Case 13
Dysgerminoma
Clinical History: The patient was 17 years old. A right adnexal mass was discovered and the
patient was taken to surgery where a large right ovarian tumor was removed. There was no
evidence of extraovarian tumor spread and the contralateral ovary was grossly normal.
Gross Pathology: The tumor replaced the ovary. It measured 17.0 cm in maximum diameter and
weighed 1040 gm. The external surface was smooth and glistening. Cut sections revealed a solid
tan tumor that was firm and rubbery.
Diagnosis: Dysgerminoma of the ovary.
Dysgerminoma
Case 13 provides an introduction to the topic of germ cell tumors of the ovary. These are
uncommon tumors, but most pathologists are at least somewhat familiar with them because
ovarian and testicular germ cell tumors are histologically similar, and surgical pathologists see
the testicular tumors with some frequency.
Germ Cell Tumors of the Ovary
Dysgerminoma
Yolk Sac Tumor
Embryonal Carcinoma
Polyembryoma
Choriocarcinoma
Teratoma
Mixed Germ Cell Tumor
Gonadoblastoma
Mixed Germ Cell-Sex Cord-Stromal Tumor
Dysgerminoma is one of the two most common malignant germ cell tumors of the ovary.
(1, 2) Still, it accounts for only 1-2% of all malignant ovarian tumors. Dysgerminoma occurs
mainly in children and young women. (3-5) The average age is 22 years, and 90 percent of
patients are less than 30 years of age. About 20 percent of malignant ovarian tumors detected
during pregnancy are dysgerminomas. The usual presentation is with nonspecific findings such
as abdominal distention, an abdominal mass, or abdominal pain. Some patients have menstrual
abnormalities or gastrointestinal or urinary symptoms. Rare patients have hypercalcemia. (6)
Serum lactic dehydrogenase (LDH) is frequently elevated but increased levels of serum alphafetoprotein or human chorionic gonadotropin are generally not detected. If increased, they
suggest that other germ cell elements are present in the tumor. Of note, however, about 3% of
patients with a pure dysgerminoma have increased amounts of beta-hCG in the blood, secreted
by syncytiotrophoblastic cells within the tumor. (7) Dysgerminoma is the most common
malignant gonadal tumor in patients with gonadal dysgenesis.
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 1
Dysgerminoma is confined to the ovaries (stage I) at diagnosis in 60–80 percent of
patients. It is usually unilateral, which is characteristic of all malignant germ cell tumors.
Dysgerminoma is unique among these tumors in that it is the only one with a significant
incidence of bilaterality; both ovaries contain tumor (stage IB) in 5–15 percent of cases. The
tumor in the contralateral ovary is grossly visible in half of the bilateral cases and it is a strictly
microscopic finding in the other half. Some oncologists recommend biopsy of an apparently
normal contralateral ovary if treatment is to be by unilateral salpingo-oophorectomy only.
Dysgerminoma metastasizes via the lymphatics to the paraaortic lymph nodes, with subsequent
spread to the mediastinal lymph nodes, and by transperitoneal spread to the pelvic and abdominal
peritoneum. (8)
Unilateral encapsulated dysgerminoma (FIGO stage IA) can be treated by salpingooophorectomy with a 5-year survival rate of greater than 90 percent. (9) Postoperative therapy
has been advocated for patients with localized disease, but there is an increasing trend to follow
such patients closely and administer chemotherapy only to those who develop a recurrence. (10,
11) Recurrences can usually be successfully managed. When dysgerminoma develops in a
dysgenetic gonad, the appropriate treatment is bilateral gonadectomy. The standard treatment for
advanced disease (stage >IA) is total abdominal hysterectomy, bilateral salpingo-oophorectomy,
limited debulking, and postoperative chemotherapy or radiotherapy. If they are not involved by
tumor, the uterus and the contralateral ovary may be conserved in young patients when
preservation of fertility is important. (12) Chemotherapy with platinum-based regimens is highly
effective against dysgerminoma and is less likely than radiation to cause ovarian failure and
infertility. Overall survival of optimally treated patients now exceeds 90 percent. (2, 9)
Recurrences usually become evident within two years of primary treatment.
Gross Pathology
Dysgerminoma is a large solid tumor, usually more than 10cm in diameter. It has a
smooth outer surface and the cut surface tends to be fleshy, homogeneous or nodular, and gray,
tan, or white. Hemorrhage and necrosis are often present, especially in large tumors.
Microscopic Pathology
Dysgerminoma is composed of polygonal cells
with abundant granular eosinophilic or clear
cytoplasm and distinct cell membranes. As
shown in Fig. 13-1, the nuclei are round,
medium sized and relatively uniform with
vesicular chromatin and prominent nucleoli.
Mitotic figures are usually numerous. The cells
grow in sheets, nests or trabeculae that are
separated by fibrous septa, as shown in Fig. 132. The septa vary from thin wisps of connective
tissue to thick fibrous bands. Lymphocytes are
Fig. 13-1 Polygonal cells, vesicular nuclei
usually present in the septa and in lesser
numbers among the tumor cells. Most of the lymphocytes are T-cells, particularly those among
the tumor cells, with B-cells mainly confined to the septa. (13, 14) When numerous lymphoid
cells are present in the stroma germinal centers may be present. Epithelioid cells and
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 2
Fig. 13-2. Trabecula with lymphocytes
multinucleated Langhans type giant cells are
present in many dysgerminomas in loose
aggregates or sarcoid-like granulomas.
The diagnosis of dysgerminoma is
straightforward in typical cases, but there are a
number of variations in appearance that can
cause diagnostic problems, particularly in small
biopsies or frozen sections. Necrosis is
occasionally so extensive that it obliterates so
much of the underlying tumor that it is difficult
to recognize. Focal or extensive fibrosis can be
present in dysgerminoma, and can overshadow
the tumor cells. I have never seen a case in
which the tumor is completely replaced by fibrous tissue, as sometimes occurs in testicular
seminomas. When granulomatous inflammation is very extensive it may be difficult to see the
tumor cells among the epithelioid cells. Edema and loss of intercellular cohesion sometimes
result in formation of gland-like spaces or microcysts, a pattern that has been called “tubular”
dysgerminoma. Dysgerminomas with marked nuclear atypia and increased mitotic figures (more
than 30 mitotic figures per 10 high power fields) dysgerminoma can mimic embryonal
carcinoma. Such tumors were called “anaplastic” dysgerminomas in the past, but since the higher
grade histology is not correlated with more aggressive clinical behavior they are now simply
viewed as a variant histologic pattern of dysgerminoma. Poor fixation can result in clumping of
the nuclear chromatin and dense basophilic cytoplasm, raising the question of embryonal
carcinoma. About 3% of dysgerminomas contain syncytiotrophoblastic giant cells. (7) When
STGC are present, the patient can have a positive pregnancy tests and/or elevated serum levels of
beta-human chorionic gonadotropin. Dysgerminomas with STGC lack cytotrophoblastic cells
and no other germ cell elements are present so these tumors are classified as variants of
dysgerminoma, not as choriocarcinoma or as a mixed germ cell tumor. Although dysgerminoma
variants can be difficult to diagnose, there is no evidence that their clinical behavior is any
different than that of typical dysgerminomas. The correct diagnosis can usually be established by
study of additional slides that reveal more typical histologic features or by performing
immunohistochemical stains.
Dysgerminoma Variations: Unusual Histologic Patterns That Can Cause Diagnostic
Difficulties
Extensive necrosis
Extensive fibrosis
Extensive granulomatous reaction
Alveolar, tubular or microcystic pattern
Anaplastic tumor cells and/or high mitotic rate
Poor fixation artifacts
Syncytiotrophoblastic giant cells
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 3
Molecular Pathology and Immunohistochemistry
Chromosome 12p abnormalities are present in many malignant germ cell tumors. The
most common abnormality is an isochromosome, i12p, but over-representation of chromosome
12p material is sometimes found present in addition to or instead of an i12p. In one study, an
i12p was identified in 16 of 21 dysgerminomas and over-representation of chromosome 12
material was detected in 5 dysgerminomas. (15) c-KIT mutations have been identified detected
in about 25% of dysgerminomas, but they are located in exon 17, not the exon 11 location that
confers sensitivity to imatinib. (16, 17) There is no correlation between the presence or absence
of a c-KIT mutation and immunohistochemical staining for CD117.
Best Immunohistochemical Markers for Dysgerminoma
Marker
Staining Pattern
D2-40
Membrane
CD117 (c-Kit)
Membrane
PLAP
Membrane and cytoplasm
OCT4
Nuclear staining
NANOG
Nuclear staining
SALL4
Nuclear staining
Numerous immunohistochemical stains are available to confirm a diagnosis of
dysgerminoma. These fall into two main groups: antibodies against cytoplasmic and
membranous antigens and antibodies against nuclear antigens. The first group includes placental
alkaline phosphatase (PLAP), CD117 (c-kit) and D2-40. (18, 19) All are excellent markers for
dysgerminoma. PLAP was the first of these markers to be introduced and is the most widely
available, but I prefer the newer markers CD117 and D2-40. Staining for PLAP and limited
staining for D2-40 can be seen in other types of germ cell tumors. Cytoplasmic staining is often
present but only membrane staining is considered to be indicative of dysgerminoma. Remember
that cytoplasmic staining for CD117 is seen in some tumors that can mimic dysgerminoma, such
as melanoma, but membrane staining is characteristic of dysgerminoma. In general, staining is
strongest for D2-40, while CD117 is least likely to stain necrotic background debris. The second
group of immunostains, those for nuclear antigens, includes OCT-4, NANOG, and SALL4 (Figs.
4c and 4d). (16, 18, 20, 21) These are nuclear transcription factors that are present in primitive
germ cell tumors. Positive staining is not limited to dysgerminoma; all three are positive in
embryonal carcinoma and SALL4 also stains yolk sac tumor. Diffuse strong nuclear staining is
characteristic of dysgerminoma but a definitive diagnosis requires a panel of stains that enable
the pathologist to identify the specific types of germ cell neoplasia that are present.
