Ovarian Tumors in Children and Young Women: Selected Important Issues in Differential Diagnosis
Robert H. Young
Massachusetts General Hospital
I begin this presentation by considering the frequency of the various categories of
ovarian tumors (and tumors within each category) during each of the first three decades and when
indicated within parts of individual decades. These comments are aimed at highlighting one important
aspect of gonadal pathology, namely, that although the diagnosis ultimately rests with the light
microscopic findings, it strengthens the approach to the differential diagnosis to be aware of the
statistical likelihood of any diagnosis. I will then consider three tumors of the young that have all
been highlighted in the last three decades. I will conclude by noting briefly the issues associated
with ovarian masses encountered during pregnancy. Two comprehensive reviews of ovarian tumors in
childhood and adolescence were undertaken in recent times by Dr. Ernest Lack and colleagues
have selected from his comprehensive list of references a selected group that I believe represents a good
synopsis of the literature on this topic
and have extended the time frame of coverage until the
end of the third decade. The reason for this is that, although there are obviously exceptions, it is
only when someone is over 30 that they start to progressively be at risk for most of the common ovarian
neoplasms, both benign and malignant.
There are marked differences in the frequency of ovarian neoplasms in the first three
decades compared with later years and then, to a lesser degree, within each of the first three decades.
In these decades there is a much higher percentage of germ cell and sex cord-stromal tumors because of
the lesser frequency of surface epithelial neoplasms and great rarity of metastatic tumors. This is
borne out by the over 50 years experience at the Children's Hospital in Boston (even allowing for that
consideration being only of the first two decades); 70% of the tumors were germ cell and 13% sex
cord-stromal . One-third of the germ cell tumors were in the primitive category, a much greater
percentage than seen beyond 30 years. The surface epithelial tumors accounted for 16% of the neoplasms.
Tumor-like lesions accounted for almost one-third of ovarian masses. This exceeds the figure for later
years because of the relative high frequency of follicle cysts in the first two decades, which has two
time periods, the neonatal and perimenarchal, when these lesions are common.
The first decade has a unique aspect related to tumor-like lesions, namely, the
contribution to the numbers of ovarian masses provided by the occurrence, just noted, of follicle cysts
in the neonatal period as a response to maternal stimulation. Sixteen of the 76 tumor-like lesions in
the Children's Hospital series were in this category. These cysts are larger than follicle cysts seen
later (except for those related to pregnancy), averaging 8.3 cm. in the Children's Hospital series.
Their size makes them prone to torsion with significant symptomatology as a result.
Other pertinent comments about the first decade are as follows. Dermoid cysts are rare
in the first two years but become progressively more common thereafter. Primitive germ cell tumors are
seen but are much commoner in the next two decades. As an example of this in the Children's Hospital
Series, only one of 8 patients with dysgerminoma was in the first decade . Surface epithelial tumors
of any type are exceptionally rare. Granulosa cell tumors, particularly of the juvenile type are seen
occasionally, although it should be remembered that adult granulosa cell tumors are also seen in the
young. Sertoli-Leydig cell tumors are seen occasionally and the retiform subtype accounts for a greater
percentage than in any other decade except the second. The sex cord tumor with annular tubules, both
Peutz-Jeghers Syndrome associated and unassociated with the syndrome, is rarely encountered in the first
decade, being much commoner in the second and third , indeed being as common in those two decades as
at any other time. Two, to date, unique, ovarian sex cord tumors associated with Peutz-Jeghers Syndrome,
each responsible for sexual precocity, occurred in the first decade . The small cell carcinoma of
hypercalcemic type is rare before 10 years, only three examples being known, the youngest a 14-month old
. Miscellaneous other tumors such as primaries sarcomas are seen but rarely. Within the family of
sarcomas, as one might expect, the rhabdomyosarcomas of embryonal and alveolar type, particularly the
former, which have a skew to young individuals in general, are seen occasionally in the first three
decades. Of the thirteen ovarian rhabdomyosarcomas reported by Nielsen et al , one was in a 7-year
old, one in a 10-year old, and one in a 14-year old. Three of the remaining patients were in their
20's. Two of the tumors were alveolar, the remainder, embryonal. One infantile hemangioendothelioma has
been reported in a neonate  but vascular sarcomas become commoner in the third decade. One tumor
with a predilection for children, the neuroblastoma, accounts for the majority of the rare cases of
ovarian metastasis in children and may also be seen in young adults. In the largest series of cases
looking at spread to the ovary in children, eight of the 14 tumors were neuroblastomas . Seven were
primary in the adrenal gland and one in the posterior mediastinum. The other tumors were accounted for
by three rhabodmyosarcomas, primary in the ethmoid sinus, right occipital region and left side
respectively, and individual examples of Ewing's sarcoma, rhabdoid tumor of the kidney and a carcinoid
tumor of the lung. Follicle cysts are rare after the first six months and other tumor-like lesions are
rare at any time in this decade. A corpus luteum cyst does rarely occur, however, in neonates .
