Gynecologic Pathology - Differential Diagnosis of Ovarian Tumors
Moderators: Robert H.Young and Jaime Prat
Case 2 -
Professor and Chairman of Pathology
Hospital de la Santa Creu i Sant Pau
Autonomous University of Barcelona, Spain
A 43-year old woman was admitted to the hospital because
of massive abdominal enlargement and pain. Pelvic ultrasound revealed a large multilocular cystic
tumor. CA 12.5: 422 mU/L; CA 19.9: 1260 mU/L. At laparotomy, the right ovary was replaced by a tumor,
38 cm in greatest diameter. The outer surface was grayish-white and smooth with prominent blood vessels,
but there was an area of rupture of 9.5 cm in diameter. On section, the tumor was predominantly cystic
with a solid component. The cysts, up to 24 cm in diameter contained thick mucinous fluid. The solid
tissue was grayish-yellow and exhibited several foci of hemorrhage and necrosis. A total abdominal
hysterectomy with bilateral salpingo-oophorectomy, omentectomy, and appendectomy were done.
Case 2 - Figure 1
- Unilateral ovarian tumor, 38 cm in greatest diameter
- Predominantly cystic
- Capsular rupture, 9.5 cm
- Solid component with focal hemorrhage and necrosis
- Grayish-white, firm tissue (6.0 cm) attached to proximal
- Cysts and glands lined by atypical epithelium of
- Benign, borderline, and malignant components
- Thin and branching papillae (borderline)
- Stratification of goblet and signet-ring cells with
moderate to severe
nuclear atypia (intraepithelial carcinoma)
- Numerous foci (up to 10.2 sq. mm. in area) of infiltrating
anaplastic tumor cells
- Extensive "dirty" necrosis with "amputated" glands
- Metastasis to the mesoappendix (Stage III)
The patient received chemotherapy. One year later she developed peritoneal carcinomatosis.
Subsequently, she died with hepatic and pulmonary metastases.
Mucinous tumors are characterized by cysts and glands lined by epithelial cells that contain
intracytoplasmic mucin. The tumor cells may resemble those of the endocervix, gastric pylorus, or
intestine. Mucinous tumors account for 10-15% of all ovarian tumors.  Approximately 75% are
benign; 10%, borderline; and 15%, carcinomas.  Although they generally occur in older women
(mean ages 51-54 years), mucinous borderline tumors and carcinomas are more common in the first two
decades than their serous counterparts.  Mucinous tumors tend to be the largest of all ovarian
tumors. Many of them are 15-30 cm in diameter and weigh up to 4000 g or more. 
Mucinous borderline tumors
Mucinous borderline tumors (MBTs) exhibit an epithelial proliferation greater than that seen in their
benign counterparts, but without destructive stromal invasion. They are almost as common as serous
borderline tumors (SBTs) and constitute 40-50% of all non-benign mucinous tumors and 71% of those that
are stage I.  MBTs have been subclassified into two different clinicopathologic forms: the
most common form is composed of intestinal-type epithelium and has been designated MBT of intestinal type (IMBT). A second and less common variant of MBT contains
endocervical-type epithelium and has been named MBT endocervical-like
Mucinous borderline tumors of intestinal type
IMBTs account for approximately 85% of MBTs and occur most frequently in the fourth to seventh decades
with an average age of 52 years.  From 80-90% of them are stage I and only about 5% are
It should be noted that metastatic mucinous tumors in the ovary often mimic
primary ovarian mucinous neoplasms, particularly adenocarcinomas of the pancreas and large
intestine.  Microscopically, the metastatic tumor may appear deceptively 'benign,'
'borderline,' or malignant. It has been recently established that most, if not all, ovarian mucinous
tumors associated with 'pseudomyxoma peritonei' (PP) are metastatic tumors, frequently from appendiceal
mucinous neoplasms.  Bilaterality is exceptional in stage I ovarian mucinous tumors;
therefore, tumor involvement of both ovaries should rise the suspicion of metastatic carcinoma.
On gross examination, the tumors average 19 cm in diameter, are usually cystic and multilocular, and
contain mucinous fluid.  Papillae and polypoid excrescences may line the cysts. IMBTs cannot
be distinguished grossly from mucinous cystadenomas and cystadenocarcinomas. These tumors should be
sampled extensively since variations in the degree of epithelial proliferation and nuclear atypia (from
benign to borderline, and to carcinoma) are frequent within an individual neoplasm.
Microscopically, IMBTs are composed of cysts and glands lined by atypical epithelium of
gastrointestinal type. The cysts may contain papillae which are typically thin and branching. The
lining epithelium almost always contains goblet cells and may have argyrophil cells, and occasional
Paneth cells. The epithelial cells are usually stratified to two or three layers, nuclear atypia is mild
to moderate, and mitotic figures vary from few to numerous. Stromal invasion is not seen. The overall
appearance is similar to that of a hyperplastic or adenomatous colonic polyp.
