)
the management viewpoint. A second common appearance has obvious epithelial arrangements, including insular and trabecular as well as anastomosing cords of granulosa cells, on a background of conspicuous but usually minor fibrothecomatous stroma. Although follicular patterns are often emphasized, they are absent in the majority of tumors and are conspicuous in only a minority. The microfollicular pattern is characterized by small, generally regular, follicles (Call– Exner bodies) that may contain eosinophilic material with nuclear debris, hyalinized basement membrane-like material, or, rarely, basophilic secretion. In our experience, Call–Exner bodies are overall uncommon. The macrofollicular pattern is even less common and is composed of large, relatively uniform follicles typically containing eosinophilic secretions. Other patterns such as “watered-silk” (parallel, thin, winding cords) and gyriform (a zigzag arrangement of cords) are at least in aggregate usually more striking than follicular patterns. A pseudopapillary pattern has been recently described [56]. On gross examination, there is often a friable appearance that may suggest a surface epithelial tumor. Under the microscope, papillae are lined by several layers of typical granulosa cells that often become detached from the surface are seen. The resultant appearance may make a papillary transitional cell carcinoma, in particular, an initial consideration in differential diagnosis. A third low-power appearance of AGCT may closely resemble either a cellular fibroma or a thecoma due to a prominent stroma but, when a minority (but >10 %) component of the tumor is composed of granulosa cells, the tumor is considered a granulosa cell tumor. Sometimes, granulosa cell elements in these tumors are best seen at the periphery. Cystic AGCTs have cysts that are usually lined by many layers of granulosa cells which may show focal follicle formation and granulosa cells may be present in the cyst walls [82]. Denudation of the cyst lining may occasionally be significant and
cause confusion with other cystic lesions of the ovary. Although granulosa cells usually have scant cytoplasm, it may be abundant and eosinophilic, resulting in a luteinized appearance [84, 85], a feature as noted below more typical of juvenile neoplasms. Nuclei of AGCT are typically pale and round, oval, or angular and are often haphazardly oriented. Nuclear grooves are common but may be relatively inconspicuous especially in tumors with a diffuse pattern or which are luteinized; nucleoli are occasionally moderately prominent, particularly in the latter. Significant pleomorphism is usually absent, but approximately 2 % of AGCTs contain cells with large, bizarre, hyperchromatic nuclei (Fig. 9b) [86] that have no adverse impact on prognosis. The mitotic rate is usually ≤2 per 10 high-power fields, but higher rates do not exclude this diagnosis. A thecomatous or fibromatous stromal component is usually present and may, as noted above, predominate and may be richly vascular. Exceptionally, hepatocytes and Leydig cells are seen but these findings have not been associated with endocrine manifestations [87, 88].
Fig. 14 Sertoli cell tumor. This neoplasm has an alveolar arrangement with some fibrous septa and occasionally, as in the testis, this can result in confusion with germinoma, particularly if lymphocytes are present
Endocr Pathol Table 3 Androgenic tumors 1. Sertoli and Sertoli–Leydig cell tumor 2. Granulosa cell tumor (particularly when cystic) 3. Stromal tumors with lutein cells 4. Leydig (hilus) cell tumor 5. Steroid cell tumor, NOS 6. Tumors with functioning stroma 7. Gonadoblastoma
We restrict comments on the differential diagnosis of AGCT to one important tumor, small cell carcinoma of the hypercalcemic type, as this tumor, before being characterized, was likely misdiagnosed as AGCT because both tumors may have follicles and cells with scant cytoplasm. However, there are other morphologic features that differ between these two tumors including lack of grooves, high mitotic rate, extensive necrosis, and extension outside the ovary in approximatelytwo third of small cell carcinomas of the hypercalcemic type [89]. Furthermore, inhibin is a useful marker in the diagnosis of AGCT and is negative in small cell carcinoma of the hypercalcemic type [19, 90]. However, of note, some AGCTs may be inhibin negative. A recurrent somatic point mutation (402C→G) in FOXL -2 has been described in almost all AGCTs [91], and these tumors as mentioned earlier are FOXL-2 positive by immunohistochemistry [63]. They also express inhibin, calretinin, WT-1 and SF1 and not infrequently CD99 [24, 59, 71, 92, 93]. Although, a known entity now for several decades, the juvenile granulosa cell tumor (JGCT) merits some emphasis here as it is often functioning and issues in differential diagnosis remain common. The JGCT occurs in the first two decades in about 80 % of cases and most of the remainder