The second decade is noteworthy for the acceleration of the frequency of all the
primitive germ cell tumors as shown by the average age of occurrence of all of them being circa 18 - 19
years. One rare but important monodermal teratoma, the primitive neuroectodermal tumor , is seen
much more often in the second than in the first decade. The commoner monodermal tumors, struma ovarii
and carcinoid, are uncommon in the first three decades. Surface epithelial tumors remain uncommon
although measurably more frequent than in the first decade. Virtually the only cell types seen are
serous and mucinous. In the Children's Hospital series serous slightly outnumbered mucinous. In our
consultation material mucinous tumors are much more numerous. This is accounted for presumably by the
fat that the serous tumors are almost always benign whether in the mucinous group, tumors in the
borderline or low-grade carcinoma categories are encountered with some frequency and are more likely to
provoke a consultative opinion. At least one mucinous tumor in a teenager had foci of anaplastic
carcinoma . We have seen one low-grade endometrioid carcinoma in a teenager  but this and other
surface epithelial carcinomas in teenagers are a great rarity. The small cell carcinoma of
hypercalcemic type begins to be seen with an accelerated pace once children enter the second decade and
this tumor is only somewhat less common in the second, compared to the third decade. Metastatic
carcinomas which are virtually unheard of in the first decade are seen occasionally in the teenage years
with well documented examples of Krukenberg tumor and even metastatic colonic carcinoma (we have seen one
of the latter in a 12-year-old) being documented. Lymphoma and leukemia involving the ovary is
occasionally seen in the second decade and even before having no great predilection for any of the first
three decades. Ovarian involvement by the intra-abdominal desmoplastic small round cell tumor with
divergent differentiation is commonest in the teenage years, the three original cases of this type
reported by us being in the mid teens  and subsequent experience has borne out a peak in this
decade. As this is a time when the small cell carcinoma of hypercalcemic type is being seen with
increased frequency, it is important that these two tumors be carefully distinguished.
One significant aspect of the third decade, particularly when compared to the prior two,
is the appreciably greater frequency of surface epithelial tumors, particularly as the decade moves
along. For example, serous borderline tumors, which are exceptionally rare before 20 are seen with some
frequency in the third decade although there pace of occurrence accelerates even more after the age of
30. Of all tumors with any malignant potential in the surface epithelial category, serous borderline
tumors and mucinous borderline tumors account for the majority encountered in the third decade. Mucinous
carcinomas are occasionally seen, but less frequently than borderline tumors and serous carcinomas remain
exceptionally rare in the third decade. Indeed, the extent to which they are dwarfed by serous
borderline tumors is worthy of comment and in this age group one should always favor a borderline tumor
rather than serous carcinoma unless evidence for the latter is incontrovertible. Germ cell tumors of all
types are seen with slightly greater frequency than in the second decade. The exception to that comment
is secondary malignant change in teratomas, and monodermal teratomas, which remain rare until patients
pass beyond 30 years. However, the validity of the comment just made not withstanding, one can actually
rarely see this phenomenon in patients younger than 30, although almost never younger than 20. Three of
19 cases of squamous cell carcinoma arising in dermoid reported by Pins et al  were in patients of
21, 25, and 30 years of age. One other patient in his series with a squamous cell carcinoma and
associated endometriosis was a 29-year-old and another patient without an association with either a
dermoid cyst or endometriosis was a 27-year-old.
