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Endocrine Pathology of the Ovary

In Tribute to Robert E Scully, MD

Esther Oliva &Robert H. Young

Published online: 14 January 2014# 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 sad-

ness, 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. Scullys 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 greatinterest to him.

As is usually the case, it is hard, if not impossible, to

improve on Dr. Scullys 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

endocrine manifestations, the fascinating phenomenon of

ovarian tumors with functioning stroma (Table1), a concept

Dr. Morris and Dr. Scully had introduced in a review article ayear before their book was published [3], and finally, and

briefly, paraendocrine disorders. Dr. Scullys interest in endo-

crine 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 [715] and wrote one of the last comprehensive

reviews on functioning stroma in 1987 [16]. Dr. Scully em-

phasized traditional pathology, but his curious mind was al-ways interested in new techniques in a balanced way. Indeed,

as soon as immunohistochemistry became available, he ex-

plored its use and was one of the first to write about it

regarding ovarian tumors in both peer-reviewed articles

[1720] and in a review[21].

Non-neoplastic Lesions

This category (Table2) 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 com-

ponent of lutein cells placing the process in the category of

stromal hyperthecosis. Before the advent of immunohisto-

chemistry, 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

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]

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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 histologi-

cally and histochemically abnormal cells. These findings par-

allel 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 endometrialhyperplasia) 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 [2527]. In some in-

stances, 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 hyperthecosismay 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

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 reason-able 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 associ-

ated 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 some-

times associated with menstrual irregularities presumptivelydue 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 his-

tologic findings in isolation are not diagnostic. Of interest, the

granulosa cells lining follicles in PCOD are negative for-

inhibin and positive for-subunits. In contrast, the hyperplas-

tic theca cells exhibit distinct positivity for all inhibin subunits

[34]. They also produce excess activin or insufficient

Table 1 Outlinecategories of functioning ovarian lesions

1. Non-neoplastic lesions

2. Thecoma

3. Other stromal lesions

4. Granulosa cell tumors

5. Sertoli and SertoliLeydig cell tumors

6. Sex cord tumor with annular tubules

7. Miscellaneous other neoplasms with endocrine function

8. Ovarian tumors with functioning stroma

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. Atleft

are portions of the title pages of

Dr. Scullys original description

and his later study of 74 cases

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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 estro-

gen 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 bilat-

eral, are a component of the McCuneAlbright syndrome,

characterized by the triad of polyostotic fibrous dysplasia,

caf-au-lait skin pigmentation, and precocious puberty [39]

due to post-zygotic activating mutations of arginine 201 in the

guaninenucleotide-binding protein (G protein) -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

[41]. A variant of follicle cyst, so-called large follicle cyst of

pregnancy and the puerperium is, enigmatically, not associat-

ed with endocrine function. Although the pathogenesis of

these cysts is unknown, high levels of human chorionic go-

nadotropin stimulation probably play an important role in their

development [4244]. 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 func-

tioning 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 [4550]. 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 in-

variably bilateral in contrast to pregnancy luteoma (bilateral

only in up to 40 %) [51,52]. The morphology of pregnancyluteoma 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

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

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

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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 areless often associated with pelvic symptomatology due to their

smaller size (average 7 cm). They are typically solid, lobulat-

ed, and yellow to white. Microscopic examination shows

sheets and nodules of pale graycells with ill-defined cyto-

plasmic 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 typi-

cally positive for inhibin [19], a 32-kDa heterodimeric glyco-

protein hormone composed of an- and a-subunits that innormal conditions is secreted by ovarian granulosa cells.

Inhibin is also produced by testicular Sertoli cells, and extra-

gonadal 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 follicle-

stimulating hormone secretion by the pituitary gland. Thus,

inhibin acts as a modulator of folliculogenesis [9]. These

tumors are also typically positive for calretinin, a more sensi-

tive 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 calciumions 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 de-

velopment and it is typically expressed in adult and juvenile

granulosa cell tumors. This is a sensitive marker of sex cord-

stromal 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. 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

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

Fig. 3 Pregnancy luteoma. Follicle-like spaces containing colloid-like

material are relatively common in this entity

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difficulty of the differential diagnosis of thecoma versus gran-

ulosa cell tumor in some cases. Of note, and although unre-

lated to endocrine manifestations, consistent numerical chro-

mosomal aberrations have been described in 21 of 29 ovarian

tumors in the thecomafibroma group, trisomy or tetrasomy

12 being most common [65].