Fig. 15 Sertoli–Leydig cell tumor with heterologous elements. At low power (a), the typical dark blue lobules of Sertoli cells are associated with aggregates of Leydig cells with conspicuous eosinophilic cytoplasm. The middle of the illustration shows cords of Sertoli cells in a background of conspicuous stroma, and the bottom shows heterologous mucinous epithelium, seen at higher power in (b)
prior to 30 years. The young age distribution results in many patients being pre-menarchal and estrogen produced by the tumor typically results in a dramatic clinical presentation with isosexual pseudoprecocity [80]. Rarely, androgenic manifestations may occur, an association with cystic tumors again being evident [82]. Like AGCT, the tumors are typically unilateral and stage I at diagnosis. The only clinical difference apparent to date is lack of late recurrences often seen in patients with AGCT, and a tendency of the rare malignant JGCT to recur early [80]. The spectrum of gross appearances is similar to that of the AGCT, and their microscopic spectrum is almost as varied (Figs. 12 and 13). Certain specific microscopic differences set this neoplasm apart. The first is the more immature mitotically active (including atypical forms) nature of the cells which typically lack nuclear grooves and in up to 15 % of cases are strikingly pleomorphic (Fig. 12a) [80]. As more experience accumulated other differences became apparent, specifically, abundant cytoplasm, generally eosinophilic, and an irregular follicular architecture, follicles being variable in both size and shape. Other differences include a nodular architecture (Fig. 12b), in which some of the nodules occasionally may show marked sclerosis as well as a basophilic background. The variability in the aforementioned features results in a varied differential diagnosis, including yolk sac tumor, the coma (uncommon
Endocrine Pathology of the Ovary In Tribute to Robert E Scully, MD Esther Oliva & Robert H. Young
# Springer Science+Business Media New York 2014
Keywords Ovary . Function . Endocrine . Pathology
It is a pleasure and honor to be asked to contribute to this anniversary issue of the journal. Although tinged with sadness, it is fortuitous we were asked to write on the endocrine pathology of the ovary. This is the very same title as the wonderful book on the ovary written by our mentor, Dr. Robert E. Scully, with a gynecologist Dr. J.M Morris, in the mid 1950s and published in 1958 [1]. We began to work on this issue on Dr. Scully’s birthday, August 31, the first since his death in late October 2012, and the day, and time since working on this essay, has produced much reflection. We dedicate these pages to Dr. Scully knowing he would be happy we are focusing on an area of ovarian pathology of great interest to him. As is usually the case, it is hard, if not impossible, to improve on Dr. Scully’s approach; accordingly, we follow the outline of his book except that space constraints will not allow for a coverage of anatomic and embryological aspects or indeed all aspects of the topic overall. However, Dr. Scully devotes a chapter to this topic in his fascicle [2]. We highlight areas we find of greatest interest, expand to a degree on aspects such as immunohistochemistry, and update the literature review. We discuss the following categories in turn: non-neoplastic lesions, sex cord-stromal tumors, other neoplasms with E. Oliva : R. H. Young James Homer Wright Pathology Laboratories, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA E. Oliva (*) Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Warren 219, Boston, MA 02114, USA e-mail: [email protected]
endocrine manifestations, the fascinating phenomenon of ovarian tumors with functioning stroma (Table 1), a concept Dr. Morris and Dr. Scully had introduced in a review article a year before their book was published [3], and finally, and briefly, paraendocrine disorders. Dr. Scully’s interest in endocrine manifestations of ovarian lesions was shown in many ways, such as making a reference to it in his seminal paper on gonadoblastoma in 1953 [4] and considering it in even more detail in his 1970 magnum opus (Fig. 1) [5], and co-authoring a major contribution on metastatic tumors to the ovary with functioning stroma in 1961 [6]. He continued to explore endocrine function by non-neoplastic and neoplastic lesions over the years [7–15] and wrote one of the last comprehensive reviews on functioning stroma in 1987 [16]. Dr. Scully emphasized traditional pathology, but his curious mind was always interested in new techniques in a balanced way. Indeed, as soon as immunohistochemistry became available, he explored its use and was one of the first to write about it regarding ovarian tumors in both peer-reviewed articles [17–20] and in a review [21].