Immunostains for cytokeratin typically show very focal cytoplasmic dot or rim-like staining in
dysgerminoma; the type of diffuse strong cytoplasmic or membranous staining that is seen in
embryonal carcinoma and yolk sac tumor is not present. (22) Dysgerminoma is generally
negative for epithelial membrane antigen (EMA). (22) Since many of the positive markers for
dysgerminoma lack specificity a panel of stains, usually including CD117 and/or D2-40, OCT4
and/or SALL4 and cytokeratin must be used to confirm the diagnosis. Immunostains for hCG are
generally negative, but the syncytiotrophoblastic giant cells that are present in dysgerminomas
from patients with elevated serum beta-hCG show positive cytoplasmic staining. Immunostains
for -fetoprotein (AFP) are negative.
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 4
Differential Diagnosis
Many clear cell tumors occur in or spread to the ovaries, as detailed in the discussion of
Case 3. A number of them enter the differential diagnosis of dysgerminoma, including other
types of malignant germ cell tumors and various types of non-germ cell tumors can also be
confused with dysgerminoma. Dysgerminoma is the most common component of mixed germ
cell tumors of the ovary, so it is important to search carefully to exclude other germ cell elements
before making a diagnosis of a pure dysgerminoma.
Dysgerminoma Mimics: The Most Important Differential Diagnostic Considerations
Malignant mixed germ cell tumor
Embryonal carcinoma
Yolk sac tumor
Clear cell carcinoma
Lymphoma
Melanoma
Embryonal carcinoma is mainly seen as a minor component in mixed germ cell tumors
and only infrequently occurs in pure form in the ovary. If it is extensive and the cells grow in
solid sheets embryonal carcinoma can resemble dysgerminoma, particularly if the cytoplasm is
pale or clear. Also, as previously mentioned, anaplastic variants of dysgerminoma can be
confused with embryonal carcinoma. Embryonal carcinoma cells have larger more pleomorphic
nuclei and the chromatin is coarser. The cytoplasm is most often amphophilic or basophilic
rather than clear or eosinophilic. Neither granulomas nor a lymphoid stroma are present in
embryonal carcinoma. Careful evaluation often reveals poorly formed glands. There is positive
staining for the nuclear transcription factors OCT4, NANOG, and SALL4 in both embryonal
carcinoma and dysgerminoma so these stains do not differentiate the two. Dysgerminoma is
usually strongly positive for CD117 and D2-40, while embryonal carcinoma is generally strongly
positive for CD30 and cytokeratin. The anti-cytokeratin antibody AE1/AE3 shows a
membranous staining pattern in embryonal carcinoma. Strong keratin staining excludes
dysgerminoma.
Yolk sac tumor grows in a confusing variety of patterns, most of which are unlikely to
raise the question of dysgerminoma. A solid pattern of growth of cells with clear cytoplasm can,
however, resemble dysgerminoma. The tumor cell nuclei tend to be smaller and darker in yolk
sac tumor, and the overall cell size is also smaller. Thorough study generally reveals additional
more characteristic patterns of yolk sac tumor. Immunostains are helpful in this differential
diagnosis. Both dysgerminoma and yolk sac tumor are positive for SALL4, but yolk sac tumor
does not stain for OCT4 or NANOG, nor have we observed membranous staining for CD117 or
D2-40. Staining for PLAP is less extensive in yolk sac tumor than in dysgerminoma. Yolk sac
tumor shows diffuse strong cytoplasmic staining for cytokeratin, and most examples are positive
for alpha-fetoprotein and glypican-3, which are negative in dysgerminoma. Knowledge of the
clinical presentation is helpful, as patients with yolk sac tumor generally have an elevated serum
alpha-fetoprotein.
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 5
Clear cell carcinoma patients are usually older than those with dysgerminoma, and
endometriosis is often found in patients with clear cell carcinoma. The solid pattern of clear cell
carcinoma can mimic dysgerminoma, but the tumor cell nuclei are larger. Most clear cell
carcinomas also exhibit areas of tubulocystic and papillary growth. Immunostains for cytokeratin
and EMA are strongly positive in clear cell carcinoma, but are negative or only focally and
weakly positive in dysgerminoma. Clear cell carcinoma is negative for most dysgerminoma
stains discussed above, PLAP being the only one that might show staining in a carcinoma.
Lymphoma can resemble dysgerminoma because it is a monotonous proliferation of cells
with medium sized nuclei and the cell cytoplasm can be clear or pale. Lymphoma often
surrounds residual ovarian structures, rather than displacing them, as occurs in dysgerminoma.
Dysgerminoma cell nuclei tend to be vesicular, while the nuclear chromatin is often coarsely
granular in lymphoma and lymphoma cells usually have less cytoplasm. Most lymphomas of the
ovary are B-cell lymphomas, and accordingly stain for leukocyte common antigen and various
markers of B-cell differentiation, all of which are negative in dysgerminoma. Lymphomas do not
stain for dysgerminoma markers.
Melanoma of the ovary is most often metastatic, but it can be primary, arising in a
teratoma. The histologic appearance is variable, and melanoma can mimic a variety of
neoplasms, including dysgerminoma. Melanoma often exhibits a variety of growth patterns and
the tumor cell nuclei tend to be pleomorphic while dysgerminoma is monotonous, so
examination of an adequate number of sections generally differentiates melanoma from
dysgerminoma. Melanoma cells sometimes contain visible brown melanin pigment.
Immunostains for melanoma markers such as S100, SOX10, HMB45 and Melan A are almost
always positive in melanoma, but negative in dysgerminoma. Dysgerminoma markers are
negative in melanoma, although cytoplasmic, but not membranous, staining for CD117 occurs in
melanoma.
References
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Smith HO, Berwick M, Verschraegen CF, Wiggins C, Lansing L, Muller CY, et al. Incidence and survival
rates for female malignant germ cell tumors. Obstet Gynecol. 2006;107(5):1075-85.
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Lee KH, Lee IH, Kim BG, Nam JH, Kim WK, Kang SB, et al. Clinicopathologic characteristics of
malignant germ cell tumors in the ovaries of Korean women: a Korean Gynecologic Oncology Group Study. Int J
Gynecol Cancer. 2009;19(1):84-7. Epub 2009/03/05.
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Asadourian LA, Taylor HB. Dysgerminoma. An analysis of 105 cases. Obstet Gynecol. 1969;33:370-9.
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Bjorkholm E, Lundell M, Gyftodimos A, Silfversward C. Dysgerminoma. The Radiumhemmet Series
1927-1984. Cancer. 1990;65:38-44.
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Gordon A, Lipton D, Woodruff JD. Dysgerminoma: a review of 158 cases from the Emil Novak Ovarian
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Masahito H, Hara F, Tomishige H, Nishida Y, Kato T, Okumura N, et al. 1,25-dihydroxyvitamin Dmediated hypercalcemia in ovarian dysgerminoma. Pediatr Hematol Oncol. 2008;25(1):73-8.
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Zaloudek CJ, Tavassoli FA, Norris HJ. Dysgerminoma with syncytiotrophoblastic giant cells: a
histologically and clinically distinctive subtype of dysgerminoma. Am J Surg Pathol. 1981;5:361-7.
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Kumar S, Shah JP, Bryant CS, Imudia AN, Cote ML, Ali-Fehmi R, et al. The prevalence and prognostic
impact of lymph node metastasis in malignant germ cell tumors of the ovary. Gynecol Oncol. 2008;110(2):125-32.
Epub 2008/06/24.
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Chan JK, Tewari KS, Waller S, Cheung MK, Shin JY, Osann K, et al. The influence of conservative
surgical practices for malignant ovarian germ cell tumors. J Surg Oncol. 2008;98(2):111-6. Epub 2008/06/20.
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10.
Patterson DM, Murugaesu N, Holden L, Seckl MJ, Rustin GJ. A review of the close surveillance policy for
stage I female germ cell tumors of the ovary and other sites. Int J Gynecol Cancer. 2008;18(1):43-50. Epub
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Gershenson DM. Management of ovarian germ cell tumors. J Clin Oncol. 2007;25(20):2938-43. Epub
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Pectasides D, Pectasides E, Kassanos D. Germ cell tumors of the ovary. Cancer Treat Rev. 2008;34(5):42741. Epub 2008/04/02.
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Dietl J, Horny HP, Ruck P, Kaiserling E. Dysgerminoma of the ovary: An immunohistochemical study of
tumor-infiltrating lymphoreticular cells and tumor cells. Cancer. 1993;71:2562-8.
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Stewart CJR, Farquharson MA, Foulis AK. Characterization of the inflammatory infiltrate in ovarian
dysgerminoma: An immunocytochemical study. Histopathology. 1992;20:491-7.
15.
Cossu-Rocca P, Zhang S, Roth LM, Eble JN, Zheng W, Karim FW, et al. Chromosome 12p abnormalities
in dysgerminoma of the ovary: a FISH analysis. Mod Pathol. 2006;19(4):611-5.
16.
Hoei-Hansen CE, Kraggerud SM, Abeler VM, Kaern J, Rajpert-De Meyts E, Lothe RA. Ovarian
dysgerminomas are characterised by frequent KIT mutations and abundant expression of pluripotency markers. Mol
Cancer. 2007;6:12. Epub 2007/02/06.
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Cheng L, Roth LM, Zhang S, Wang M, Morton MJ, Zheng W, et al. KIT gene mutation and amplification
in dysgerminoma of the ovary. Cancer. 2011;117(10):2096-103. Epub 2011/04/28.
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Chang MC, Vargas SO, Hornick JL, Hirsch MS, Crum CP, Nucci MR. Embryonic Stem Cell Transcription
Factors and D2-40 (Podoplanin) as Diagnostic Immunohistochemical Markers in Ovarian Germ Cell Tumors. Int J
Gynecol Pathol. 2009;28(4):347-55.
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Sever M, Jones TD, Roth LM, Karim FW, Zheng W, Michael H, et al. Expression of CD117 (c-kit)
receptor in dysgerminoma of the ovary: diagnostic and therapeutic implications. Mod Pathol. 2005;18(11):1411-6.
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Cao D, Guo S, Allan RW, Molberg KH, Peng Y. SALL4 is a novel sensitive and specific marker of ovarian
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Cheng L, Thomas A, Roth LM, Zheng W, Michael H, Karim FW. OCT4: A Novel Biomarker for
Dysgerminoma of the Ovary. Am J Surg Pathol. 2004;28(10):1341-6.