Other Stromal Tumors

Although fibromas are conventionally considered non-

functioning, 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 ig-

nores 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 diagnos-

tic adjunct in the differential diagnosis with diffuse type adult

granulosa cell tumor [70]. They also express SF-1 (adrenal 4-

binding protein), a nuclear transcription factor that regulates

genes that are involved in steroidogenesis, development of the

gonads and adrenal glands, sexual differentiation, reproduc-

tion, 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 cord-

stromal 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. 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 amicrocysticappearance (c). A

representative example of the

sclerosing peritonitis of this entity

is seen in d

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

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eosinophilic cytoplasm (in contrast to the more common pale

vacuolated appearance) are present in abundance, as seen forexample during pregnancy (Fig.6), hormone production may

be striking including even virilization [7375]. 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), al-

though 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

been reported to be endocrinologically active, although the

possibility exists [57,78]. However, the former often showspositivity for CD10, vimentin, and WT-1 and also has -

catenin 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.

Scullys appreciation circa the late 1960s that in young fe-

males 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 perimeno-

pausal 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 constella-

tion 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

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


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

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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 endo-

metrial hyperplasia or even low-grade endometrioid adeno-

carcinoma. Rarely, AGCT may be androgenic, a finding for

unknown reasons disproportionally seen with cystic neo-plasms. Sometimes, estrogenic and androgenic manifestations

can coexist. Cystic AGCTs are also notable grossly as they

may have smooth cyst linings and suggest other more

common cystic tumors. The gross spectrum of the AGCT iswide, 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, and11). 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 stromais 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


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

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 nodularaggregates (b)

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the management viewpoint. A second common appearance

has obvious epithelial arrangements, including insular andtrabecular as well as anastomosing cords of granulosa cells,

on a background of conspicuous but usually minor

fibrothecomatous stroma. Although follicular patterns are of-

ten 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, CallExner

bodies are overall uncommon. The macrofollicular pattern is

even less common and is composed of large, relatively uni-

form 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 pat-

terns. 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 micro-

scope, papillae are lined by several layers of typical granu-

losa cells that often become detached from the surface are

seen. The resultant appearance may make a papillary tran-

sitional cell carcinoma, in particular, an initial consider-

ation in differential diagnosis.

A third low-power appearance of AGCT may closely re-

semble either a cellular fibroma or a thecoma due to a prom-

inent stroma but, when a minority (but >10 %) component of

the tumor is composed of granulosa cells, the tumor is con-

sidered 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]. Denu-

dation of the cyst lining may occasionally be significant and

cause confusion with other cystic lesions of the ovary. Al-

though granulosa cells usually have scant cytoplasm, it maybe abundant and eosinophilic, resulting in a luteinized appear-

ance [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 inconspic-

uous 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 usually2

per 10 high-power fields, but higher rates do not exclude this

diagnosis. A thecomatous or fibromatous stromal compo-

nent is usually present and may, as noted above, pre-

dominate and may be richly vascular. Exceptionally, he-

patocytes and Leydig cells are seen but these findings

have not been associated with endocrine manifestations

[87, 88].

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 adultcounterpart, degenerative changes

may result in a striking

pseudopapillary appearance (b)

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

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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 hyper-

calcemic type [19,90]. However, of note, some AGCTs may

be inhibin negative. A recurrent somatic point mutation

(402CG) 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 diag-

nosis remain common. The JGCT occurs in the first two

decades in about 80 % of cases and most of the remainder

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 manifes-

tations 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 inpatients 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 cy-

toplasm, generally eosinophilic, and an irregular follic-ular architecture, follicles being variable in both size

and shape. Other differences include a nodular architec-

ture (Fig. 12b), in which some of the nodules occasion-

ally may show marked sclerosis as well as a basophilic

background. The variability in the aforementioned fea-

tures results in a varied differential diagnosis, including

yolk sac tumor, the coma (uncommon

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tumors are subclassified into well, intermediate, and poorly

differentiated depending largely on the degree of tubular

(Sertoli) differentiation. Although in general the Sertoli tu-

bules have a characteristic morphology, they may show some

variation that may be confusing, particularly when

endometrioid-like [109]. There are some clinical and gross

differences related to morphologic variants, perhaps the most

important being SLCT with a retiform appearance [103] oc-

curring on average a decade earlier. As these tumors are less

often androgenic than the other subtypes, and have an appear-

ance that is often unfamiliar to the pathologist, they are par-

ticularly apt to be misdiagnosed. These tumors often exhibit

polypoid grape-like excrescences or have a soft spongy

consistency [110]. They are typically composed microscopi-

cally of slit-like (retiform) branching tubules into which pro-

trude cellular papillae or edematous fronds that may mimic to

a striking degree a serous papillary tumor. Another category

likely to cause confusion is SLCT with heterologous elements

which include most commonly intestinal-type epithelium

(Fig.15a, b) that may or not be associated with carcinoid

and less often rhabdomyosarcoma, chondrosarcoma, or

both. Heterologous mesenchymal elements tend to be seen

in poorly differentiated tumors while endodermal differentia-

tion occurs most frequently in SLCT of intermediate differen-

tiation [103,110117].