The third decade sees a peak in the frequency of Sertoli-Leydig cell tumors, which occur
at an average age of 25 years . Seventy-five percent of all Sertoli-Leydig cell tumors occur in the
first three decades. Granulosa cell tumors of both adult and juvenile types continue to be seen with
some frequency in this decade. Steroid cell tumors are also seen in this decade and even in the first;
about 7% of these tumors occur in prepubertal girls . Pure stromal tumors, except the sclerosing
stromal tumor remain rare; the latter has an average age of 27 years and is commoner in the third decade
than any other. Enigmatically, the rare primary angiosarcoma of the ovary appears to be commoner in the
third decade . Three of 11 cases of granulocytic sarcoma of the female genital tract reported
relatively recently involved one or both ovaries of patients from 13 to 30 years of age . These
neoplasms must be distinguished in the conventional manner from malignant lymphoma and other neoplasms.
I shall now consider individually three important and morphologically interesting tumors
of the young.
Juvenile Granulosa Cell Tumor
Dr. Robert Scully became alerted to this neoplasm in the early 1970's when he noted that
in young females granulosa cell tumors often had alarming microscopic features. Although these atypical
features are occasionally observed in tumors from older women, their strong predilection for young
females led to his designating them juvenile granulosa cell tumors (JGCTs).
On gross examination, the tumors have a spectrum of appearances similar to those of the
adult granulosa cell tumor
. Microscopic examination typically reveals diffuse sheets or nodules
of cells with abundant eosinophilic cytoplasm interrupted to varying degrees by follicles. The
follicles may be round to oval but more typically vary in shape and size and often contain
mucicarminophilic, eosinophilic or basophilic material. The nuclei of the granulosa cells appear more
immature than those in the adult type of tumor. They are more hyperchromatic and frequently exhibit
considerable mitoic activity; nuclear grooves are rare. Up to 15% of the tumors, show marked nuclear
The major differences between the adult and juvenile forms of granulosa cell tumor are
cytologic, specifically the hyperchromatic, mitotically active nuclei without grooves in the juvenile
form. Another important difference is the typical luteinization of the cells in the juvenile tumor. In
adult granulosa cell tumors, one may see luteinized cells, but they are usually a minor component and
only very rare tumors in this category are extensively luteinized . Finally, the nature of the
follicles in the JGCT differs in many cases from those in the adult form of neoplasm in that they exhibit
much more variability in size and shape.
The differential diagnosis of the JGCT includes various other neoplasms. As malignant
germ cell tumors are common in the age group in which the JGCT is most often encountered, and may even be
functioning, the immature nuclei of the JGCT may lead to the misdiagnosis of a yolk sac tumor or
embryonal carcinoma. However, the follicle formation which is seen at least focally in the great
majority of JGCTs is diagnostic with one caveat. Cysts in the polyvesicular vitelline variant of yolk
sac tumor can potentially be misconstrued as cystic follicles of a JGCT. Cellular stroma between the
cysts of the polyvesicular tumor and foci of typical yolk sac tumor both may be helpful. Paradoxically,
the extreme nuclear atypia of some JGCTs exceeds that of a yolk sac tumor.
The JGCT is sometimes misinterpreted as a thecoma, because of the absence or rarity of
follicles in some specimens, the usual presence of abundant cytoplasm in the neoplastic cells and the
occasional predominance of theca cells. Thorough sampling to demonstrate follicles and the performance
of reticulum stains to help recognize the granulosa cell nature of at least some of the tumor cells are
important in establishing the correct diagnosis. Also, thecomas lack significant mitotic activity in
almost all the cases, occur before 30 years of age in less than 10% of the cases, and very rarely occur
in children. An important differential diagnosis is with the small cell carcinoma of hypercalcemic type,
an issue discussed below.