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Cossu-Rocca P, Jones TD, Roth LM, Eble JN, Zheng W, bdul Karim FW, et al. Cytokeratin and CD30
expression in dysgerminoma. Hum Pathol. 2006;37(8):1015-21.
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 7
Case 14
Immature Teratoma
Clinical History:
TR64-13818: The patient was a 16 year old girl. Four weeks prior to admission she developed
abdominal pain and rebound tenderness, suggestive of peritonitis. She had a mild fever.
Antibiotics were administered and the discomfort slowly diminished and the temperature
returned to normal. There was a suggestion of enlargement of the right ovary. She was seen 3
weeks later at which time a physician palpated a large mass extending almost to the umbilicus.
The patient was taken to surgery and a large mass of the left ovary was found and removed.
TR90-26689: The patient was a 30 year old woman who presented with a 1-week history of
pelvic pain. At surgery, a large right ovarian tumor was found and removed.
Gross Pathology:
TR64-13818: A large ovarian tumor measuring 12.0 cm in diameter was removed. It had a
smooth glistening external surface. The cross sections showed a large cyst and several smaller
cysts with solid masses measuring up to 7.0 cm in diameter projecting into the lumens. A few
hairs grew from one of the smaller masses into one of the cysts. The cut surfaces had areas of
hemorrhage and there were small foci of calcification.
TR90-26689: The right ovary measured 15 cm in maximum dimension. It was predominantly
solid with rubbery white tan cut surfaces. There were multiple cysts ranging from 0.2 to 10 cm in
maximum dimension. Brown hair was noted and there were focal gritty areas of calcification.
There were occasional foci of hemorrhage and necrosis. A biopsy of a bowel adhesion showed
fibrosis, but no tumor.
Diagnosis: Immature Teratoma, with microscopic foci of yolk sac tumor in TR64-13818
Teratoma
A type of teratoma, the benign cystic teratoma (dermoid cyst), is the most common
ovarian neoplasm, accounting for more than a quarter of all ovarian tumors. (1, 2) Most
teratomas have a 46XX karyotype and appear to be derived from postmeiotic germ cells. There
are numerous benign and malignant variants of teratoma of the ovary. Those in which one
element greatly predominates are termed “monodermal” teratomas.
Immature Teratoma
Immature teratoma is the most common malignant germ cell tumor of the ovary,
representing 20-35% of such tumors at major cancer centers (3, 4) and in the U.S. population. (5)
Immaturity in teratomas has been linked to stages of fetal development. An immature
teratoma contains at least some tissue of a type seen prior to a fertilization age of 8 weeks while
a mature teratoma consists exclusively of tissues similar to those seen at a fertilization age of 8
weeks or more. (6) High-grade immature teratoma is characterized by the presence of immature
neuroepithelial structures, and low-grade immature teratoma by the presence of somite
organogenesis.
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 8
Clinical Features
Like other malignant germ cell tumors, immature teratoma occurs predominantly in
children and young women. Patients are rarely younger than 7 or older than 40. The average
patient age is about 20 years. While it is uncommon, immature teratoma occasionally occurs in
an older or postmenopausal woman. (7)
The clinical presentation is generally nonspecific with pelvic or abdominal pain,
abdominal distention, or a palpable abdominal mass. Occasional patients have acute abdominal
symptoms caused by infarction or rupture of the tumor. A rare but dramatic presentation is with
the sudden onset of severe psychiatric or neurologic symptoms, including coma (“teratoma
coma”) in some cases. The symptoms are the result of a paraneoplastic encephalitis that is a form
of autoimmune disease caused by antibodies to anti-N-methyl-D-aspartate receptors (antiNMDAR). Neural tissues in the teratoma are thought to initiate development of the antiNMDAR antibodies. Treatment includes removal of the teratoma followed by immunotherapy.
(8, 9) Alpha-fetoprotein is elevated in the serum in many patients with pure immature teratoma.
(10, 11) CA 125 is also frequently elevated, albeit not to the levels seen in patients with serous
tumors of the ovary. (10)
Most (50-80%) patients have localized tumors (stage I) at diagnosis. Immature teratoma
is almost always unilateral, although spread to the contralateral ovary can occur in patients with
advanced disease. A benign cystic teratoma is present in the contralateral ovary in 10-15% of
cases. Immature teratoma spreads mainly within the abdomen to the peritoneum and the
omentum.
Since immature teratoma occurs mainly in young patients, treatment is generally as
conservative possible, with the goal of preserving fertility. Patients whose tumors are confined to
the ovary (stage IA) are generally treated by unilateral salpingo-oophorectomy. A few have even
been successfully treated by cystectomy, sometimes followed by adjuvant chemotherapy. (12)
Advanced tumors in young patients are treated by unilateral salpingo-oophorectomy and excision
of extra-ovarian tumor. (4, 13) Hysterectomy and bilateral salpingo-oophorectomy is the usual
treatment for older patients and those with extraovarian tumor spread involving the contralateral
ovary or the uterus.
Immature teratoma is unique among the malignant germ cell tumors in that treatment is
based not only on the tumor stage, but also on the tumor grade. Patients with stage IA grade 1
tumors have an excellent prognosis after surgery and usually do not receive chemotherapy. (4,
14) Adult patients with localized grade 3 immature teratomas and those who have advanced
disease require postoperative chemotherapy. Whether or not adult patients with stage IA grade 2
tumors should have chemotherapy is controversial, but the current NCCN guidelines suggest that
these patients be treated. In children, the prognosis appears to be more favorable and independent
of tumor grade. (15) Children accordingly generally do not have chemotherapy unless they have
metastases containing other malignant germ cell elements such as yolk sac tumor. (11, 16)
Cisplatin-containing regimens such as BEP (cisplatin, etoposide, and bleomycin) are highly
effective as adjuvant chemotherapy for patients with no residual tumor after surgery, with
survival rates of 90-100%. (5, 17) The prognosis is less favorable when there is residual gross
tumor after primary surgery and in cases of recurrent immature teratoma. (18)
The microscopic appearance of extraovarian tumor deposits is important in determining
whether additional therapy is necessary. Sometimes the extraovarian tumor deposits, which are
usually in the omentum, on the peritoneum, or in lymph nodes, consist entirely of mature tissues,
most often glial predominant neural tissue. Such completely mature deposits are graded as grade
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 9
0. Grade 0 tumor deposits do not adversely affect the prognosis, and do not require
chemotherapy. A stage > I is assigned only if the extraovarian tumor is immature. Masses
composed of mature teratoma are sometimes detected after chemotherapy in patients with
incompletely resected immature teratoma. They are generally resected to prevent local
complications and to avoid development of a “growing teratoma syndrome.” (19, 20) We have
seen small grade 0 tumor deposits that have persisted for more than 40 years after resection of an
ovarian teratoma and caused no signs or symptoms. Rare examples of a malignant tumor arising
in long-standing incompletely resected low-grade teratoma implants have been reported. (21-23)
Gross Pathology
Immature teratoma generally has an obviously different appearance than the usual benign
teratoma, as it is mostly solid. It is a unilateral tumor that varies in size; the average diameter is
18 cm. Solid areas within the tumor are white, tan, gray or brown and can be soft or firm. If
cartilage or bone is present the tumor is hard and gritty. Scattered small cysts are typically
present and about 25% of immature teratomas have large cysts that contain keratinous debris or
hair, as seen in a benign cystic teratoma. (24)
Microscopic Pathology
Tissues derived from any of the three germ
cell layers can be present. Immature tissues are
most often of ectodermal and mesodermal origin. A
mixture of mature and immature tissues is present in
most tumors, with mature elements usually greatly
predominating. Immature neuroectodermal elements
are the dominant immature element, and they are
also the easiest immature tissue to recognize and
quantitate for purposes of grading (Fig. 14-1). (25,
26) Immature neuroectodermal tissues include
neuroepithelial tubules or trabeculae lined by
mitotically active columnar cells with stratified
hyperchromatic nuclei (Fig. 14-2), sheets and nests
of neuroblasts, sometimes containing neuropil and
Homer Wright rosettes, hypercellular mitotically
active immature glia, and primitive retinal tissue
with melanin pigmentation. (27, 28) Prominent but
benign vascular proliferations are occasionally
associated with the neural elements in an immature
teratoma. (29) Rosettes lined by one or two layers
of ependymal cells are present in some benign
teratomas; they should not be mistaken for the
primitive rosettes seen in an immature teratoma.
The cells lining ependymal rosettes have ample
cytoplasm, the nuclei form only one or two layers,
and mitotic figures are not present.
Immature mesodermal tissue is hypercellular and consists of small spindle cells with
hyperchromatic nuclei. Mitotic figures are usually present. Immature cartilage is often present in
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 10
immature teratomas. Two main features distinguish it from the more common “fetal” or
“mature” cartilage that is often present. First, chondroid cells within the lacunae have medium
sized round nuclei with open chromatin, as opposed to the small nuclei with dark chromatin seen
in fetal cartilage. Second, foci of immature cartilage are surrounded by primitive small round
mesenchymal cells rather than by the fibroblasts that typically surround mature cartilage.
Endodermal tissues are usually less extensive than ectodermal or mesodermal tissues in
an immature teratoma, and are only infrequently the predominant type of immature tissue
present. Immature endodermal tissues that can be seen include primitive glands lined by
columnar cells with subnuclear and supranuclear vacuoles resulting in an “enteroblastic”
appearance, glands lined by partially differentiated stratified columnar intestinal epithelium with
goblet cells, and islands of fetal liver tissue. (30, 31) Pediatric pathologists have proposed that
foci of immature liver and glands with subnuclear vacuoles similar to immature endoderm or
fetal lung are well differentiated forms of yolk sac tumor, (15) although gynecologic pathologists
tend to view limited amounts of these elements as components of the teratoma. (30) Immature
renal (metanephrogenic) tissue is another rare type of immature tissue that can be seen in
teratomas. (32)
Immature teratoma is graded from grade 1 for a neoplasm composed almost entirely of
mature tissues to grade 3 for a neoplasm containing easily detected immature tissue. The current
grading system is based on the amount of immature neuroepithelium present. (26) A two-grade
system in which grade 1 tumors are designated as low grade and grades 2 and 3 as high grade
was proposed but it is not widely used. (33)
Grade
1
2
3
Grading of Immature Teratoma of the Ovary
Amount of Immature Tissue
Amount of Immature
Neuroepithelium
+
Rare, not > 1 LPF/slide
++
Common, but not > 3 LPF/slide
+++
Prominent, ≥ 4 LPF/slide
LPF = Low power field (40x, 4x objective, 10x eyepiece)
Occasionally, a mature teratoma contains only one or a few microscopic foci of
immature tissue. There is very limited information about the outcome for patients with such
tumors, but a in a study of 10 mature cystic teratomas with microscopic foci of immature tissue
no patient had a recurrence. (24) Follow-up was available in 9 of the 10 cases ranging from 11
months to 7 years. When only a miniscule amount of immature tissue is present in an otherwise
mature ovarian teratoma, I make a diagnosis of a benign teratoma with a microscopic focus of
immature tissue and suggest that it may be most appropriate for the patient to have clinical
follow-up rather than additional therapy.
