Epithelial Tumors in the Ovary

The Good, The Bad, and the Ugly

Charles Zaloudek, MD
Professor, Department of Pathology
University of California, San Francisco
505 Parnassus Ave., M563
San Francisco, CA 94143
charles.zaloudek@ucsf.edu

Case 1
High Grade Serous Carcinoma
Clinical History: The patient was a 68-year-old woman with bilateral adnexal masses and an
elevated CA125 (793). She had had a hysterectomy in 2008 for postmenopausal bleeding. In
2011, a CT scan confirmed the presence of bilateral adnexal masses and revealed multiple small
omental nodules. At operation in 2011 she had 6-8 L of ascites. She underwent bilateral
salpingo-oophorectomy and tumor debulking including a transverse colon resection. Tumor was
noted to extensively involve the diaphragm, the anterior peritoneum, and the transverse colon,
the mesentery of the small bowel, the sigmoid colon and the bladder peritoneum.
Gross Pathology: The ovaries were small. The right ovary was a pale-tan firm multinodular
solid mass 4 cm in maximum dimension with tumor involving the surface. The left ovary was 5
cm in maximum dimension and was cystic and solid, with papillary excrescences in the linings
of some cysts. Solid areas were yellow-white. No abnormalities were noted in the fallopian
tubes. A 21 cm segment of transverse colon and omentum was riddled with small nodules
measuring 0.2 to 1 cm, with a dominant mass 4.5 cm in greatest dimension in the mesentery. The
bowel mucosa was unremarkable.
Diagnosis: High-grade serous carcinoma of the left fallopian tube and left and right ovaries with
extensive extraovarian tumor spread.
High Grade Serous Carcinoma
Serous carcinoma is the most common type of ovarian cancer, accounting for 68% of
ovarian cancers and 88% of stage III and IV cancers in a large population based study. (1)
Mutations of the P53 gene are present in most cases and are thought to be critical events in the
pathogenesis of this type of carcinoma. (2) Intraabdominal metastases are usually present at the
time of diagnosis, as in this patient, involving the omentum, the peritoneum or the abdominal
lymph nodes. (1) Occasional metastases are found in unusual distant sites, such as the brain,
lung, distant lymph nodes or the breast. (3)
General Clinical Features of Epithelial Tumors, Especially High Grade Serous Carcinoma
Ovarian carcinoma occurs mainly in peri- and postmenopausal women. About 10% of
patients with ovarian cancer have an inherited predisposition to develop the cancer (BRCA
mutation or Lynch Syndrome). (4) More than 70 percent of women with ovarian cancer have
extensive extraovarian tumor spread at the time of diagnosis. One reason for this is that the
symptoms caused by epithelial tumors are vague and non-specific. Common symptoms include
pelvic discomfort or pain, a sensation of abdominal fullness or pressure, gastrointestinal
disturbances, urinary frequency, and occasionally, menstrual abnormalities. Women with
advanced ovarian cancer often have ascites, which interferes with gastrointestinal function,
leading to nausea and vomiting. Ovarian enlargement in a woman over 45 raises the question of
ovarian cancer and requires further evaluation. The identification of a solid or complex mass by
sonography or some other imaging technique is worrisome.

The CA-125 monoclonal antibody blood test detects an antigenic site on MUC16, a high
molecular weight glycoprotein of uncertain function. (5, 6) The test is most useful in women
with serous carcinoma although women with other types of ovarian cancer sometimes have
elevations of CA-125 as well. The CA-125 is usually elevated in women with advanced
borderline and malignant epithelial tumors and in some women with localized disease. (7, 8) The
response to therapy correlates with the serum CA-125 level, with the CA-125 dropping into the
normal range in patients in clinical remission and rising again if the tumor recurs. (9) Increased
CA-125 levels also occur in patients with other types of cancers, and in some with benign
conditions including benign ovarian tumors and cysts, pregnancy, endometriosis, pelvic
inflammatory disease, leiomyomas, liver disease, and some collagen-vascular disorders. (10)
The treatment of ovarian tumors is primarily surgical. Invasive carcinoma of the ovary
directly invades into adjacent organs or spreads via the peritoneal fluid to the omentum, the
peritoneum, the serosal surfaces of the abdominal viscera and the diaphragm. Lymph node
metastases are common and distant metastases are occasionally detected in the lungs and other
sites. The stage, which is based on the surgical and pathologic findings, is the most important
prognostic factor.
FIGOStagingofOvarianCancer
IAOneovary,intactcapsule,notumoronsurface,cytologynegative
IBBothovaries,intactcapsule,notumoronsurface,cytologynegative
ICOneorbothovaries,withrupturedcapsule,tumoronsurfaceorpositivecytology
IIASpreadtouterusand/orfallopiantubes,cytologynegative
IIBSpreadtootherpelvictissues,cytologynegative
IICPelvicspread,anysite,positivecytology
IIIAMicroscopicperitonealmetastasesoutsidethepelvis
IIIBMacroscopicperitonealmetastasesoutsidethepelvis2cm
IIICMacroscopicperitonealmetastasesoutsidethepelvis>2cmand/orlymphnodemetastases
IVDistantmetastases(excludesperitonealmetastases)

The treatment of ovarian cancer usually includes surgery and chemotherapy. (11-13) The
standard surgical treatment is hysterectomy, bilateral salpingo-oophorectomy, omentectomy,
pelvic and para-aortic lymph node dissection, and staging biopsies and appendectomy if
indicated. Gynecologic oncologists generally try to remove as much extraovarian tumor as
possible (cytoreductive surgery). The prognosis is most favorable in early (stage III) stage
disease. In this group the patients age, the stage, the tumor grade and the results of peritoneal
cytology studies influence the prognosis. (14) A tumor type of high-grade serous carcinoma and
a positive cytology are the most important unfavorable prognostic findings in early stage disease.
(15) Young women with some types of stage IA or IC adenocarcinomas can be treated by
unilateral salpingo-oophorectomy, omentectomy, and thorough staging if they are unwilling to
have a hysterectomy. (16-18) Some women with advanced ovarian cancer (stage IIIC-IV)
receive chemotherapy prior to surgery. This is known as neoadjuvant chemotherapy and it can
reduce tumor volume and make resection easier. Neoadjuvant chemotherapy followed by
cytoreductive surgery resulted in approximately the same survival rate as primary cytoreductive
surgery followed by chemotherapy in a recent European trial, but there was less morbidity. (19)
The survival results were less favorable than those currently reported for patients treated with
primary cytoreductive surgery followed by chemotherapy in the US, and American gynecologic

oncologists appear to be taking a cautious approach to adopting neoadjuvant chemotherapy as

the standard treatment of all patients. (20) Neoadjuvant chemotherapy sometimes causes changes
in the histologic appearance of a tumor such that it is difficult to classify, (21, 22) although
immunohistochemical staining patterns are less altered and may be of some use in classifying
treated tumors. (23)
Combination chemotherapy with carboplatin and paclitaxel is the standard first line
chemotherapy for women with high-grade stage IA carcinomas and for those with extraovarian
spread or positive peritoneal cytology. (24) Optimally debulked patients with stage III
carcinomas may be candidates for treatment with IV paclitaxel followed by intraperitoneal
chemotherapy with cisplatin and paclitaxel. (25, 26) This regimen is reported to result in
increased survival compared to standard IV chemotherapy, but it is more toxic. Chemotherapy
results in partial or complete clinical remission in about 85 percent of women with advanced
cancer, but most patients relapse within 23 years and the long-term survival rate is less than 20
30 percent. (27)
Gross Pathology
Serous carcinoma tends to be large and is often bilateral. There is often a mixture of
cystic, papillary, and solid growth. The solid areas are tan or white and there are foci of
hemorrhage and necrosis. Carcinoma frequently invades through the ovarian capsule and grows
on the surface of the ovary. Serous surface papillary carcinoma grows predominantly on the
surface of the ovary, with minimal parenchymal invasion and no intracystic growth. When there
is extensive extraovarian serous carcinoma with only focal (<0.5cm) surface growth on the
ovaries, the process can be viewed as primary peritoneal serous carcinoma with involvement of
the ovaries. While most serous carcinomas are large tumors, small high-grade serous carcinomas
occur and can be associated with widespread metastasis throughout the abdomen.
Microscopic Pathology
The tumor cells exhibit marked nuclear atypia and frequent (often 30-50 or more mf/10
hpf) mitotic figures. The nuclei are hyperchromatic and variably pleomorphic, and often contain
one or more prominent nucleoli. The nucleus to cytoplasm ratio is high, and the nucleus typically
appears to occupy most of the cell. Papillary growth is usually present at least focally and is
frequently the predominant growth pattern (Fig. 1-1). Some papillae have fibrovascular cores
that are lined by stratified tumor cells. The tumor cells often pile up to form tufts that project
above the surfaces of the papillae. A micropapillary pattern in which long thin tufts of tumor
cells grow into cystic spaces is also common. Tumor cells line glands and cystic spaces,
diffusely infiltrate fibrotic stroma, or form solid nests and sheets (Fig. 1-2). Elongated slit-like
glands within foci of solid growth are a characteristic finding in high-grade serous carcinoma.
Foci of microcystic growth, sometimes
GrowthPatternsinHighGradeSerousCarcinoma
with admixed signet ring type cells, are
Papillary
noted occasionally. (28) Geographic
Micropapillary
zones of necrosis may be present. Rare
Glandular
examples of high grade serous
Slitlikeglands
carcinoma apparently evolve from a
Cribriform
borderline serous tumor or a low grade
Cystic
serous carcinoma, (29, 30) and in these,
Microcystic
areas of high grade carcinoma are
Solid
Transitionalcellcarcinomalike

admixed with areas of borderline tumor or low grade carcinoma.

The histologic classification of high-grade
Fig.11Papillarygrowthpattern
ovarian carcinomas is of controversial. Some
authorities think that a diagnosis of high-grade
serous carcinoma is only appropriate for
predominantly papillary tumors with minor
glandular or solid areas. (31) Some who favor this
view think that neither the immunophenotype nor
the presence or absence of p53 mutations
separates high grade serous carcinoma from high
grade endometrioid carcinoma and that the
distinction must be made based on the histology,
such that tumors with papillae and slit like glands

are high grade serous carcinomas and those where

there is sheet like growth of tumor cells or glands

Fig.12Solidgrowth,markedatypia
are high grade endometrioid carcinomas. (32)
Others have adopted a more inclusive
classification scheme, and view most high grade
carcinomas with some features of serous
differentiation as types of high grade serous
carcinoma, including tumors with extensive solid
areas, tumors with high grade glandular areas
without squamous differentiation, and some
tumors with clear cell or transitional cell areas.
(33-37) High grade serous carcinomas with clear
cell areas are variants of high grade serous
carcinoma and not mixed serous-clear cell carcinomas, and they should be classified
accordingly.(38) Immunohistochemical and molecular studies support the concept that these are
variants of high-grade serous carcinoma and diagnosing them as such results in a more
reproducible and useful classification system. (33) Tubal intraepithelial carcinoma is associated
with serous carcinoma.