Non-neoplastic Lesions This category (Table 2) includes processes in which the ovary is not grossly abnormal or, if so, is to a limited degree as well as those that are typically associated with a mass and may be misconstrued as neoplasms, at least in some instances. The first group includes stromal hyperplasia/hyperthecosis (Fig. 2) and hilus cell hyperplasia. Pure stromal hyperplasia is rare as in most cases careful scrutiny shows at a least a minor component of lutein cells placing the process in the category of stromal hyperthecosis. Before the advent of immunohistochemistry, Dr. Scully reported oxidative enzyme activity by histochemistry in both luteinized and non-luteinized stromal cells in about 60 % of normal ovaries leading to the
Endocr Pathol Table 1 Outline—categories of functioning ovarian lesions 1. Non-neoplastic lesions 2. Thecoma 3. Other stromal lesions 4. Granulosa cell tumors 5. Sertoli and Sertoli–Leydig cell tumors 6. Sex cord tumor with annular tubules 7. Miscellaneous other neoplasms with endocrine function 8. Ovarian tumors with functioning stroma
introduction of the term “enzymatically active stromal cells” [15]. It was surmised that this was evidence of a spectrum from normal to histochemically abnormal to both histologically and histochemically abnormal cells. These findings parallel those observed today with inhibin or calretinin (Fig. 2c, d) [19, 22]. This spectrum may explain the occasional case in which there is some but usually not striking evidence of hormonal production (most often in the form of endometrial hyperplasia) in postmenopausal patients whose only ovarian pathology is stromal hyperplasia. These cells also express calretinin [23, 24]. When lutein cells are present, especially in significant numbers (stromal hyperthecosis) (Fig. 2a), the frequency of endocrine manifestations, most often estrogenic but occasionally androgenic, increases [25–27]. In some instances, the combined proliferation of stroma and lutein cells results in a grossly evident fibroma-like mass, but one that rarely exceeds 7 cm and in contrast to most fibromas is typically bilateral. When lutein cells are exuberant and form nodular aggregates up to 0.5 cm, the descriptive designation “nodular hyperthecosis” may be used (Fig. 2b). A greater size by convention would be considered a so-called stromal luteoma”, although this term is falling out of favor, as in the new World Health Organization (WHO) classification, they
Fig. 1 Gonadoblastoma (right). Note large aggregate of lutein cells which may account for endocrine manifestations beneath typical nests containing sex cord and germ cells and the common calcification of this entity. At left are portions of the title pages of Dr. Scully’s original description and his later study of 74 cases
are considered a small steroid cell tumor without further subcategorization (see below) [28]. Hilus cell hyperplasia, if strictly defined, is a much less common phenomenon and typically androgenic [29]. Small aggregates of hilar (Leydig) cells are common and hilus cell hyperplasia should only be diagnosed when one or more confluent nodules are present. As with the spectrum of stromal hyperthecosis/stromal luteoma, a cutoff of 0.5 cm is a reasonable arbitrary criterion for the distinction between hilus cell hyperplasia versus hilar cell tumor. It should be noted that as with hilar cell tumors, hilus cell hyperplasia may exhibit degenerative-type atypia. Rarely, these lesions may be associated with androgenic manifestations [30]. These hyperplastic hilar cells are typically inhibin and calretinin positive [19, 23, 31] and they also express relaxin-like factor also known as Leydig cell insulin-like factor which also shows weak to moderate staining in theca and granulosa cell tumors [32]. Non-neoplastic lesions that are grossly visible include massive edema and fibromatosis, both rare. They are sometimes associated with menstrual irregularities presumptively due to estrogen production and more strikingly have been associated with androgenic manifestations, both explained by the presence of