Hormone-producing tumors ofthe ovaryG Olt and R MortelMilton S Hershey Medical Center, Penn State University School of Medicine,Hershey, Pennsylvania 17033, USA

(Requests for offprints should be addressed to G Olt)

IntroductionHormone-producing tumors of the ovary are

extremely uncommon and are thus unfamiliar tomost practicing gynecologists. Because of this itwould seem ideal to organize this review bypresenting signs and symptoms. Unfortunately,patients may have similar tumors but very differentclinical manifestations depending on their age.Furthermore, many tumors may produce eitherestrogens or androgens. Therefore, for clarity, we

have chosen to organize the review by histo-pathology, placing all tumors into either sex cord\x=req-\stromal or germ cell classification. A summaryorganized by tumor type is presented in Table 1 andby reproductive status and presentation in Table 2.

Diagnosis of hormone-secreting tumors isusually straightforward as most ovarian masses can

be palpated during pelvic examination. Additionally,vaginal ultrasound can be very helpful in identifyingvery small, non-palpable ovarian masses. For extra\x=req-\ovarian masses, computed tomography or magneticresonance imaging can detect very small lesions.Rarely, ovarian tumors such as hilus cell tumors maybe undetectable. In these very rare instances, ovarianvein catheterization with measurement of selectivevenous samples has been reported to be of benefit.However, this procedure requires great expertise tobe successful and should rarely be necessary.

Sex cord-stromal tumorsThis category of ovarian neoplasms includes tumors

containing granulosa cells, theca cells, Sertoli cells,Leydig cells, or ovarian stromal cells singly or in

combination. They account for, in total, 8% ofovarian tumors. However, those that producehormonal manifestations represent less than one-halfof this group. The most common hormonally activesex cord-stromal tumors in decreasing order offrequency are granulosa cell tumors, thecomas,Sertoli cell tumors, and Sertoli-Leydig cell tumors.

Granulosa cell tumorsGranulosa cell tumors of the ovary are uncommon,comprising 1-2% of ovarian neoplasms. Althoughmost patients are diagnosed at an early stage, eitherearly or late recurrences can occur and, therefore,granulosa cell tumors are considered to represent a

low grade malignancy. Granulosa cell tumors foundin young women tend to recur within several yearsfollowing diagnosis while recurrences in olderpatients may be found 10-20 years later. Because oftheir notable differences in behavior and histology,these tumors are frequently subdivided into adult andjuvenile categories. The adult form is much more

common, representing 95% of all granulosa celltumors. Although juvenile granulosa cell tumors are

usually found in young women and children theymay also rarely occur in older patients.

Adult granulosa cell tumorsAdult granulosa cell tumors are the most common

estrogen-secreting ovarian neoplasms. They occur

most frequently in peri- or postmenopausal femaleswith a mean age at presentation of 50 years and a

usual range of 40-70 years of age (Pankratz et al.1978). Thus, approximately one-half of patients are

premenopausal and one-half are postmenopausal. As

( a

2

8io

II¡2 "5

o

il2.10. 5)

lì

O

3

3(03

o

o> c.£ o

-Q 'S

CDO)O

o >^ CU

CD O

fi3 id

cu enQ. 2o c|.»cu ->en cu

Q- Q.1 ^o jSO- -O

i*o _>-

o

c

om

¡DO

o

ó

cu o > <-c =13 cu-> o

o ¿c —

"5c/) o

CÏI

coZJo

.ro H cill€ o- § 1*1topIli.2 ro

> '-

o

¡r3

. >

en c 4=cu en 2 >· CD

< ¡5

c:S) S»S c?S tfl< cu

3 a

cd o

/-, P (-1

CDQ_

UL

2 ES ¡co'ÎS o

I

CDCD

CC

I

CDO)O

-C

cSg:-o r-~

S¿-£ enE -g-* CD

CD GCU CDO- "O

3

o t:'5 CU

û- J=

"OS

E

CDet

I

1ra

8igen<

9 <=-c oO Ol

< >

CD -o

Z ro -o

ot5

X W c3 o

Table 2 Hormone-producing ovarian tumors by reproductive age and symptomatology.

Reproductive stage Symptom Tumor type

Prepubertal

Reproductive

Postmenopausal

VirilizingFeminizingDysfunctional uterine bleedingVirilizing

Postmenopausal bleeding

Virilizing

Sertoli-Leydig cell tumorJuvenile granulosa cell tumorGranulosa cell tumorSertoli-Leydig cell tumorHilus cell tumorSertoli cell tumorGranulosa cell tumor (rarely)Granulosa cell tumorThecomaHilus cell tumor

would be expected, the symptoms of estrogenoverproduction differ depending on the patients'menstrual status.

Postmenopausal women with granulosa celltumors most frequently complain of vaginalbleeding. Conversely, premenopausal patients most

commonly describe menorrhagia, irregular men¬

struation, or amenorrhea (Fox & Agrawal 1975,Evans et al. 1980). Endometrial findings in patientswith granulosa cell tumors are variable, and maydemonstrate proliferation, atrophy, hyperplasia, or

adenocarcinoma. The reported incidence of co¬

existing endometrial adenocarcinoma ranges from 5to 25% (Stenwig et al. 1979, Evans et al. 1980).However, when endometrium from all patientsincluded in a series was evaluated utilizing strictcriteria for the diagnosis of endometrial adeno¬carcinoma, the incidence was less than 5% (Stenwiget al. 1979). It appears that carcinoma is about twiceas common in postmenopausal patients (Gusberg &Kardon 1967). Additionally, as many as 50% ofpatients with granulosa cell tumors may haveassociated endometrial hyperplasia.

