70 year old women with post-menopausal bleeding.
On low-power microscopic evaluation both cases
demonstrate architectural patterns associated with clear cell carcinoma. Case A demonstrates
predominantly papillary and solid growth patterns, which are also found in case B. In addition, case B
has focal tubular and cystic growth patterns. In both cases there is abundant, hyalinized stroma in the
papillary cores and in the regions of tubulo-cystic growth, a classic feature of clear cell carcinoma.
Examination on higher-power magnification reveals a marked difference in the degree of cytologic atypia
between the two cases. Case B shows mild to moderate cytologic atypia and only rare hob-nail cells while
case A is composed of cells with high nuclear grade with prominent hob-nail cells and numerous atypical
mitotic figures. Despite the difference in the cytologic atypia both of these cases would be classified
as clear cell carcinoma of the endometrium.
Molecular Genetic Evaluation:
Both cases were analyzed for mutations in
the p53 and PTEN tumor suppressor genes and for
microsatellite instability (MI). Case B showed microsatellite instability and a mutation in PTEN, but was negative for a p53 mutation. Case A
had only a p53 mutation and lacked microsatellite instability or a PTEN mutation.
Although clear cell carcinoma of the endometrium is recognized
as a distinct morphologic entity, the biological behavior of this tumor type has generated controversy in
the literature. It is usually classified as an aggressive tumor type similar to that of serous carcinoma
of the endometrium. However, some studies have suggested that it is less aggressive than serous
carcinoma, with one study reporting a survival similar to Grade III endometrioid carcinoma.
The two cases presented here are examples of a larger study we have completed. We have analyzed 11
cases of pure and 5 cases of mixed clear cell carcinoma of the endometrium for mutations in the p53 and PTEN genes and microsatellite instability.
The results suggest that clear cell carcinoma of the endometrium may represent a heterogeneous group of
Nine of the 11 cases of pure clear cell carcinoma did not show mutations in either gene or any
evidence of MI. The other three cases showed a PTEN mutation in one case, a
PTEN mutation and MI in one case (Case B presented here) and a p53 mutation in one case. These results suggest that even in the pure phenotype,
there is genetic heterogeneity. A review of the clinical features of the three pure cases that showed
mutations did not reveal any significant difference from those pure tumors that lacked any detectable
mutations. Also, as with the cases seen today, there were no differences in the overall architecture of
the tumors. However, as seen in the cases presented today, cases with p53
mutations had more cytologic atypia than those without p53 mutations.
Of the four mixed tumors with mutations, identical mutations were detected in the clear cell and the
non-clear component. In two cases of mixed clear cell carcinoma (one mixed with serous carcinoma and one
with sarcomatous differentiation) both components showed identical mutations in the p53 gene. Furthermore, a mixed clear cell/endometrioid carcinoma had identical
mutations in the p53 and PTEN genes and similar
patterns of microsatellite instability in both components. These findings support the monoclonal origin
of the two components in all four of these tumors and suggest that the morphological divergence occurred
after neoplastic transformation. We considered the possibility of cross contamination during the
microdissection procedure as a possible reason for the presence of identical mutations in the clear cell
and the non-clear cell components. However, microsatellite studies showed different loss of
heterozygosity patterns in the different components of one case making this possibility unlikely. In
addition to underscoring the monoclonal nature of these tumors, the results suggest that the morphologic
divergence may be driven by underlying genetic divergence.
Previous studies have shown that PTEN mutations and microsatellite
instability are common in endometrioid carcinoma, occurring in approximately 50-80% and 20-25% of cases,
respectively. Of note, these genetic alterations are very rare in serous carcinoma of the endometrium.
Although p53 mutations are present in both endometrioid and serous carcinoma
of the endometrium they are much more common in serous carcinoma. Mutations in p53 are detected in 90% of serous carcinoma while they are found in only 10-15% of
endometrioid carcinoma and they are confined to Grade 3 tumors. Thus, the results of this study suggest
that clear cell carcinoma represents a heterogeneous group of tumors, some with genetic alterations
similar to endometrioid and others more like serous carcinoma, as shown in the two cases presented
today. Furthermore, if clear cell carcinomas have mixed histology this should be reported as it may help
predict the biological behavior of individual clear cell carcinomas. Clearly, similar studies are needed
on a larger group of clear cell carcinoma with clinical follow-up to determine the impact of the
molecular genetic profiles on biological behavior. Until such studies are available the biological
behavior of clear cell carcinomas will remain controversial.
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a distinctive profile of p53, Ki-67, estrogen, and progesterone receptor
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- Malpica A, Tornos C, Burke TW, Silva EG. Low-stage clear-cell carcinoma of the endometrium. Am J
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carcinoma of the endometrium: comparison of clinicopathologic features and survival. Int J Gynecol
Pathol. 1995 Jan;14(1):30-8.
- Tashiro H, Blazes MS, Wu R, Cho KR, Bose S, Wang SI, Li J, Parsons R, Ellenson LH. Mutations in PTEN
are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res.
1997 Sep 15;57(18):3935-40.
- Lax SF, Kendall B, Tashiro H, Slebos RJ, Hedrick L. The frequency of p53, K-ras mutations, and
microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct
molecular genetic pathways. Cancer. 2000 Feb 15;88(4):814-24.