lutein cells in the background. Some have occurred during pregnancy; however, there is no specific relation to it [33]. Non-neoplastic lesions that are cystic include polycystic ovarian disease (PCOD). It has been historically considered an important disorder in the realm of endocrine pathology but is now considered primarily a clinical diagnosis, and ovaries are rarely sent for pathologic examination. Furthermore, the histologic findings in isolation are not diagnostic. Of interest, the granulosa cells lining follicles in PCOD are negative for αinhibin and positive for β-subunits. In contrast, the hyperplastic theca cells exhibit distinct positivity for all inhibin subunits [34]. They also produce excess activin or insufficient
Endocr Pathol Table 2 Non-neoplastic lesions potentially associated with function 1. Stromal hyperplasia 2. Stromal hyperthecosis 3. Hilus cell hyperplasia 4. Polycystic ovarian disease 5. Massive edema 6. Fibromatosis 7. Follicle cyst 8. Hyperreactio luteinalis 9. Pregnancy luteoma
follistatin which may contribute to theca cell hyperplasia [35]. Much more common are follicle cysts, a frequent cause of ovarian enlargement and symptomatology, the latter including endocrine manifestations. In the reproductive age group, the not infrequent menstrual irregularities are likely due to estrogen production but it is in the premenarchal years that a more dramatic presentation, isosexual pseudoprecocity, may be seen [36, 37]. Immunostaining of the cyst fluid with inhibin may be of value in confirming the presence of granulosa cells, thus establishing this diagnosis [38]. Theca and granulosa cells of follicle cysts are also typically positive for calretinin [23, 24]. Occasionally, follicle cysts, often multiple and bilateral, are a component of the McCune–Albright syndrome, characterized by the triad of polyostotic fibrous dysplasia, café-au-lait skin pigmentation, and precocious puberty [39] due to post-zygotic activating mutations of arginine 201 in the guanine–nucleotide-binding protein (G protein) α-subunit [40]. Ovarian cyst formation and regression in these patients is often described as a sign of ovarian follicle hyperactivation; however, there is heterogeneity of the clinical manifestations Fig. 2 Stromal hyperthecosis (a). Steroid-type cells with eosinophilic cytoplasm are scattered within the ovarian stroma. A large nodule of such cells, but not forming a gross mass, is descriptively considered “nodular hyperthecosis” (b). In some cases, cortical stroma without evident lutein cells shows immunoreactivity for inhibin (c) and luxuriant staining for inhibin, or calretinin (d), is typical of overt hyperthecosis
[41]. A variant of follicle cyst, so-called large follicle cyst of pregnancy and the puerperium is, enigmatically, not associated with endocrine function. Although the pathogenesis of these cysts is unknown, high levels of human chorionic gonadotropin stimulation probably play an important role in their development [42–44]. A characteristic feature of these cysts that also differs from conventional follicle cyst is the presence focally of bizarre nuclei in 10 to 50 % of the lining cells [42]. Two important non-neoplastic lesions that may be functioning are pregnancy luteoma (Fig. 3) and hyperreactio luteinalis (Fig. 4), both of which may be associated with androgenic manifestations in about 25 and 15 %, respectively, but only the former is associated with virilization of female offspring, seen in 60 to 70 % of the cases [45–50]. These two lesions differ dramatically grossly, as pregnancy luteoma is composed of multiple solid nodules (∼50 %) and shows a brown, reddish cut surface, whereas hyperreactio luteinalis is composed of multiple thin-walled cysts and it is almost invariably bilateral in contrast to pregnancy luteoma (bilateral only in up to 40 %) [51, 52]. The morphology of pregnancy luteoma has recently been reviewed in detail [53]. The cysts of hyperreactio are in isolation similar to typical follicle cysts, differing only in their number and additionally stromal edema and luteinization are common.
