Case 4 -
Recurrent Postchemotherapy Clear Cell Carcinoma
Johns Hopkins University School of Medicine
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A 42 y/o nulligravid Asian female presented with increasing intra-abdominal lymphadenopathy shortly after carboplatin/paclitaxel treatment for her previous "ovarian carcinoma" in an outside hospital. Unfortunately, the original tumor tissue was not available to review at that moment. She developed postoperative venous thromboembolism. Past history was significant for endometriosis. The sections were obtained from lymph node dissection.
Case 4 - Figure 1
The tumor shows a heterogeneous growth pattern including microcysts, solid and glandular features.
Case 4 - Figure 2
Cytologically, the tumor cells contain moderately atypical nuclei with infrequent mitotic figures. The cytoplasm is not particularly clear. Hyalinization in tumor stroma is also appreciated.
Case 4 - Figure 3
Cytologically, the tumor cells contain moderately atypical nuclei with infrequent mitotic figures. The cytoplasm is not particularly clear. Hyalinization in tumor stroma is also appreciated.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The tumor shows a
heterogeneous growth pattern including microcysts, solid and glandular features. Cytologically, the
tumor cells contain moderately atypical nuclei with infrequent mitotic figures. The cytoplasm is not
particularly clear. Hyalinization in tumor stroma is also appreciated.
High-grade serous carcinoma Low-grade serous carcinoma Clear cell carcinoma
Recurrent postchemotherapy clear cell carcinoma
The diagnosis of this case was based on both clinicopathologic and molecular
studies. The outside slides of patient's primary tumor were subsequently available for review and showed
a classical ovarian clear cell carcinoma. The tumor is positive for HNF-1beta, but negative for WT1 and
PBX1, markers associated with high- grade serous carcinoma. Molecularly, the recurrent tumor, like its
primary counterpart, harbored a somatic mutation in PIK3CA gene. The TP53, beta-catenin, KRAS and BRAF
were all wild-type. Thus, this case represents an example to demonstrate the many unique aspects of
ovarian clear cell carcinoma.
Ovarian Clear Cell Carcinoma
Although ovarian clear cell carcinoma (CCC) represents less than 10% of ovarian cancers in the United
States, it appears to occur more frequently in Asian women and its incidence in this population has
increased in recent years
. Multivariate analysis on a large series of CCC shows that women with
CCC present at a younger age and earlier clinical stages than (high-grade) serous carcinoma  . The
mean age of patients with CCC is 57 years. Approximately 50% of CCCs present as stage I diseases
and despite being diagnosed at an early stage they are generally considered highly malignant  .
Whether CCC has a worse clinical outcome as compared to high-grade serous carcinoma is a subject of
controversy. In some studies, the prognosis appears similar to that for other ovarian carcinomas  ,
but in others, the prognosis is reported to be worse. In a multivariate study that analyzed 1,411 CCC
patients, CCC had a significantly worse prognosis than serous carcinoma but the difference is only modest
at most  . In summary, when controlled for stage, the survival of women with CCC may be slightly lower
than that of patients with serous carcinoma. Symptoms usually relate to a pelvic or abdominal mass. The
most remarkable clinical condition associated with women with CCC is the paraneoplastic syndromes
including venous thromboembolism, hypercalcemia and subacute cerebellar degeneration. For example, CCC
patients have a 2.5-times greater risk of disease related venous thromboembolism t han women with other
histologic types of epithelial ovarian cancer  .
Previous morphological and molecular studies have indicated that CCC develops in a stepwise fashion
from endometriosis, atypical endometriosis to CCC
. In fact, CCC is the most common ovarian
carcinoma that is associated with endometriosis. A recent study by analyzing a large series of CCCs
proposed dividing CCC into cystic or adenofibromatous types because the investigators found that there
was a significant difference in a number of clinicopathologic features including stage at presentation,
association with endometriosis, histologic patterns and survival between these two types  . Cystic
CCCs presented more often at stage I, had a better prognosis, and were more frequently associated with
endometriosis compared with adenofibromatous CCC. Histologically, cystic CCC frequently displayed a
papillary architecture and was associated with a trend toward a more favorable outcome compared with
tumors in which a tubulo-cystic pattern predominated. The latter pattern occurred more frequently in
adenofibromatous CCC. Finally, the 5-year survival for stage I cystic CCC (90%) was superior to the
adenofibromatous type (50%). By reporting these two types of CCC may have a potential impact in clinical
management of CCC patients if future additional studies can confirm these findings.