Given the young age of many patients with SLCTs, and for

that matter some with either form of GCT, it is obvious that an

occasional tumor will be discovered in a patient who is preg-

nant. In this situation, the tumors may be particularly difficult

to diagnose due to changes in their morphology apparently

due to pregnancy. Most challenging is the tendency to show

abundant intercellular edema as well as increased number of

Leydig cells or lutein cells as the case may be [118]. The

edema effaces the typical architecture of these tumors and

additionally imparts a loose appearance reminiscent in some

cases of a reticular pattern of a yolk sac tumor. Further

confusion may be caused when, as is occasional, the SLCT

is associated with elevation of serum -fetoprotein levels

[116, 119125]. However, elevations are rarely as high as

seen with yolk sac tumor and judicious sampling and aware-

ness of this pitfall should enable correct diagnosis. As with

JGCT, the morphologic diversity of SLCT results in a broad

differential diagnosis ranging from endometrioid carcinoma to

yolk sac tumor to malignant mixed mesodermal tumor (when

mesenchymal heterologous elements present) to teratoma

(when endodermal heterologous elements present).

Inhibin may be used to confirm the diagnosis of Sertoli cell

tumor or SLCT, being particularly helpful in the former in our

experience. However, it is important to note that staining for

inhibin is always less extensive and lighter in Sertoli cells

when compared to Leydig cells. It is also important to remem-

ber that Sertoli cells can be positive for keratins and rarely for

EMA, thus a panel of antibodies that include inhibin and

EMA, is helpful. Other markers that can be used include

Table 4 Miscellaneous other neoplasms with endocrine function, i.e.,

non sex-cord-stromal tumors with endocrine activity unrelated to stromal

luteinization

1. Steroid cell tumors (includes Leydig cell tumor) (usually androgenic)

2. Struma ovarii (thyroid hyperfunction)

3. Carcinoid tumors (carcinoid syndrome )

4. Mucinous tumors (ZollingerEllison syndrome)

5. Steroid cell tumorspituitary adenoma in dermoid(Cushings syndrome)

6. Pituitary adenoma in dermoid (hyperprolactinemia)

Table 5 Categories of ovarian tumors with functioning stroma

1. Tumors with syncytiotrophoblast cells

2. During pregnancy

3. Idiopathic

Primary and metastatic mucinous tumors

Miscellaneous other tumors

Rete cystadenoma and monodermal teratoma

(luteinization usually peripheral)

Fig. 18 Dysgerminoma with syncytiotrophoblast giant cells. Although

not seen in this illustration, the giant cells frequently induce luteinization

of the stroma which may lead to endocrine manifestations

Fig. 19 Mucinous cystadenoma with stromal luteinization. Mucinous

tumors are associated with this phenomenon more often than other

primary ovarian neoplasms

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calretinin (positivity not related to hormonal function), WT-1,

and SF1. The latter seems to be a very specific marker of sex

cord differentiation [19,24,31,59,71,9499]. Approximate-

ly 50 % of SertoliLeydig cell tumors have been recently

reported to express FOXL2, and only rarely are associatedwithFOXL2 mutations [63,126].

Sex Cord Tumor with Annular Tubules

This is an unusual tumor (Fig. 16a) that may be associated

with PeutzJeghers syndrome [127] in which instance it is

typically bilateral, multiple, small, and non-functioning.

When unassociated with the syndrome, they are typically

unilateral and grossly visible, and 40 % are associated with

some evidence of estrogen production [128] and occasional

tumors have produced progesterone [129]. The latter is a rare

manifestation of ovarian tumors overall and sex cord tumor

with annular tubules (SCTAT) is the neoplasm most common-

ly associated with it [130]. The non-PeutzJeghers associated

tumors may be grossly cystic, and this may also be noted at the

microscopic level (Fig.16b).