Microscopic foci of yolk sac tumor are occasionally detected in an immature teratoma.
These foci tend to be subtle and often go unrecognized. Several are present in one of the cases
used in this seminar. Their presence suggests that the tumor developed via a primitive germ cell
pathway, by maturation from embryonal carcinoma, as discussed above. As long as there are
only a few microfoci of yolk sac tumor ( 3) and they are less than 3 mm in diameter they do not
appear to adversely impact the prognosis. (33) If they are larger or numerous, a diagnosis of
mixed germ cell tumor would be appropriate.
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 11
Deposits of teratoma are not uncommonly detected in the omentum, on the peritoneum,
and in lymph nodes in patients with immature teratoma of the ovary. Immature tissue is
occasionally present in such implants, but they most often consist predominantly of mature
neural tissue and the deposits are accordingly often designated as “gliomatosis.” (34) Similar
tumor deposits also occasionally occur in patients with a mature teratoma. The deposits are
typically not composed only of glial cells; neurons and neurofilaments are also frequently
present and other benign mesenchymal and epithelial elements are sometimes seen as well.
Florid vascular proliferations like those that occasionally occur in immature teratoma in the can
also be seen in the implants. (35) When only mature tissues are present in an implant it is
designated as grade 0. Occasional implant consist of an admixture of mature teratomatous
elements and endometriosis. (36, 37) The implants were long thought to represent a form of
extraovarian spread from the teratoma but recent molecular pathology studies have shown
genetic differences between grade 0 tumor deposits and the primary ovarian tumors. Instead, the
deposits have a genetic pattern similar to normal tissue from the patient. (38, 39) In another
study, multiple omental and peritoneal implants were analyzed and found to have mutually
exclusive genetic differences. (40) These findings suggest to some that the extraovarian tumor
deposits must represent a form of metaplasia rather than metastases from the ovarian tumor, a
conclusion that is not universally accepted. (41)
Immunohistochemistry and Molecular Pathology
Genetic studies of a limited number of cases have revealed that an isochromosome 12p,
which is characteristic of primitive germ cell tumors, is often present in the immature teratoma
component of a mixed germ cell tumor, (42) compatible with its derivation from a less
differentiated component of the tumor. On the other hand, an i12p is typically not present in pure
immature teratomas, suggesting a different pathogenesis for such tumors. (42, 43) The
histogenesis of immature teratomas is still unsettled however, since immature teratoma is
typically diploid, whether it is found as a pure tumor or as a component of a mixed germ cell
tumor, while other germ cell elements such as yolk sac tumor are aneuploid, (44, 45) and an i12p
has been detected in a pure immature teratoma. [Rogriguez, 1995]
Immunohistochemistry is not as widely used in the diagnosis of immature teratoma as it
is in the diagnosis of other types of malignant germ cell tumors. In most cases, the diagnosis and
grade are based on the appearance of the tumor on hematoxylin and eosin stained slides. It has
been proposed that expression of glial cell line-derived neurotropic factor receptor alpha-1
(GFRalpha-1) might be useful for the identification of immature neuroepithelium, (46) but this
antibody is not widely available, and is usually not needed. Primitive neuroepithelium may stain
for CD99 and bcl-2, and immature cartilage for CD34 and bcl-2. (6) Staining for glial fibrillary
acidic protein (GFAP) can help identify glial differentiation. Primitive neuroepithelial cells do
not stain with GFAP, but they sometimes stain for neurofilaments or neuron specific enolase
(NSE). (28, 47) Intestinal and respiratory epithelium contains argyrophilic cells that stain for
synaptophysin and chromogranin and with antibodies to a variety of neurohormonal peptides.
Some of the tissues in immature teratomas can show staining with antibodies generally
thought of as markers of more primitive germ cell tumors; this can complicate identification of
primitive elements in a mixed germ cell tumor. For example, alpha-fetoprotein, generally used as
a marker for yolk sac tumor, shows positive staining in immature liver and immature endodermal
glands. (6, 30, 48) Foci of immature liver can also be confirmed with immunostains for antihepatocyte antibody (Hepar) and arginase. SALL4, a marker for embryonal carcinoma,
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 12
dysgerminoma, and yolk sac tumor, SOX2, a marker for embryonal carcinoma, and glypican-3, a
marker for yolk sac tumor, all show occasional staining in immature teratomas. Staining can be
seen in immature neuroepithelium, blastomatous stroma, liver and immature glands. (49-51)
Elevated levels of serum alpha-protein are sometimes detected in patients with immature
teratomas. This does not necessarily indicate the presence of yolk sac tumor, as immature liver
and immature endodermal glands can be AFP positive and thus may be the source of the AFP in
the serum.
It can be tricky to identify microfoci of yolk sac tumor in an immature teratoma. Such
foci can be detected on H&E stained slides, but they can be difficult to confirm with
immunohistochemistry because they do not always stain for AFP. Staining for AFP can be weak
and focal, so when very limited amounts of yolk sac tumor are present they may be AFP
negative. Newer stains, such as SALL4 and glypican-3 are more sensitive than AFP and they are
generally positive in microfoci of yolk sac tumor, as in this case. Other stains that can be helpful
include HNF-1, which is positive in yolk sac tumor cell nuclei, and keratin, which typically
shows cytoplasmic staining in yolk sac tumor.
Differential Diagnosis
It is sometimes difficult to decide whether a teratoma is immature or mature. The
question of whether a teratoma that has only a miniscule amount of immature tissue should be
classified as an immature teratoma is discussed above; our approach is to classify such tumors as
mature teratomas with microscopic foci of immature tissue. (24) Sometimes it is not clear
whether a component of a teratoma should be considered to be immature or mature. One
approach is to view any tissue type that could be seen in fetal development after a fertilization
age of 8 weeks as “fetal” type tissue indicative of a mature teratoma. (6) A few specific findings
seem especially likely to cause diagnostic problems. Ependymal tubules are occasionally seen in
mature teratomas and can be mistaken for immature neuroepithelial tubules. However, they are
lined by a single layer of cells, show no mitotic activity, and show minimal staining for
proliferation markers such as MIB-1. Cerebellar type tissue is sometimes detected in mature
teratomas. A fetal external granular layer can be present in this tissue and should not be mistaken
for the primitive neuroectodermal cells of an immature teratoma. Glial tissue in mature teratomas
can be surprisingly cellular but unless it is hypercellular and mitotically active it should be
viewed as compatible with a mature teratoma. (27) The fetal type cartilage seen in mature
teratomas consists of hyaline matrix with chondrocytes in lacunae. The chondroid foci are
surrounded by fibrous stroma. Embryonal cartilage, which is indicative of an immature teratoma,
consists of chondroid matrix containing plump chondroblasts with pale round nuclei. This type
of cartilage is surrounded by cellular immature stroma.
Malignant mixed germ cell tumor is a neoplasm that contains two or more malignant
germ cell elements. Immature teratoma is a frequent constituent of such tumors so whenever it is
identified a careful search for other malignant germ cell elements is mandatory. Generally, this
requires evaluation of one block per cm of tumor diameter. Microfoci of yolk sac tumor are
present in 5 to 10% of immature teratomas. (33) As long as they are small (< 3mm) and there are
only a few of them, they do not warrant designating the tumor as a mixed germ cell tumor,
although their presence should certainly be noted in the pathology report. Larger foci of yolk sac
tumor are indicative of a mixed germ cell tumor.
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 13
Mixed mesodermal tumor or carcinosarcoma is a high grade neoplasm that could
potentially be mistaken for an immature teratoma. This is because carcinosarcoma, like teratoma,
contains a mixture of epithelial and mesenchymal tissues. (47) However, carcinosarcoma is a
tumor of older women, outside of the age range of immature teratoma. It is entirely of
mesodermal derivation and is composed of a mixture of carcinoma and sarcoma, not the
immature elements seen in an immature teratoma. Neither ectodermal or endodermal elements
are present. The epithelial component can be any type of ovarian carcinoma but endometrioid,
serous, squamous cell, and undifferentiated carcinoma patterns are most common. Likewise, the
mesenchymal component can be any type of homologous or heterologous sarcoma with a
nonspecific fibrous sarcoma and rhabdomyosarcoma being the most common types of
homologous and heterologous sarcomatous elements.
Primitive neuroectodermal tumor (PNET) is a rare variant of immature teratoma that
contains neuroectodermal cells growing in patterns reminiscent of various tumors of the central
nervous system. Tumors of this type also occur in the testis where they are often associated with
teratomas. The diagnosis of neuroectodermal tumor of the testis is made when the
neuroectodermal component measures at least 1cm in diameter.(52) It seems reasonable to apply
this size standard to ovarian tumors as well, although, in ovarian tumors, the neuroectodermal
component generally comprises most or all of a large neoplasm, overgrowing the underlying
teratoma. Primitive neuroectodermal tumors consist of nests and sheets of small cells with
hyperchromatic mitotically active nuclei.(53-55) Some cells have fibrillary cytoplasm and some
tumors contain rosettes with central lumina, neuropil, neuroblastic rosettes, or foci of glial
differentiation. PNETs can resemble medulloepithelioma, ependymoblastoma, medulloblastoma
or neuroblastoma.
