This presentation briefly summarizes our current knowledge of the two most common types of
non-endometrioid adenocarcinoma, uterine serous carcinoma (USC) and clear cell carcinoma (CC),
emphasizing recent findings. The goal of the latter half of this discussion is to identify outstanding
questions that could be addressed by members of our society.
Compared to endometrioid adenocarcinoma USC and CC: 1) portend a worse prognosis; 2) affect
African Americans disproportionately and 3) likely differ in etiology
and pathogenesis. Given, that these aggressive neoplasms are difficult to cure, early detection and
prevention would be highly desirable, but this would require knowledge that we current lack.
Incidence data from the Surveillance, Epidemiology, and End Results Program
(SEER) for the period 1992-1998 demonstrate that USC / CC (combined) are rare. The incidence of typical
endometrial adenocarcinomas (mainly endometrioid) among white Hispanics and African Americans are
similar, whereas the rate is about double for white Non-Hispanics. In contrast, the rate of USC/CC is
about twice as high for African Americans compared to the other two groups.
Incidence / 105 (C.I.)
Incidence / 105 (C.I.)
The following table compares rates and cumulative relative 5-year survival (survival of
endometrial cancer patients to patients without endometrial cancer matched on age and race) for USC and
CC separately. Survival data are not available for Hispanics.
Incidence (per 105) 5-Year Survival
Clear Cell Carcinoma
Incidence (per 105) 5-Year Survival
Incidence and survival patterns are similar for USC and CC among African Americans and whites;
in both groups USC is more common and has a worse prognosis than CC. Several previous studies have shown
that among African American women USC/CC accounts for a higher percentage of total endometrial
adenocarcinomas than among whites, however analyses of percentages cannot distinguish whether this
results from relatively fewer typical endometrial cancers among African Americans or a true excess of
USC/CC. These demonstrate that the absolute incidence of USC/CC is significantly higher among African
Americans (and the incidence of typical adenocarcinomas is lower). Typical endometrial cancers account
for about 47% and USC/CC account for 18% of total mortality among African Americans, whereas among
whites, the comparable figures are 64% and 12% respectively. Survival is worse for African Americans as
compared to whites for all malignant tumors of the uterine corpus, including USC/CC. Only
carcinosarcomas have a worse cumulative relative survival than USC and CC. The reasons for these racial
differences are unknown.
Uterine Serous Carcinoma (USC)
The low incidence of USC has limited the
collection of population-based data. Registry data provide useful descriptive data, but are limited by
pathologic misclassification and lack of detailed clinical and epidemiologic data. One case-control
study found that two established risk factors for endometrial cancer, obesity and use of exogenous
estrogen, were not clear risk factors for USC. However, early age at menarche seemed to have been
associated with increased risk for both tumor types and the relationships with protective factors (oral
contraceptive use, parity and smoking) were similar. This analysis also found serum levels of all
estrogenic hormones were lower among USC patients compared to controls, after adjusting for age and body
mass index (differences for albumin-bound estradiol, estrone were significant). In another small
retrospective case-control study, limited by access to consenting living subjects, women with USC tended
to have a slightly higher non-obese weight compared to controls at 18 years of age (124 V.S. 117 lbs.),
but similar weights at diagnosis. Among estrogen replacement users, USC was associated with a slightly
longer mean duration of use. Overall, data favor a different etiology for USC and endometrioid
adenocarcinomas, but a large well controlled epidemiologic study is needed to conclusively confirm and
elucidate this finding.
The average age of women diagnosed with
USC is higher than that of women diagnosed with endometrioid adenocarcinoma and nearly all are
post-menopausal (median age ~65-70 years in most studies). Women generally present with abnormal
bleeding and probably are more likely to present with an abnormal Pap smear or evidence of disseminated
disease, especially ascites, than patients with usual histologic types of endometrial cancer.
Historically, pathologic criteria for USC were formally codified in a seminal
paper by Hendrickson et al, which identified this entity as a frequent case of recurrence in clinical
stage I endometrial cancer. This paper helped clarify confusion regarding the pathologic classification
and behavior of papillary adenocarcinomas, by emphasizing the distinction of USC from villoglandular
endometrioid adenocarcinoma. The term "serous carcinoma" has gained favor ("papillary" has been
dropped), emphasizing that it is cellular differentiation not papillary formation that defines tumors
with this distinctive clinical phenotype. Numerous clinicopathologic studies have been published on USC
in the last 20 years, for the most part demonstrating consistent results.