Noninvasive IMBTs may exhibit areas of epithelial cell proliferation of four or more layers, scattered
foci of cribriform or stroma-free papillary architecture, and moderate (grade 2) or severe atypical
(grade 3) nuclei. Whether tumors with such areas should be classified as noninvasive carcinomas or as
borderline tumors has been a subject of controversy for many years.
however, have demonstrated that these tumors are almost always clinically benign
and it has been recommended that they be classified as mucinous borderline tumors with intraepithelial carcinoma (BIEC).  The latter diagnosis is mainly
based on cytologic features. Because of their in situ malignant change, BIECs require more extensive
sampling than pure IMBTs to rule out stromal invasion.
Approximately 10% of IMBTs contain one or more foci of stromal microinvasion (arbitrarily defined as
not exceeding 10 square mm in area). The presence of these foci does not seem to alter the favorable
prognosis of IMBT, on the basis of the few cases reported.
Stage I IMBTs are treated similarly to SBTs. While performing a frozen section, the pathologist
should be aware that additional postoperative sampling may disclose a carcinomatous component and the
surgeon should be informed that the diagnosis could be changed after examination of the permanent
sections. When this is done, the surgeon is more likely to undertake appropriate staging. If there is
PP or bilateral ovarian tumors, removal of the appendix as well as exploration of the abdomen for a
possible source of metastasis are recommended.
According to the FIGO annual report,  MBTs are confined to one or both ovaries (stage I)
in 82% of the cases, are stage II in 6%, stage III in 10%, and stage IV in 2%. Almost all stage II-III
IMBTs are associated with PP and, as stated earlier, there is convincing evidence that most of these
tumors are secondary to mucinous tumors of the appendix. This finding, as well as the near 100% 5-year
survival of stage I IMBTs, has raised the question of whether the noninvasive mucinous ovarian tumors
have any malignant potential. Some investigators  have proposed to abandon the borderline
denomination for these tumors and replacing it with 'atypical proliferative mucinous tumors.'
however, believe that the term 'borderline' should be retained because it better
reflects the view that these tumors represent intermediate stages of mucinous tumorigenesis and may be
accompanied by intraepithelial and frankly invasive carcinomas; also, it is possible that some IMBTs may
account for the rare cases of PP in which the appendix does not contain a mucinous tumor. 
The establishment of the borderline subcategory of mucinous tumors as well as the increasing
recognition of metastatic adenocarcinomas that resemble primary ovarian mucinous tumors, and the recent
interpretation of most ovarian mucinous cystic tumors associated with PP as metastatic tumors from the
appendix, have narrowed significantly the number of mucinous ovarian tumors currently diagnosed as
carcinoma. Thus, the reported frequency of 15% for mucinous adenocarcinomas primary in the ovary may be
overestimated, and most of the recent observations about the behavior of these tumors have been based on
a relatively small number of cases.
Mucinous carcinomas are usually large, unilateral, multilocular or unilocular cystic masses containing
mucinous fluid. They often exhibit papillary and solid areas which may be soft and mucoid or firm,
hemorrhagic, and necrotic. The tumors are bilateral in only 5% of the cases. Bilateral mucinous
carcinomas or unilateral carcinomas < 10 cm in greatest dimension should rise the suspicion of
Over 80% of frankly invasive mucinous carcinomas have components of IMBT or mucinous cystadenoma or
both, suggesting a progression from benign to malignant neoplasia. The remaining 20% of the carcinomas
appear exclusively malignant. Recently, it has been proposed to divide mucinous carcinomas into two
categories: an expansile type without demonstrable destructive stromal
invasion, but exhibiting back-to-back or complex malignant glands without or with minimal intervening
stroma and exceeding 10 square mm in area ( >3 mm in each of two linear dimensions); and an infiltrative type, characterized by obvious stromal invasion in the form of
glands, cell clusters, or individual cells, disorderly infiltrating the stroma and frequently associated
with a desmoplastic stromal reaction.  The expansile pattern of growth has also been referred
in the literature as the 'noninvasive,' 'intraglandular'  or 'confluent glandular'
The most important differential diagnosis of mucinous ovarian carcinoma is with metastatic mucinous
carcinoma that may present clinically as a primary ovarian tumor. Most of these originate in the large
intestine, appendix, pancreas, biliary tract, stomach, or cervix.
that favor a primary mucinous carcinoma are an expansile pattern of invasion and a complex papillary
pattern.  Common features favoring a metastatic mucinous carcinoma are bilaterality, a
multinodular growth pattern microscopically, ovarian surface involvement by epithelial cells (surface
implants) and vascular invasion. 