Non-specific findings are similar to those ofpatients with other ovarian malignancies. Abdominalbloating, distension, or pain are frequently noted.Occasionally, patients may complain of breasttenderness. Interestingly, patients who present withfatigue or weight loss have a very high disease-associated mortality within the first year of diagnosis(Pankratz etal. 1978). Pelvic examination will reveala palpable mass in 80-85% of patients. Ascites ispresent in roughly 10% and rarely a pleural effusionis found. On occasion, cystic granulosa cell tumors

may rupture resulting in an acute abdomen secondaryto hemoperitoneum or the enlarged adnexa may torse

(Fox efe Agrawal 1975, Bjorkholm <fe Pettersson1980, Young efe Scully 1987 ).

Rarely, androgen-secreting granulosa cell tumorshave been reported, accounting for less than 3%of adult granulosa cell tumors (Nakashima et al.1984). The majority of these patients exhibitmasculinization, most frequently clitoromegaly andhirsutism and less frequently deepening of the voice,male escutcheon, and male pattern balding. Mostpatients with androgenic granulosa cell tumors haveelevated serum testosterone levels.

At exploration, the appearance of granulosa celltumors is quite variable. The average size is about12 cm in diameter but ranges from tumors whichnearly fill the entire abdomen to those onlymicroscopically detectable (Dockerty <fe MacCarty1939, Fox & Agrawal 1975). Only rarely are bothovaries involved with greater than 95% noted to beunilateral and equally distributed between bothovaries. Tumors may be predominately cystic, solid,or mixed. Interestingly, androgenic granulosa celltumors are more frequently associated with pre¬dominately cystic tumors (Nakashima et al. 1984).When cut, they range from yellow to gray dependingon intracellular lipid content and may be soft or firmin consistency depending on the amount offibrothecomatous stroma present (Young & Scully1987a). The most frequent finding is a mixed solidand cystic tumor with the cystic cavities filled withhemorrhage.

Microscopic evaluation of well-differentiatedadult granulosa cell tumors may show numerous

patterns, including microfollicular, macrofollicular,insular, trabecular, solid-tubular, and hollow-tubular(Young efe Scully 1987a). Call-Exner bodies, whichare small cavities containing eosinophilic fluid and

resembling developing ovarian follicles, are

frequently present. Watered-silk, gyriform, or diffusepatterns are more often seen in less well-differentiated tumors. Nuclei are usually oval, pale,and grooved (coffee bean appearance) which aids indifferentiating granulosa cell tumors fromundifferentiated carcinomas, adenocarcinomas, andcarcinoids. It is important to identify these tumorscorrectly as their prognosis and treatment differgreatly.

Surgical treatment of patients with adultgranulosa cell tumors is similar to that undertaken forother ovarian cancers. The FIGO stagingclassification for epithelial ovarian cancers iscurrently applied to these tumors as well and ishelpful since stage is one of the most importantprognostic factors. However, although surgery is theprimary therapy for granulosa cell tumors, the extentof surgery required remains controversial. Becausemost patients are stage I and bilateral ovarianinvolvement is very rare, it seems reasonable topreserve uninvolved organs in women with unilateralovarian disease and who desire to maintainreproductive potential. Several large series haveretrospectively compared survival of patientsundergoing bilateral versus unilateral adnexectomywith conflicting results (Anderson et al. 1971,Pankratz et al. 1978, Evans et al. 1980, Ohel et al.1983). Unfortunately, accurate staging was notaccomplished in all patients and thus the role ofovarian preservation remains undefined. Because ofthe rarity of these tumors and their proclivity for laterecurrences, a prospective randomized trialcomparing unilateral versus bilateral adnexectomy isunlikely. If a hysterectomy is not performed, a

dilation and curettage should be undertaken to ruleout co-existing endometrial pathology. Patients withadvanced disease or those who are peri- or

postmenopausal should undergo bilateral salpingo-oophorectomy.

Radiotherapy has been utilized as adjunctivetherapy and to treat recurrences with mixed results.In a series of 61 patients, 48 patients receivedpostoperative irradiation with a slight but notstatistically significant improvement in survival(Pankratz et al. 1978). These patients varied in theirsurgical treatment as well as extent of radiotherapyand thus the effect of adjuvant irradiation is unclear.In another study, patients who received postoperativeradiotherapy had a higher recurrence rate (Evans et

al. 1980). Therefore there are presently few data tosupport the use of adjuvant postoperative radio¬therapy. Radiotherapy for recurrent disease has beenhelpful but reports of long-term responses are

unusual. Patients who are considered for radiationtherapy should be selected for sites of recurrence as

well as their ability to undergo other treatmentmodalities, such as surgery or chemotherapy. Themajor role for the use of radiotherapy of recurrentdisease may be in the palliation of symptoms.