Potential diagnostic pitfalls and differential diagnosis
Because CCCs respond poorly to conventional chemotherapy and there is enthusiasm to initiate clinical
trials for CCC, it is important for pathologists to make an accurate diagnosis. Diagnosis of CCC is
usually not a problem  because most cases display the typical features of CCC, namely those with
papillary, tubulo-cystic and solid patterns containing polygonal tumor cells with clear (glycogen rich)
or, less commonly, eosinophilic (granular) cytoplasm. When the latter feature becomes diffuse, the term
"oxyphilic" CCC could be used. In some cases, cytoplasmic vacuoles harbor homogeneous eosinophilic
globules, creating a "targetoid" appearance, but their presence is not diagnostic for CCC. In CCCs with
predominant tubulopapillary architecture, the cells are often columnar with a hobnail appearance.
Another classical feature of CCC is the hyalinized and homogeneous eosinophilic stromal fibrosis which
can be detected in the majority of cases. Given the characteristic morphologic features of CCC, the
diagnosis can be at times difficult for various reasons, in particular when the typical clear cell
features are not clear. It is not infrequently to encounter mixed ovarian epithelial carcinomas with
clear cell and serous components. These mixed tumors have been studied based on clinicopathological and
immunostaining features. The conclusion is that the mixed tumors may likely represent variants of
high-grade serous carcinoma  . Future molecular studies are required to support this view. It has
also been reported that neoadjuvant chemotherapy may be associated with extensive clear cell changes in a
serous carcinoma  . Moreover, the case as discussed in this specialty section represents another
diagnostic pitfall that CCC may show serous differentiation after chemotherapy. Besides, the "classical"
differential diagnosis of CCC includes dysgerminoma, york sac tumor, endometrioid carcinoma with
secretory change and metastatic clear cell carcinoma from kidney and gastrointestinal tract  . Of
note, metastatic clear cell neoplasms from outside the female genital tract do occur but they are
exceptionally rare. When oxyphilic tumor cells predominate, steroid cell tumor, hepatoid york sas tumor
and hepatoid carcinoma may also be considered. Clinicopathological features are important to distinguish
CCC from other morphologic mimickers. The presence of typical CCC morphology and association with
endometriosis or an adenofibromas or an admixture with endometrioid carcinoma may be helpful to diagnose
CCC. Patients with york sac tumor with or without hepatoid features and dysgerminoma are usually much
younger than CCC and have elevated serum AFP levels. As compared to york sac tumors, the papillary
structures in CCCs appear more complex and have hyalinized stromal cores. Hepatoid carcinoma lacks the
foci of typical CCC. Endometrioid carcinoma with secretory changes can be confused with CCC, especially
when the changes are extensive. The tall columnar epithelium with sub- or supranuclear vacuoles
resembling early secretory endometrium suggests an endometrioid carcinoma with secretory changes.
Finally, immunohistochemistry could be helpful in the differential diagnosis and this will be discussed
in the following section.
Recent advances in molecular genetic findings
The most common molecular genetic changes known so far in CCC is the somatic activating mutation of
PIK3CA  , which were detected in nearly 48% of affinity-purified fresh
tumors and cell lines. In contrast, the frequency of PIK3CA mutations is
relatively low in the conventional high-grade serous carcinoma. Besides, PTEN, a tumor suppressor gene involved in the PIK3CA
signaling pathway, decreases its expression in approximately one third of CCC  , supporting the role
of aberrant PIK3CA pathway in the development of CCC. LOH at the PTEN locus in both the carcinoma and associated endometriosis has been reported in
some CCCs, suggesting that inactivation of the PTEN tumor suppressor, when
it occurs, is a relatively early event in the development of CCC  . Although mutations in KRAS, BRAF, and TP53 are
present in some CCCs their frequency is generally very low (review in  ) . For example, TP53 mutation and BRAF mutation were found in 8.3%
and 6.3% of CCCs, respectively. Although studies to date are rather limited, the CCCs do not appear to
share many other changes with endometrioid carcinomas, as canonical Wnt signaling pathway defects and
microsatellite instability have rarely been in CCC  .