These tumors are generally classified separately, although they might also be viewed as
high grade variants of immature teratoma. Rare examples of the peripheral type of PNET, a
tumor in the Ewing sarcoma/PNET family have also been reported in the ovary. These can bear a
resemblance to the more common central type of PNET, but they are not associated with other
teratomatous elements, and they have the chromosomal translocation that characterizes tumors in
the Ewing sarcoma/pPNET family. (56)
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Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 16
Case 15
Granulosa Cell Tumor
Clinical History: A 47 year old woman was operated on for “fibroids.” At surgery, the uterus
contained leiomyomas, but there was also a 14.9 cm diameter left ovarian tumor. She had
multiple peritoneal and lymph node biopsies and no tumor was identified outside the ovary.
Gross Pathology: The ovary contained a pink tan mass measuring 14.9 cm in maximum
dimension. The exterior of the ovary was smooth and glistening, with no evidence of external
tumor growth. The cut surfaces were fleshy and ranged from light tan to pink to tan-yellow.
There were fibrous septa between lobules of tumor.
Diagnosis: Granulosa Cell Tumor Follow-up: The patient was alive and well in November, 2011 (10 years after treatment), when
she was last seen.
Granulosa Cell Tumor
1–2 percent of all ovarian tumors are granulosa cell tumors. (1) Granulosa cell tumor is
the most common malignant sex cord-stromal tumor. There are two types of granulosa cell
tumor: an adult type that occurs mainly in peri and postmenopausal women and a juvenile type
that occurs mainly in children.
Adult Granulosa Cell Tumor
Adult granulosa cell tumors are most often detected in postmenopausal women, but they
occur over a wide age range, from teenagers to the elderly. The average patient age is 45–55
years. Granulosa cell tumors characteristically secrete estrogens, which stimulate the
endometrium to proliferate. The usual presenting symptom is postmenopausal bleeding in older
women and menorrhagia, metrorrhagia, or amenorrhea in younger women. In the past, the
endometrium was reported to be hyperplastic in 30–40% of patients and 5–10% had endometrial
adenocarcinoma. (2-5) Based on my experience this is no longer the case. Proliferative types of
endometrium are common, but hyperplasia is rarely seen these days, and I have never seen a case
of endometrial carcinoma that I could attribute to a granulosa cell tumor. Most likely, earlier
diagnosis these days prevents the development of more extreme types of endometrial pathology.
Still, if the treatment is not going to include hysterectomy, the clinician should perform an
endometrial biopsy to ascertain the status of the endometrium. Rare adult-type granulosa cell
tumors, most occurring in young women 15–35 years of age, secrete androgens and cause the
patient to become virilized. (6-11) Typical symptoms of virilization are hirsutism, enlargement
of the clitoris, deepening of the voice and amenorrhea. About 25% of patients with granulosa cell
tumors have presenting symptoms that are not hormone related. These include abdominal
distention, pain, or a palpable mass. Rupture of the tumor or torsion with infarction and
intratumoral hemorrhage can cause acute abdominal symptoms. Most women with a granulosa
cell tumor have a palpable unilateral adnexal mass; bilateral tumors are uncommon.
The tumor is limited to the ovary (FIGO stage I) at diagnosis in 80–90% of cases. Most
patients are older and the standard treatment is total abdominal hysterectomy and bilateral
salpingo-oophorectomy. Unilateral salpingo-oophorectomy is suitable treatment for stage IA
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 17
tumors in young women who wish to conserve their fertility. All granulosa cell tumors have
malignant potential, although most do not recur or metastasize. The recurrence rate is 10–15%
for stage IA tumors and 20–30% overall. (4, 12-17) Extraovarian spread is to the peritoneum and
omentum and occasionally to the liver or lungs. (18, 19) Lymph node metastases are uncommon
so routine dissection of the pelvic and abdominal lymph nodes is unnecessary. (20, 21) When
intra-abdominal spread is present at diagnosis (stage III) or the tumor recurs a majority of
patients die of tumor. Granulosa cell tumors are indolent and metastases, if they develop, are
often detected more than 5 years after initial treatment. There are many reports of disease-free
intervals of more than 20 years. (22) Chemotherapy for advanced or recurrent granulosa cell
tumor is less than optimal. Some patients respond to combinations of drugs that includes
cisplatin, (23-26) but responses are seldom durable. One group reported that women who
completed 6 full cycles of BEP chemotherapy were less likely to have additional recurrences.
(27) Anti-angiogenesis therapy with bevacizumab has resulted in partial or complete remission in
some patients.(28) The value of radiotherapy is unclear, but there is some evidence that in
selected cases adjuvant radiotherapy can result in a longer disease free survival. (29)
Several potential tumor markers have been identified in the sera of women with granulosa
cell tumors, including estradiol, müllerian inhibiting substance, follicle regulatory protein, and
inhibin. Inhibin has emerged as the most widely used tumor marker, as serum inhibin levels are
elevated in nearly all patients with primary or recurrent granulosa cell tumor. (30, 31) Inhibin is
not specific for granulosa cell tumor, as elevated serum concentrations can be observed in
women with other types of ovarian tumor, but once the diagnosis has been established it can be
used for monitoring treatment and detecting recurrence.
Gross Pathology
Granulosa cell tumors vary in size from small incidentally discovered tumors only a few
millimeters in diameter to large neoplasms more than 30 cm in diameter. The average size is
about 10 cm. Some are totally solid, but most are partly cystic. The solid portions are pink, tan,
brown, or light yellow and vary from soft to firm in consistency. Rare granulosa cell tumors are
entirely cystic with a wall only a few millimeters thick. These seem to be more likely than other
granulosa cell tumors to be androgenic. (7, 15)
Microscopic Pathology
The tumor cells resemble normal granulosa cells. They are small and round, cuboidal, or
spindle-shaped with pale cytoplasm and ill-defined cell borders. The nuclei are round or oval
with fine chromatin and a single small nucleolus (Fig. 15-1). Longitudinal folds or grooves are
often present in the nuclei and are a characteristic feature of adult granulosa cell tumor.
Numerous mitotic figures, nuclear pleomorphism and atypia are unusual findings, but may be
present. Some tumors contain cells with bizarre nuclei, but this finding does not appear to impact
the prognosis.(32-34) A rare finding, present in about 1% of cases, is extensive (> 50% of cells)
luteinization of the tumor cells. Luteinized granulosa cells have abundant eosinophilic
cytoplasm, well-defined cell borders, and central nuclei, and resemble the luteinized granulosa
cells of the corpus luteum. A nodular pattern, as seen at low magnification, and myxoid
background stroma are characteristic. Luteinized granulosa cell tumors occur in pregnancy, in
patients with androgenic tumors, and as idiopathic findings. (6, 35, 36)
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 18
Various histologic patterns have been
described in granulosa cell tumors. These are
typically mixed and do not have and prognostic
significance, but they help identify a tumor as a
granulosa cell tumor. The microfollicular pattern is
the most characteristic one and consists of nests and
sheets of granulosa cells in which there are small
spaces containing eosinophilic secretions and
cellular debris (Fig. 15-2). The spaces resemble the
Call–Exner bodies of developing follicles. In the
macrofollicular pattern there are large rounded or
irregularly shaped follicles lined by stratified
granulosa cells. The macrofollicular pattern is seen
most often in juvenile granulosa cell tumors. The
tumor cells grow in anastomosing bands, ribbons,
and cords in the trabecular pattern; as closed or
even open tubules in the tubular pattern; in irregular
undulating ribbons in the gyriform or watered-silk
pattern; and in nests and islands in the insular
pattern. There are large irregular sheets of tumor
cells with no organized substructure in the solid or
diffuse pattern. Small or large cysts lined by one or
more layers of granulosa cells are often present;
they frequently contain blood and hemosiderinladen macrophages are often present in the cysts
and the cyst wall. Rare tumors grow as large
unilocular cysts lined by stratified granulosa cells, among which microfollicles or trabecular
growth are present. Occasionally, there are areas in cystic granulosa cell tumors where the tumor
cells line blunt or branching papillae that project into cystic spaces; this finding is more common
in juvenile granulosa cell tumors than in adult type tumors. (37)
Granulosa cell tumors have a variable amount of fibrous or thecomatous stroma. Tumors
with abundant fibrothecomatous stroma were formerly designated as granulosa-theca cell tumors.
Currently, any tumor in which granulosa cells comprise more than 10 percent of the cellular
population is classified as a granulosa cell tumor. Spindle cell gonadal stromal tumors with only
a minor granulosa cell component are best classified as a thecoma or fibroma with minor sex
cord elements. (38) Some granulosa cell tumors are composed of spindle shaped cells. These
differ from a thecoma in that the cells tend to be shorter and have the nuclear features of
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 19
granulosa cells, they have more abundant cytoplasm, and other patterns of granulosa cell tumor
are often present. A reticulin stain can be helpful in evaluating such tumors, since in a granulosa
cell tumor the reticulin fibers tend to surround groups of cells, while in a thecoma or fibroma the
fibers surround individual tumor cells. Rare granulosa cell tumors contain heterologous
mucinous epithelium or are composite tumors with mucinous elements. (39-43) A few granulosa
cell tumors with focal hepatocellular differentiation have been reported. (44, 45) The hepatoid
cells are difficult to differentiate from luteinized cells or Leydig cells in H&E stained slides;
immunostains are necessary to make the distinction.
Unfortunately, it is difficult for pathologists to provide prognostic information; the
pathologic findings correlate poorly with the clinical behavior, although some findings correlate
to a degree with the outcome. (46) The prognosis is less favorable for large tumors more than 15
cm in diameter, for bilateral tumors, and for those that have ruptured or spread beyond the ovary
(i.e., FIGO stage >IA). The stage is the single most powerful prognostic indicator, so it is
important to provide adequate staging information in the pathology report. (16, 47, 48) Tumors
with diffuse moderate or marked nuclear atypia or frequent mitotic figures (variably defined as
greater than 2 or 4 mitotic figures per 10 high power fields) have been thought to be more likely
to recur, but in recent studies neither the mitotic rate nor the proliferation rate as measured by the
frequency of Ki-67 positive nuclei has correlated with the clinical outcome. (48-50) As
mentioned above, there is no correlation between the microscopic pattern and the clinical
outcome.