Chemotherapy is usually reserved for patientswith advanced or recurrent disease. Completeresponses have been reported with single agentCytoxan or melphalan or with combinations such as

cisplatin, Adriamycin, and Cytoxan or vincristine,Adriamycin, and Cytoxan. However, response isusually of short duration. The GynecologicOncology Group studied actinomycin D, vincristine,and Cytoxan and found a 20% partial response rate(Slayton et al. 1985). More recently greater successhas been achieved with vincristine, bleomycin, andcisplatin or etoposide, bleomycin, and cisplatin.There is no evidence to support the use of adjuvantchemotherapy to prevent recurrence.

Several tumor markers, urinary and serum

estrogen, serum inhibin, and follicle regulatoryprotein, have been evaluated in patients withgranulosa cell tumors. Estradiol levels are elevated insome patients and levels usually fluctuate in relationto disease. However, the lack of sensitivity and widerange of normal values limit its clinical use. Further¬more, the production of estradiol by granulosa cellsrequires the production of testosterone by adjacenttheca cells which may be sparse in some granulosacell tumors and are always absent in métastases.More recently, inhibin, a peptide hormone which isproduced by granulosa cells, has been studied in thesera of patients with primary and recurrent disease(Lappohn et al. 1989, Jobling et al. 1993). Inhibinlevels appear to be elevated in most patients withgranulosa cell tumors and levels correlate well withdisease status. Furthermore, elevations of serumlevels have been reported 2 years prior to clinicaldetection of recurrence. In a similar fashion, follicleregulatory protein may be helpful as well, althoughfew data are presently available (Rodgers et al.1989).

duvenile granulosa cell tumors

Juvenile granulosa cell tumors are a histologicalsubtype which are most frequently found in youngwomen and children. Although they are occasionallydiagnosed in postmenopausal patients, 97% occur inthe first three decades (Young et al. 1984). Age at thetime of diagnosis ranges from newborn to the seventhdecade.

Because of the marked developmental differ¬ences in females of this age range, presentingsymptoms are dependent on the age and menstrualstatus of the individual. Roughly one-third of alljuvenile granulosa cell tumors occur prior to the ageof 8 years and 80% of these patients manifestsymptoms of sexual pseudoprecocity includinguterine bleeding, vaginal discharge, or the develop¬ment of secondary sex characteristics (Young et al.1984). Following puberty, abdomino-pelvic masses,pain or swelling are the usual presenting symptoms.Menstrual abnormalities such as menometrorrhagiaor amenorrhea may occur as well. Juvenile granulosacell tumors have, on occasion, been associated withOllier's disease (enchondromatosis) or Maffucci'ssyndrome (enchondromatosis and skin hemangio-matosis) (Tamimi <fe Bolen 1984, Young etal. 1984).Androgenic manifestations, primarily clitoromegaly,may be present; however, this is a rare findingpresent in less than 5% of patients.

At exploration, juvenile granulosa cell tumorsmay be cystic, solid, or mixed. Tumors are rarelybilateral and are usually confined to the ovary butmay be adherent to the omentum, bowel or pelvicstructures. The surface is usually smooth and sizeranges from 5 to 30 cm in diameter. Ascites is rare,but when present may be bloody. When cut, solidportions of the tumor are tan or gray. Cysts are filledwith serous or sero-sanguinous fluid and areas ofhemorrhage or necrosis may be present.

Microscopically, juvenile granulosa cell tumorsexhibit solid areas of granulosa and theca cells withintermixed mucin containing follicles of varioussizes. However, Call-Exner bodies (uniform micro-follicles) are rare (Young et al. 1984). The theca cellswhich are present often appear luteinized. Granulosacells have abundant eosinophilic cytoplasm andnuclear atypicality which is usually mild to moderatebut may be marked. Mitotic rate ranges from lessthan 1-30 mitosis/10 high power fields. Juvenilegranulosa cells are differentiated from their adult

counterparts by the abundant luteinized cytoplasmand round nuclei which lack grooves.

Treatment of juvenile granulosa cell tumors issimilar to that of the adult form. As these tumorsoften occur in young women, care should be given topreservation of contralateral adnexa and the uterus.

Chemotherapy for advanced disease is usuallybleomycin, etoposide, and cisplatin. A majority ofpatients retain their reproductive ability after suchtherapy.

Thecoma

Thecomas are estrogen-producing tumors whichcontain lipid-laden stromal cells resembling thecacells. They occur about one-third as commonly as

granulosa cell tumors and typically are found in an

older population (Bjorkholm efe Pettersson 1980).Most tumors are diagnosed between the ages of 50and 70 and uncommonly before age 30. Thecomasoccur rarely, if ever, before puberty. Because themajority of patients are postmenopausal, the mostcommon presenting complaint is postmenopausalbleeding which was reported in approximately 75%of this group (Bjorkholm & Pettersson 1980).Premenopausal patients noted irregular bleeding or

amenorrhea in 50% of cases. Other frequentcomplaints for both groups included abdominaldistension or pain.

At exploration, thecomas are usually 3-10 cm indiameter and are infrequently bilateral. The over¬

whelming majority of tumors are FIGO stage la.When sectioned, tumors appear yellow and are

usually solid with cysts and hemorrhage is rarelynoted.

Microscopic evaluation reveals oval cells withbland oval- or spindle-shaped nuclei and cytoplasmcontaining moderate to abundant amounts of lipid.Mitoses are infrequent but most tumors exhibitnotable hyaline plaques. Reticulum stainingdemonstrates extensive reticulum fibrils surroundingindividual cells in contrast to granulosa cell tumors.