DNA copy number alteration is another common molecular genetic hallmark in human cancer and such
change can be detected at a genome-wide scale by several techniques including high-density SNP array.
Based on SNP array analysis on purified tumor cells isolated from fresh cancerous tissue, Kuo et al. have
recently reported frequent amplification of the ZNF217 (zinc finger protein
217) locus and deletion of the CDKN2A/2B locus in CCCs, suggesting that
pathways involving these two genes are important in CCC tumorigenesis  . ZNF217 encodes a nuclear protein with Krüppel-like zinc finger domains and serves
as a common protein in forming transcriptional repressor complexes with HDAC2 and LSD1. Previous reports have shown frequent
amplification and overexpression of ZNF217 in other carcinomas including
breast, colorectal, and prostate. In breast carcinomas, increased ZNF217
expression was found to be associated with a poor prognosis and ectopic expression of ZNF217 immortalized epithelial cells and resulted in the loss of TGF-beta
responsiveness  .
Like in other cancer types
, ZNF217 expression has been shown to be
essential role in maintaining cellular proliferation and survival in CCC, further supporting a role for
ZNF217 in CCC tumorigenesis.
The degree of overall DNA copy number changes has been used to reflect the chromosomal instability
(CIN) levels in cancer. Based on the CIN index (the total numbers of DNA copy number gains or loss in an
individual tumor), CCC is much more similar to low-grade serous carcinoma than to high-grade serous
carcinoma. The molecular genetic analysis of CCCs described herein reflects an initial step toward
revealing the genomic landscape of this disease and provides a useful foundation for future studies aimed
at elucidating the molecular pathogenesis of CCC and at development of target-based therapeutics for this
highly aggressive ovarian malignancy.
Gene expression profile and immunohistochemistry markers
Analyses of gene expression patterns have demonstrated that CCCs are distinct from other histological
types of ovarian carcinomas (review in  ) . When compared to normal tissues including colon,
endometrium, and fallopian tube, the overall gene expression profile of CCC is most similar to that in
normal endometrium, supporting the view that the cell of origin of CCC may likely come from endometriosis
 . An increasing number of genes have been reported to be preferentially expressed in CCC. A very
recent study based on a comprehensive gene expression analysis proposes the "CCC signature" which
consists of HNF-1beta, versican (VCAN), and several genes involved in oxidative stress  .
Interestingly, expression of those CCC signature genes is induced by treatment of immortalized ovarian
surface epithelial cells with the contents of endometriotic cysts, suggesting that the CCC signature may
be dependent on the tumor microenvironment and its pathogenesis is related to endometriosis. Other
upregulated genes in CCC include glutathione peroxidase 3, plasma membrane-associated sialidase (NEU3),
osteopontin, annexin A4, tissue factor pathway inhibitor 2 and MAP3k5/ask1, CD26, hypoxia-inducible
protein 2, and genes involved in nucleotide excision repair, just to name a few  . Among these
upregulated genes, HNF-1beta is most consistently reported and appears to be a relatively specific marker
associated with CCC  . HNF-1beta is a nuclear homeodomain protein that is responsible for regulating
transcriptional activity including genes relatively specific to CCC genes and those involved in
glucose/glycogen metabolism. It is likely that HNF-1beta up-regulation may participate in the generation
of the glycogen-rich, clear-appearing cytoplasm, a cytological feature characteristic of CCC. Knockdown
of HNF-1beta expression in CCC cells induces apoptosis, suggesting that HNF-1beta is essential for
survival of cancer cells  . DNA hypomethylation may be one of the mechanisms involved in
upregulating HNF-1beta and other CCC-associated genes  .