Grading of Serous Carcinoma

Grading of ovarian carcinomas has not been standardized. Silverberg and colleagues
developed a universal grading system that they thought could be used for all types of ovarian
carcinomas. (39) In their system, the grade is determined by the degree of nuclear atypia, the
mitotic index, and the extent to which the tumor cells form papillae or glands. More recently, a
binary grading system, in which low-grade serous carcinoma almost always falls into grade 1 of
the universal grading system, has gained greater acceptance than the universal grading
system because it better reflects the current concept that high and low grade serous carcinomas
represent two different tumor types rather than two different grades of the same tumor. In the
binary system, low-grade serous
HighGradevsLowGradeSerousCarcinoma
carcinoma exhibits mild to moderate

Atypia
MF/10hpf
BL
nuclear atypia and 12 or fewer mitotic
LGSerous MildMod
12
+
figures per 10 high power fields. (40) In
HGSerous Marked
>12

BL=associatedwithborderlinetumorelements

high-grade serous carcinoma there is marked nuclear atypia, considerable pleomorphism and
often prominent macronucleoli. Mitotic activity is high; while a floor of 12 mf/10 hpf has been
proposed as a lower limit of mitotic activity in high grade serous carcinoma, there was a median
of 38 mf/10 hpf in one study. (40) Apart from their differences in nuclear atypia and mitotic
activity, low and high-grade serous carcinoma grow in different architectural patterns, and the
correct diagnosis can generally be determined at low magnification without any need for mitosis
counting. Also, most low-grade serous carcinomas are associated with a borderline serous tumor,
so in a primary ovarian tumor the finding of patterns of a borderline tumor favors low-grade
serous carcinoma. Tumors with intermediate nuclear grades (grade 2 serous carcinoma) are
similar in their growth patterns and molecular features to high-grade serous carcinoma and
exhibit the same aggressive behavior, so they are viewed as high-grade tumors. (41)
P53 and High Grade Serous Carcinoma
Mutations of the TP53 gene have long been associated with high-grade serous carcinoma.
TP53 mutation has been thought to be an early event in serous carcinogenesis, a point that has
been re-emphasized by recent studies of a p53 positive putative cancer precursor in the fallopian
tube known as the p53 signature lesion. (42) p53 signatures show positive immunostaining for
p53 and they have TP53 mutations. The p53 signature is currently viewed as a non-obligate
premalignant condition, illustrating just how early in the carcinogenic process TP53 mutations
may occur. Recent studies of high-grade serous carcinoma reveal a high frequency of TP53
mutations in such tumors. Yemelyanova et al studied 43 high-grade serous carcinomas; only 6
lacked TP53 mutations. (43) Ahmed and colleagues found TP53 mutations in 96.7% (119/123)
of patients with advanced stage high-grade serous carcinomas. (2) The Cancer Genome Atlas
Research Network analyzed whole exome DNA sequences in 316 high-grade high stage serous
carcinomas and found that 96% had TP53 mutations. (44) Thus, almost all high-grade serous
carcinomas have TP53 mutations. The high and rather consistent frequency of TP53 mutations is
somewhat surprising, since I would have expected that variations in the way high-grade serous
carcinoma is diagnosed and classified to impact the percentage of positive cases.
High-grade serous carcinoma frequently shows immunohistochemical evidence of the
presence of a p53 mutation. This can be manifest as diffuse strong staining of nearly all tumor
cell nuclei. (45) In some cases, the p53 mutation results in the complete absence of p53 protein,
in which case there is no staining in any tumor cell nuclei. Both of these results are considered
positive test results. Tumors that do not have a p53 mutation generally show weak to moderate
Interpretationofp53Immunostaining
Pattern

TestResult

Diffusestrongpositivenuclearstaining(Positive
stainingin>50%oftumorcellnucleiandusually
in>80%)

Positive

Patchyweakstainingin<50%oftumorcell
nuclei

Negative

Absolutelynostaininginanytumorcellnuclei

Positive

staining in some tumor cell nuclei. In one study, there was complete absence of p53 expression
in 30.3% of cases, focal expression in 12.0% and overexpression in 57.7%, (46) and similar
results were observed in another study. (43) By recognizing the patterns of positive staining
pathologists can identify which ovarian cancers are likely to have TP53 mutations and hence
which are best classified as high-grade serous carcinomas. Among patients with probable TP53
mutations, those with complete absence of expression had an increased risk of recurrence
compared with those with overexpression. (46) Other markers that are generally positive in highgrade serous carcinoma, and that complement p53 as immunohistochemical markers of highgrade serous carcinoma, are p16 and HGMA2. A positive stain for p16 in this context is diffuse
strong staining of the cytoplasm and nuclei of all or nearly all tumor cells. (47-49) The range of
staining that should be expected for HGMA2 is less well worked out; in one study about two
thirds of high grade serous carcinomas showed moderate to strong nuclear staining in 40-100%
of tumor cells. (50) Low grade serous carcinoma, in contrast, rarely shows the type of strong
staining for p53 or p16 seen in high grade serous carcinoma, (45, 48, 51, 52) and these markers
are generally negative in borderline and benign tumors as well.
BRCA Mutations and High Grade Serous Carcinoma
High-grade serous carcinoma is the type of ovarian cancer most associated with
mutations in the BRCA genes. Large, clinically detected tumors in BRCA mutation carriers are
mostly high-grade serous carcinomas, although other types of ovarian cancer occasionally occur
in these patients. (53) In the range of 10-15% of ovarian carcinomas occur in women with
germline mutations of BRCA1 or BRCA2. In a recent analysis of 1342 unselected Canadian
women 176 or 13.3% carried a mutation (107 BRCA1, 67 BRCA2, and 2 with mutations in both
genes). (54) The hereditary breast and ovarian cancer syndrome, caused by mutations in these
genes, is inherited in an autosomal dominant fashion. The lifetime risk of a woman with a BRCA
mutation developing breast cancer is 50-80% and the lifetime risk of developing ovarian cancer
is 30-50%. The risks reported in various studies depend partly on how the cases were
ascertained, with higher risks reported in studies of cancer families and lower risks in studies
where carriers were identified independent of their family histories. Women with BRCA
mutations or who have a family history of ovarian cancer are treated by risk-reducing bilateral
salpingo-oophorectomy (RRSO), which has been shown to markedly lower the risk of
developing carcinoma. (55-58) Cancer risk is not eliminated as these patients are still at risk for
peritoneal serous carcinoma and for breast cancer, although the risk for peritoneal cancer is very
low.
There are two BRCA genes, BRCA1 and BRCA2. They are classified as tumor
suppressor genes. BRCA1 is located on chromosome 17 at 17q21-22 and BRCA2 is located on
chromosome 13 at 13q12-13. The BRCA2 gene is larger, having about twice as many amino
acids as the BRCA1 gene (3148 vs 1863). These genes are both involved in many intercellular
processes but their main function is to protect the genome from double-stranded DNA damage
during DNA replication. BRCA1 is involved in checkpoint activation and DNA repair and both
BRCA1 and BRCA2 are involved in homologous recombination as a means to repair double
stranded DNA breaks. (59) When BRCA is deficient, double stranded breaks cannot be repaired
by the error free homologous recombination process, and they are instead repaired by alternate
methods, such as end joining and single strand annealing, that lead to genomic instability
resulting in the cancer predisposition that is associated with BRCA loss.

BRCA associated ovarian cancers theoretically might be more responsive to

chemotherapy with drugs like cisplatin that damage DNA, since their tumor cells are less able to
repair the DNA breaks that such drugs cause. In addition, BRCA associated cancers may be
amenable to therapy with PARP (poly (ADP-ribose) polymerase) inhibitors, the activity of which
are dependent on loss of BRCA function. In recent analyses, conflicting results have been
published. Analysis of the Cancer Genome Atlas Project data indicated that patients with
BRCA1 associated tumors were likely to be slightly younger than those with BRCA2 or wild
type cancers. Patients whose tumors had somatic mutations had the same clinical characteristics
as patients with wild type tumors. Among those with germline mutations, only patients with
BRCA2 mutations had improved survival and better response to platinum based chemotherapy.
(60) On the other hand, patients with BRCA1 inactivation due to germline mutations or promotor
hypermethylation had the same outcome as those with wild type BRCA. The authors of another
study, which pooled data from 26 studies, concluded that women with BRCA1 and BRCA2
germline mutations both had improved survival relative to those with wild type BRCA, although
those with BRCA2 mutations appeared to have the best survival. {Bolton, 2012 #36408}
Loss of BRCA function is often due to a germline mutation in either BRCA1 or BRCA2,
but it can also be due to somatic BRCA mutations and in the case of BRCA1, to promotor
hypermethylation. (61) Regardless of the cause of BRCA dysfunction, recent pathologic studies
suggest that a combination of histologic findings may predict that a given ovarian tumor is
BRCA related. One set of histologic criteria was published by Soslow et al, {Soslow, 2012
#36680} and another was published in abstract form only by Fujiwara et al. Histologic features
that may be BRCA related include serous/undifferentiated histologic type; solid,
pseudoendometrioid or transitional growth patterns; marked atypia and giant bizarre nuclei;
numerous tumor infiltrating lymphocytes; and a very high mitotic rate. According to these
authors, combinations of these features, when present, may be indicative of BRCA dysfunction,
but it is not clear that the histologic criteria differentiate tumors with BRCA1 mutations from
those with BRCA2 mutations, nor do the criteria differentiate tumors with germline mutations
from those with BRCA dysfunction due to somatic mutations or promotor hypermethylation.
CausesofBRCALossofFunction
GermlineBRCAmutation 1015%
SomaticBRCAmutation
510%
Promotor
30%
Hypermethylation
Other(microRNA,etc)
?

Fallopian Tube Surprise

While small tumors are
occasionally identified in the ovaries,
most of the intraepithelial and early
invasive serous carcinomas detected in
RRSO specimens have been found in
the fallopian tubes.(62-69) Tubal
intraepithelial carcinoma is less
common in salpingectomy specimens from patients without a BRCA mutation, but it is
occasionally detected; in one study tubal intraepithelial carcinoma was found in 8% of patients
with a BRCA mutation and in 3% of patients with no mutation. (69) Interestingly, complete
sectioning of the fallopian tubes in patients with a clinical diagnosis of a primary ovarian or
primary peritoneal serous carcinoma, regardless of whether it occurs in a woman with a germline
BRCA mutation, frequently reveals foci of serous tubal intraepithelial carcinoma or small
apparently primary foci of invasive serous carcinoma of the fallopian tube. (66, 70-72) This has
led to the hypothesis that many, if not all, serous carcinomas of the ovary and peritoneum are

actually metastases from tubal tumors, not primary neoplasms of the ovary or peritoneum. (70,
73, 74) Rare high-grade serous carcinomas appear to arise from a low grade serous carcinoma or
a borderline serous tumor. (30) The histogenesis of serous carcinoma of the ovary and its
relationship to tumors of the fallopian tube is an area of active research.