Patients with thecomas are treated withabdominal hysterectomy and bilateral salpingo-oophorectomy. Because these tumors are rarely, ifever, malignant, patients who desire to maintainreproductive potential may undergo a unilateraladnexectomy.

Sertoli-Leydig cell tumors

Sertoli-Leydig cell tumors are ovarian stromaltumors which recapitulate testicular differentiationand were originally designated as arrhenoblastomasor androblastomas indicating androgen production.Because the majority of tumors are non-functioning,the descriptive designation Sertoli-Leydig cell tumoris preferable. They contain Leydig cells, Sertoli cells,fibroblasts, and occasionally heterologous elementsin varying proportions. Tumors are categorized intofour groups based on WHO guidelines: welldifferentiated, intermediate differentiation, poorlydifferentiated, and with heterologous elements(Serov et al. 1973). A fifth category, retiform, hasbeen proposed by Young <fe Scully (1983) as an aidin diagnosis.

While Sertoli-Leydig cell tumors may be foundin women of all ages, they occur most frequently inyoung women. In a series of 207 patients, with agesranging from 2 to 75 years, three-quarters of thecases were found before age 30 (Young e& Scully1985). Well-differentiated tumors occur, on average,10-15 years later than less well-differentiatedtumors.

The reported frequency of virilization associatedwith Sertoli-Leydig cell tumors is quite variable anddependent on each authors' definition. Virilization,as defined by clitoromegaly, deepening of voice or

hirsutism, occurs in approximately one-third ofpatients; however, the number of patients whopresent with complaints of masculinization issomewhat less (Roth et al. 1981, Young & Scully1985). Other common presenting complaints includeamenorrhea, pelvic mass, pelvic pain, or postmeno¬pausal bleeding. Rarely, Sertoli-Leydig cell tumorsproduce estrogenic manifestations, primarily meno-

metrorrhagia.The gross appearance of Sertoli-Leydig cell

tumors is variable and not distinct. Well-differentiated tumors usually have smooth externalsurfaces while poorly differentiated tumors are more

likely to be adherent or have ruptured preoperatively.The majority of tumors are solid and cystic but maybe completely solid or cystic. Tumors containingheterologous or retiform components are more likelyto be cystic. Nearly all tumors are unilateral (1-2%bilateral). Most range from 5 to 15 cm in diameter;however, their size tends to increase with decreasingdifferentiation (Young efe Scully 1985). It is

worthwhile to note that size alone is not an

independent prognostic factor.Microscopically, well-differentiated Sertoli-

Leydig cell tumors exhibit tubular patterns withassociated stromal tissue appearing as bands ofmature fibroblasts. Nuclear atypia is minimal or

absent and mitotic figures are rare. Crystalloids ofReinke are present in 20% of tumors (Young &Scully 1984). In tumors of intermediate and poorerdifferentiation, Sertoli and Leydig cells may exhibitvarious degrees of immaturity. Additionally, thestroma appears immature and may resemblefibrosarcoma in poorly differentiated tumors.Heterologous tumors may contain foci of intestinalepithelium, carcinoid, cartilage, or rhabdomyo-sarcoma. Young <& Scully (1983) have described a

series of Sertoli-Leydig cell tumors which containelongated branching tubules which resemble the retetestis. This retiform pattern, which is found in 15%of less well-differentiated tumors, can be frequentlymisinterpreted as endodermal sinus tumor or serous

adenocarcinoma.Surgical therapy is usually hysterectomy and

bilateral oophorectomy. However, in reproductiveage women, unilateral oophorectomy may beconsidered if the disease is limited to one ovary.Sertoli-Leydig cell tumors are of low malignantpotential with 5-year survival ranging between 70and 90%. Nearly all patients are stage I (97.5%) andpatients with advanced or recurrent disease usuallyhave poorly differentiated tumors (Young efe Scully1985). For patients with advanced or recurrentdisease, vincristine, Adriamycin, and cyclo-phosphamide combination chemotherapy hasprovided some response and is frequentlyrecommended. Radiation therapy appears to be ofbenefit, as well, in selected cases.

Sertoli cell tumorsSertoli cell tumors are neoplasms of gonadal stromalorigin made up of Sertoli cells in a tubulararrangement within a fibrous stroma and lacking a

Leydig cell component. These extremely rare

neoplasms comprise less than 5% of all Sertolistromal tumors. All patients with Sertoli cell tumorsreported to date have had unilateral disease limited tothe ovary. Sertoli cell tumors are of low malignantpotential with recurrence occurring very rarely.

The age range of patients with Sertoli cell tumorsis from 7 to 79 years with a median age of 33(Tavassoli efe Norris 1980). The majority of patients

are of reproductive age; however, roughly 10% ofpatients are either prepuberal or postmenopausal.

Prepuberal patients present with symptoms ofprecocious puberty including vaginal bleeding,breast development, and pubic hair growth. Severalcases of precocious puberty secondary to Sertoli celltumors have been found in association with Peutz-Jeghers syndrome. In one series of 28 patients, 36%of adults presented with menometrorrhagia and 10%showed evidence of virilization including hirsutism,amenorrhea, breast atrophy, clitoromegaly, anddeepening of the voice (Tavassoli <fe Norris 1980).Overall, 17 of 28 patients exhibited unusualhormonal manifestations.