Sex Cord-Stromal Tumors Thecoma This is one of the two ovarian tumors classically associated with estrogen production. The frequency of estrogenic
Endocr Pathol
Fig. 3 Pregnancy luteoma. Follicle-like spaces containing colloid-like material are relatively common in this entity
manifestations is hard to ascertain with certainty, but in one series as many as 21 % of patients had endometrial carcinoma, presumptively due to estrogen production [54]. These tumors are less common than granulosa cell tumors and differ from them from the clinical, gross, and microscopic viewpoints. They occur about 10 years later (63 versus 53 years) and are less often associated with pelvic symptomatology due to their smaller size (average 7 cm). They are typically solid, lobulated, and yellow to white. Microscopic examination shows sheets and nodules of pale “gray” cells with ill-defined cytoplasmic borders (Fig. 5) [55]. In our opinion, the lipid rich quality of the cells has been often overemphasized in the literature. Another well-known feature, hyaline plaques, are indeed common but may be seen in other tumors including fibromas, microcystic stromal tumors [56, 57], and even endometrioid stromal sarcoma [57, 58]. Thecomas are typically positive for inhibin [19], a 32-kDa heterodimeric glycoprotein hormone composed of an α- and a β-subunits that in normal conditions is secreted by ovarian granulosa cells. Inhibin is also produced by testicular Sertoli cells, and extragonadal expression has been demonstrated in the placenta, pituitary gland, and adrenal gland. Inhibin has autocrine and paracrine effects in addition to its role in suppressing folliclestimulating hormone secretion by the pituitary gland. Thus,
Fig. 4 Hyperreactio luteinalis. Part of four cysts separated by ovarian stroma are seen. Individually, the cysts are identical to follicle cysts of the non-pregnant ovary
Fig. 5 Thecoma. Typical pale cytoplasm which is less lipid-rich than often stated in the literature. Calcification, focally seen here, may be striking, particularly in tumors of younger patients
inhibin acts as a modulator of folliculogenesis [9]. These tumors are also typically positive for calretinin, a more sensitive but less specific marker than inhibin in the diagnosis of sex cord-stromal tumors in general [59]. As calretinin is a calcium-binding protein, and these proteins as well as calcium ions are involved in endocrine secretion by theca interna cells and corpus luteum in the normal ovary, calretinin positivity in theca interna cells, and some luteinized granulosa cells of the corpus luteum may suggest its expression is related to steroid secretion [60, 61]. Although melan-A has not been reported in ovarian thecomas, Zhang and colleagues have reported fibrothecomas of the testis to be positive for this marker [62]. The FOXL2 gene encodes a transcription factor that is required for granulosa cell function and ovarian follicle development and it is typically expressed in adult and juvenile granulosa cell tumors. This is a sensitive marker of sex cordstromal tumors and it can also be positive in thecomas [63]. FOXL-2 mis-sense mutations have been reported in ∼20 % of thecomas [64]. However, it has to be noted that some tumors diagnosed as thecomas and having this mutation have been reclassified as granulosa cell tumors, highlighting the
Fig. 6 Sclerosing stromal tumor. This example from a pregnant patient shows lutein cells in greater number and with a more robust appearance than is typical, likely due to the HCG stimulation of pregnancy. Note a striking ectatic vessel, a typical feature of this neoplasm, although it may be seen in other stromal tumors
Endocr Pathol Fig. 7 Luteinized thecoma of type associated with sclerosing peritonitis. In some cases, the ovaries are not enlarged but have a striking cerebriform contour, something also seen microscopically (a). Lutein cells are seen in this lesion (b). Another common feature is stromal edema sometimes imparting a “microcystic” appearance (c). A representative example of the sclerosing peritonitis of this entity is seen in d
difficulty of the differential diagnosis of thecoma versus granulosa cell tumor in some cases. Of note, and although unrelated to endocrine manifestations, consistent numerical chromosomal aberrations have been described in 21 of 29 ovarian tumors in the thecoma–fibroma group, trisomy or tetrasomy 12 being most common [65]. Other Stromal Tumors Although fibromas are conventionally considered nonfunctioning, and usually are, they may be associated with endocrine manifestations if they contain lutein cells. Such tumors, until recently, were placed in the “luteinized thecoma” category [66, 67], but the upcoming WHO classification ignores the lutein cells with regard to nomenclature, although they should be mentioned in a note if they help explain hormone function [28, 68]. A similar comment pertains to cases in which lutein-like cells in stromal neoplasms contain crystals of Reinke, enabling them to be designated as Leydig cells. These rare neoplasms have been reported as “stromal– Leydig cell tumor” [69], but the current WHO classification does not include this tumor as a specific entity [28]. Some fibromas containing lutein cells have been associated with androgenic manifestations [67, 68]. Finally, even when lutein cells are not seen, some fibromas may express inhibin as well as calretinin, indicative of limited endocrine activity [19, 24, 59]. These tumors although positive for FOXL-2 lack the FOXL-2 mutation, and this finding may be a helpful diagnostic adjunct in the differential diagnosis with diffuse type adult granulosa cell tumor [70]. They also express SF-1 (adrenal 4binding protein), a nuclear transcription factor that regulates genes that are involved in steroidogenesis, development of the