Immunohistochemistry of Serous Tumors

All serous tumors have immunohistochemical features in common. They usually show
positive staining for cytokeratin 7 and they do not stain for cytokeratin 20 or CDX2. (75) They
show variable staining for estrogen and progesterone receptors, with less staining being present
in high-grade serous carcinoma than in lower grade serous tumors. Borderline serous tumors and
serous carcinomas generally show membrane staining for OC-125. (76) One of the most helpful
features of serous tumors is that they show nuclear staining for WT-1. (77-80) This helps
differentiate them from other types of ovarian tumors, such as endometrioid and clear cell
carcinomas. Staining for WT-1 is also helpful in differentiating ovarian serous carcinoma from
endometrial serous carcinoma, which has a similar microscopic appearance but is less likely to
stain for WT-1. (77, 81, 82) Borderline serous tumors and low grade serous carcinomas are more
likely to show nuclear staining for PAX2 than are high grade serous carcinomas; variable strong
staining is generally seen in the former categories of serous tumors while staining is typically
absent in high grade carcinomas. (83) PAX8 appears to be a reliable marker of female genital
tract tumors, and it is almost always positive in serous tumors, although staining can vary in
extent and intensity. (84-86) HMGA2 is another marker that is positive in a majority of highgrade serous carcinomas but uncommon in other types of ovarian cancer. (50) Patients with highgrade serous carcinoma are frequently treated with chemotherapy, either after or before surgery.
The postchemotherapy immunophenotype is similar to that of untreated serous carcinoma. (23)
ImmunohistochemicalStaininginHighGradeSerousCarcinoma
CK7
+
CK20

PAX8
+
CA125
+
WT1
+
p53
Diffusestrongpositiveorcompletelynegative
p16
Diffusestrongpositive
HMGA2
+
PAX2

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13

Case 2
Borderline Serous Tumor, Micropapillary Type
Clinical History: None provided.
Gross Pathology: The left ovary was 29 cm in maximum diameter. The surface was smooth to
finely granular but there were areas of surface papillary growth measuring up to 5 cm in
maximum dimension. Most of the cyst lining was smooth, but areas of soft tan papillary growth
up to 2 cm were present in the lining. The right ovary was 10 cm in diameter. An area of
papillary growth on the surface measured 8 cm in maximum dimension. The cut surface showed
tan cysts up to 0.3 cm.
By report, the tumor spread beyond the ovaries to involve the omentum, the uterine serosa and
the cul de sac.
Diagnosis: Borderline Serous Tumor, Micropapillary Variant.

Borderline Serous Tumor

Tumor is confined to the ovaries in most patients (60-85%). (1, 2) A minority of patients
has pelvic or peritoneal implants and pelvic or abdominal lymph nodes contain tumor in up to
40% of patients. (3). Spread to parenchymal organs or outside the abdominal cavity is
uncommon, although it does rarely occur. (4) Long-term survival is more than 90% for patients
with all stages of disease, (1, 2, 5, 6) but the longer patients with extraovarian disease are
followed the greater the percentage who will have recurrences, since many recurrences are
detected more than 5 years after initial diagnosis. (7) Survival approaches 100 percent for
patients with tumor confined to the ovaries (stage I). Tumor-related deaths fall into three main
categories: 1) the patient develops low grade serous carcinoma and dies of carcinoma; 2) the
patient develops a fatal complication of a borderline tumor, such as fibrous adhesions leading to
bowel obstruction; or 3) the patient dies of a complication of treatment.
Conservative treatment is generally indicated for patients with borderline tumors, except
for the small proportion whose tumors exhibit features consistently associated with aggressive
behavior, such as invasive peritoneal implants or recurrence as low-grade serous carcinoma.
Oncologists treat patients with invasive implants or low-grade serous carcinoma with
chemotherapy although such patients tend to have long survivals regardless of therapy and tumor
response to chemotherapy is less than satisfactory (i.e., available chemotherapy is less than
optimal for such patients).
The standard surgical treatment for a borderline tumor is total abdominal hysterectomy,
bilateral salpingo-oophorectomy, omentectomy, and complete staging with resection of
extraovarian tumor implants if any are present. Many women with borderline tumors are young
and want to retain their childbearing capability. Unilateral salpingo-oophorectomy, or even
cystectomy, can be considered as a treatment option in some circumstances, although patients
treated in this way have about a 25 percent risk of recurrence in the contralateral ovary. (1, 8)
Laparoscopic management has been utilized, even in women with small peritoneal implants. (9,
10) Conservative surgery to preserve fertility appears possible in some circumstances, even in

14

patients with extraovarian tumor spread. Patients with micropapillary borderline serous tumors
are more likely than those with typical borderline serous tumors to have tumor spread beyond the
ovary. When corrected for stage and implant type, however, no difference in survival has been
demonstrated.(11) Whether women who have been inadequately staged during their initial
operation should be restaged is controversial. The tumor stage is changed in about 15% of
women who have restaging surgery, but the risk of recurrence appears to the same in women
who are restaged and those who are not. Restaging is most valuable in women with
micropapillary borderline serous tumors, since they have a greater risk of having invasive
peritoneal implants. Recurrences are generally detected many years after primary therapy, and
recurrent disease can be slowly progressive. Recurrent tumor can be as borderline serous tumor,
low grade serous carcinoma, or, rarely, high grade serous carcinoma. (12, 13) Some authors have
reported an increased rate of disease progression when recurrence is as low-grade serous
carcinoma. (1) Surgical resection of contralateral or extraovarian tumor deposits is the most
effective treatment for women with progressive or recurrent tumors. Oncologists are not in
complete agreement, but most give chemotherapy or radiotherapy only when there is progressive
disease that cannot be resected. The survival rate is high, even for women with advanced stage
tumors. (14)
Gross Pathology
Borderline serous tumors are large, usually multilocular cystic neoplasms. They are
bilateral in 3540% of cases. Coarse papillary excrescences arise from the cyst linings and, in
4050% of cases, from the surface of the ovary. Papillary growth is a focal finding in some
tumors and an extensive confluent one in others. Areas of solid growth are unusual except in the
form of adenofibromatous and hemorrhage or necrosis are seldom present.
Microscopic Pathology
Borderline serous tumors have a characteristic pattern of papillary growth with a complex
hierarchical branching pattern (Fig. 2-1). The papillae grow from the cyst linings into the
lumina, or from the surface of the ovary. Complex papillary and glandular patterns and
secondary cyst formation are typical. The
Fig.21Branchingpapillarygrowth
papillae have fibrovascular cores that are
conspicuous even in smaller branches. The
papillae are lined by proliferating columnar cells
that pile up into several layers. Ciliated cells are
not uncommon. The cells form tufts from which
clusters of cells and single cells are detached
into the cyst lumens. There is low grade nuclear
atypia and scattered mitotic figures are present.
Cells with abundant eosinophilic cytoplasm, the
indifferent or metaplastic cells, are scattered
singly or in small clusters among the columnar
tumor cells; they tend to be most conspicuous at
the tips of the papillae. Plaques or nodules of
loose fibrous tissue containing glands and papillae are occasionally noted in borderline serous
tumors, either inside the tumor or more commonly on the surface of the ovary. They resemble
desmoplastic peritoneal implants (see below) and have been termed autoimplants.

15

Autoimplants tend to be detected in high stage tumors, but do not appear to have prognostic
significance. (1, 15) The wall of a borderline serous tumor is generally thicker than that of a
cystadenoma. Some tumors have a fibromatous stromal component that is prominent enough that
they can be classified as borderline serous adenofibromas or cystadenofibromas.
The main microscopic finding that differentiates a serous borderline tumor from a serous
carcinoma is the absence of diffuse stromal invasion in the borderline tumor. In a borderline
tumor, papillae and glands that appear to be within the stroma are usually an artifact resulting
from tangential cutting of complicated infoldings of the cyst lining. Such glands are not
infiltrative and there is no stromal fibroblastic or inflammatory reaction around them.
Stromal Microinvasion
Limited foci of stromal invasion are occasionally identified in a borderline serous tumor,
called microinvasion by analogy with foci of minimal invasion seen in other sites, such as the
cervix. Various arbitrary size limits have been proposed for microinvasion, ranging from 3 mm
to 5 mm, but in practice foci of microinvasion are almost always smaller than 3 mm. (16) A
largest dimension of invasive growth of 3 mm is accordingly a reasonable maximum size limit
for microinvasion. (17) Multiple foci of microinvasion are typically present, usually 2 or 3 but
ranging up to 10 or even more. A number of patterns of microinvasive growth have been
described. The most common is one in which small clusters and cords of cells with eosinophilic
cytoplasm, round vesicular nuclei, and prominent nucleoli are haphazardly distributed in the
fibrous stroma of the cyst wall or a papilla. A stromal reaction usually is not seen around the
microinvasive cells. They are occasionally found within lymphatic spaces, but the clinical
significance of this finding is unclear. (18) A systematic study of borderline serous tumors using
sections stained with the lymphovascular endothelial marker D2-40 revealed intratumoral
lymphovascular space invasion in 60% of borderline tumors with microinvasion but in none of
the tumors without it. (19) In a second pattern the stroma is invaded by papillae, small glands,
cribriform glands, cords of cells, or even confluent nests of tumor cells. (18) Less common
patterns include complex branching micropapillae in the stroma, usually within clear clefts, and a
macropapillary pattern of invasion in large papillae with thick fibrous cores, also generally
surrounded by clear spaces, are lined by one or two layers of tumor cells. Intrastromal tumor
cells can lie in unremarkable stroma or they can be surrounded by inflamed or myxoid fibrous
stroma. When microinvasion is detected the pathologist should conduct a thorough evaluation to
exclude larger areas of invasion that would be indicative of low-grade serous carcinoma. It is
difficult to identify stromal microinvasion at low magnification; immunostains for cytokeratin or
epithelial membrane antigen can be used to accentuate the microinvasive epithelial cells in the
stroma in questionable cases.
The clinical significance of microinvasion is unclear. Most patients have been reported to
have an uneventful course and an unfavorable outcome observed in a few patients has been
attributed to other factors, such as invasive implants or incomplete staging. (18, 20-23) The
authors of recent studies of borderline serous tumors have noted progressive disease in a few
patients with microinvasion, (24, 25) and one group found microinvasion to be a significant
adverse finding. (1)
The epithelium in borderline serous tumors includes eosinophilic metaplastic or
indifferent cells. These cells tend to be more numerous in tumors in which microinvasion is
identified, and they are often prominent in tumors removed from pregnant patients. For unknown
reasons, microinvasion seems to be detected more frequently in tumors from pregnant women.