Rarely, the JGCT is confused with carcinomas of surface epithelial type. Tumors with
marked atypia may be misinterpreted as undifferentiated carcinomas if foci of follicle differentiation
are overlooked. In some cases, the tubulocystic variant of clear cell carcinoma is suggested when the
follicles are lined by cells with features of hobnail cells. The absence of other patterns of clear cell
carcinoma, the young age of the patient, the presence of follicles and focal areas of more typical JGCT
should help resolve this problem. In some JGCTs with prominent follicles a pseudopapillary appearance
may be encountered leading to a superficial resemblance to transitional cell carcinoma. Small follicles
in the lining at the base of the pseudopapillae exclude transitional cell carcinoma. A metastatic tumor
that may be confused with a JGCT is malignant melanoma because in some of the latter follicle-like spaces
in a neoplasm composed of cells with abundant eosinophilic cytoplasm imparts a striking resemblance to a
JGCT. We have not seen the basophilic mucicarminophilic fluid that is often present in the follicles of
JGCTs in the follicle-like spaces of metastatic melanoma. When the diagnosis of JGCT is being considered
in a patient over 20 years of age, the diagnosis of malignant melanoma should be excluded.
Immunohistochemical staining for both S-100 protein and HMB-45, and electron microscopic examination,
should establish the diagnosis if other clinical and routine pathologic features do not.
Small Cell Carcinoma of Ovary, Hypercalemic Type
It is appropriate to discuss this tumor next because it is often follicle forming, like
the juvenile granulosa cell tumor. This distinctive ovarian cancer is the most common form of
undifferentiated ovarian carcinoma in women under 40 years of age. It was recognized by Dr. Scully in
the early 1970's and first presented in detail by him in his first fascicle and in 1982 "officially"
described . It was the unusual occurrence in young women of a small cell carcinoma that was
associated with paraneoplastic hypercalcemia that led it to being recognized as a distinct entity. The
patients have ranged from 14 months to 43 (mean, 24) years of
age . Most patients present with signs
and symptoms related to an abdominal or pelvic mass, but rarely the clinical presentation is related to
the hypercalcemia. Occasional familial cases have been encountered. In the largest series in the
literature the stage of the tumor was IA in 33%, 1B in 1%, 1C in 16%, stage II in 5%, stage III in 43%,
and stage IV in 1% . This carcinoma has a dismal prognosis. The overall survival rate is
approximately 16%; the corresponding figures are 33% for Stage 1A tumors and 7% for tumors >stage IA
. Favorable prognostic factors in the largest study included an age >30 years, a normal
preoperative serum calcium, bilateral oophorectomy, tumors <10 cm, no large cell component, and the
administration of adjuvant radiotherapy . No chemotherapy has proven to be of significant consistent
benefit in the management of patients with this highly malignant tumor.
The tumors are almost always unilateral, usually large, solid, soft and white. This
appearance is similar to that of dysgerminoma and lymphoma and may contribute to confusion with these
neoplasms as considered below. Necrosis and hemorrhage are conspicuous in many small cell carcinomas.
On microscopic examination, the most common pattern is a more or less diffuse arrangement of small,
closely packed cells with scant cytoplasm but evidence of their epithelial nature is provided by the
focal presence of small nests, cords, and clusters of cells. An important feature that is seen in about
80% of the tumors is follicles that vary from small to large but are more often the latter. They are
usually round to oval and contain eosiniphilic fluid. The tumor cells have small nuclei containing
single nucleoli and, despite the aggressive nature of this tumor, are relatively monotonous in appearance
with the exception noted below. Mitotic figures are numerous.