Small non-neoplastic granulosa cell proliferations that somewhat resemble small adult
granulosa cell tumors are occasionally seen in the ovaries of women who are pregnant or
postpartum. (51) These are small, multifocal, and confined to the antra of atretic follicles and
they do not have the luteinized myxoid appearance of a granulosa cell tumor in pregnancy. (52)
Strips and clusters of non-neoplastic granulosa cells are occasionally seen in vascular channels,
perhaps being misplaced during surgery, pathologic evaluation or at ovulation. {McCluggage,
2004 #17426
Immunohistochemistry and Molecular Pathology
A missense somatic point mutation that is characteristic of adult granulosa cell tumors
has recently been identified in the FOXL2 gene (402C to G) located at 3q22.3. (53-55) This
mutation is present in more than 90% of adult granulosa cell tumors, as well as in occasional sex
cord-stromal tumors of other types, mainly thecomas, but so far not in other ovarian tumor types.
(56, 57) Studies of tumors diagnosed as granulosa cell tumors that lack the mutation indicate that
many, if not all, were other types of tumors misclassified as granulosa cell tumors. There is no
correlation between the presence or absence of the mutation and immunostaining for FOXL2.
Immunohistochemical stains can be very helpful in the diagnosis of granulosa cell tumor.
Nearly all granulosa cell tumors are vimentin positive. (58-60) Most granulosa cell tumors are
keratin negative, but up to a third show focal or diffuse staining for keratin, particularly with
antibodies directed against low molecular weight cytokeratins 8 and 18.(60) Dot-like or globoid
perinuclear staining is particularly suggestive of a granulosa cell tumor, but extensive perinuclear
or diffuse cytoplasmic staining can be seen. Absence of staining for epithelial membrane antigen
(EMA) is an important characteristic of granulosa cell tumors and other sex cord-stromal tumors
that helps to differentiate them from various types of epithelial tumors.(61, 62) There is positive
staining for smooth muscle actin in most tumors, but granulosa cells generally do not stain for
desmin.(62, 63) About 50 percent of granulosa cell tumors show positive nuclear or cytoplasmic
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 20
staining for S-100 protein.(62) There is membrane staining for CD99 (MIC2 gene product) in
about 70 percent of granulosa cell tumors.(64-67)
There are a number of positive markers for granulosa cell tumor, all of which are also
positive to varying degrees in other types of sex cord-stromal tumors. (67) Most granulosa cell
tumors show cytoplasmic staining for inhibin, although it is often patchy and variable in
intensity. (68-76) Most epithelial tumors are inhibin-negative, but focal or diffuse positive
staining is occasionally detected. Calretinin is also an excellent marker for granulosa cell tumors,
with staining in both the cytoplasm and the nuclei of the tumor cells. It too is positive in other
types of sex cord-stromal tumors and in mesotheliomas and in mesothelial hyperplasia.(75, 77,
78) Two newer immunostains, steroidogenic factor-1 (SF-1) and FOXL2, are nuclear stains that
are almost invariably positive in granulosa cell tumors. (79) FOXL2 staining is present in
virtually all granulosa cell tumors irrespective of whether or not they have a FOXL2 mutation.
FOXL2 and SF-1 stain most types of sex cord tumors, but FOXL2 tends to be negative in steroid
cell tumors. Other immunostains that are typically positive in granulosa cell tumors are WT1,
(67) which shows nuclear staining, and CD56, (80, 81) which shows strong membrane staining.
These antibodies react with various other tumor types as well. Granulosa cell tumors can show
cytoplasmic staining for CD10, but it tends to be weak and focal. (82) A good limited
immunohistochemical staining panel for the diagnosis of granulosa cell tumor could include
inhibin and FOXL2 as positive markers and EMA, which should be negative. I also like to stain
for cytokeratin, which, along with EMA picks up most carcinomas. SF-1 and calretinin are also
useful at times. Vascular endothelial growth factor (VEGF) and its receptor can be demonstrated
in many granulosa cell tumors with immunohistochemistry. (83) Depending on how clinical
therapy for granulosa cell tumors develops, this test could become relevant as clinicians are
starting to treat some patients with recurrent granulosa cell tumors with the monoclonal antibody
bevacizumab, and positive staining for these antigens might suggest a greater likelihood of a
favorable response. (28)
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 21
Probably many of you have noted that this case is not a typical granulosa cell tumor
because a second, different histologic pattern is present. The appearance of the tumor varies from
slide to slide. This is what the contributing pathologist had to say about the case:
Microscopic Description:
Sections of the left ovarian mass reveal a granulosa cell tumor with a variable histologic appearance. Approximately
half of the sections examined exhibit a macrofollicular pattern typically seen with a juvenile granulosa cell tumor.
The remaining sections exhibit histologic patterns ranging from microfollicular to trabecular to insular to solid areas
of tumor growth. Areas of necrosis and degeneration are identified. In the most mitotically active regions of the
tumor the mitotic rate is approximately 18 mitotic figures per 10 high-powered fields (block A6,). Focal cytologic
and nuclear atypia are also identified. The capsule appears to be intact histologically. All staging biopsies, lymph
nodes, and omentum are free of tumor.
Pathologist Comment:
It is difficult to classify this granulosa cell tumor into either the juvenile or adult type. Approximately one-half of the
tumor is composed of a macrofollicular pattern of growth which is typically seen within juvenile granulosa cell
tumors. The remaining tumor exhibits a variety of histologic patterns typically seen in adult granulosa cell tumors.
The presence of a large macrofollicular pattern, the increased rate of mitotic activity, and the size of this tumor are
possibly suggestive of a more aggressive biological behavior. However, the behavior of stage I granulosa cell
tumors cannot be accurately predicted on the basis of histologic appearance alone.
This is a granulosa cell tumor with a mixture of adult and juvenile granulosa cell tumor
patterns. I have seen a few other examples. Their existence is surprising, since the adult and
juvenile types of granulosa cell tumor are two different tumor types, not simply two grades of the
same tumor. The FOXL2 mutation that is present in adult granulosa cell tumors is not present in
the juvenile type. One occasionally sees mixtures of different patterns of sex cord stromal tumors
in ovarian neoplasms, and this seems to be an example of such a case. Thus, the diagnosis is:
Diagnosis: Granulosa cell tumor with a mixed pattern of adult granulosa cell tumor and
juvenile granulosa cell tumor.
Juvenile Granulosa Cell Tumor
Fewer than 5 percent of granulosa cell tumors occur in children and teenagers. Most of
those that do have distinctive clinicopathologic features. (84, 85) Juvenile granulosa cell tumors
are the most common sex cord-stromal tumors in children. (86) They also occur in the testes in
young boys.
Although they are called juvenile granulosa cell tumors, this type of neoplasm can occur
at any age, from infancy to old age. Most do occur in children. (84, 85) The average patient age
is 15 years, but in a study limited to children in a pediatric tumor registry, the average age was
only 7.1 years.(87)
Juvenile granulosa cell tumors often secrete estrogens secreted that cause isosexual
precocious pseudopuberty. Premenarcheal girls often (50–75 percent) have breast development,
growth of pubic and axillary hair, vaginal bleeding, and increased bone age and an estrogen
effect can be seen in a vaginal smear. Older children and premenopausal women develop
menstrual abnormalities, including amenorrhea. A third to half of all patients have only nonspecific symptoms such as abdominal distention, pain, or a palpable abdominal mass or they
develop acute abdominal symptoms due to torsion or rupture of the tumor. An adnexal mass is
palpable in more than 70% of patients. With rare exceptions, juvenile granulosa cell tumors are
unilateral, and more than 95% are limited to the ovary (stage I). The prognosis appears to be
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 22
worse for patients with stage IC tumors, so it is important to collect peritoneal washings for
cytologic evaluation and to pay close attention to the status of the capsule. There is an
association between juvenile granulosa cell tumor and Ollier’s (enchondromatosis) and
Mafucci’s (enchondromatosis and multiple subcutaneous hemangiomas) syndromes. (84, 88-91)
Juvenile granulosa cell tumor is typically encapsulated and confined to one ovary at
diagnosis (stage IA) and is treated by unilateral salpingo-oophorectomy. (92) Most patients are
young, so hysterectomy and bilateral salpingo-oophorectomy used only for the few patients who
present with advanced disease, or for the occasional older patient with this type of tumor. Pelvic
and abdominal lymph node metastases are uncommon and it does not appear to be necessary to
dissect them for staging or treatment purposes. (21) The long-term survival is good, but patients
whose tumors rupture, or who have positive peritoneal cytology or extraovarian tumor spread
have a significant risk of recurrence. (84, 85, 93) If the tumor does recur, the recurrence is
generally detected within 3 years. Some patients with advanced, persistent or recurrent disease
respond to platinum-based combination chemotherapy. (94, 95) Inhibin and müllerian inhibitory
substance can be used as tumor markers for the follow-up of patients with juvenile granulosa cell
tumors.
Gross Pathology
Juvenile granulosa cell tumors vary greatly in size, from 2.5 to 30 cm in diameter; the
average is 12cm. Most tumors are partly solid and partly cystic, but they can be completely solid
or mainly cystic. Solid areas are yellow or tan.
Hemorrhage is frequent, but necrosis is
uncommon.
Microscopic Pathology
The granulosa cells in juvenile
granulosa cell tumors are large, polygonal to
spindled in shape and they have a variable, but
usually abundant, amount of amphophilic or
pink cytoplasm. Focal or extensive
luteinization is a typical finding. The tumor
cells have large round hyperchromatic nuclei
that lack grooves and may contain
conspicuous nucleoli (Fig. 15-4). Cells with
enlarged pleomorphic nuclei and
multinucleated cells are common. Mitotic
figures tend to be numerous and average
around 6 per 10 hpf.
There is typically a mixture of cysts
and solid areas in juvenile granulosa cell
tumors. The solid areas have a lobulated or
nodular appearance at low magnification.
Macrofollicular, diffuse solid, and cystic
growth patterns are characteristic of juvenile
granulosa cell tumor. The macrofollicles tend
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 23
to vary considerably in size and they have irregular shapes (Fig. 15-3, irregular macrofollicles).
Their lumens contain mucinous material, they are lined by one or more layers of granulosa cells,
and they are sometimes surrounded by a rim of theca cells. The solid areas consist of sheets of
granulosa cells with a variable admixture of spindle shaped thecal or fibroblastic stromal cells.
Vague or well defined papillae lined by granulosa cells occasionally grow into cystic spaces.(37)
The typical growth patterns of adult granulosa cell tumors, such as the microfollicular and
insular patterns are usually not present, but the granulosa cells grow in a trabecular or tubule-like
pattern in some tumors.