16

(26) Mucin secretion and stromal decidual reactions have also been noted in tumors removed
from pregnant women.
Micropapillary Variant of Borderline Serous Tumor
The term micropapillary serous carcinoma was proposed for a group of proliferative
serous tumors with excessive epithelial proliferation, including some non-invasive tumors in the
borderline category as well as some low grade invasive serous carcinomas. (27, 28) While no
one doubts that invasive micropapillary tumors are forms of low grade serous carcinoma, the
nature of the non-invasive tumors is still controversial, with most gynecologic pathologists
considering them to be variants of borderline serous tumors. Gene expression analysis indicates
that micropapillary borderline serous tumors are more closely related to low grade serous
carcinoma than to typical borderline serous tumors. (29) Clinical follow-up of patients with
micropapillary serous tumors indicates that most patients with stage I tumors are cured by
surgery. (30, 31) However, patients with micropapillary borderline serous tumors are more likely
to have bilateral tumors, surface papillary growth, extraovarian disease and invasive implants.
Survival rates appear to be similar to those for conventional borderline serous tumors, once
adjusted for stage and implant type. (11, 24, 31-34) Although it remains a somewhat
controversial entity, I view non-invasive micropapillary serous tumors as high grade or
excessively proliferative variants of borderline serous tumors.
Grossly, micropapillary borderline serous tumors are cystic and solid tumors that average
89 cm in diameter. They tend to be bilateral, and to exhibit both intracystic and surface
papillary tumor growth.
Microscopically, micropapillary borderline serous tumors are characterized by foci of
micropapillary growth in the background of a typical borderline serous tumor. The
micropapillary growth must be > 0.5 cm (an
Fig.22.Micropapillarygrowth.
arbitrary size) for a borderline serous tumor to
be classified as the micropapillary type. (30) If
there is micropapillary growth < 0.5 cm the
tumor is simply classified as a borderline
serous tumor.
This pattern is characterized by the
presence of long micropapillary tufts of
epithelial cells with little or no fibrovascular
stroma sprouting from bulbous fibrovascular
stromal papillae, from the cyst wall. When
proliferative micropapillae are tangentially
sectioned, they are packed together with larger
papillae resulting in a very busy histologic
appearance. However, the pattern is one of
proliferation into cystic spaces rather than growth into the stroma, so the proliferation is not an
invasive one. In another arbitrary definition, the papillae supposedly should be five or more
times longer than they are wide. Tumors with foci of cribriform growth along the surfaces of
papillae are also classified as micropapillary borderline serous tumors. The tumor cells are often
somewhat different from those in the background borderline serous tumor. They tend to be
cuboidal, hobnail-shaped, or low columnar, rather than the taller columnar cells seen in typical
borderline serous tumors. The tumor cell nuclei are uniform and there is only mild or moderate

17

atypia. Mitotic figures are infrequent. Ciliated cells are seen less often in micropapillary
borderline serous tumors than in typical borderline serous tumors.
Peritoneal and Omental Implants
Microscopic or macroscopic peritoneal or omental tumor implants are found in 1530
percent of women with serous borderline tumors. These are most often small superficial
excrescences measuring only a few millimeters, although larger solid or cystic implants are
occasionally present. There is controversy as to whether these represent metastases from the
ovarian tumor or sites of synchronous peritoneal neoplasia, although an increasing number of
studies show similar genetic profiles in the ovarian and extraovarian tumors, favoring the view
that they represent spread from the ovarian tumor. (35-39) Several types of implants occur.
In non-invasive epithelial implants, papillary serous borderline tumor grows on the
ClassificationofPeritoneal/OmentalImplantsofBorderlineSerousTumors
Noninvasiveepithelialimplant
Noninvasivedesmoplasticimplant
Indeterminateimplant
Invasiveimplant(generallyviewedasaformoflowgradeserouscarcinoma)

surface of the peritoneum or in cystic spaces just beneath it. The implants are circumscribed and
do not invade the underlying stroma. Often, immunostains for calretinin delineate mesothelial
cells in the lining of the subsurface cysts, although the tumor cells are negative.
Non-invasive desmoplastic implants are plaques of vascular fibrous stroma that contain a
few epithelial cells, small clusters of cells, or scattered small glands lined by bland epithelial
cells. The implants appear plastered on to the peritoneal surface and there is no invasion into the
underlying stroma.
Mixtures of these two types of non-invasive implants are common; sometimes noninvasive papillary growth overlies a desmoplastic implant or the patterns may lie side by side.
Patients with non-invasive implants tend to have a favorable prognosis, although a small
percentage develop progressive disease and die of tumor. (1, 7, 33) Non-invasive implants can
also cause adhesions leading to bowel obstruction.
Invasive implants are rare (510 percent) but, together with advanced tumor stage, are the
most significant adverse prognostic findings in patients with borderline serous tumors. (6, 11, 24,
34, 40) Some studies are difficult to evaluate because the authors did not use standard definitions
of invasive implants. No invasive implants were found in one hospital-based study of 57 patients
that did not include any consultation cases, indicating that practicing pathologists will not see
invasive implants very often. (41) The distinguishing features of invasive implants are 1) an
infiltrative pattern of growth into the surrounding tissues and 2) abundant epithelium, often in the
form of micropapillae surrounded by clear clefts. Invasive implants essentially have the
microscopic appearance of low grade serous carcinoma. In practice, I like to use the term
invasive implant for microscopic foci of invasive growth most typically seen in the omentum
of patients with borderline serous tumors in the ovary, and low grade serous carcinoma for
macroscopic amounts of invasive growth as seen in the ovaries or the peritoneum/omentum.
Expanded criteria for invasive implants have been proposed, but remain controversial. (42)
These include a micropapillary pattern of growth, clear spaces or clefts around clusters of tumor
cells and infiltrative glands that do not extend into underlying tissues. It can be very difficult to

18

classify implants. When clear cut invasion is not present the term indeterminate implant is
often used. Pathologists need to realize that a diagnosis of invasive implant generally leads to
chemotherapy. Since chemotherapy in this setting is not particularly effective, I prefer to be
conservative with the diagnosis of invasive implants; I like to see tissue invasion as well as
increased cellularity before making such a diagnosis.
Pathologic Findings in Lymph Nodes
Tumor is present in pelvic or para-aortic lymph nodes in up to a third of patients with
advanced borderline tumors. (3, 43) There are two main patterns of lymph node involvement. In
one, the tumor grows in a branching papillary pattern similar to that observed in a primary
ovarian borderline serous tumor. In the other, tumor cells are present singly or in small nests in
the subcapsular sinuses. Lymph node involvement by hyperplastic mesothelial cells is a rare
mimic of the latter pattern. (44) This is a very rare finding that I have never encountered. The
presence of peritoneal mesothelial hyperplasia, the appearance of the cells, and positive
immunostaining for mesothelial markers such as calretinin differentiate hyperplastic mesothelial
cells from tumor cells. A rare but prognostically unfavorable pattern of lymph node involvement
by borderline serous tumor is one in which the lymph node parenchyma is replaced by a nodular
proliferation of tumor cells growing in reactive fibroblastic stroma. This pattern represents low
grade serous carcinoma in the lymph node and is similar in appearance to an invasive peritoneal
implant. Borderline serous tumors mainly involve intra-abdominal lymph nodes, but tumor is
rarely found in extra-abdominal lymph nodes, either at the time the ovarian tumors are removed
or at some later time. (4, 45)
Epithelial inclusions lined by low columnar cells, many of which are ciliated, are found
in the pelvic or para-aortic lymph nodes in 525% of patients who are operated on for uterine
cancers. These inclusions, which are called benign epithelial inclusions or endosalpingiosis, are
much more common in patients with borderline serous tumors than in the general population. It
has been proposed that they represent a precursor lesion or a type of lymph node involvement by
a borderline serous tumor.(3, 46, 47) Some pathologists have proposed that lymph node
involvement by borderline serous tumors represents synchronous neoplasia arising in epithelial
inclusions rather than metastases from the ovarian tumor. For staging purposes the inclusions are
viewed as benign and not as lymph node involvement. Regardless of its origin, lymph node
involvement by a borderline serous tumor is most often found in women who have peritoneal or
omental implants and it does not appear to be an independent adverse prognostic finding. (3, 48,
49) Foci of low grade serous carcinoma in a lymph node on the other hand are an unfavorable
finding.(3)

Low Grade Serous Carcinoma

Low-grade serous carcinoma is relatively uncommon, accounting for no more than 10%
of serous carcinomas. (50) In a large population based study only 3.4% of ovarian cancers were
low grade serous carcinomas. (51) Although clearly of serous type, this tumor is now recognized
as a distinct type of ovarian carcinoma and it is no longer viewed simply as the low grade end of
a continuum with high grade serous carcinoma at the most malignant end of the spectrum. Lowgrade serous carcinoma has a different molecular basis than high-grade serous carcinoma. It is
characterized by BRAF or KRAS mutations, with the latter the most common, rather than TP53
mutations. (52) The DNA ploidy pattern of low grade serous carcinoma is more similar to that of
borderline serous tumor than high grade serous carcinoma. (53) Low grade serous carcinoma has

19

been proposed to arise via stepwise progression of a serous tumor from benign to borderline to
low-grade carcinoma. (54) Low-grade serous carcinoma is typically intermixed with areas of
borderline serous tumor, supporting its origin from the borderline tumor. Low-grade serous
carcinoma does not appear to be linked to BRCA mutations. (55) Low-grade serous carcinoma
occurs in younger patients than high-grade serous carcinoma (average age in the mid-40s) and
the clinical course is usually more indolent. The median survival is considerably greater than for
patients with high-grade serous carcinoma; (56) in the largest series published to date the median
overall survival of patients with stage II-IV low-grade serous carcinoma was more than 80
months. (57) Although women with low-grade serous carcinoma tend to have slowly progressive
disease, it is difficult to treat. Primary and recurrent low grade serous carcinoma tends to be
resistant to standard ovarian cancer chemotherapy regimens.(58, 59) The clinical behavior of
low-grade serous carcinoma that develops as a recurrence of a borderline serous tumor appears to
be similar to that of de novo low-grade serous carcinoma. (60)
Low-grade serous carcinoma cells are cuboidal to low columnar and they have relatively
uniform round to oval nuclei with evenly distributed chromatin and small nucleoli. There is mild
to moderate nuclear atypia, and the mitotic rate is low (<12/10 hpf). Crowded glands, simple or
complex micropapillae, and solid or
Fig.23Infiltrativegrowthinlowgradeserous
cribriform nests of tumor cells infiltrate
carcinoma.
fibrous stroma (Fig. 2-3). (54) Less common
patterns of invasion include a macropapillary
pattern in which large papillae with broad
stromal cores lined by tumor cells invade the
stroma, (61) a solid pattern of growth and a
single cell pattern of invasion. (62) Variable
amounts of mucin are present, in tumor cell
cytoplasm, in gland lumens, or in the stroma.
Clusters of tumor cells are often surrounded
by clefts or clear spaces. Zones of invasive
carcinoma may be mixed with zones of serous
borderline tumor of the typical or more often
the micropapillary type. (56) Distant metastases from an ovarian low grade serous carcinoma,
such as those to lymph nodes, breast or to the mediastinum, can be difficult to diagnose because
they can mimic borderline serous tumors or other types of carcinomas. (63, 64)
Psammoma bodies are small laminated calcifications that form around products of
cellular degeneration. They are often seen in serous tumors, particularly serous carcinomas, and
are occasionally numerous. Rarely, psammoma bodies are so numerous in a low-grade serous
carcinoma that they obscure the epithelial elements of the tumor. Carcinomas with innumerable
psammoma bodies are called serous psammocarcinomas. They are extremely rare, but they seem
have a favorable prognosis when they can be completely removed. (65) Similar tumors can arise
as primary peritoneal neoplasms. The prognosis for a high-grade serous carcinoma with
numerous psammoma bodies is unfavorable and such tumors should not be diagnosed as
psammocarcinomas. Psammoma bodies are suggestive of a serous tumor, but they are also found
in other types of tumors, especially those with papillary growth, and in association with nonneoplastic conditions such as epithelial inclusion cysts and endosalpingiosis.