Although the CCC associated genes can be the clues to study the biology of this tumor
type, their roles in differential diagnosis remain largely unclear except HNF-1beta. From a practical
perspective, several "classical" markers have been proven useful in distinguishing CCC from other tumor
types that may be confused with CCC. For example, as compared to germ cell tumors, CCCs almost always
are CK7+, EMA+, AFP-, CD10-, OCT-. A diagnostic panel consisting of WT1, ER, and HNF-1beta has been
reported to be useful in distinguishing CCCs (HNF-1beta+, WT1-, ER-) from high-grade serous carcinoma
(HNF-1beta-, WT1+, ER+)  . Of note, the rare expression of WT1 in CCC may be attributed to the
frequent WT1 promoter methylation in CCCs but not in high-grade serous carcinoma
Markers that can predict the treatment outcome in CCC patients have been a subject of
intense study. The rationale is that CCC typically presents with stage I or II disease and in this
setting prognostic markers could have an impact on clinical management, in particular the decision to
treat with adjuvant chemotherapy  . IGF2BP3 (IMP3) expression has been reported as an independent
marker of reduced disease-specific survival in CCC, but not in high-grade serous or endometrioid
carcinomas of the ovary. The prognostic significance of IGF2BP3 expression for reduced disease-specific
survival was confirmed in an independent series of cases from three different centers in North America
 . Similarly, enhanced expression of Annexin A4 in CCC and its association with chemoresistance to
carboplatin have been recently reported  .
Where CCC stands in the dualistic model of ovarian cancer development?
In an attempt to elucidate the molecular pathogenesis of ovarian carcinoma, a dualistic model of
ovarian carcinogenesis has been proposed for ovarian carcinomas
. This model is based on
extensive clinicopathologic and molecular genetic studies, and classifies ovarian carcinomas into type I
and type II tumors. It should be emphasized that the model describes pathways of tumorigenesis and the
terms, type I and type II, are not specific histopathologic terms. In this model, low-grade serous,
mucinous, and endometrioid carcinomas are designated as "type I" tumors. These neoplasms share many
features including development in a stepwise fashion from well-recognized precursors termed "borderline"
tumors that originate from cystadenomas/adenofibromas and endometriosis. They typically are low-grade,
present as large cystic tumors confined to the ovary, and have an indolent behavior. In contrast,
high-grade serous carcinoma, undifferentiated carcinoma and malignant mixed mesodermal tumors
(carcinosarcomas) are designated as "type II" tumors. In contrast to type I tumors, these high-grade
malignancies are not associated with benign precursor lesions. Recent studies have suggested that type
II tumors develop from serous intraepithelial carcinomas in the fimbriated portion of the fallopian tube
 . Regardless of their origins, type II tumors are invariably highly aggressive and the disease often
is in advanced stages at the time of diagnosis. Compared to type I tumors at the molecular level, type
II tumors have high chromosome instability and are characterized by frequent TP53 mutations. In contrast, type I tumors have moderate chromosome instability
and contain frequent somatic mutations of genes participating in signal transduction pathways, including
KRAS/BRAF, PTEN/PIK3CA and CTNNB1. In contrast, the mutations in
those genes are rarely detected in type II tumors.
CCC appears to exhibit features of both type I and type II neoplasms. Similar to type I tumors, CCCs
develop from well characterized benign precursors (e.g., endometriosis) and present as large cystic
tumors confined to the ovary. However, when the disease spreads beyond the ovary CCC is typically
high-grade, high-staged, and very aggressive. So, does CCC belong to type I or type II tumor? Recently,
Kuo et al. found that CCCs have a chromosomal instability index very similar to that of low-grade serous
carcinomas and much lower than that of high-grade serous carcinomas  . Rare TP53 mutations but frequent PIK3CA activating
mutations have also been detected in CCCs  . The above molecular genetic findings are in stark
contrast to results obtained in high-grade serous carcinomas and strongly support classifying CCC as a
type I tumor from both clinicopathologic and molecular perspectives.
Challenges and new promise in managing advanced stage disease
As discussed above, although most CCCs are indolent, typically presenting in one ovary (stage I) when
surgical intervention is effective in eradicating the disease, CCC in advanced stage can be highly
aggressive because of its resistance to conventional chemotherapy
. This represents a major
challenge in treating patients with advanced stage CCC and accounts for their dismal prognosis. The
relatively high frequency of PIK3CA mutations holds promise for new
therapeutic approaches using small molecule inhibitors targeting PI3K, the protein encoded by PIK3CA. New PI3K targeting drugs, including GDC-0941  ,
PI-103  ,
and SF1126, a LY294002 prodrug  , have recently been developed and are being evaluated
in clinical trials
. In the future, it will be important to design clinical studies to
evaluate the safety and efficacy of such inhibitors by correlating clinical response with PIK3CA mutational status or pathway activation. If such studies show promising
results, this would be an important step in the development of customized treatment for ovarian CCC at
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