Sertoli cell tumors are solid, smooth-surfacedneoplasms which are rarely adherent to other pelvicstructures. Their size varies considerably but istypically 7-10 cm in diameter. When cut, they appearfleshy and are yellow or tan in coloi.

Microscopic examination usually revealscuboidal, columnar, or round cells arranged in a

tubular pattern. Nuclei are spherical or oval withdistinct nuclear grooves and rarely demonstrateatypia. The appearance of the cytoplasm varies withthe amount of lipid present. Some cells containabundant lipid and are designated as lipid-rich Sertolicell tumors.

Hysterectomy and bilateral adnexectomy isappropriate surgical therapy for peri- andpostmenopausal patients with Sertoli cell tumors.Because of the unilaterality and low malignantpotential of these neoplasms, unilateral adnexectomymay be performed in patients who desire to maintainfertility. Limited experience in the treatment ofrecurrent disease limits recommendation of chemo or

radiation therapy.

Steroid cell tumorsSteroid cell tumors are ovarian neoplasms composedentirely of cells resembling lutein, Leydig, or adrenalcortical cells which normally secrete steroidhormones (Taylor efe Norris 1967). Previously termedlipid cell tumor and lipoid cell tumor, the preferreddesignation is steroid cell tumor (Scully 1979).

Hilus cell tumorHilus cell tumors arise from Leydig cells located inthe hilus of the ovary and are morphologicallyidentical to testicular Leydig cells. Ovarian hilar

Leydig cells are found adjacent to non-myelinatednerve fibers as well as lymphatic and vascularspaces. Hirsutism and virilization are the mostcommon manifestations associated with hilus celltumors and occur in three-quarters of patients.Occasionally, estrogenic effects are noted and one

case has been described in association with endo¬metrial carcinoma (Huang & Holaday 1970).

Most patients with hilus cell tumors present withsymptoms secondary to androgen production.Hirsutism, deepening of the voice, and male patternbalding are noted in 50-75% of patients (Dunnihoo etal. 1966). Amenorrhea occurs most frequently butpatients may also describe postmenopausal bleedingor menorrhagia suggestive of estrogenic production.Infrequently these tumors are large enough to bepalpated during pelvic examination. Ages reportedfor hilus cell tumors range from 4 to 86 with an

average age of 58 years.

At exploration, tumors are small, usually 1-5 cm

in diameter but may be as large as 15 cm. Hilus celltumors are reddish-brown to yellow in color, are

located in the hilum of the ovary and are rarelybilateral.

Microscopic examination reveals masses ofsteroid cells with abundant eosinophilic cytoplasmwith prominent lipochrome pigment (Young &Scully 1987a). Crystals of Reinke are usually presentand confirm the diagnosis.

Because only a single case of malignant hilus celltumor has been reported, hysterectomy and bilateraladnexectomy is adequate therapy. For patients whodesire to maintain reproductive potential, unilateraladnexectomy is appropriate.

Adrenal cortical-type steroid cell tumors

These extremely rare tumors are thought to arisefrom adrenal cortical nests within the ovary. Threecases of malignant ovarian steroid cell tumors havebeen reported (Marieb et al. 1983, Young <& Scully19876). All patients had symptoms of Cushing'sdisease when diagnosed as well as elevated cortisollevels. At exploration all had stage III disease whichwas resistant to cytotoxic chemotherapy and all ofthem died of disease within 2 years.

Germ cell tumors

DysgerminomaOnly very rarely are dysgerminomas associated withendocrine manifestations, primarily production ofchorionic gonadotropin. The great majority of thesetumors have choriocarcinomatous elements andvery rare examples of pure dysgerminomas con¬

taining syncytiotrophoblastic giant cells are noted. Itseems likely that the extremely rare pure dys¬germinomas which produce chorionic gonadotropinmay represent tumors which contain unidentifiedchoriocarcinomatous elements or syncytiotropho-blasts. Therefore, they are not included in thisdiscussion.

Struma ovariiStruma ovarii are considered to represent a form ofteratoma in which there is development of onlythyroid tissue. Although thyroid tissue isoccasionally present in mature cystic teratomas, thediagnosis of struma ovarii is made if thyroid tissue ispredominantly present, if thyroid tissue can berecognized macroscopically, or if the patient exhibitssymptoms of hyperthyroidism which resolvefollowing surgery. Struma ovarii are rare andrepresent only 2.7% of all mature teratomas(Gusberg efe Danforth 1944).

The typical age of patients with struma ovarii issimilar to that of mature cystic teratomas and rangesbetween 6 and 74 years (Nieminen et al. 1963).Roughly one-half of patients are less than 50 years ofage. Most patients present with an asymptomaticmass or occasionally with pain secondary to themass. Only rare patients exhibit signs ofthyrotoxicosis, however mild symptoms may beeasily overlooked. Thyrotoxicosis is estimated tooccur in 5-15% of cases of struma ovarii (Emge1940, Dalgaard efe Wetteland 1956). Interestingly,struma ovarii are occasionally associated with co¬

existing enlargement and hyperactivity of the thyroidgland, thus suggesting similar stimulatory controlmechanisms of both sites. In rare cases thyroid glandenlargement is noted following removal of thestruma ovarii.