20

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23

Case 3
Clear Cell Carcinoma
Clinical History: The patient was a 72 year old woman admitted to the hospital for evaluation of
a large pelvic mass. A pelvic examination performed 8 months prior to admission had not
revealed a mass. She was treated by TAHBSO followed by instillation of radioactive chromic
phosphate into the abdominal cavity.
Gross Pathology: The left ovary was enlarged and cystic, measuring 12 cm in diameter. The
capsule was intact, but there were adhesions to the uterus. The cut surfaces revealed many cysts
as well as solid areas. The cysts were up to 10 cm and solid areas were up to 3 cm. Small dark
pink velvety tumor masses lined the inner surfaces of the cysts.
Diagnosis: Clear Cell Carcinoma
Clear Cell Tumors
Clear cell tumors were for many years thought to be of mesonephric origin, but were
shown by Scully and Barlow to arise from endometriosis or from the surface epithelium or
epithelial inclusions. (1) Most clear cell tumors are carcinomas, but benign and borderline clear
cell tumors also occur. (2-6) Women with borderline clear cell tumors generally have a favorable
prognosis. Rare patients with borderline clear cell tumors have developed metastases or died of
their tumors. (6, 7) While borderline clear cell tumors, even those with intraepithelial carcinoma,
are thought to have a favorable prognosis, it is important to keep in mind that few cases have
been studied, and even fewer have had long follow-up, so the behavior of such tumors should be
viewed as incompletely determined.
ClearCellTumorsoftheOvary
ClearCellAdenofibroma
BorderlineClearCellAdenofibroma
BorderlineClearCellAdenofibromawithIntraepithelialCarcinoma
ClearCellCarcinoma
More than 90 percent of clear cell tumors are carcinomas. Clear cell carcinoma comprises
from 5 to 12 percent of ovarian cancers in North America and other western countries, with the
highest percentages having been reported most recently. (8) Clear cell carcinoma is often
detected at an early stage, so studies that deal only with advanced stage tumors contain a lower
percentage of clear cell carcinomas. Clear cell carcinoma constitutes a higher percentage of
epithelial ovarian cancers (20-25 percent) in Japan than in western countries. (9, 10) Survival
rates that are favorable, or at least equivalent to those observed with other types of ovarian
carcinoma have been found in many studies of clear cell carcinoma, particularly for patients with
early stage tumors. (11-14) The trend recently, however, has been to view clear cell carcinoma as
an unfavorable histologic type because of a worse prognosis in advanced stages compared to
other common epithelial tumors, and a poor response to platinum-based chemotherapy. (9, 1518) Nevertheless, current NCCN guidelines call for treatment of patients with clear cell
carcinoma, even in stage IA, with 3-6 cycles of IV taxane/carboplatin therapy. Recurrent clear

24

cell carcinoma appears to be particularly resistant to chemotherapy and it is accordingly difficult

to treat. (19)
Several paraneoplastic syndromes occur in women with clear cell carcinoma. (20) Clear
cell carcinoma is more likely than other types of epithelial carcinoma to be associated with
hypercalcemia, (21) and women with clear cell carcinoma also are more likely to have
thromboembolic events such as deep venous thrombosis and pulmonary emboli. (22)
There is a strong association between clear cell carcinoma and endometriosis, with clear
cell carcinoma patients often having endometriosis in the ovaries or elsewhere in the pelvis. (2325) Atypical endometriosis has been proposed as a possible precursor of clear cell carcinoma,
(24, 26). Recently, mutations in the ARID1A gene have been detected in ovarian cancers
associated with endometriosis, and in endometriosis itself, including 46-57 per cent of patients
with clear cell carcinoma. (27, 28). An origin in or an association with endometriosis has
correlated with a more favorable outcome in some studies. (24, 29) Clear cell carcinoma appears
overrepresented among women with the Lynch syndrome. (30)
Benign Clear Cell Tumors
Benign clear cell tumors are unilateral solid tumors. They range from small tumors 3 or 4
cm in diameter to large ones measuring up to15cm in diameter. Small cysts are usually visible on
close inspection of the white or tan cut surfaces. Microscopically, all benign clear cell tumors are
adenofibromas. (4, 6). The fibromatous stroma contains spindle-shaped fibroblasts and collagen
bundles. Scattered within the stroma are small tubules or cysts lined by cuboidal or hobnail cells
with clear or granular eosinophilic cytoplasm. There is no cytologic atypia or mitotic activity.
Borderline Clear Cell Tumors
Borderline clear cell tumors are unilateral and predominantly solid. They typically
measure 1015cm in diameter. The cut surface is white, gray, or tan and contains small to
medium sized cysts. Borderline clear cell tumors, like the benign ones, are all adenofibromas. (4,
6) Two tumors reported as purely cystic borderline clear cell tumors might also be interpreted as
cysts lined by intraepithelial clear cell carcinoma. (31) Tubules and cysts are irregularly
distributed in a fibrous stroma. The tubules and cysts are lined by cuboidal or hobnail cells that
have clear or eosinophilic cytoplasm. Occasionally, the epithelium is stratified or tufted, or grows
as small solid circumscribed nests. Some tumor cells exhibit mild to moderate nuclear atypia and
there may be scattered mitotic figures (usually <1 per 10 high power fields). Rare clear cell
tumors grow in a parvilocular pattern in which cysts lined by clear cells are surrounded by
stroma. Most of such tumors exhibit sufficient atypia or mitotic activity to be classified as
borderline tumors. The absence of stromal invasion or confluent growth differentiates clear cell
adenofibroma from clear cell carcinoma. Non-invasive clear cell adenofibromas with significant
nuclear atypia or mitotic activity can be classified as borderline tumors with intraepithelial
carcinoma. As mentioned above, very few of these have been reported and their clinical behavior
is accordingly not well defined. The diagnosis of a benign or borderline clear cell tumor should
be made only after thorough histologic study, since bland-appearing areas are often present in
clear cell carcinoma.

25

Clear Cell Carcinoma

Gross Pathology
Clear cell carcinomas are usually large tumors, ranging from 10 to 30cm in diameter.
They can be solid or cystic with solid gray-tan nodular areas in their walls. The cut surfaces are
soft and tan or gray-white. Some clear cell carcinomas may arise from clear cell adenofibromas
like Case 3, (32) while others appear to arise from endometriosis. In one study, cystic tumors
were more likely to be diagnosed at an early stage, to be associated with endometriosis, to
exhibit a papillary growth pattern and to have a more favorable outcome than solid
adenofibromatous tumors, (24) while in another study adenofibromatous tumors were more
likely to be of low stage at diagnosis and to have a more favorable prognosis. (33) The
significance, if any, of the various growth patterns is thus unclear and needs further study.
Tumors that are confined to the ovaries (stage I) are usually unilateral, but when tumors of all
stages are considered, about 30 percent are bilateral.
Microscopic Pathology
Clear cells carcinoma grows in a variety of patterns and contains various cell types,
including, usually, cells with clear cytoplasm. The diagnosis is not based simply on the presence
of cells with clear cytoplasm, as many types of ovarian tumors contain clear cells, but on the
combination of the presence of characteristic cell types growing in the typical patterns of clear
cell carcinoma.
Clear cell carcinoma contains clear cells, cells with granular eosinophilic cytoplasm, and
hobnail cells; usually, a mixture of the various cell types is present. Clear cells are flat, cuboidal,
low columnar, or polygonal and have abundant clear cytoplasm, central often fairly uniform
vesicular nuclei and, usually, conspicuous nucleoli. PAS stains and electron microscopic studies
reveal that they contain abundant cytoplasmic glycogen, which accounts for the cytoplasmic
clearing. Cells with eosinophilic cytoplasm are similar in size, shape, and nuclear features to the
clear cells, but they have granular eosinophilic cytoplasm. Hobnail cells are columnar and have
either granular eosinophilic or clear cytoplasm. Their most dramatic feature is their
hyperchromatic apical nuclei that bulge into the lumina of cysts or tubules. Mitotic activity tends
to be lower in clear cell carcinoma than in other types of ovarian carcinoma (average, about 5
mf/10 hpf); (34) the low proliferation rate has been proposed as a possible reason for the poor
response to chemotherapy. (35)
CytologicFeaturesofClearCellCarcinoma
CellTypes
Flat
Cuboidal
LowColumnar
Polygonal
Hobnail
CytoplasmTypes
Clear
Eosinophilic
Oxyphilic

26

Fig.31Papillarygrowthpattern

The rare oxyphilic clear cell carcinoma is

composed predominantly of large polygonal cells
with abundant eosinophilic cytoplasm.(36)
Thorough sampling is necessary to reveal areas
that are more typical of clear cell carcinoma,
thereby establishing the diagnosis.
There is typically a mixture of growth
patterns in clear cell carcinoma.(34) The tumor
cells line short stubby papillae with fibrous or
sometimes hyaline cores in the papillary pattern
(Fig. 3-1) and line tubules or cysts in the
tubulocystic pattern (Fig. 3-2). Occasionally, long
branching papillae are present, but marked
Fig.32Tubulocysticgrowthpattern
stratification or tufting of tumor cells on the
surfaces of papillae is not a feature of clear cell
carcinoma. Ring-like tubules lined by cuboidal
cells with clear cytoplasm and filled with
eosinophilic secretions are particularly
characteristic. There can be areas of solid growth
composed of polygonal cells with clear or
eosinophilic cytoplasm. Adenofibromatous clear
cell carcinomas contain crowded angulated and
infiltrative tubules growing through fibrous
stroma. Compared to what is seen in a borderline clear cell adenofibroma, the tubules are more
crowded and infiltrative in carcinoma, and there are usually typical areas of confluent
tubulocystic or papillary growth, or sheets of tumor cells.
HistologicPatternsofClearCellCarcinoma
Tubulocystic
Notglandslinedbycolumnarcells
Papillary
Notpapillaewithsurfacestratificationortuftedgrowth
Solidsheetsofpolygonalcells
Adenofibromatous
A few ancillary findings can help suggest the possibility of clear cell carcinoma.
Eosinophilic hyaline globules are often scattered among the tumor cells.(37) Amorphous
eosinophilic hyaline material is a frequent finding in the stroma and the cores of the papillae. The
hyaline material is PAS positive and appears to be basement membrane-like material, based on
its ultrastructural appearance and immunohistochemical staining for type IV collagen and
laminin.