gonads and adrenal glands, sexual differentiation, reproduction, and metabolism. Of interest, this gene is thought to regulate the inhibin gene, thus is expressed in cells that are also inhibin positive, but this marker has been reported to be more sensitive than inhibin in the diagnosis of sex cordstromal tumors and it is more frequently positive in this category of tumors than inhibin [71]. Sclerosing stromal tumor is a morphologically distinctive neoplasm with interesting clinical and pathological features but it is only briefly mentioned here as it is rarely functioning [72]. At first glance, this is surprising as a definitional feature of the tumor is a component of lutein cells but they usually have a degenerative appearance presumably explaining the lack of function. When “robust” lutein cells with abundant
Fig. 8 Adult granulosa cell tumor. One of many gross appearances is a solid mass which may be characterized by multiple discrete yellow nodules separated by firm white areas representative of the common background stroma of this neoplasm
Endocr Pathol Fig. 9 Adult granulosa cell tumor with bizarre nuclei. Characteristic features are seen (a), but a significant component of this tumor is characterized by bizarre nuclear atypia (b), a finding not of adverse prognostic significance
eosinophilic cytoplasm (in contrast to the more common pale vacuolated appearance) are present in abundance, as seen for example during pregnancy (Fig. 6), hormone production may be striking including even virilization [73–75]. These tumors, although usually not clinically functioning, express inhibin and calretinin [19, 24, 59]. They are also FOXL-2 positive but lack FOXL -2 mutations [63]. The so-called luteinized thecoma associated with sclerosing peritonitis (Fig. 7), although it has lutein cells, rarely is associated with estrogenic or androgenic manifestations. However, the lutein cells are typically inhibin positive in contrast to the spindle cells which show negative or only rarely show focal positive expression of this marker [76]. These tumors are also positive for FOXL2 and SF-1 [70]. Parenthetically, although sclerosing peritonitis is typically associated with this distinctive stromal neoplasm, it has been described with one granulosa cell tumor [77]. As with sclerosing stromal tumor, the rarity of function is likely related to the weak nature of the luteinization (Fig. 7b). Other rare entities in the stromal tumor category such as microcystic stromal tumor and signet ring cell stromal tumor have not
Fig. 10 Adult granulosa cell tumor. A tumor that has a background resembling a cellular fibroma is punctuated by aggregates of cells with an epithelial-like arrangement (a) and their granulosa cell nature is highlighted by strong staining for inhibin (b). A reticulin stain from another case (c) shows large areas devoid of reticulin, a finding that helps substantiate granulosa cell differentiation in a tumor with a prominent stroma
been reported to be endocrinologically active, although the possibility exists [57, 78]. However, the former often shows positivity for CD10, vimentin, and WT-1 and also has βcatenin mutations [79] but is negative for inhibin [57]. Granulosa Cell Tumors For approximately the last two decades, granulosa cell tumors have been subdivided into two categories following Dr. Scully’s appreciation circa the late 1960s that in young females these tumors often had distinctive microscopic features, leading him to designate them “juvenile granulosa cell tumor” [80]. This, of necessity, resulted in the need for a companion name for the well-known tumors that peak in the perimenopausal age group and the term “adult granulosa cell tumor” was introduced. It should be emphasized, however, that these designations are terms of convenience to capture a constellation of findings, and there is overlap between the two tumor types, some neoplasms having microscopic features of both subtypes. Furthermore, it must be noted that the classic adult
Endocr Pathol Fig. 11 Adult granulosa cell tumor. This neoplasm, in part, had a very typical pattern of regular anastomosing cords (a), but in other areas had a peculiar clear cell morphology (b), potentially leading to a broad differential diagnosis in the absence of typical granulosa cell foci