Miscellaneous Other Neoplasms with Endocrine Function

Steroid Cell Tumor

This category has traditionally included Leydig cell tumor,

stromal luteoma, and steroid cell tumor, not otherwise speci-

fied (NOS). As noted earlier, the upcoming WHO classifica-

tion no longer recognizes stromal luteoma as a separate entity

[28]. Nonetheless, it is of note that in a series on stromal

luteomas, the tumors were most often associated with estro-

genic manifestations in postmenopausal patients [131] where-

as other steroid cell tumors, when functioning, are more often

androgenic, often occurring in younger patients.

Leydig cell tumors are typically androgenic although usu-

ally not to the degree present in SLCTs and not with such adramatic rapid onset. They usually occur in postmenopausal

patients (mean age 63 years) and they are typically small

(Fig. 17a) and located in the hilus. Although technically

crystals of Reinke should ideally be seen, the diagnosis can

be made in their absence when a variety of other morphologic

features are seen including clustering of tumor cells and

fibrinoid necrosis of vessel walls (Fig.17b)[132].

Steroid cell tumors, NOS, occur in younger patients on

average (mean age 43 years), compared to Leydig cell tumors

and are also often androgenic, sometimes causing virilization

[131]. These tumors like Leydig cell tumors are almost always

unilateral but are typically larger. In contrast to Leydig cell

tumors which usually have uniform eosinophilic cytoplasm,

steroid cell tumors, NOS, usually have, at least in part, pale

and vacuolated (lipid-rich) cytoplasm. It is also in this group

Fig. 20 Krukenberg tumor. The tubular pattern and many intervening

luteinized stromal cells may cause confusion with SertoliLeydig cell

tumor

Fig. 21 Ovarian hemangioma.

Numerous small vessels are

evident but their close apposition

and additional content of

numerous luteinized stromal cells

may result in diagnostic difficulty

(a). A CD31 stain highlights

the vascular nature of the

neoplasm (b)

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that malignant features may be seen and rare tumors have been

associated with Cushings syndrome.

These tumors in general are inhibin, calretinin, SF1, and

CD99 positive, and frequently express Melan A and androgen

receptor, and rarely may express AE 1/3 immunopositivity

[19,59,71,133136]. FOXL2 has only been evaluated in a

one study, and was not expressed in Leydig cell tumors or

stromal luteomas, but was expressed in a single steroid celltumor NOS [63].

Miscellaneous Other Neoplasms with Endocrine Function

These are listed in Table 4 and are not considered here because

of their overall rarity and lack of new information since

reviewed by Dr. Scully; the reader is referred to that compre-

hensive coverage and other reports [2,137].

Ovarian Tumors with Functioning Stroma

This is a much more common phenomenon than the rare,

albeit interesting ones listed in Table 4 and merits more

comment. It is also a phenomenon Dr. Scully first highlighted

and furthermore can cause clinical confusion in as much as

endocrine symptoms, either androgenic or estrogenic, due to

stromal luteinization in diverse tumors, may suggest the pres-

ence of an endocrine type tumor (sex cord-stromal or steroid

cell tumor) when the responsible neoplasm is in fact in a

different category. Tumors in this category can be considered

in three groups (Table 5). In the first two, it is thought thatstromal luteinization is secondary to HCG stimulation, either

due to syncytiotrophoblast cells, most often within a germ cell

tumor (Fig.18) but occasionally with other neoplasms includ-

ing carcinomas [138] or pregnancy. The greater number is

however in the idiopathic group and the mechanism is obscure

but HCG may again play a role. In a study of 100 ovarian

tumors, HCG positivity was more frequently found in those

with luteinized cells than in those with an inactive stroma [139].

However, HCH-like substances as well as other factors may

play a role in stromal activation. Among primary epithelial

tumors, there is a particular association with mucinous tumors

(Fig.19) and interestingly this association with mucinous epi-

thelium also exists with metastatic tumors, as colorectal carci-

nomas in the ovary and Krukenberg tumors (Fig. 20) frequently

show luteinization [140]. Rarely, unusual primary ovarian tu-

mors may be associated with luteinization, and this enhances

diagnostic difficulty (Fig. 21). In the majority of cases, the

lutein cells are randomly seen in the stroma but in a subset they

are distributed peripherally. For unknown reasons, a dispropor-

tionate number of these tumors have been monodermal terato-

mas, particularly struma ovarii (Fig. 22). In the one series

reported, 42 % of patients had androgenic manifestations, while

29 % had evidence of estrogenic and 4 % progestational

manifestations [10]. The second most common cause is related

to rete cysts [141]. In some of these cases, the hormone-

producing cells had crystals of Reinke, indicating a Leydig cell

nature and not surprisingly were more often associated with

androgenic manifestations than typically lutein cells [10].