27

Clear cell carcinoma can be graded using the universal grading system proposed by
Silverberg and his colleagues, but histologic grading has not proven to be of prognostic value in
most studies. (38, 39) Clear cell carcinoma is accordingly not graded.
Clear cell carcinoma is strongly associated with endometriosis, either within the involved
ovary or elsewhere in the pelvis, and occasional examples of clear cell carcinoma arise directly
from endometriosis. The percentage of cases associated with endometriosis, including atypical
endometriosis, approaches or exceeds 50 percent in some series. (24, 29, 40, 41)

Stain
CK7
EMA
HNF1
ER
PR
P53
P16
WT1
PAX8
SALL4
Glypican3

ImmunohistochemistryofClearCellCarcinoma
Result
Pattern
Positive
Positive
Positive
Usuallynegative
Usuallynegative
Negative;weakmoderatestaining
insometumorcells
Negative;patchypositivestaining
Negative
Positive
Negativeorfocalandweak
Negativeorfocalandweak

Cytoplasm/membranes
Cytoplasm/membranes
Nucleus
Nucleus
Nucleus
Nucleus
Cytoplasmandnucleus
Nucleus
Nucleus
Nucleus
Cytoplasm

Immunohistochemistry and Molecular Pathology of Clear Cell Tumors

Clear cell tumors share many immunohistochemical features with other primary epithelial
tumors of the ovary. Clear cell carcinoma is typically positive for cytokeratin, cytokeratin 7 and
epithelial membrane antigen. (42, 43) It stains for CD15 and is usually cytokeratin 20 negative. (42)
Staining for estrogen and progesterone receptors is minimal or totally absent.(43, 44) A new
antibody, hepatocyte nuclear factor-1beta (HNF-1) has emerged as a sensitive marker for clear cell
tumors, particularly clear cell carcinoma. (44-46) HNF-1 is a nuclear antigen, and diffuse strong
nuclear staining is observed in more than 80% of clear cell carcinomas. A panel that includes HNF1, WT-1, and ER may help differentiate between clear cell carcinoma and serous carcinoma. (44)
HNF-1 is likely to be positive in clear cell carcinoma, while WT-1 and ER are likely to be positive
in serous carcinoma. HNF-1 has been reported as being highly specific for clear cell tumors and
unlikely to stain serous carcinoma (95% specific). (44) However, the most commonly used antibody
is a polyclonal antibody and we have recently begun to observe positive staining in cases of serous
and endometrioid carcinoma. Therefore, diffuse strong nuclear staining for HNF-1 supports a
diagnosis of a clear cell tumor, but I do completely rely on positive staining to exclude a serous or
endometrioid tumor. Diffuse positive nuclear staining for p53 has been reported by some, (42) but
not by others. (47, 48) We find that staining for p53, when present, is usually irregular in
distribution and less intense than is observed in serous carcinoma, in which nuclear staining tends to
be strong and diffuse when present. Clear cell carcinoma frequently contains waxy eosinophilic
hyaline material in its stroma. This material appears to be basement membrane material based on its
electron microscopic appearance and positive staining for laminin and type IV collagen. (49, 50) In
summary, the typical clear cell tumor immunophenotype is cytokeratin 7, EMA, and hepatocyte

28

nuclear factor-1beta positive and estrogen receptor, progesterone receptor, WT-1 and p53 negative.
(34)
Recent developments in molecular pathology have provided interesting information about
clear cells carcinoma, some of use to surgical pathologists. The observation that HNF-1 is one of
the genes that is upregulated in clear cell carcinoma led to the introduction of HNF-1
immunostaining as a diagnostic aid. (51) More recently, it has been observed that mutations of the
tumor suppressor gene ARID1A occur in clear cell carcinoma and result in loss of ARID1A
immunostaining. (27, 28) ARID1A mutations also occur in endometrioid carcinoma, but it is
possible that immunostaining for ARID1A may prove helpful in the differential diagnosis with
serous carcinoma and other types of ovarian tumors with clear cells. In tumors that show loss of
ARID1A, the protein is also generally lost in adjacent precursors, such as atypical endometriosis,
endometriosis, and clear cell adenofibromas, suggesting that ARID1A mutation, along with
mutations of PIK3CA are early events in tumorigenesis. (52) Mutations are known to be present in
the following genes in clear cell carcinoma: PIK3CA, KRAS, ARID1A and PPP2R1A. (28)
Differential Diagnosis
A wide variety of tumors that can involve the ovary contain clear cells and can be
considered in the differential diagnosis of clear cell carcinoma.
ClearCellCarcinomaDifferentialDiagnosis
SerousCarcinoma
BorderlineSerousTumor
EndometrioidCarcinoma
YolkSacTumor
Dysgerminoma
SteroidCellTumor
MetastaticClearCellCarcinoma
Melanoma
Others

Some clear cell carcinomas contain minor admixtures of endometrioid carcinoma or other
types of surface epithelial carcinoma, but this is a diagnosis that should be made with caution.
Other types of epithelial ovarian tumors, especially serous carcinoma and endometrioid
carcinoma, occasionally contain clear cells and pathologists are frequently tempted to diagnose
them as having a component of clear cell carcinoma. (53) The diagnosis of clear cell carcinoma
should only be made if there is a combination of the characteristic cytologic features,
architectural growth patterns, and immunophenotype, rather than simply the presence of tumor
cells with cytoplasmic clearing. Carcinomas with overlapping features of clear cell carcinoma
and serous carcinoma are occasionally encountered; these are best regarded as variants of serous
carcinoma. (54) Papillary clear cell carcinomas are occasionally mistaken for borderline serous
tumors, a significant diagnostic error. (55) Features that suggest the correct diagnosis include a
unilateral tumor, non-branching papillae, a monotonous tumor cell population, the presence of
more characteristic patterns of clear cell carcinoma, and an association with endometriosis.
Yolk sac tumor and clear cell carcinoma were thought for many years to be variants of the
same tumor type, the mesonephroma, so it is not surprising that yolk sac tumor is sometimes

29

considered in the differential diagnosis of clear cell carcinoma. Knowledge of the clinical details of
the case, especially the patients age and the serum alpha-fetoprotein level is helpful in arriving at
the correct diagnosis. Clear cell carcinoma is generally alpha-fetoprotein negative while yolk sac
tumor is positive although staining for alpha-fetoprotein can be weak or focal. (56) Other recently
introduced stains for yolk sac tumor such as glypican-3 and SALL4 tend to be negative in clear cell
carcinoma or to stain only focally and weakly. (57, 58) Keep in mind that both clear cell carcinoma
and yolk sac tumor show positive nuclear staining for HNF-1. Clear cell carcinoma stains strongly
for epithelial markers such as CD15, (59) EMA and cytokeratin 7, (56), which are generally
negative in yolk sac tumor, although exceptions occasionally occur. (60)
Metastatic clear cell renal cell carcinoma is generally not a diagnostic issue as renal cell
carcinoma rarely spreads to the ovaries. (61, 62) Ovarian clear cell carcinoma shows positive
staining for CK7 and CA125 while metastatic clear cell renal cell carcinoma is rarely CK7 positive,
(43, 63, 64) although it shows positive staining for CD10. (65) Renal cell carcinoma antigen (RCC),
and PAX2 are generally positive in metastatic renal cell carcinoma, (43, 66) but ovarian clear cell
tumors also occasionally stain for these markers. (67) Both renal and ovarian clear cell carcinomas
show positive nuclear staining for PAX8 and hepatocyte nuclear factor-1beta. (68)
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33

Case 4
Metastatic Adenocarcinoma
Clinical History: The patient was a 43-year-old Mexican woman. She had bilateral ovarian
tumors and peritoneal metastases. Review of the history revealed that the patient had had a
gastric resection 7-8 years previously in Mexico, but the pathologic findings were unknown.
Gross Pathology: The ovaries were solid and moderately enlarged, the left measuring 7 cm and
the right 8 cm in maximum diameter. The cut surfaces were rubbery and lobulated, with graywhite glistening trabeculated cut surfaces.
Diagnosis: Metastatic adenocarcinoma, signet ring cell type, compatible with a gastric primary
(Krukenberg Tumor).
Metastatic Tumors in the Ovary
Metastatic tumors involve the ovaries more often than any other part of the female genital
tract. It is often said that 510% of all malignant ovarian tumors are metastatic, so the possibility
that an ovarian tumor might be metastatic always has to be considered, particularly if the gross or
microscopic pattern is unusual for a primary tumor. Possible metastatic pathways to the ovary
include retrograde lymphatic spread, transperitoneal spread, and hematogenous metastasis. (2)
Based on the appearance of the involved ovaries and on clinical and operative findings,
lymphatic and transperitoneal spread account for most ovarian metastases, particularly from
primary sites within the abdomen. (3) Adenocarcinomas of the breast, large intestine,
endometrium, and stomach are the most common primary sites, but a wide variety of malignant
tumors can metastasize to the ovaries. (1) These include cancers of the cervix, (4-6) appendix, (7,
8) pancreas, (9, 10) bile duct and gallbladder, (11, 12) liver, (13, 14) kidney, (15-18) urinary
tract, (19) and lung, (20) as well as melanoma, (21, 22) malignant lymphoma and various types
of soft tissue and gastrointestinal sarcomas. (21, 23-26) It is often difficult to differentiate
metastatic endometrial adenocarcinoma in the ovary from synchronous primary endometrioid
adenocarcinomas of the endometrium and ovary.
Clinically significant ovarian metastases are most often detected in women who are
already known to have an extraovarian cancer, most often one of the colon or rectum. (27) The
average time between diagnosis of the primary tumor and detection of the ovarian metastases is
about 2 years, but the length of the interval varies and ranges from a few months to many years.
NongenitalPrimarySitesofOvarianMetastases(1)
PrimarySite
%
Colorectal
32.3
Appendix
20.3
Breast
8.5
Stomach
6.8
Smallintestine
6.8
Pancreas
5.1
Otherorunknown
20.3

(28) Some patients have no history of a primary extraovarian tumor. They present with

34

symptoms of a pelvic tumor, such as pelvic or abdominal pain, gastrointestinal or urinary

disturbances, abdominal distention, or abnormal uterine bleeding, and are at least initially
thought to have primary ovarian cancer. In most such patients a locally advanced gastrointestinal
primary cancer is discovered at the same time as the ovarian metastases but occasionally the
primary site is only discovered months or years after the ovarian tumors are removed. Not all
ovarian tumors that are detected in women with a history of cancer are metastases. For example,
when a woman with a history of colorectal cancer develops a new pelvic mass the most likely
diagnosis is metastatic adenocarcinoma, but primary benign or malignant ovarian tumors are
discovered in a significant percentage of cases (26 percent benign and 17 percent primary
ovarian cancers in one study). (28) The possibility of treating women with cancers that have a
significant risk of metastasizing to the ovaries with prophylactic oophorectomy is sometimes
considered, but it has not been shown to improve survival and its efficacy is at present unclear.
(29, 30) The prognosis is poor for women with ovarian metastases, (27) but resection appears to
lengthen survival and relieve symptoms. Some have found that ovarian metastases are more
likely to develop in premenopausal women, but this has not been confirmed by others.
Gross Pathology
Metastatic tumors in the ovary vary in appearance depending on the primary site.
Metastatic colorectal cancer is bilateral in 5070 percent of cases. The ovarian metastases
average 1011 cm in diameter, have a smooth surface, and tend to be cystic or solid and cystic.
(31-33) The cysts are unilocular or multilocular and are filled with mucin. In one study, 90% of
mucinous carcinomas were correctly classified as primary or metastatic by assuming that all
bilateral mucinous tumors or mucinous tumors smaller than 10 cm were metastatic, and all
unilateral mucinous tumors larger than 10 cm were primary. (34) The criteria were subsequently
modified by increasing the size cutoff to 13 cm, resulting in improved performance of the
algorithm. (35) Metastatic colorectal and cervical adenocarcinomas proved to be the most
difficult to correctly identify.
Metastatic stomach cancer usually has the appearance of a Krukenberg tumor. The
ovaries tend to retain their shape but are symmetrically or asymmetrically enlarged. They are
firm and have areas of nodularity on the surface. The cut surface is gray, tan, or white and
edematous and honeycombed with small mucinous cysts. Most other types of metastatic tumors
tend to be solid and grow as multiple nodules in the cortex and medulla, often with implants on
the serosa.
Microscopic Pathology
General microscopic features that raise the possibility that an ovarian tumor might be
metastatic include bilaterality, a multinodular growth pattern, implants on the surface of the
ovary or just beneath it, numerous emboli of metastatic carcinoma in lymphatic spaces,
especially in the hilum and mesovarium, a desmoplastic or unusually fibrous or myxoid stromal
reaction, an unusual microscopic pattern for a primary ovarian tumor, such as a signet ring cell
appearance, a colloid carcinoma, a linear so-called Indian file pattern of invasion, and a higher
nuclear grade than would be expected for the architectural pattern (for example, high grade
nuclei and frequent mitotic figures in a purely glandular tumor with low grade architecture). (36)
Luteinization of the stroma occurs around some metastatic tumors, but it also occurs around
primary ovarian tumors and does not necessarily imply that a tumor is metastatic. The luteinized