Variant features may be seen which complicate the interpretation in many cases. The
commonest of these is the presence in about half of the cases of a component of large cells with abundant
eosinophilic cytoplasm, a pattern for convenience referred to as the "large cell variant." This pattern
is quite distinctive in many cases because of the frequent presence of a prominent stroma which often is
myxoid. Overall the small cell carcinoma has relatively unimpressive fibrous stroma in most cases but it
is occasionally focally relatively prominent. The large cells may have eccentric nuclei and dense
globular cytoplasm. Nucleoli are usually more prominent in foci of the large cell variant. Rarely some
cells in the small cell carcinoma have clear cytoplasm. This may suggest a dysgerminoma but the
architectural and cytologic difference between the two tumors are so striking that simply considering
small cell carcinoma should enable it to be diagnosed when its features are indeed present. Gross
similarities mentioned earlier may enhance confusion, however, and it should also be remembered that the
dysgerminoma may also be associated with hypercalcemia . Another intriguing finding in about 10% of
these tumors is minor foci of mucinous epithelium that typically stands out sharply from the background
sea of small cells. Occasionally, however, the mucinous epithelium is less conspicuous and more
cytologically atypical, and may merge with the small cells. Rarely signet-ring type cells are seen.
Electron microscopical examination has so far failed to reveal any specific features to
identify the cell type of the tumor. McMahon and Hart  found the most consistent and striking
finding to be the presence of abundant dilated rough endoplasmic reticulum, forming large vesicles filled
with homogeneous, granular (proteinaceous) material of variable density. They considered these
ultrastructural features to be of diagnostic value in the differential diagnosis of this tumor.
Ultrastructural examination in some cases has shown numerous whorls of microfilaments to account for the
globular cytoplasm. Immunohistochemical studies have also not helped identify the cell of origin but
have simply confirmed an epithelial nature
. Evidence for a sex cord derivation is lacking.
This tumor is often confused with a granulosa cell tumor of either adult or juvenile
types. However, the cells of the small cell carcinoma do not have the characteristic pale grooved nuclei
of the adult granulosa cell tumor and the mitotic rate in the small cell carcinoma far exceeds that
encountered in adult granulosa cell tumors. Distinction from the juvenile form of granulosa cell tumor
is generally easy because the cells of the small cell carcinoma usually lack the abundant eosinophilic
cytoplasm that is an almost invariable feature of the cells of the juvenile granulosa cell tumor. Even
in cases of small cell carcinoma in which there are cells with abundant eosinophilic cytoplasm,
distinction can usually be made because such cells are most often a focal finding and, in addition, they
differ in appearance from the cells of the juvenile granulosa cell tumor, because of the dense, sometimes
globular cytoplasm; the cells in a JGCT rarely have this appearance. When they do it is helpful that
in cases of small cell carcinoma containing cells with abundant cytoplasm, there is generally a more
disorderly architecture than seen in the juvenile granulosa cell tumor. Finally, with regard to
distinction from both forms of granulosa cell tumor, it is often helpful that the small cell carcinoma
has spread beyond the ovary at presentation, something which would be unusual for either variant of
granulosa cell tumor.
Because their peak frequency is at about the same time, they may be grossly
indistinguishable, and both may cause hypercalcemia, the dysgerminoma and small cell carcinoma may be
confused as noted earlier. Although the small cell carcinoma may have prominent fibrous stroma it
differs in quality generally from the delicate fibrous septa of the dysgerminoma and although, like any
tumor, there may be some non-specific inflammatory cell infiltrate, the classic lymphocytic infiltrate
that tends to hug the septa, typical of dysgerminoma, is lacking in the small cell carcinoma. The
squared off nuclei of dysgerminoma are not seen in the small cell carcinoma, although this feature, and
others for that matter, are not as overt in cases of dysgerminoma that are poorly preserved. If
necessary, the typical immunostaining profile of dysgerminoma for placental-like alkaline phosphatase and
OCT 3/4 will be helpful.
The differential diagnosis of the small cell carcinoma is also with other small cell
malignant tumors that may involve the ovaries. Only those that characteristically occur in the same age
range as the small cell carcinoma, or if not, have in our experience caused an interesting morphologic
dilemma will be considered here. These include primary primitive neuroectodermal tumors, metastatic
neuroblastoma, malignant lymphoma and leukemia, metastatic round cell sarcomas, metastatic malignant
melanoma, and the intra-abdominal desmoplastic small round cell tumor. Even large cell carcinomas can be
in the differential in cases with a significant component of the so-called large cell variant and this
issue will also be briefly considered.