At exploration, struma ovarii are similar inappearance to mature cystic teratoma. The surface isusually smooth and without adhesions. Most tumorsare less than 10 cm in diameter but, on occasion, maybe considerably larger, particularly if associated with

other teratomatous elements. Most struma ovarii areunilateral but the contralateral ovary may contain a

cystic teratoma with thyroid elements. When cut, thetumor is frequently composed of amber-coloredthyroid tissue and cystic areas with necrosis andhemorrhage occasionally present.

Microscopically, struma ovarii usually have theappearance of mature thyroid tissue. Acini, whichmay be quite variable in size, contain periodic-acid-Schiff's staining colloid lined by a single layer ofcolumnar epithelium (Talerman 1987). Occasionally,the appearance may resemble that of hyperactivethyroid gland or nodular adenomatous goiter. Rarely,struma ovarii are malignant and exhibit a follicularpattern or papillary carcinoma. Malignant strumaovarii are very rare and may be difficult to diagnose,particularly if well differentiated, unless there ismetastatic malignant disease present. Peritonealspread of mature thyroid tissue, termed benignstrumosis, may occur and does not representmalignancy.

The usual therapy for patients with struma ovariiis hysterectomy and bilateral adnexectomy. Inpatients for whom ovarian conservation isappropriate, unilateral adnexectomy is reasonable.Because of their rarity, little information is availableon the therapy of malignant struma ovarii. Post-operatively, whole body I (5-10 mCi) scintillationscanning may be helpful in identifying métastases. Ifmetastasis is present, therapy with I (100 mCi)may be curative.

Ovarian carcinoidPrimary carcinoids of the ovary are classified as

insular (arising from the midgut), trabecular (arisingfrom the foregut or hindgut) or mucinous. Of these,only the insular form is associated with serotoninproduction and carcinoid syndrome and thus will bediscussed. In a similar situation, strumal carcinoids,composed of thyroid tissue and carcinoid, have notbeen associated with specific clinical presentationsand are not known to produce serotonin.

Insular carcinoid occurs rarely with approxi¬mately 70 cases reported, although more cases

certainly exist. Carcinoids may be found as a com¬

ponent of mature cystic teratomas but 40% are pureinsular carcinoids (Talerman 1984). Most tumorsoccur in peri- or postmenopausal patients butreported ages range from 31 to 79 years (Scully1979).

Approximately one-third of patients with insularcarcinoid tumors exhibit signs of carcinoid syndromeprior to surgery (Robboy et al. 1975). Unlike ilealcarcinoids, ovarian carcinoid tumors may producecarcinoid syndrome without métastases because theirsecreted serotonin does not directly enter the portalsystem and is therefore not metabolized as rapidly bythe liver. Symptoms of carcinoid syndrome, such as

flushing, telangectasias, diarrhea, and bronchialconstriction resolve shortly after tumor excision.Patients without carcinoid syndrome usually havecomplaints related to a pelvic mass.

At exploration, the tumor may range in size frommicroscopic to 28 cm in diameter but most are

5-10 cm (Robboy et al. 1975). Primary ovariancarcinoid tumors are nearly always unilateral andthe presence of bilateral ovarian involvementindicates likely métastases from the small bowel.However, the ipsilateral ovary may contain a secondcystic teratoma, mucinous cystadenoma or mucinouscystadenocarcinoma (Robboy et al. 1975). Thetumor surface is usually smooth and withoutadhesions. Tumors associated with carcinoidsyndrome are frequently predominantly solid withcut surfaces appearing tan or yellow. Those notassociated with carcinoid syndrome usually havehair and sebum-containing cysts with a firm nodulein the cyst wall (Robboy et al. 1975). Largercarcinoid tumors are more likely to producecarcinoid syndrome.

Microscopically, insular carcinoids contain nestsand small acini composed of epithelial cells withabundant cytoplasm with round centrally locatedbland nuclei (Talerman 1984). Mitotic activity islow. The cytoplasm contains red or brown granulesand electron microscopy reveals neurosecretorygranules. Immunohistochemistry demonstrates thepresence of serotonin.

Treatment is usually hysterectomy and bilateraladnexectomy. If ovarian conservation is appropriate,the contralateral ovary should be carefully inspected.Malignant primary ovarian carcinoid is very rare andlittle information is available from which todetermine adequate therapy. Metastatic carcinoid hasbeen treated with cytotoxic chemotherapy with littlesuccess.

ChoriocarcinomaNon-gestational, ovarian choriocarcinoma isexceedingly rare in its pure form. Although found

more frequently in association with other germ cellelements, even mixed tumors are rare, accounting forless than 2% of germ cell tumors in children (Abelletal. 1965). This tumor has been primarily diagnosedin premenarchal children in whom a gestationalorigin could be excluded, and thus this young agegroup may be over-represented.

In premenarchal patients, symptoms of isosexualprecocious puberty are frequently noted and are dueto high levels of chorionic gonadotropin production.These patients may exhibit breast development,vaginal bleeding, or growth of axillary and pubichair. Postpubertal patients usually present withsymptoms related to their mass.

At exploration, the gross appearance of non-

gestational choriocarcinoma is non-specific. Mostcases are unilateral unless advanced disease hasresulted in metastasis to the contralateral ovary.Tumors range greatly in size but are frequently verylarge.