35

GeneralFeaturesSuggestingthatanOvarianTumorCouldBeMetastatic
Historyofanextraovarianprimarycarcinoma
Clinicalevidenceofanextraovarianprimarycarcinoma
Bilateraltumors
Smallsize(formucinoustumors<13cm)
Tumorormucingrosslypresentonthesurfaceoftheovary
Microscopicimplantsonorjustbeneaththesurfaceoftheovary
Multinodularpatternofinvasivegrowth
Desmoplasticormyxoidstromalreaction
Highnucleargradeorfrequentmitoticfiguresbutlowarchitecturalgrade
Unusualhistologicpatternsignetringcells,colloidcarcinomapattern,etc.
Lymphovascularspaceinvasion,especiallyinthehilumoftheovary

cells occasionally secrete sufficient amounts of estrogen or androgen to cause clinical symptoms.
(37)
Krukenberg Tumor and Metastatic Stomach Cancer
A Krukenberg tumor is a form of metastatic adenocarcinoma, sometimes found in a
young woman, in which malignant signet ring cells comprise more than 10 percent of the tumor
and often infiltrate a hypercellular stroma. (38, 39) The last case of Krukenberg tumor that we
saw was an unexpected finding in a 25 year old woman in who a gastric primary was
subsequently detected at endoscopy. Gastric cancer is not common in young patients, but when it
occurs, it occurs in women more often than me and more than 50% of young women with signet
ring cell carcinoma of the stomach develop Krukenberg tumors. While the primary carcinoma is
usually in the stomach, signet-ring cell carcinomas of the breast, colon, gallbladder, and other
sites can also give rise to metastases of this type. Krukenberg tumors are relatively rare in the
USA and Europe, but are common in populations in which there is a high incidence of gastric
carcinoma, such as in Japan and in women of Japanese extraction.
Microscopically, the signet-ring cells grow as single cells, in variably sized nests
or cords, or in widely scattered tubules. The malignant cells contain cytoplasmic mucin globules
that compress and flatten the hyperchromatic nucleus against the cell wall (Fig. 4-1). Small
polygonal or cuboidal cells with eosinophilic cytoplasm and eccentric nuclei are present in some
tumors. Some Krukenberg tumors contain prominent tubular glands in addition to signet ring
cells. These have been designated tubular Krukenberg tumors. (40) The hilar lymphatics often
contain tumor cells, which may be cohesive or form glands. The stroma of a Krukenberg tumor
is abundant, hypercellular, and focally edematous,
Fig.41Metastaticsignetringcellcarcinoma
and it may contain pools of mucin. The malignant
cells can be obscured by the stroma, but they are
easily be identified in sections stained for neutral
mucins with PAS or mucicarmine, or with
immunohistochemical stains for cytokeratin or
epithelial membrane antigen. The tumor cells tend
to be cytokeratin 7 positive, but staining for
cytokeratin 20 and CDX2 is variable. Diffuse types
of gastric carcinoma can lack membrane staining

36

for e-cadherin, similar to what is seen in

lobular carcinoma of the breast. It is
unclear whether staining for e-cadherin,
along with ER and other breast markers,
might help to pinpoint the primary site if
it is unknown. The e-cadherin stain was
negative in this case. The reactive
stromal cells may show strong staining

for inhibin. Rare Krukenberg tumors

Otherprimarysitesincludessmallintestine,
have been designated as primary
appendix,pancreas,uterus,bladder,renalpelvis
Krukenberg tumors because an
extraovarian primary could not be
identified. (41) Rare ovarian mucinous tumors have a component of signet ring cells and have
overlapping features with a Krukenberg tumor, although they are generally not classified as such.
(42) Gastrointestinal primary cancers, particularly those of the stomach, can remain undetected
even after careful investigation, so it is best to consider all Krukenberg tumors to be metastatic
until proven otherwise by clinical follow-up or autopsy. Nevertheless, a rare patient survives
long-term after resection of a Krukenberg tumor or no primary site is identified at autopsy,
raising the possibility of the existence of a very rare primary type of signet ring Krukenberg
tumor. (43)
KrukenbergTumorPrimarySites

%
Stomach
76
Colonandrectum
11
Breast
4
Gallbladderandbiliary
3
Others
6

Metastatic Colorectal Adenocarcinoma

Colorectal carcinoma is the cancer that most often metastasizes to the ovaries. Metastatic
colorectal adenocarcinoma often simulates a primary adenocarcinoma of the ovary. (31-33, 44,
45) The typical colorectal adenocarcinoma, in which absorptive cells predominate and goblet
cells are inconspicuous, mimics endometrioid adenocarcinoma. Metastatic colorectal
adenocarcinoma forms large complex glands and
Fig.42Dirtynecrosisinmetastaticcoloncancer
cysts that contain necrotic debris. The debris is
coarsely granular and contains nuclear fragments
and inflammatory cells, resulting in a distinctive
appearance, termed dirty necrosis (Fig. 4-2).
While extensive necrosis is characteristic of
metastatic colorectal adenocarcinoma, it can also
be seen in a primary ovarian adenocarcinoma,
especially an endometrioid adenocarcinoma. The
malignant cells lining the glands and cysts stratify
or grow in cartwheel, garland, or cribriform
patterns with foci of segmental epithelial necrosis. The degree of nuclear atypia and mitotic
activity tends to be greater than is seen in an endometrioid adenocarcinoma of similar
architectural grade. Findings that are typical of primary endometrioid carcinoma, such as
squamous metaplasia, a focal adenofibromatous pattern of growth and adjacent endometriosis are
generally absent.
Metastatic colorectal adenocarcinoma mimics primary mucinous carcinoma of the ovary
when goblet cells are numerous and there is abundant mucin production. (34) Metastatic
adenocarcinoma from the pancreas or biliary tract typically has a mucinous phenotype and thus
also enters the differential diagnosis, (9-12, 45) as can metastases from urachal adenocarcinomas

37

of the bladder. (46, 47) Metastatic mucinous adenocarcinomas exhibit the general gross and
microscopic features of metastases, including surface implants and at least focally infiltrative
growth, (36) but it may be necessary to compare the microscopic appearance of the metastasis
with that of the primary or to perform immunohistochemical studies in order to arrive at the
correct diagnosis.
Immunohistochemical stains are often essential in the differential diagnosis between a
primary adenocarcinoma of the ovary and metastatic colorectal adenocarcinoma.(2, 48, 49)
Immunostains for cytokeratin subtypes and CDX2 are the most useful ones. Primary
adenocarcinoma of the ovary is almost always strongly positive for cytokeratin 7, (50) while
colorectal adenocarcinoma is usually cytokeratin 7-negative. (33, 51) Immunostains for
cytokeratin 20 and CDX2 are negative in endometrioid carcinoma. Stains for cytokeratin 20 and
CDX2 are generally positive in ovarian mucinous adenocarcinoma but staining is often only
weak to moderate and focal (50, 52) in contrast to the diffuse strong positive staining for
cytokeratin 20 and CDX2 in most cases of metastatic colorectal adenocarcinoma. (33, 50, 53)
Thus, a cytokeratin 7 positive/cytokeratin 20 negative or weak/CDX2 negative or weak
immunophenotype strongly suggests a primary ovarian carcinoma, while a cytokeratin 7

Stain
CK7
CK20
CDX2
PAX8
CA125
ER

ImmunohistochemistryofMetastaticColorectalAdenocarcinoma
MetastaticColon
Endometrioid
Mucinous

+
+
+

+/
+

+/

+
+/

negative/cytokeratin 20 positive/CDX2 positive immunophenotype strongly favors metastatic

adenocarcinoma.(50, 51, 53, 54) While colonic adenocarcinoma is almost invariably cytokeratin
7 negative, some rectal adenocarcinomas and adenocarcinomas from more proximal portions of
the gastrointestinal tract, including the appendix, small intestine, and stomach, can be cytokeratin
7 positive. (54-56) Other immunohistochemical stains that may help differentiate between
primary and metastatic neoplasms include beta-catenin, (57, 58) which shows positive nuclear
staining in some colorectal and endometrioid carcinomas, but which is usually negative in
primary mucinous carcinoma; OC 125 (CA 125), which shows positive membrane staining in
endometrioid carcinoma, but is usually negative in primary mucinous carcinoma and metastatic
colorectal carcinoma; (59, 60) PAX8, which shows positive nuclear staining in endometrioid
adenocarcinoma and often to at least a limited degree in mucinous carcinoma, but which is
negative in metastatic colorectal adenocarcinoma; (61) alpha-methylacyl-CoA racemase (also
known as P504S), (58) which shows granular cytoplasmic staining in some metastatic colorectal
adenocarcinomas and primary mucinous adenocarcinomas, but which tends to be negative in
endometrioid adenocarcinomas; and carcinoembryonic antigen (CEA), where negative or weak
staining favors an ovarian primary over metastatic colorectal adenocarcinoma.(32)
Metastatic Tumors from the Appendix and Pseudomyxoma Peritonei
Metastatic tumors from the appendix are rare and account for only 1 percent of ovarian
metastases. (62) Most appendiceal tumors that metastasize to the ovary are signet ring cell