Neuroblastoma and primitive neuroectodermal tumors occur in the same age group as the
small cell carcinoma. In cases of neuroblastoma, the presence of Homer-Wright rosettes is diagnostic,
although such structures may be few in number. Appreciation of fibrillar material may also be important
in the diagnosis in these cases and is even more crucial in cases of the primitive neuroectodermal
tumor. In the latter tumor the cells are even smaller than in the small cell carcinoma and lack the
distinctive follicles and other patterns. Rarely immunostains may be called upon to assist in the
Malignant lymphoma or leukemia occasionally presents as a unilateral or bilateral ovarian
mass and enters the differential diagnosis of the small cell carcinoma. The cells of these neoplasms may
grow in a variety of patterns, such as insular, cord-like, and alveolar. The distinctive cytologic
features of the malignant lymphoid or leukemic cells, however, differ from those of the cells of the
small cell carcinoma, and the frequent follicle-like spaces of the latter are helpful in this
differential. Immunostains will obviously provide aid if necessary.
Melanoma metastatic to the ovary is rarely composed of small cells with scanty cytoplasm
and follicle-like spaces that produces a pattern similar to that of small cell carcinoma . These
tumors, however, also usually contain nevoid aggregates of cells that suggest melanoma. The history of a
primary malignant melanoma and immunohistochemical staining of the ovarian tumor for S-100 protein and
HMB-45 may be important in establishing the diagnosis and immunohistochemistry was decisive in one case
of primary malignant melanoma of the ovary we have seen in which the cells were small and in which there
were follicle-like spaces.
The most recently described small cell tumor that may involve the ovary and potentially
be confused with the hypercalcemic form of small cell carcinoma is the intra-abdominal desmoplastic small
round cell tumor (DSRCT)
. The ovarian involvement is much more often bilateral in cases of DSRCT.
Although the hypercalcemic tumor may have an insular pattern, it is generally absent or only focal,
whereas in the DSRCT discrete nests of tumor cells are characteristic. Additionally, the latter tumor
has, as its name implies, a typically prominent desmoplastic stroma, which is either absent, or only a
focal finding in the hypercalcemic small cell carcinoma. The nests in the DSRCT often have a basaloid
appearance, which is not a feature of the hypercalcemic tumor and its cells, although small, are more
reminiscent of those of the pulmonary form of small cell carcinoma than the hypercalcemic tumor.
Finally, if any difficulty in the distinction of the DSRCT and hypercalcemic small cell carcinoma remains
on the basis of the examination of routinely stained sections, immunohistochemical examination will be
diagnostic as the staining of the DSRCT for desmin is not a feature of the hypercalcemic tumor.
The possibility of a small cell carcinoma may be raised in cases of metastatic alveolar
rhabdomyosarcoma, because the follicle-like spaces of the small cell carcinoma may be simulated by cystic
changes in the alveolar spaces of the rhabdomyosarcoma . However, the distinctive and prominent
alveolar pattern of rhabdomyosarcoma is not a feature of small cell carcinoma. The distinctive giant
cells that are seen in some rhabdomyosarcomas have not been encountered in the hypercalcemic small cell
carcinoma. One Ewing's sarcoma metastatic was initially thought possibly to represent a small cell
Finally, as alluded to earlier, the differential diagnosis of the small cell carcinoma,
enigmatically, may actually be that of a large cell carcinoma when the tumor is predominantly the
so-called large cell variant. The evaluation of large cell malignant tumors of the ovary is a topic on
to itself, which can only be briefly considered here. It can bring up such diverse malignant lesions as
malignant steroid cell tumor, malignant melanoma, anaplastic carcinoma arising in a mucinous tumor,
anaplastic carcinoma arising in a dermoid, and of course, the neoplasm of interest to us here. Although
there is a great temptation to rush to immuno in this circumstance, it is important to emphasize that
good old-fashioned thorough sampling is just as likely to be helpful, if not more so. Certainly finding
of focal evidence of a dermoid cyst or an underlying mucinous cystic neoplasm may be very helpful in
capturing the diagnosis of two of the entities just mentioned. Although mucinous epithelium may be seen
in association with a small cell carcinoma, it is minor foci that has not to date simulated the picture
of a parent mucinous cystic tumor. Also, although the possibility exists of a small cell carcinoma being
entirely of the large cell variant, I do not believe we have seen to date a case that did not at least
somewhere have minor foci of the typical small cell morphology, which rules out all the lesions just
considered except melanoma and that is certainly one area where admittedly immunohistochemistry is most
appropriately something that should be called upon.