Immunohistochemistry and Molecular Pathology
The FOXL2 (C402G) mutation that characterizes adult granulosa cell tumors is absent in
juvenile granulosa cell tumors. (53, 96) These two tumors, both of which are derived from
granulosa cells, thus likely have a different histogenesis.
The immunohistochemical features of juvenile granulosa cell tumor are similar to those
of adult granulosa cell tumors, with a few differences. The tumor cells are vimentin positive and
they stain for low molecular weight cytokeratin in a quarter to half of the cases. Sex cord stromal
markers are usually positive. There is cytoplasmic staining for inhibin, nuclear and cytoplasmic
staining for calretinin, nuclear staining for FOXL2 and steroidogenic factor-1 (SF-1) and
membrane staining for CD99 and CD56. (79) Staining for CD99 tends to be more intense in
juvenile granulosa cell tumors than in the adult type, and a greater percentage of tumors stain, so
this marker is more useful for this type of granulosa cell tumor. EMA tends to be negative, but in
contrast to what is seen in adult type granulosa tumors, which are always EMA negative, some
juvenile granulosa cell tumors show focal weak staining for EMA. (97)
It is unclear whether there is any significance to the pattern of staining for FOXL2. Some
authors report that more intense staining for FOXL2 correlates with more aggressive clinical
behavior, (96) while others have reported exactly the opposite, namely that tumors that show loss
of staining for FOXL2 are more aggressive. (98) Further study of this question is obviously
indicated.
Differential Diagnosis
The differential diagnostic considerations obviously vary according to the type of granulosa cell
tumor. For adult type tumors, the most significant differential diagnostic issue by far is
carcinoma, either primary or metastatic. The differential diagnosis with thecoma is discussed
above. Carcinoid tumors and lymphoma are other considerations. For juvenile granulosa cell
tumor, the main differential diagnostic problems are yolk sac tumor and small cell carcinoma of
the hypercalcemic type. Other considerations are listed in the tables.
Primary and metastatic carcinomas were not infrequently misdiagnosed as granulosa cell tumors
in the past. This happens less often now, due to the wide availability of immunohistochemistry.
The types of ovarian carcinomas that most often cause diagnostic problems are undifferentiated
carcinoma, which grows in diffuse sheets mimicking the diffuse pattern of granulosa cell tumor,
and endometrioid carcinoma, in which areas of spindle cell differentiation can mimic solid
patterns of granulosa cell tumor, and which can form small tubular glands that mimic
microfollicles. Among metastatic carcinomas, metastatic breast cancer is particularly likely to
form microfollicle like glands that can cause confusion with a granulosa cell tumor. The degree
of nuclear atypia and mitotic activity is generally much greater in a carcinoma than in a
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 24
Differential Diagnosis of Adult Type Granulosa Cell Tumor
Thecoma and other sex cord stromal tumors
Primary or metastatic carcinoma
Carcinoid
Lymphoma
Endometrial stromal sarcoma, primary or metastatic from uterus
Melanoma
granulosa cell tumor, so marked nuclear atypia or frequent mitotic figures should cause the
pathologist to question a diagnosis of a granulosa cell tumor. Strong staining for keratin and
EMA and lack of staining for granulosa cell tumor markers such as inhibin, calretinin and
FOXL2 help establish the correct diagnosis.
Carcinoid tumors are composed of small to medium sized cells that grow in some of the same
patterns as granulosa cell tumors, such as insular and trabecular patterns, so it is not surprising
that they can be misdiagnosed as granulosa cell tumors. Carcinoid tumors are commonly
associated with teratomas. The tumor cell nuclei frequently have distinctive coarse “salt and
pepper” chromatin and the cytoplasm contains eosinophilic neuroendocrine granules that can be
seen in H&E stained slides. These tumors show positive staining for markers of neuroendocrine
granules such as chromogranin and synaptophysin, and they do not stain for granulosa cell
markers.
Lymphoma can involve the ovary, usually as part of a systemic process, but occasional primary
ovarian lymphomas occur. Lymphoma is somewhat similar to granulosa cell tumor at low
magnification, in that both are tumors of small darkly stained cells. Lymphoma tends to infiltrate
around ovarian structures, such as follicles, while granulosa cell tumor pushes them aside. At
higher magnification, lymphoma cells have characteristic morphology which is different from
that of a granulosa cell tumor. In problematic cases, immunostains readily resolve the differential
diagnosis, and lymphoma cells mark for a variety of lymphoma markers and not for granulosa
cell tumor markers. Most ovarian lymphomas are B-cell lymphomas and they show strong
staining for CD20, as well as general markers like CD45 (LCA).
Juvenile granulosa cell tumor is most likely to be mistaken for a germ cell tumor or for small cell
carcinoma of hypercalcemic type.
Small cell carcinoma of hypercalcemic type occurs in the same age range as juvenile granulosa
cell tumor, and has some similar histologic features, including growth of tumor cells in diffuse
sheets and the formation of irregular macrofollicles. The tumor cells tend to be smaller and
darker than those in juvenile granulosa cell tumor, and the mitotic rate is often higher. Luteinized
tumor cells do not occur, although luteinized stromal cells are occasionally present in the
background. A large cell variant of small cell carcinoma has been described, but the tumor cells
have a rhabdoid appearance with less cytoplasm than is present in the luteinized cells of juvenile
granulosa cell tumor. Small cell carcinoma tumor cells are EMA positive and they do not stain
for markers of juvenile granulosa cell tumor such as inhibin and, in very limited studies, FOXL2.
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 25
Differential Diagnosis of Juvenile Granulosa Cell Tumor
Small cell carcinoma of hypercalcemic type
Yolk sac tumor
Dysgerminoma with an alveolar pattern
Desmoplastic small round cell tumor
Various small round blue cell tumors
Germ cell tumors such as dysgerminoma and yolk sac tumor can have areas that resemble a
juvenile granulosa cell tumor. Alveolar patterns in dysgerminoma mimic the irregular
macrofollicles of a juvenile granulosa cell tumor. Areas of solid growth, labyrinthine growth,
papillary growth and myxoid areas in yolk sac tumors mimic similar patterns that occur in
juvenile granulosa cell tumor. The overall appearance of these tumors as seen in multiple slides
is generally sufficiently distinctive to permit their differentiation from juvenile granulosa cell
tumor, however. The nuclei of yolk sac tumor cells have a primitive, embryonal appearance that
is not seen in juvenile granulosa cell tumors. Dysgerminoma is typically strongly positive for
CD117, D2-40, OCT4 and SALL4, while yolk sac tumor shows staining for SALL4, glypican-3,
and AFP, none of which are positive in juvenile granulosa cell tumor cells. The germ cell tumors
lack staining for granulosa cell tumor markers. One thing to watch out for is the presence of
luteinized stromal cells in the background of germ cell tumors; these often stain for sex cordstromal tumor markers, but the actual germ cell tumor cells are negative. Another potential pitfall
is the presence of hepatoid cells in granulosa cell tumors, which might stain for AFP and
glypican-3, but the staining would be focal and limited to the hepatoid cells.
A variety of other small cell tumors can involve the ovaries either as primary or metastatic
tumors and they can sometimes enter the differential diagnosis of granulosa cell tumor. (99)
Apart from the tumor types discussed above, these include small cell carcinoma of
neuroendocrine type, either primary or metastatic, desmoplastic small round cell tumor, PNET of
central or peripheral type, endometrial stromal sarcoma, rhabdomyosarcoma, and neuroblastoma.
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Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 30
Case 16
Steroid Cell Tumor
Clinical History: The patient was a 50 year old woman who presented with menometrorrhagia.
During the course of her workup she had a pelvic ultrasound that revealed a slightly enlarged
right ovary. It was thought to contain a 2.5 cm dermoid. She was followed, but the enlargement
persisted and she elected to have a laparoscopic hysterectomy and BSO. At surgery, the ovaries
appeared normal and the ovarian mass seen on ultrasound could not be visualized.
Gross Pathology: The right ovary measured 3.5 x 3.0 x 2.5 cm. The external surface was tan,
lobular and intact. Cross sections revealed a 2.5 cm solid orange nodule.
Diagnosis: Steroid cell tumor, nos.
Steroid Cell Tumors
This category of ovarian tumors is a heterogeneous group of gonadal stromal tumors. (1)
It includes the various types of Leydig cell tumors and the stromal luteoma, all of which are
usually small and clinically benign. The other tumors in this category are steroid cell tumors, not
otherwise specified (NOS), a group that includes small clinically benign tumors and larger
pathologically and clinically malignant tumors.
Steroid Cell Tumors of the Ovary
Leydig cell tumor, hilar type
Leydig cell tumor, nonhilar type
Stromal Leydig cell tumor
Stromal luteoma
Steroid cell tumor, nos
Leydig Cell Tumor
Most ovarian Leydig cell tumors develop in the hilum, presumably from hilus cells. This
is why hilar Leydig cell tumors were called “hilus cell tumors” in the past. Leydig cell tumors
can also develop from the ovarian stroma outside the hilum where they are called non-hilar or
stromal Leydig cell tumors depending on their morphology. (2-4) These tumors account for
about 20% of steroid cell tumors.
Leydig cell tumors mainly occur in postmenopausal women. The average patient is in her
upper 50s and almost all patients are more than 30 years old. (5) The usual clinical presentation
is with hirsutism or signs of virilization such as acne, hair loss, deepening of the voice,
development of a male body contour or hypertrophy of the clitoris. The serum testosterone
concentration is elevated in virilized patients, but urinary 17-ketosteroids are generally within
normal limits. Patients who are not virilized usually present with abnormal uterine bleeding. The
tumor is an incidental finding at surgery for some other condition in a small percentage of cases.
The endometrium is usually atrophic, but in a minority of patients peripheral conversion of
testosterone to estrogen results in an abnormal endometrial pattern, including postmenopausal
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 31
proliferative endometrium, hyperplasia or even adenocarcinoma, (6) Symptoms are often present
for several years before the diagnosis is made. This is partly because Leydig cell tumors are
usually small and difficult to localize, leading to consideration of other diagnoses, such as
adrenal dysfunction. Non-palpable tumors can sometimes be detected by imaging studies. It is
not uncommon for the clinician to have to measure hormone concentrations in blood obtained by
selective catheterization of the ovarian veins to determine which ovary contains the tumor. (7-9)
From a practical point of view Leydig cell tumors are benign and cured by surgery. (2, 5) Signs
of virilization ordinarily regress following removal of the tumor.