38

adenocarcinomas that arise from the base of the mucosa and infiltrate the wall of the appendix.
They contain signet ring cells, tubules, and goblet cells in varying proportions. (7, 8) Carcinomas
with a prominent tubular component lined by goblet cells have been classified as goblet cell or
mucinous carcinoids, or as mixed carcinoid-adenocarcinomas in the past. (63) Such tumors are
biologically aggressive and do not always exhibit the typical staining pattern of a carcinoid
tumor (argentaffin positive and immunoreactive for chromogranin and/or synaptophysin). Such
metastases often fulfill criteria for classification as a classical or tubular Krukenberg tumor (see
above). Other metastatic appendiceal adenocarcinomas are glandular adenocarcinomas of
colorectal or mucinous intestinal types. (7) These metastases are usually immunoreactive for
cytokeratin 20, but are also cytokeratin 7 positive in about 50 percent of the cases, so they can
potentially be mistaken for primary ovarian carcinomas. (7)
Pseudomyxoma peritonei is an uncommon condition in which mucinous ascites causes
progressive abdominal distention and gastrointestinal dysfunction. The mucus is viscous,
loculated, yellow-brown or red, and contains foci of fibrous organization that form adhesions to
adjacent structures. Pseudomyxoma peritonei in women is often associated with ovarian tumors
that resemble borderline mucinous tumors or, less often, a mucinous cystadenoma, and in the
past it was thought to be the cause of death of nearly all women who die of borderline mucinous
tumors. It also occurs in patients with tumors of the gastrointestinal tract, particularly those of
the appendix, and rarely with tumors of other sites.
Three different microscopic patterns have been described in pseudomyxoma peritonei.
(64-67) In the first, the mucin is superficial. It lies on the surface of the ovaries, on the peritoneal
surfaces or on the omentum and may contain inflammatory cells, macrophages, fibroblasts and
an ingrowth of capillaries. In some cases no epithelium is present, while in others there is a small
amount of low-grade mucinous epithelium. This has been termed the acellular or superficial
organizing pattern of pseudomyxoma peritonei, depending on whether or not epithelium is
present. Second, and most common, is a pattern in which the mucus dissects through the
involved tissue. Bands of fibrous tissue surround the mucin and there is organization, with
ingrowth of fibroblasts and capillaries. Occasional strips of low-grade mucinous epithelium are
present in the mucus or in or adjacent to the fibrous bands. (68) This is the pattern that has been
designated as disseminated peritoneal adenomucinosis (DPAM) by some authors. (65) It is found
in women with benign or borderline-appearing mucinous tumors of the ovary. Finally, in a third
pattern, the mucus contains more epithelial cells and the cells exhibit high-grade nuclear atypia
or there are clear-cut features of mucinous adenocarcinoma, such as proliferative malignant
glands, solid growth, or signet ring cells. This pattern can be designated as metastatic mucinous
carcinoma or peritoneal mucinous carcinomatosis. The prognosis is related to the type of
peritoneal mucinous lesion present. Patients with acellular or superficial organizing mucin have
the best prognosis. A diagnosis of acellular mucin requires careful study, since epithelial cells
are usually found if sufficient slides are studied. Patients with so-called DPAM have an
intermediate prognosis with a high rate of recurrence, a protracted clinical course and, in many
cases, eventual death due to complications of pseudomyxoma peritonei. Patients with markedly
atypical or malignant cells in the mucus have an unfavorable prognosis, and usually die of
carcinomatosis within a few years of diagnosis. Radical forms of therapy for pseudomyxoma
peritonei involving peritonectomy and intra-abdominal chemotherapy have been developed in
recent years and appear to have some therapeutic benefit. (69-71)
The nature of the ovarian tumors that occur in women with pseudomyxoma peritonei has
been a source of controversy. Recent clinicopathologic studies have shown that nearly all women

39

with pseudomyxoma peritonei have a tumor in the appendix or, in a few cases, elsewhere in the
gastrointestinal tract. These studies have led to the conclusion that the ovarian tumors are
secondary, with the primary site usually being in the appendix. (64, 72, 73) Findings that favor
this hypothesis include: the tumors in the ovary and appendix are usually synchronous; the
tumors in the ovary and appendix are histologically similar; the ovarian tumors are frequently
bilateral, a finding that is more in keeping with a secondary neoplasm than with a primary
borderline mucinous tumor; when unilateral, the ovarian tumors are most often right sided, near
the appendix; implants are present on the surfaces of the ovaries, a finding characteristic of
metastases; the gross and microscopic appearance is not exactly typical of a primary mucinous
tumor; the ovarian involvement may be superficial; pseudomyxoma ovarii is almost always
present, and frequently contains epithelial cells with an appearance identical to those in the
abdominal mucin; immunostains for cytokeratin 7 are negative in some ovarian tumors; (74) the
ovarian and appendiceal tumors show immunohistochemical staining and molecular marking for
MUC2, a marker of intestinal neoplasms, while primary ovarian mucinous tumors express
MUC5AC but not MUC2; (75, 76) and there are molecular similarities between the ovarian and
appendiceal tumors in some cases. (77-79) The current consensus is that the ovarian tumors in
women with pseudomyxoma peritonei are secondary to a gastrointestinal neoplasm, usually one
located in the appendix, in almost all cases. (68, 80, 81) The pathologist should keep in mind that
the appendix tends to be abnormal in patients with pseudomyxoma peritonei, even when it is
grossly unremarkable and ovarian tumors are present. If possible, the appendix should be
removed and processed in its entirety for histologic study. The type of tumor present in the
appendix, if any, and the histologic appearance of the tumor cells in the peritoneal mucin are
important prognostic factors in pseudomyxoma peritonei, and should be described in the
pathology report. In most patients, the appendiceal tumor is a low-grade appendiceal mucinous
neoplasm, sometimes associated with a diverticulum, (82) although in a minority of patients it is
an adenocarcinoma. (83-85) In a small minority of patients, no extraovarian primary tumor can
be identified. In some of these patients, the explanation for the pseudomyxoma peritonei appears
to be that an intestinal mucinous type tumor arising in a benign cystic teratoma has spread to the
peritoneum and given rise to pseudomyxoma peritonei. (86-88) Such tumors can have the
immunophenotype of intestinal (cytokeratin 7 negative, cytokeratin 20 positive, CDX-2
positive), not ovarian (cytokeratin 7 positive, cytokeratin 20 and CDX-2 variable) mucinous
tumors. In a few patients, the derivation of the pseudomyxoma peritonei is difficult to reconcile
with current concepts of the disease and, in such cases, the pseudomyxoma peritonei may arise
from an ovarian mucinous tumor or from an occult primary mucinous tumor in some other organ.
Fig.43.Metastaticbreastcarcinomaofductaltype

Metastatic Breast Cancer

Breast cancer is a common
metastatic tumor of the ovary, but it is
rarely clinically significant. Historically,
most examples of metastatic breast cancer
have been small, sometimes even
microscopic, foci of tumor cells found in
ovaries removed for hormonal therapy of
breast cancer. (89, 90) Adnexal masses in
women with a history of breast cancer are
more likely to be primary ovarian

40

neoplasms than metastases. (91) It is unusual to find metastatic breast cancer in risk reducing
salpingo-oophorectomy specimens, even though many patients who undergo this procedure have
been diagnosed with breast cancer. (92) Metastatic breast cancers that present clinically as
primary ovarian tumors, prior to discovery of the breast primary, often pose diagnostic problems.
(27, 93) Metastases from the breast are sometimes an incidental microscopic finding, but in about
one-third of cases the ovaries are enlarged by solid diffuse or nodular metastases. Most
metastases resemble infiltrating ductal (Fig. 4-3) or lobular carcinoma, and are easy to recognize
as metastatic from the breast. Uncommon microscopic patterns that can be difficult to
differentiate from primary tumors or metastases from other organs include a single cell pattern, a
diffuse, solid growth pattern, and a
cribriform growth pattern. (89)
MetastaticCarcinomaBreastvsOvarian
Metastatic breast cancer needs to be

Breast
Ovary
differentiated from ovarian cancer not only
CK7
+
+
in the ovary but also in various intraER
+
+
abdominal metastatic sites. Considerable
GCDFP15
+

study has been devoted to the use of

Mammaglobin
+

immunohistochemistry to resolve this

PAX8

+
differential diagnosis, and antibodies are
WT1

+
now available that make it possible to
CA125

+
correctly diagnose most cases. Breast cancer
is typically cytokeratin 7 positive,
cytokeratin 20 negative, and it may show nuclear staining for estrogen and progesterone
receptors, an immunophenotype that overlaps with that of many primary ovarian carcinomas.
Positive immunohistochemical staining for gross cystic disease fluid protein (GCDFP)-15 and
mammaglobin provide support for a diagnosis of metastatic breast cancer, (94) although it should
be noted that mammaglobin is occasionally positive in primary tumors of the female genital
tract. (95) Metastatic breast cancer is generally negative for WT-1, OC125 and PAX8, (96, 97)
so staining for GCDFP-15, mammaglobin, WT-1, OC125 and PAX8 can generally clarify
whether a tumor is a primary ovarian neoplasm or metastatic breast cancer. Metastases from a
signet ring cell type of infiltrating lobular carcinoma are a rare cause of Krukenberg tumors in
the ovary; the primary site can generally be correctly identified due to positive staining for ER,
mammaglobin, and, sometimes GCDFP-15. (98)
Female Genital Tract
Carcinomas of the endocervix and endometrium not infrequently metastasize to the
ovaries where they can be difficult to differentiate from primary neoplasms.
Synchronous endometrioid carcinomas in the endometrium and ovary are not uncommon;
there is endometrioid carcinoma in the endometrium in 1020% of women who have ovarian
endometrioid carcinomas. These are thought most often to be separate synchronous primary
tumors. The endometrial cancer is usually superficial and well-differentiated, and would not be
expected to spread to the ovary. The survival rate is high when the carcinomas are confined to
the uterus and ovary. (99, 100) This favors the interpretation that the ovarian and endometrial
carcinomas are separate, synchronous primary tumors since advanced stage endometrial or
ovarian carcinoma would have such a favorable prognosis. In some patients with simultaneous
tumors, however, the ovarian tumor is a metastasis from the endometrial carcinoma. Features
that suggest that the ovarian carcinoma might be metastatic include: the endometrial carcinoma

41

is high grade, the endometrial cancer is deeply invasive into the myometrium, there is
myometrial or ovarian hilar lymphovascular invasion; aggregates of malignant cells are present
in the fallopian tube lumen, the ovarian tumor is small; the ovarian tumor is multinodular and
solid, there is a desmoplastic stromal reaction, the ovarian tumor is bilateral, surface implants are
present on the ovary, and extraovarian metastases are present in a distribution characteristic of
endometrial adenocarcinoma (i.e., lymph node metastases more likely than peritoneal
metastases). Immunostains do not help determine whether the ovarian tumor is primary or
metastatic. In the future molecular diagnostic techniques may provide more definitive diagnostic
information but at this time they are not in routine clinical use.
Endocervical adenocarcinoma metastasizes to the ovaries, but less often than endometrial
carcinoma. When it involves the ovaries cervical adenocarcinoma can mimic either endometrioid
adenocarcinoma or mucinous adenocarcinoma. The ovarian tumors average about 13 cm in
diameter, are usually multicystic, and are unilateral in two thirds of cases. These features would
certainly prompt consideration of a primary ovarian tumor in many instances, as would the
microscopic resemblance to a primary borderline tumor or low-grade adenocarcinoma. Clues to
the correct diagnosis include knowledge that the patient has or had a cervical adenocarcinoma
and recognition in the ovarian tumor of certain morphologic features of endocervical
adenocarcinoma, including an endometrioid appearance at low magnification but apical
mucinous cytoplasm at high magnification, numerous mitotic figures and elongated
hyperchromatic nuclei that are more abnormal than expected for a tumor with well formed
glands, floating mitoses (mitotic figures in the apical cytoplasm above the nuclei) and
apoptotic bodies along the base of the epithelium. Somewhat surprisingly, the cervical
adenocarcinoma is not always deeply invasive, (4) and even cases of apparently in situ cervical
adenocarcinoma have been associated with ovarian metastases. (101) Immunohistochemical
staining for p16 and in situ hybridization for HPV can help confirm that an ovarian
adenocarcinoma is metastatic from the cervix.

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