Retiform Sertoli-Leydig Cell Tumor
Sertoli-Leydig cell tumors (SLCTs) are classified into five major categories: well
differentiated, of intermediate differentiation, poorly differentiated, heterologous and retiform. The
last variant is of interest to us here because of its particular tendency to occur in the young (average
age 15 years} and its intriguing morphology
. They account for about 10% of SLCTs. Clinically
they are less often androgenic than other variants of SLCT, having these signs or symptoms only about 20%
of the time. That observation is of relevance in that androgenic manifestations tend to have the
diagnosis of Sertoli-Leydig cell tumor come to mind in a oung person; conversely their absence and
unusual morphology may lead to the diagnosis being overlooked. Retiform tumors are often soft and
spongy, cystic with edematous intraluminal polypoid excrescences or combinations thereof.
Retiform SLCTs are so named because they are characterized microscopically by growth
patterns that simulate those of the rete testis. The basic pattern is an irregular network of elongated,
often slit-like tubules and cysts which often contain papillae. The papillae may be short and rounded or
blunt, often containing hyalinized cores, or larger with fibrous or edematous cores. Cysts may be
markedly dilated with eosinophilic secretion imparting a struma-like appearance in some cases. The
tubules are usually lined by a single layer of cuboidal epithelial cells with round to oval nuclei
although stratification is conspicuous in some cases. The cytoplasm is typically scanty and mitotic
activity variable, but sometimes marked. Similar cells typically line the papillae and cysts, but large
cysts may be lined by flattened cells. The stromal component varies from moderately cellular fibrous
tissue (which is occasionally focally hyalinized) to markedly edematous (accounting for the soft, spongy
consistency) to very cellular, immature mesenchymal tissue which may show heterologous differentiation.
Retiform SLCTs may be misinterpreted as a variety of other tumors. Because of the young
age of the patient and presence of papillae in many cases the diagnosis of yolk sac tumor is often
considered. It should be remembered that like many ovarian tumors the retiform SLCT may contain hyaline
bodies. Resemblance to a serous borderline tumor may be imparted by the presence of small papillary
clusters in the cyst lumens. The clefts, papillae and a complex branching pattern associated with
cellular stratification and atypicality may suggest a serous adenocarcinoma. The admixture of retiform
tubules with immature mesenchymal tissue which may show heterologous differentiation can suggest the
diagnosis of a malignant mixed mesodermal tumor. The presence in most cases of typical foci of SLCT,
although sometimes very small in amount, and other clinical and pathologic features of the tumors should
enable the diagnosis of a retiform SLCT to be established. Any pattern of SLCT may co-exist with the
retiform pattern but typically the retiform foci merge with long, thick ribbons of immature cells
consistent with Sertoli cells. When a tumor is entirely retiform, knowledge of the existence of this
distinctive subtype of SLCT is essential in enabling the pathologist avoid a serious error in diagnosis.
Issues Related to Ovarian Tumors Discovered During Pregnancy
As the era from menarche through the end of the third decade accounts for a significant
component of the reproductive era in females, it is obvious that during this time, by happenstance, a
number of ovarian neoplasms will develop, or at least be discovered, in patients who are pregnant.
Furthermore, pregnancy itself is responsible occasionally for the development of some specific tumor-like
lesions. In this brief summary I will comment upon four issues, namely 1. Tumor-like lesions associated
with pregnancy; 2. Alterations in sex cord stromal tumors due to pregnancy which may hinder their
microscopic recognition; 3. Non-specific changes in ovarian neoplasms associated with pregnancy; and 4.
Ovarian tumors with functioning stroma related to pregnancy.