The morphologic diversity of USC has been described; tumors may occur in pure form, in
association with benign polyps or combined with other histologic types of endometrial adenocarcinoma
(clear cell, endometrioid). USC usually arises in an atrophic background; when endometrial hyperplasia
is identified, the tumor often shows mixed endometrioid and serous differentiation. In such cases, the
areas of endometrial hyperplasia may give rise to the endometrioid component, whereas serous
differentiation may represent "tumor progression." However, it is also possible that these tumors arise
de novo with dual differentiation – more studies are needed.
Architecturally, USC may contain papillae (of diverse appearances), glands or solid areas.
Tumors characteristically show areas of well-formed glands or papillae (well differentiated architecture)
associated with marked nuclear atypia (poor cytologic grade). Given the universally high nuclear grade
and poor prognosis of USC, tumors may be considered "high-grade" without further specification. Nearly
all tumors are associated with strong, diffuse immunoreactivity for p53 antigen, which reflects
cytoplasmic accumulation of mutant p53, which has increased stability (as opposed to wild type p53 which
is usual unstable and undetectable). Most USCs consist of large, pleomorphic bizarre cells with
hyperchromatic smudgy chromatin and irregular outlines, but in some cases the nuclei are monotonously
atypical. Mitoses including abnormal figures are frequent. The tumor cells may be cuboidal, polygonal
or hobnail in shape. The cytoplasm may be eosinophilic or clear and when the latter pattern is prominent
a diagnosis of mixed serous / clear cell adenocarcinoma is appropriate. Most tumors deeply invade the
myometrium, usually in a contiguous pattern, but sometimes a deceptively dispersed pattern is found.
Vascular invasion is frequent.
Recognition that most cases of USC are not associated with endometrial
hyperplasia has prompted studies to identify the "precursor" or "earliest identifiable" manifestation of
these tumors. Multiple groups have found that malignant replacement of the endometrial surface
epithelium or the surface of an otherwise typical polyp represents a morphologic lesion that may be
found early in the natural history of USC; this lesions has been designated as "endometrial
intraepithelial carcinoma (EIC)," "carcinoma in situ," "uterine surface carcinoma,' and "noninvasive
endometrial serous carcinoma." This proliferation of terms represents multiple efforts to identify the
best terminology for a rather unique gynecologic lesion, which has been increasingly well characterized
in recent years. The identification of EIC suggests that USC may develop directly from the endometrial
surface of atrophic endometrium or the surface of benign polyps. In addition, these observations present
clinical challenges: 1) what are the pathologic criteria for EIC and early USC; 2) what is the optimal
management for these lesions and 3) what are their prognoses.
Several studies (including case reports and small series) have described cases
of USC in which there was either no invasion identified in the uterus or invasion limited to the
endometrial stroma or to the stroma of a polyp. A broad consensus has emerged that these patients
require meticulous staging. Patients with any amount of extra-uterine disease have a poor prognosis.
Although the prognosis is better for USC confined to the uterus, a proportion of these tumors also
relapse fatally. Distinguishing EIC from minimally invasive USC, especially when the lesion occurs in a
polyp may be challenging; however, both lesions require staging, the results of which direct subsequent
management. The term minimal uterine serous carcinoma (MUSC) has been proposed for cases of EIC or
invasive USC < 1cm, which do not display lymph or blood vessel invasion to emphasize their similar
behavior. The mechanism of dissemination outside the uterus in cases of MUSC has been debated;
multi-focal disease ("field effect"); transtubal expulsion and unrecognized invasion of the myometrium or
vessels represent possibilities. In a few cases, results of immunohistochemical or clonality assays have
suggested that the extra-uterine foci in such cases represent metastases. Careful examination of the
endometrium to search for MUSC should be performed in patients have who presented with abdominal
carcinomatosis to avoid a misdiagnosis of primary peritoneal carcinoma.
The diagnosis of EIC may be challenging. Endometrial metaplasia likely
represents the most perplexing differential diagnosis, especially when compounded by stromal breakdown
with epithelial regeneration that results in nuclear degeneration and mitoses. Marked nuclear atypia,
advanced age, strong diffuse p53 staining and a high Ki67 index favor a diagnosis of EIC; most
metaplastic lesions occur in peri-menopausal women and nuclear atypia and p53 staining are generally less
diffuse. The differential diagnosis of MUSC also includes endometrial hyperplasia in a polyp. Marked
cellular pleomorphism, severe nuclear atypia and an atrophic background favor a diagnosis of EIC.