granulosa cell tumor may occur in children and young women [81] and conversely but less often the juvenile form can occur in older women [80]. Adult granulosa cell tumors (AGCT) are often associated with estrogenic manifestations with a frequency that varies but can broadly be considered seen in half to two thirds of the patients. They include postmenopausal bleeding or menstrual irregularities in younger women. In children, they, like the juvenile form, may cause isosexual pseudoprecocity. If the endometrium is evaluated pathologically, it may show endometrial hyperplasia or even low-grade endometrioid adenocarcinoma. Rarely, AGCT may be androgenic, a finding for unknown reasons disproportionally seen with cystic neoplasms. Sometimes, estrogenic and androgenic manifestations can coexist. Cystic AGCTs are also notable grossly as they may have smooth cyst linings and suggest other more Fig. 12 Juvenile granulosa cell tumor. Marked nuclear pleomorphism (a) is more common in this tumor than in the adult neoplasm. Note the helpful finding of focal follicular differentiation. Some juvenile granulosa cell tumors grow only in the form of large nodular aggregates (b)
common cystic tumors. The gross spectrum of the AGCT is wide, ranging from cystic, to solid and cystic, to solid (Fig. 8.). They may be unilocular or multilocular and not uncommonly large, 20 cm or more [82]. Inhibin, mentioned earlier as an immunohistochemical adjunct in the identification of lutein or endocrine active ovarian stromal cells, can also be used as a serum marker to monitor disease course [83]. Only a few comments will be made on the microscopic appearance of the AGCT which is remarkably varied (Figs. 9, 10, and 11). The most common is a diffuse growth of round, oval, or, less often, spindle-shaped cells that almost always is associated with minor foci of obvious epithelial patterns, most often in the form of delicate cords. In these tumors, the stroma is usually minimal to absent. Tumors in which spindled cells dominate have been referred to as “sarcomatoid” but that designation is discouraged as it may cause confusion from
Endocr Pathol Fig. 13 Juvenile granulosa cell tumor, cystic forms. One neoplasm (a) shows a cyst with a thick lining of neoplastic granulosa cells underlain by theca cells whereas another cyst has a much less conspicuous component of lining cells. In cystic juvenile granulosa cell tumors, as in the adult counterpart, degenerative changes may result in a striking pseudopapillary appearance (b)
the management viewpoint. A second common appearance has obvious epithelial arrangements, including insular and trabecular as well as anastomosing cords of granulosa cells, on a background of conspicuous but usually minor fibrothecomatous stroma. Although follicular patterns are often emphasized, they are absent in the majority of tumors and are conspicuous in only a minority. The microfollicular pattern is characterized by small, generally regular, follicles (Call– Exner bodies) that may contain eosinophilic material with nuclear debris, hyalinized basement membrane-like material, or, rarely, basophilic secretion. In our experience, Call–Exner bodies are overall uncommon. The macrofollicular pattern is even less common and is composed of large, relatively uniform follicles typically containing eosinophilic secretions. Other patterns such as “watered-silk” (parallel, thin, winding cords) and gyriform (a zigzag arrangement of cords) are at least in aggregate usually more striking than follicular patterns. A pseudopapillary pattern has been recently described [56]. On gross examination, there is often a friable appearance that may suggest a surface epithelial tumor. Under the microscope, papillae are lined by several layers of typical granulosa cells that often become detached from the surface are seen. The resultant appearance may make a papillary transitional cell carcinoma, in particular, an initial consideration in differential diagnosis. A third low-power appearance of AGCT may closely resemble either a cellular fibroma or a thecoma due to a prominent stroma but, when a minority (but >10 %) component of the tumor is composed of granulosa cells, the tumor is considered a granulosa cell tumor. Sometimes, granulosa cell elements in these tumors are best seen at the periphery. Cystic AGCTs have cysts that are usually lined by many layers of granulosa cells which may show focal follicle formation and granulosa cells may be present in the cyst walls [82]. Denudation of the cyst lining may occasionally be significant and
cause confusion with other cystic lesions of the ovary. Although granulosa cells usually have scant cytoplasm, it may be abundant and eosinophilic, resulting in a luteinized appearance [84, 85], a feature as noted below more typical of juvenile neoplasms. Nuclei of AGCT are typically pale and round, oval, or angular and are often haphazardly oriented. Nuclear grooves are common but may be relatively inconspicuous especially in tumors with a diffuse pattern or which are luteinized; nucleoli are occasionally moderately prominent, particularly in the latter. Significant pleomorphism is usually absent, but approximately 2 % of AGCTs contain cells with large, bizarre, hyperchromatic nuclei (Fig. 9b) [86] that have no adverse impact on prognosis. The mitotic rate is usually ≤2 per 10 high-power fields, but higher rates do not exclude this diagnosis. A thecomatous or fibromatous stromal component is usually present and may, as noted above, predominate and may be richly vascular. Exceptionally, hepatocytes and Leydig cells are seen but these findings have not been associated with endocrine manifestations [87, 88].