Microscopically, choriocarcinoma is composedof small polygonal cytotrophoblasts and large multi-nucleated syncytiotrophoblasts. The syncytiotropho-blasts are responsible for chorionic gonadotropinsecretion. Frequently, other germ cell tumorelements are present.

The treatment of non-gestational chorio¬carcinoma is primarily surgical and is usually hyster¬ectomy, bilateral salpingo-oophorectomy, andcomplete surgical staging. Some gynecologiconcologists do not perform routine pelvic and para-aortic lymphadenectomy as all patients will requireadjuvant chemotherapy. Radiation therapy has rarelybeen helpful and does not appear to play a role in themanagement of patients with these tumors. Someresponses have been noted, however, in patientstreated with vincristine, bleomycin, and cisplatin or

bleomycin, etoposide, and cisplatin. However, long-term responses are unusual and most patients withadvanced disease are not cured.

GonadoblastomaGonadoblastoma is an unusual steroid-secretingtumor made up of both germ cells and sex cord-stromal derivatives. Sex cord-stromal derivativesconsistently present are immature Sertoli or

granulosa cells. Frequently, Leydig and lutein cellsare noted as well. Germ cells are represented bydysgerminoma in 50% of cases and other germ cellmalignancies in an additional 10%. Thus, gonado-

blastoma may be thought of as an in situ tumor withinwhich germ cell tumors may develop (Scully 1970).Gonadoblastoma occurs in association with dys-genetic gonads and although patients are phenotypicfemales, most are genotypically male.

Nearly all cases of gonadoblastoma occur before30 years of age and may induce precocious puberty.Patients may or may not be virilized. Non-virilizedpatients most frequently have amenorrhea which isfrequently primary, but may be secondary. Virilizedpatients almost always have primary amenorrhea.Most gonadoblastomas are discovered incidentallyduring evaluation of primary amenorrhea. Becausethese tumors are frequently small, symptoms relatedto the mass are uncommon.

At exploration, tumors range in size frommicroscopic to 8 cm in diameter but may be muchlarger if overgrown by dysgerminoma (Talerman1987). Gonadoblastomas are solid tumors whichmay be fleshy or hard depending on the degree ofcalcification. The cut surface is usually yellow or

gray. Tumors are bilateral in at least 40% of cases

(Scully 1970). Gonadoblastoma is not malignant andthus involvement of the pelvis and abdomen bymetastatic tumor implies the presence of a malignantgerm cell component.

Microscopically, gonadoblastoma is composedof nests containing a mixture of germ cells and sex

cord derivatives surrounded by connective tissue(Talerman 1987). The sex cord derivatives areimmature Sertoli and granulosa cells. The germ cellsare larger and round and mitotic activity may bepresent. The stroma may contain cells whichresemble Leydig or lutein cells. Calcification andhyalinization are seen in most cases. In one-half ofcases there is overgrowth by dysgerminoma which issimilar in appearance to pure dysgerminoma.

Treatment is primarily surgical and consists ofremoval of the affected gonad as well as thecontralateral testis if present. If a normal-appearinguterus is present, consideration should be given forleaving it in place for potential assisted reproductionwith donor oocytes. Gonadoblastoma is notmalignant and no adjuvant therapy is indicated.Patients with overgrowth of dysgerminoma or othergerm cell tumor should be considered for adjuvanttherapy utilizing bleomycin, etoposide, and cisplatinchemotherapy.

ReferencesAbell MR, Johnson VJ efe Holtz F 1965 Ovarian neoplasms

in childhood and adolescence: Tumors of germ cellorigin. American Journal of Obstetrics and Gynecology92 1059-1081.

Anderson W, Levine A & MacMillan D 1971 Granulosa-theca tumours: Clinical and pathologic study. AmericanJournal of Obstetrics and Gynecolgy 110 32-35.

Bjorkholm E efe Pettersson F 1980 Granulosa-cell andtheca-cell tumors. Acta Obstétrica et GynecologicaScandinavica 59 361-365.

Dalgaard JB efe Wetteland 1956 Struma ovarii: A follow-up study of twenty cases. Acta Chirugia Scandinavica112 1-17.

Dockerty MB efe MacCarty WC 1939 Granulosa celltumors, with the report of a 34-lb specimen and a review.American Journal of Obstetrics and Gynecology 37425-434.

Dunnihoo D, Grieme e& Woolf R 1966 Hilar-cell tumors ofthe ovary: Report of two new cases and a review of theworld literature. Obstetrics and Gynecology 27 703-713.

Emge LA 1940 Functional and growth characteristics ofstruma ovarii. American Journal of Obstetrics andGynecology 40 738-750.

Evans AT, Gaffey TA, Malkasian GD e& Annegers JF 1980Clinicopathologic review of 118 granulosa and 82 thecacell tumors. Obstetrics and Gynecology 55 231-238.

Fox H efe Agrawal 1975 A clinicopathologic study of 92cases of granulosa cell tumor of the ovary with specialreference to the factors influencing prognosis. Cancer35 231-241.

Gusberg S efe Danforth D 1944 Clinical significance ofstruma ovarii. American Journal of Obstetrics andGynecology 48 537-542.