Hyperplasia in a polyp is more common among peri-menopausal women and often involves the surrounding
non-polypoid endometrium, where the diagnosis may be easier. An immunostaining pattern of p53 positive,
ER and PR negative with high Ki67 index favors a diagnosis of EIC. Rarely the differential diagnosis of
EIC/MUSC includes endocervical adenocarcinoma in situ or CIN3 with extension to the corpus; morphologic
differences, stains (as noted above) and HPV testing may all be helpful. Finally, Liang and colleagues
have suggested that lesser degrees of cellular atypia, which they have preliminarily termed, "endometrial
glandular dysplasia," may represent a forerunner of EIC.
Surgical treatment for USC includes TAHBSO, omentectomy and lymph node
dissection. To date, curative therapy for disseminated USC has not been described. Some groups have
reported that whole abdominal radiation therapy is effective. Platinum containing regimens analogous to
those used for serous carcinoma of the ovary have been tried, but some data has suggested that responses
are not as good as for ovarian carcinoma. Interestingly, some studies have found that the molecular
profiles of serous carcinomas of the endometrium and ovary also differ.
Clear Cell Carcinoma (CC)
Analysis of risk factors for CC has been limited by the rarity of this neoplasm.
Scattered clinical descriptions of cases suggest that CC may not share identical risk factors with
endometrioid adenocarcinoma, but compelling proof is lacking. Based on a retrospective clinicopathologic
study of 21 CCs, one study divided cases of CC into two variants: "typical CC" (7 cases) and "CC with
serous features" (14 cases). Both proposed types of CC were generally negative for hormone receptors and
demonstrated a higher Ki67 index than endometrioid adenocarcinoma. Whereas typical CC was associated
with endometrial hyperplasia, CC with serous features demonstrated a higher Ki67 index than typical CC,
more frequent p53 abnormalities (by immunohistochemistry) and was more often associated with EIC. CC
generally occurs at an older age than endometrioid adenocarcinoma, but the clinical presentation is
similar. Based on small sample sizes, recent studies have found that the gene expression profiles for CC
and USC revealed greater similarity than the comparison of either CC or USC with endometrioid
Histologically, CCs may display tubulocystic, papillary or solid architecture. The cells may be
cuboidal, or hobnail with clear or eosinophilic cytoplasm. Cytoplasmic clearing is attributable to
glycogen accumulation. These tumors typically display marked nuclear atypia and several mitoses per 10
high power fields, although the atypical nuclei tend to be smaller and monotonous compared to USC. As
noted above, many tumors classified as CC also show other histologic patterns, including USC, which may
merge imperceptibly with classic appearing areas of CC. Many pathologists reserve the diagnosis of CC
for tumors of mixed histology in which clear cell differentiation comprises at least 50% of the neoplasm.
PAS positive diastase resistant hyaline globules and thin appearing watery mucin within gland lumina are
characteristic when present. A thin fibrovascular network commonly traverses large regions of CC
composed of solid sheets. The prognosis of CC is poor, with stage representing the best predictor of
outcome. Generally, these tumors are not specifically graded and are simply considered high-grade. In
contrast to USC, which often spreads intra-abdominally like ovarian carcinoma diffusely encasing viscera,
CC may metastasize more similarly to typical endometrioid adenocarcinomas as solid masses.
CC is distinguished from USC by its characteristic architecture and increased
tendency to display hyaline fibrosis, hyaline globules and thin mucus. Yolk sac tumors may also contain
clear cells, but these tumors are extraordinarily unusual in the uterus, and unlike CC are immunoreactive
for AFP. It is most critical to distinguish CC from low-grade tumors with clear cells, including
secretory adenocarcinoma and endometrioid adenocarcinoma with glycogenated squamous metaplasia. Several
distinguishing features are useful, notably the more severe nuclear atypia in CC, identification of
architectural patterns and cell morphology characteristic of CC, the identification of sub-nuclear
vacuoles in secretory carcinomas and evidence of clear cells merging with foci of definite squamous
differentiation in endometrioid adenocarcinomas.
Data from selected studies of clear cell carcinoma are presented below.