When a patient is known to be pregnant that a mass lesion of the ovary, either cystic or
solid, might be non-neoplastic should always be considered assuming appropriate gross and microscopic
findings. Otherwise completely benign lesions may result in overly aggressive treatment with unfortunate
consequences upon future fertility and increased morbidity. Two lesions may mimic cystic neoplasms,
hyperreactio lutealis (multiple luteinized follicle cysts) and the large solitary luteinized follicle
cyst of pregnancy and the puerperium . It is helpful that the first lesion is bilateral in contrast
to many cystic neoplasms that might be in the differential diagnosis and certainly when a frozen section
is done on a cystic lesion of the ovaries from a pregnant patient, careful search for the distinctive
features of follicle cysts and other changes of the intervening tissue that are seen in hyperreactio
lutealis, such as edema, should be sought. When a massive unilocular smooth walled cyst is encountered
in pregnancy, the large solitary follicle cyst should be considered. In contrast to most cystic
granulosa cell tumors it has a lining of cells with copious eosinophilic cytoplasm and rather
characteristically, focal bizarre nuclei. The solid tumor-like lesion of pregnancy is the pregnancy
luteoma and it is a time honored adage that the diagnosis of steroid cell tumor should not be made in
pregnancy unless a pregnancy luteoma has been ruled out. It is helpful in many cases that the pregnancy
lutetoma is bilateral and multi-nodular, the nodules typically being beefy red in contrast to the yellow
appearance of many steroid cell tumors, although should be acknowledged that some steroid cell tumors may
be beefy and red. A well-known trap is the brisk mitotic activity of many pregnancy luteomas. The
fourth tumor-like lesion is the incidentally discovered microscopic process known as granulosa cell
tumorlets. They are likely to cause clinical mischief inasmuch even if they are considered neoplasms,
erroneously, it would be tiny microscopic ones of no clinical consequence .
As the early reproductive era sees a peak in incidence of Sertoli-Leydig cell tumors and
the majority of juvenile granulosa cell tumors and a sizable number of adult granulosa cell tumors occur
in this age range, it is obvious that occasional patients with one of these neoplasms will encountered
while she is pregnant. A pitfall is that these neoplasms may show considerable intercellular edema, or
be extensively luteinized, both features which may obscure their characteristic morphologic features and
render them, on average, more difficult to diagnose than similar neoplasms encountered outside of the
setting of pregnancy . Perhaps the most specific trap is that the edema may produce a pattern which
simulates, at least to some degree, the reticular pattern of yolk sac tumor and we have certainly seen
cases of sex cord stromal tumors erroneously considered to be yolk sac tumors during pregnancy, for this
reason. Although thorough sampling is important at any time, it is particularly so when evaluating a
perplexing mass lesion from a pregnant patient because sometimes only minor areas will show diagnostic
features of one or another form of sex cord stromal tumor, making it evident that that is the diagnosis.
Any ovarian neoplasm from a pregnant patient is more likely to undergo hemorrhagic
infaraction and rupture than outside the setting of pregnancy. This may result in a clinically dramatic
presentation and also, because of the infarction, serves to make diagnostic foci often limited and is a
further contribution to diagnostic difficulty. Many references on ovarian tumors in pregnancy are
available in the paper that is Reference 56 of this handout.
Finally, yet another mischievous feature of ovarian tumors in pregnancy is their much
greater tendency to exhibit stromal luteinization, which is often striking, and may be associated with
dramatic androgenic manifestations. This may result in a clinician being convinced the patient has the
most well-known androgenic neoplasm of young females, the Sertoli-Leydig cell tumor, and when
encountering a tubular pattern in an ovarian tumor of a young virilized female, the pathologist quite
reasonably wonders about Sertoli-Leydig cell tumor. However, in some cases of Krukenberg tumor a
striking tubular pattern simulates the sertoliform pattern of a Sertoli-Leydig cell tumor and the
luteinization of the stroma may be misconstrued as the Leydig cell component of a Sertoli-Leydig cell
tumor. A number of the tubular Krukenberg tumors of the ovary described by us some years ago were
misdiagnosed as Sertoli-Leydig cell tumors for the reasons just summarized .
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