Gross Pathology
Leydig cell tumors are unilateral small solid brown or yellow-brown tumors located in
the hilum of the ovary, or, rarely, in the medulla or cortex. The average diameter has been
reported to be between 2 and 3 cm, but tumors we have seen recently have tended to be even
smaller, and often not visible until the ovary was sectioned.
Fig. 16-1 Polygonal cells, vesicular nuclei
Microscopic Pathology
Hilar Leydig cell tumors are circumscribed
but not encapsulated. The tumor cells are typical
Leydig cells as seen in the testis and around nerves
in the hilum of the ovary. They are round or
polygonal cells and have abundant granular
eosinophilic cytoplasm (Fig. 16-1). Some cells
contain yellow or brown lipochrome pigment. The
tumor cells have round and uniform nuclei of
medium size. The nuclei are vesicular or
hyperchromatic and conspicuous nucleoli are often
present. The tumor cells grow in diffuse sheets.
There is a tendency for the tumor cells to be arranged in such a manner that their nuclei are
clustered, leaving cytoplasmic nuclear free zones within the tumor. A peculiar eosinophilic
fibrinoid change is sometimes present in the walls of blood vessels. (5) Crystalloids of Reinke
are the characteristic marker of Leydig cells. These are intracytoplasmic eosinophilic hyaline
rods with blunt or tapered ends. Intracytoplasmic eosinophilic hyaline globules, which are
thought to be precursors of Reinke crystals, are sometimes easier to find. Unfortunately, Reinke
crystalloids can only be identified in about 50 percent of hilar Leydig cell tumors, so they are an
unreliable marker of this type of tumor, which is diagnosed based on the typical tumor cell
cytology and the hilar location.
There are two types of non-hilar Leydig cell tumors, both of which are quite uncommon.
Pure non-hilar Leydig cell tumors are circumscribed tumors that are grossly and microscopically
identical to hilar Leydig cell tumors except for their location; they are usually centered in the
medulla. (4) Stromal Leydig cell tumors are fibromas or thecomas that contain clusters, nests, or
sheets of Leydig cells. (2, 3, 10) By definition, crystalloids of Reinke must be identified in the
tumor cells in order to diagnose a non-hilar Leydig cell tumor. Since only 50 percent of hilar
Leydig cell tumors contain crystalloids, it is obvious that many non-hilar Leydig cell tumors go
unrecognized and are misdiagnosed as stromal luteomas or luteinized thecomas.
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 32
Stromal Luteoma
Stromal luteoma is a rare estrogen-secreting tumor that occurs mainly in postmenopausal
women. (11) It accounts for about 20% of steroid cell tumors. The most common presentation is
with abnormal uterine bleeding, and an endometrial biopsy often reveals a proliferative pattern or
hyperplasia. Rare stromal luteomas are virilizing. A third of cases are incidental findings at
operation or autopsy. The stromal luteoma is clinically benign.
Gross Pathology
Stromal luteoma is a small unilateral neoplasm; all reported examples have been less than
3cm in diameter, but they are often smaller and may not be detected until the ovary is cut open.
The cut surface is gray, white, yellow, or brown.
Microscopic Pathology
The tumor is located in the ovarian stroma and is composed of luteinized stromal cells.
The cells are polygonal, with ample granular eosinophilic cytoplasm and small round central
nuclei. There is no nuclear atypia and mitotic figures are rare or absent. They are differentiated
from a Leydig cell tumor by their non-hilar location and by the absence of cytoplasmic
crystalloids of Reinke. The background ovary typically shows bilateral stromal hyperthecosis
and, often, hilus cell hyperplasia.(11)
Steroid Cell Tumor, NOS
This category of ovarian tumors encompasses stromal neoplasms that cannot be more
specifically classified, hence the designation “NOS” (not otherwise specified). Tumors of this
type have also been called “lipid cell tumors” because many of them have clear foamy
cytoplasm. (12) Most tumors are composed of a variable mixture of cells resembling Leydig
cells, but lacking crystalloids of Reinke, and cells resembling adrenal cortical cells. Our case 16
falls into this category.
Steroid cell tumors occur over a wide age range, from 3 to 80 years. The average patient
is a middle-aged woman about 45 years old, but these tumors occasionally occur in children or in
the elderly. (13-15) Most steroid cell tumors secrete androgenic steroids in amounts sufficient to
cause hirsutism or virilization. Serum testosterone concentrations and urinary 17-ketosteroids are
elevated in virilized patients. Some tumors secrete renin and are associated with secondary
polycythemia or hypertension. (16, 17) Rare steroid cell tumors secrete cortisol and cause
Cushing’s syndrome. (18) Patients who do not present with hormonally mediated symptoms
have abdominal distention or pain, menstrual irregularities, or postmenopausal bleeding. The
tumor is an incidental finding in a few patients.
Most tumors are confined to the ovaries at diagnosis and bilateral tumors are rare (6
percent). (19) Metastases, usually to the peritoneum, are present at the time of diagnosis in 10–
20% of cases.(12, 19) Young patients with stage IA neoplasms can be treated by salpingooophorectomy. Older patients and those with advanced tumors are generally treated by
hysterectomy and bilateral salpingo-oophorectomy. Hirsutism and signs of virilization regress
after removal of the tumor. A major difference from the other tumors in the group (Leydig cell
tumors, stromal luteoma) is that a significant proportion of steroid cell tumors, 25–43%,
including a majority of those that cause Cushing’s syndrome, are clinically malignant. (12, 18,
19) Recurrences are generally discovered within the first few years after treatment, but about
20% are detected after more than 5 years.
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 33
Gross Pathology
Steroid cell tumors are solid and range from less than 1 cm to more than 20 cm in
diameter; the average is about 7 cm. The cut surface is tan, yellow, or orange, and about 25%
have areas of hemorrhage and necrosis. A few parovarian steroid cell tumors, possibly
originating in ectopic ovarian tissue or perhaps in adrenal rests, have been reported. (20, 21)
Microscopic Pathology
A mixture of Leydig-like and adrenal cortical-like cells is generally present, although one
of these may predominate. The Leydig-like cells are round or polygonal and have abundant,
sometimes vacuolated eosinophilic cytoplasm. The nucleus is round, centrally located with a
small nucleolus. Crystalloids of Reinke are never identified. The adrenal cortical-like cells are
also round or polygonal and have abundant pale or clear vacuolated cytoplasm. The nucleus is
vesicular and may contain a small to medium sized but conspicuous nucleolus. Fat stains are
positive in adrenal-type cells. In most cases, mitotic figures are infrequent and nuclear atypia is
absent or modest. Our case is an interesting one that at first glance appears to contain a typical
mixture of Leydig-like and adrenal cortical-like cells, with the latter predominating. The cells
with eosinophilic cytoplasm, however, are the ones with the largest nuclei and the ones that show
mitotic activity, and they actually more resemble eosinophilic adrenal cortical cells than Leydig
cells.
Pathologic features that have been present in clinically malignant steroid cell tumors
include large size, hemorrhage or necrosis, 2 or more mitotic figures/10 high power fields, and
moderate or marked nuclear atypia. (19)
Immunohistochemistry of Steroid Cell Tumors
All of the tumors in this group have similar immunophenotypes. Steroid cell tumors
differ from other types of sex cord-stromal tumors in that they are mostly FOXL2 and WT1
negative. (22, 23) On the other hand, they typically show strong granular cytoplasmic staining
for melan-A or for the related marker MART-1. (23-25) There is strong cytoplasmic staining for
inhibin, cytoplasmic and nuclear staining for calretinin and nuclear staining for steroidogenic
factor-1. (23, 25) CD56 stains tumor cell membranes. In one study there was strong membrane
staining for CD99 in cells with eosinophilic cytoplasm, but cells with clear vacuolated cytoplasm
were generally negative, (24) while in other studies only a minority of steroid cell tumors stained
for CD99. (23, 26) The tumor cells are vimentin positive. There is focal staining for cytokeratin
in 30–50% of cases, most often in cells with clear vacuolated cytoplasm, and often in a
Charles Zaloudek MD  Current Issues Part Two  Case 13 Page 34
perinuclear globoid or dot-like pattern. (24, 27) Other reactions that have been reported include
positive staining for androgen receptors in about two thirds of cases, (24) positive staining for
smooth muscle actin in a third of cases,(27) and negative staining for EMA. The best
combination of stains to confirm the diagnosis is inhibin, melan-A and steroidogenic factor-1;
lack of staining for EMA helps to exclude a clear cell carcinoma.
Differential Diagnosis
Steroid cell tumors are generally not difficult to diagnose, although their subclassification
is problematic in some cases due to the difficulty of identifying crystalloids of Reinke.
Nodular hyperplasia of luteinized stromal cells or hilar cells can occasionally raise the question
of a Leydig cell tumor or a stromal luteoma, but hyperplastic nodules are microscopic and
usually multifocal.
Luteoma of pregnancy is composed of luteinized stroma cells and its appearance overlaps with
that of the tumors in this group. However, it occurs in a very particular clinical setting, namely in
a young woman who is pregnant or who has just delivered. The luteoma of pregnancy is
typically associated with a theca lutein cyst, and there are often multiple nodules in the ovary,
and in the contralateral ovary as well. No crystalloids of Reinke are present.
Clear or oxyphilic cell tumors of various types occur in the ovary, either as primary or metastatic
neoplasms. These include clear cell carcinoma, variants of endometrioid carcinoma, hepatoid
tumors of various types, and metastatic clear cell renal cell carcinoma. Most of these have an
obviously more malignant appearance than would be anticipated in a steroid cell tumor, with
marked atypia or numerous mitotic figures. They tend to be strongly positive for keratin and
EMA, and they do not stain for steroid cell tumor markers.
Luteinized granulosa cell tumor may enter the differential diagnosis. This tumor is rarely
completely luteinized, and areas of more typical granulosa cell differentiation are generally
present. Granulosa cell tumor is more likely to be estrinizing. Immunohistochemistry may be
helpful, as most granulosa cell tumors, including luteinized ones, are FOXL2 positive and this
stain is often negative in steroid cell tumors.
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