Recent studies strongly suggest that in the sequence of malignant transformation from benign and
borderline mucinous tumors to infiltrative carcinoma, intraepithelial (non-invasive) carcinomas and
carcinomas with purely expansile (not obvious) invasion represent transitional stages of mucinous
This hypothesis is also supported by recent molecular studies of genetic
alterations in mucinous tumors.  An increasing frequency of codon 12/13 K-ras mutations in benign, borderline and carcinomatous mucinous ovarian tumors
has been reported supporting the viewpoint that K-ras mutational activation
is an early event in mucinous ovarian tumorigenesis. 
FIGO stage is the single most important prognostic factor, and stage I carcinomas have an excellent
prognosis. However, the prognosis in cases with extraovarian spread is very poor.
According to the FIGO annual report,  mucinous carcinomas are confined to one or both ovaries
in 49% of the cases, are stage II in 11%, stage III in 29%, and stage IV in 10%. The 5-year survival for
patients with stage I mucinous carcinomas is 83%; stage II, 55%; stage III, 21%; and stage IV,
Recent studies have clearly demonstrated that FIGO stage is largely related to the histologic features
of the ovarian tumors. Infiltrative stromal invasion proved to be biologically more aggressive than
expansile invasion. In fact, in two recent series totaling 59 cases of invasive
all 20 cases of carcinoma with expansile invasion and follow-up information
were stage I and none of the patients had recurrent disease. Of the 25 infiltrative carcinomas with
follow-up data, only 9 of 13 patients with stage I disease and one of 12 with higher-stage disease (stage
IIA) had a favorable outcome. Furthermore, in contrast to previous reports,
one of the
two series  showed that high nuclear grade (grade 3) was predictive of behavior independent
of the surgical stage.
The combination of extensive and infiltrative stromal invasion, high nuclear grade, and tumor rupture
should be considered a strong predictor of recurrence for stage I mucinous carcinomas. 
Foci of stromal invasion <10 square mm have been designated 'microinvasive,' and cases with this
finding have had a favorable outcome.
However, experience with these tumors is still
scarce, and occasional carcinomas with stromal invasion barely beyond the limit accepted for
microinvasion have produced metastases. 
Although selected immunostains can be very helpful in distinguishing primary from secondary ovarian
tumors, immunohistochemistry is considerably less useful when the ovarian neoplasm is of mucinous type.
Most ovarian mucinous borderline tumors and carcinomas are of intestinal type and, therefore, their
immunophenotype frequently overlaps with that of metastatic gastrointestinal tumors. Cytokeratin (CK)
immunostains are the most commonly used.  Primary ovarian mucinous tumors are almost always
(up to 80%) immunoreactive for CK7 whereas colorectal adenocarcinomas are usually CK7
However, CK7 is usually positive in metastatic carcinomas of the pancreas,
notorious for masquerading as primary ovarian tumors, and it is also focally expressed by many other
carcinomas, including those of stomach, gallbladder, small bowel, appendix, lung, breast, thyroid,
uterus, and bladder.
Ovarian mucinous borderline tumors and carcinomas are
immunoreactive for CK20 in 65% and 75% of cases respectively, but the reaction is typically weak and
focal.  In contrast, colorectal adenocarcinomas are diffusely and strongly reactive for
Therefore, a CK7-negative/CK20-positive immunoprofile suggests metastatic
Although the vast majority of colorectal adenocarcinomas express CK20,
poorly differentiated and right-sided tumors can be CK20 negative. Thus, immunostains for
CK7 and CK20 should be interpreted with caution, always in the light of all clinical information, and
with the understanding that no tumor shows absolute consistency in its staining with these markers.
Other immunohistochemical stains have greater overlap in their expressions and should not be used
individually in this differential diagnosis. Nevertheless, after taking into account the
clinicopathologic findings and the results of the CK immunostains, negative stainings for vimentin,
CA125, B72.3, and gastric mucin gene MUC5AC
and strongly positive staining for
carcinoembryonic antigen (CEA) and MUC2
favor metastatic colorectal cancer over primary
ovarian adenocarcinoma. Loss of Dpc4 immunoreactivity occurs in almost 50% of metastatic carcinomas of
the pancreas, whereas most primary ovarian mucinous carcinomas are focally or diffusely
HPV DNA assessment may be helpful for distinguishing mucinous adenocarcinoma of the cervix metastatic
to the ovary from a primary ovarian mucinous carcinoma. Recently, expression of p16 has been found to be
a reliable surrogate marker for HPV. 
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