% Total Cancers
Classified as CC
Survival (5 years)
|| Stage I || Stage II |
| 21 |
| 66 |
| 27 |
29 (Stage I, II)
| 59 |
Note that the studies are small in size and retrospective, often spanning many
years of case ascertainment. In clinical reports, CC usually accounts for < 5% of all
endometrial adenocarcinomas; SEER data shows differences in incidence by race. Age of patients has been
consistent across studies. Survival is probably stage related. Overall, survival outcomes in other
studies: ~71% for 17 stage I and II patients (Malpica '95), 60% crude survival among 20 patients,
11 of 12 survivors stage I CCs (Kanbour-Shakir '91), 34% crude survival among 55 patients, all survivors
stage I (Chirstopherson '82). There are scattered reports of survival for 5 years with later recurrence
and death from tumor. In the future, as better treatment prolongs survival without necessarily achieving
complete cures, it is likely that accurate case fatality estimates will require more than 5 years of
Expanding our understanding of USC and CC is
important from an etiological, public health and clinical perspective. Given the rarity of these tumors,
it is difficult for single institutions to develop meaningful studies of these entities; enlarged study
sets that are highly enriched with consult material may be useful for addressing some questions, but are
prone to biases. Accordingly, meetings of experts in gynecological pathology, such as this companion
meeting, represent opportunities to air new concepts and hopefully foster productive collaborations. The
following short list of topics is presented in this spirit. Certainly, many of these ideas, which are
likely the subject of ongoing or planned work, could receive an added boost through further
- Establish the reproducibility of the diagnosis of USC, EIC and CC; identify
histologic features that lead to poor agreement and propose criteria for clarifying interpretation;
address the concept of sub-typing CCs into "typical" CC and a variant with "serous features"
- Although most villoglandular and serous carcinomas containing papillae are
easily distinguished, some examples showing borderline nuclear atypia may pose diagnostic
- The differential diagnosis of EIC and benign metaplasias may be difficult;
further work in this area would be helpful (molecular, immunohistochemical, image analysis)
- The concept of endometrial glandular dysplasia requires additional study
Refined criteria for distinguishing solid patterns of CC from squamous metaplasia in endometrioid
adenocarcinoma may be helpful, especially for generalists
- Determine whether CCs are
homogeneous or heterogeneous with regard to precursor lesions, behavior and etiology; the pathogenesis of
USCs associated with other histologic patterns also could be clarified
Consider protocols for histologic processing of uteri removed to treat USC or CC; should these differ
from processing protocols for endometrioid adenocarcinomas and if so how?
immunostaining patterns that are useful in the differential diagnosis of USC and CC and search for
prognostic markers in early stage lesions (tissue microarrays enriched for USC and CC may be
- Determine whether the expanded diagnostic criteria for USC that have been
used in the last 5-10 years, has obviated the needed for a FIGO grading scheme for well differentiated
endometrioid adenocarcinomas with marked nuclear atypia – are all of these tumors classified as USC
- Develop a clinical assay with high negative predictive value for extra-uterine disease among
women with pathologic stage I tumors, permitting conservative treatment.
- Using existing knowledge and emerging data from expression arrays, develop a PCR based assay
for peritoneal washes or circulating cells in blood that predicts recurrences
- Molecular profiling (RNA, DNA methylation, proteomics, etc.) of USC and CC to
identify alterations in pathways that might be exploited for diagnosis and treatment Determine whether
p53 mutation is truly an early event in the development of USC; explore the significance of p53
abnormalities in typical endometrial adenocarcinoma – does this imply that the tumor should now be
classified as a mixed USC
- Further characterizations of surface epithelium,
especially: benign atrophic, metaplastic, and surface lining of endometrial polyps; explore the apparent
association between polyps and CC and USC – is there an increased risk and if so, is this simply because
there are more about the surface cells of polyps which predisposes to USC and CC. Are the surface of
these polyps components of an endometrial hyperplasia that has regressed but left behind mutated cells or
are the cells of polyps exposed to more genetic stresses or carcinogens? How does genetic damage
accumulate in endometrial surface epithelium and does this related to the development of p53 mutations?
- Exploration of epithelial-stromal interactions
- Analysis of risk factors for USC and CC in a sufficiently large data set with expert pathology
review and access to other biological samples (blood, urine, germline DNA); confirm whether protective
factors for all types of endometrial cancer are similar. Explore whether exogenous hormones or
anti-inflammatory drugs protect against USC and possibly CC.
- Explain the increased
incidence of USC, CC and other aggressive tumors among African American women in the U.S. (and the lower
incidence of endometrioid adenocarcinomas)
- Determine whether tamoxifen is associated
with increased risk for USC, CC
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