Gusberg SB efe Kardon 1967 Proliferative endometrialresponse to theca-granulosa cell tumors. AmericanJournal of Obstetrics and Gynecology 111 633-643.

Huang efe Holaday W 1970 An ovarian hilus-cell tumorassociated with endometrial carcinoma. AmericanJournal of Clinical Pathology 54 147-150.

Jobling T, Mamers P, Healy D, MacLachlan V, Burger HG,Quinn M, Rome R efe Day AJ 1993 A prospective studyof inhibin in granulosa cell tumors of the ovary.Gynecologic Oncology 55 285-289.

Lappohn RE, Burger HG,BoumaJ, Bangah M, KransM &de Bruijn 1989 Inhibin as a marker for granulosa-celltumors. New England Journal ofMedicine 321790-793.

Marieb N, Spangler S, Kashgarian, Heimann A, SchwartzM efe Schwartz 1983 Cushing's syndrome secondaryto ectopie cortisol production by an ovarian carcinoma.Journal of Clinical Endocrinology and Metabolism 57737-740.

Nakashima N, Young R efe Scully R 1984 Androgenicgranulosa cell tumors of the ovary. Archives ofPathology and Laboratory Medicine 108 786-791.

Nieminen U, Von Numers C & Windholm O 1963 Strumaovarii. Acta Obstétrica et Gynecologica Scandinavica42 399-424.

Ohel G, Kaneti H efe Schenker J 1983 Granulosa cell tumorsin Israel: A study of 172 cases. Gynecologic Oncology15 278-286.

Pankratz E, Boyes DA, White GW, Galliford BW, FaireyRN e& Benedet JL 1978 Granulosa cell tumors. Aclinical review of 61 cases. Obstetrics and Gynecology52 718-723.

Robboy SJ, Norris HJ efe Scully RE 1975 Insular carcinoidprimary in the ovary: A clinicopathologic analysis of 48cases. Cancer 36 404-418.

Rodgers KE, Marks J, Ellefson D, Yanagihara D, TonettaS, Vasilev S, Morrow CP, Montz F & diZerega G 1989Follicle regulatory protein: A novel marker forgranulosa cell cancer patients. Gynecologic Oncology37 381-387.

Roth L, Anderson M, Govan A, Langley F, Gowing efeWoodcock A 1981 Sertoli-Leydig cell tumors: Aclinicopathologic study of 34 cases. Cancer 48 187-197.

Scully RF 1970 Gonadoblastoma: A review of 74 cases.

Cancer 25 1340-1356.

Scully R 1979 Tumors of the ovary and maldevelopedgonads. In Atlas of Tumor Pathology, 2nd series, FascileNo 16. Washington DC: Armed Forces Institute ofPathology.

Serov S, Scully R & Sobin L 1973 Histological typing ofovarian tumors. In International HistologicalClassification of Tumours vol 9. Geneva: World HealthOrganization.

Slayton RE, Park RC, Silverberg SG, Shingleton H,Creasman WT & Blessing JA 1985 Vincristine,actinomycin D, and cyclophosphamide in the treatment

of malignant germ cell tumours of the ovary. AGynecologic Oncology Group Study. Cancer 56 243-248.

Stenwig JT, Hazekamp J efe Beecham J 1979 Granulosa celltumors of the ovary. A clinicopathologic study of 118cases with long-term follow-up. Gynecologic Oncology1 136-152.

Talerman A 1984 Carcinoid tumors of the ovary. Journalof Cancer Research and Clinical Oncology 107 125-135.

Talerman A 1987 Germ cell tumors of the ovary. InBlaustein 's Pathology of the Female Genital Tract, edn3, pp 659-721. Ed RJ Kurman. New York: Springer-Verlag Co.

Tamimi H efe Bolen J 1984 Enchondromatosis (Ollier'sdisease) and ovarian juvenile granulosa cell tumor: Acase report and review of the literature. Cancer 53 1605-1608.

Tavassoli F efe Norris H 1980 Sertoli tumors of the ovary. Aclinicopathologic study of 28 cases with ultrastructuralobservations. Cancer 46 2281-2297.

Taylor H efe Norris H 1967 Lipid cell tumors of the ovary.Cancer 20 1953-1962.

Young R & Scully R 1983 Ovarian Sertoli-Leydig celltumors with a retiform pattern: A problem inhistopathologic diagnosis. American Journal ofSurgical Pathology 1 755-771.

Young R e& Scully R 1984 Well-differentiated ovarianSertoli-Leydig cell tumors. A clinicopathologicalanalysis of 23 cases. International Journal ofGynecologic Pathology 3 277-290.

Young R efe Scully R 1985 Ovarian Sertoli-Leydig celltumors. American Journal ofSurgical Pathology 9 543-569.

Young RH efe Scully RE 1987a Sex cord-stromal, steroidcell, and other ovarian tumors with endocrine,paraendocrine, and paraneoplastic manifestations. InBlaustein's Pathology of the Female Genital Tract, edn3, pp 607-658. Ed RJ Kurman. New York: Springer-Verlag Co.

Young R e& Scully R 1987b Ovarian steroid cell tumors

associated with Cushing's syndrome: A report of threecases. International Journal of Gynecologic Pathology6 40-48.

Young R, Dickersin Refe Scully R 1984 Juvenile granulosacell tumor of the ovary. American Journal of SurgicalPathology 8 575-596.