Paraendocrine Disorders

In the final section of this review, we briefly note a few of the

uncommon but fascinating tumors of different types that may

be associated with hormone production of various types, the

reason in most being unknown.

Fig. 22 Struma ovarii. This neoplasm is associated with a thick band of

lutein cells at its periphery

Fig. 23 Small cell carcinoma of hypercalcemic type. Typical small cells

with scant cytoplasm surround a follicle, the latter a helpful diagnostic

feature in many cases

Table 6 Paraendocrine disorders

1. Hypercalcemia

2. ACTH production and Cushings

syndrome

3. hCG production

4. Hypoglycemia

5. Renin production

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We first consider hypercalcemia because among the tumors

responsible for it is the intriguing small cell carcinoma of the

hypercalcemic type (Fig. 23). Indeed, it is comfortably the

ovarian tumor that exhibits this phenomenon most often [142]

and furthermore represents one of Dr. Scullys most astute

original observations. He gradually became aware of the

entity when he accrued cases of undifferentiated carcinoma

in young women, itself uncommon, and was further struck bythe fact the carcinomas had a small cell morphology contrast-

ing with the typical large cell morphology of undifferentiated

carcinoma in general. When the first 11 cases all had hyper-

calcemia clearly related to the neoplasm, he knew he had

come across a distinctive tumor. In retrospect, designating this

tumor small cell carcinoma is not ideal as the name may cause

confusion with the better known small cell carcinoma of

pulmonary type, an unrelated neoplasm. Additionally, as ex-

perience with the small cell carcinoma of the hypercalcemic

type has expanded, many tumors have been encountered in

which the cells are large with abundant eosinophilic cyto-

plasm [89]. This is the ovarian tumor most often associatedwith paraendocrine hypercalcemia, especially in young wom-

en. The underlying mechanism of the hypercalcemia in these

tumors is not well understood. Elevated serum calcium levels

are typically associated with normal parathormone (PTH)

serum levels and phosphate levels and occur in the absence

of bone metastases. In general, tumors are PTH negative

except in the series reported by Aguirre and colleagues where

one patient with elevated serum levels had scattered PTH-

positive cells in the tumor and in the series reported by Abeler

and colleagues where two patients had elevated PTH serum

levels and three of five tumors had PTH-positive cells [143,

144]. Parathormone-related peptide (PTHrp) is a hormone

closely related to PTH with autocrine and paracrine functions,

which binds to PTH receptors in bone and kidney. The gene

that encodes PTHrp is on the short arm of chromosome 12, in

a position homologous to the location of the PTH gene on

chromosome 11. As this substance has been isolated from

malignant tumors associated with hypercalcemia, it has been

postulated as a source of the hypercalcemia in these cases;

however, no genetic alterations have been reported on the

short arm of chromosome 11 [145]. Several authors found

PTHrp staining in tumor cells in 8 O-SCCHTs [146148].

However, the presence or absence of PTHrp staining in tu-

mors does not correlate with the patients serum calcium levels

[148]. The highly malignant nature of the tumor, apparent

from the outset, sadly remains with little or no progress from

the therapeutic point of view. The hypercalcemia itself only

rarely causes clinical manifestations. The only other ovarian

tumor associated with hypercalcemia with any frequency is

clear cell carcinoma, the reason again being unknown.

ACTH production has been seen with assorted ovarian

tumors rarely, no symptoms often resulting. Dramatic cases

of Cushings syndrome have been seen, mostly with steroid

cell tumors, but also with a few pituitary adenomas within a

dermoid cyst [2,149] and one carcinoid tumor [150]. Other

paraendocrine manifestations that have been described are

hypoglycemia and renin production (Table 6). The former

has been associated with diverse lesions whereas renin pro-

duction is most typically seen with Sertoli cell tumors [151].

Concluding Remarks

Although we may be biased due to our own interests, the

already numerous fascinating aspects of ovarian tumors relat-

ed to their morphology are only enhanced by the additional

pre sen ce in a mea sur able number of cas es of var iou s

endocrine/paraendocrine abnormalities which can make indi-

vidual cases as, or more, clinically interesting than they are

pathologically. This brief review presents an update on this

topic. Our knowledge of the area is largely based on what was

taught us over the years by our mentor Dr. Robert E Scullywhose teachings remain with us everyday and whose contri-

butions to ovarian pathology are unlikely to be surpassed.

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