Fig. 14 Sertoli cell tumor. This neoplasm has an alveolar arrangement with some fibrous septa and occasionally, as in the testis, this can result in confusion with germinoma, particularly if lymphocytes are present
Endocr Pathol Table 3 Androgenic tumors 1. Sertoli and Sertoli–Leydig cell tumor 2. Granulosa cell tumor (particularly when cystic) 3. Stromal tumors with lutein cells 4. Leydig (hilus) cell tumor 5. Steroid cell tumor, NOS 6. Tumors with functioning stroma 7. Gonadoblastoma
We restrict comments on the differential diagnosis of AGCT to one important tumor, small cell carcinoma of the hypercalcemic type, as this tumor, before being characterized, was likely misdiagnosed as AGCT because both tumors may have follicles and cells with scant cytoplasm. However, there are other morphologic features that differ between these two tumors including lack of grooves, high mitotic rate, extensive necrosis, and extension outside the ovary in approximatelytwo third of small cell carcinomas of the hypercalcemic type [89]. Furthermore, inhibin is a useful marker in the diagnosis of AGCT and is negative in small cell carcinoma of the hypercalcemic type [19, 90]. However, of note, some AGCTs may be inhibin negative. A recurrent somatic point mutation (402C→G) in FOXL -2 has been described in almost all AGCTs [91], and these tumors as mentioned earlier are FOXL-2 positive by immunohistochemistry [63]. They also express inhibin, calretinin, WT-1 and SF1 and not infrequently CD99 [24, 59, 71, 92, 93]. Although, a known entity now for several decades, the juvenile granulosa cell tumor (JGCT) merits some emphasis here as it is often functioning and issues in differential diagnosis remain common. The JGCT occurs in the first two decades in about 80 % of cases and most of the remainder
Fig. 15 Sertoli–Leydig cell tumor with heterologous elements. At low power (a), the typical dark blue lobules of Sertoli cells are associated with aggregates of Leydig cells with conspicuous eosinophilic cytoplasm. The middle of the illustration shows cords of Sertoli cells in a background of conspicuous stroma, and the bottom shows heterologous mucinous epithelium, seen at higher power in (b)
prior to 30 years. The young age distribution results in many patients being pre-menarchal and estrogen produced by the tumor typically results in a dramatic clinical presentation with isosexual pseudoprecocity [80]. Rarely, androgenic manifestations may occur, an association with cystic tumors again being evident [82]. Like AGCT, the tumors are typically unilateral and stage I at diagnosis. The only clinical difference apparent to date is lack of late recurrences often seen in patients with AGCT, and a tendency of the rare malignant JGCT to recur early [80]. The spectrum of gross appearances is similar to that of the AGCT, and their microscopic spectrum is almost as varied (Figs. 12 and 13). Certain specific microscopic differences set this neoplasm apart. The first is the more immature mitotically active (including atypical forms) nature of the cells which typically lack nuclear grooves and in up to 15 % of cases are strikingly pleomorphic (Fig. 12a) [80]. As more experience accumulated other differences became apparent, specifically, abundant cytoplasm, generally eosinophilic, and an irregular follicular architecture, follicles being variable in both size and shape. Other differences include a nodular architecture (Fig. 12b), in which some of the nodules occasionally may show marked sclerosis as well as a basophilic background. The variability in the aforementioned features results in a varied differential diagnosis, including yolk sac tumor, the coma (uncommon
