Yonsei Med J.  2017 Jan;58(1):59-66. 10.3349/ymj.2017.58.1.59.

Ovarian Clear Cell Carcinoma Sub-Typing by ARID1A Expression

Affiliations
  • 1Department of Pathology, Yonsei University College of Medicine, Seoul, Korea. cho1988@yuhs.ac
  • 2Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
  • 3Department of Gynecology, Yonsei University College of Medicine, Seoul, Korea.
  • 4Severance Biomedical Science Institute (SBSI), Yonsei University College of Medicine, Seoul, Korea.

Abstract

PURPOSE
Loss of AT-rich DNA-interacting domain 1A (ARID1A) has been identified as a driving mutation of ovarian clear cell carcinoma (O-CCC), a triple-negative ovarian cancer that is intermediary between serous and endometrioid subtypes, in regards to molecular and clinical behaviors. However, about half of O-CCCs still express BAF250a, the protein encoded by ARID1A. Herein, we aimed to identify signatures of ARID1A-positive O-CCC in comparison with its ARID1A-negative counterpart.
MATERIALS AND METHODS
Seventy cases of O-CCC were included in this study. Histologic grades and patterns of primary tumor, molecular marker immunohistochemistry profiles, and clinical outcomes were analyzed.
RESULTS
Forty-eight (69%) O-CCCs did not express BAF250a, which were designated as "ARID1A-negative." The other 22 (31%) O-CCCs were designated as "ARID1A-positive." ARID1A-positive tumors were more likely to be histologically of high grades (41% vs. 10%, p=0.003), ERβ-positive (45% vs. 17%, p=0.011), and less likely to be HNF1β-positive (77% vs. 96%, p=0.016) and E-cadherin-positive (59% vs. 83%, p=0.028) than ARID1A-negative tumors. Patient age, parity, tumor stage were not significantly different in between the two groups. Cancer-specific survival was not significantly different either.
CONCLUSION
We classified O-CCCs according to ARID1A expression status. ARID1A-positive O-CCCs exhibited distinct immunohistochemical features from ARID1A-negative tumors, suggesting a different underlying molecular event during carcinogenesis.

Keyword

Adenocarcinoma, clear cell; ovarian neoplasms; AT rich interactive domain 1A (SWI- like), human; estrogen receptor 2 (ER beta), human; endometriosis; prognosis

MeSH Terms

Adenocarcinoma, Clear Cell/*metabolism/mortality/pathology
Adult
Aged
Biomarkers, Tumor/metabolism
Cadherins/metabolism
Estrogen Receptor beta/metabolism
Female
Humans
Immunohistochemistry
Middle Aged
Mutation
Neoplasm Proteins/*metabolism
Nuclear Proteins/*metabolism
Ovarian Neoplasms/*metabolism/mortality/pathology
Transcription Factors/*metabolism
Biomarkers, Tumor
Cadherins
Estrogen Receptor beta
Neoplasm Proteins
Nuclear Proteins
Transcription Factors

Figure

  • Fig. 1 Histologic grades of O-CCC. (A and B) Low grade O-CCC. (A) tubulocystic or alveolar patterns are the most common patterns seen in low grade tumor. Abortive small tubules are less differentiated (H-E, ×100). (B) Psammomatous calcifications (H-E, ×100). (C and D) High grade O-CCC. (C) Diffuse, solid areas are frequently seen in high grade tumor. Desmoplasia is frequently found in association with infiltrative cells (H-E, ×40). (D) highly cellular spindle cells are parallel with infiltrating tumor cells (H-E, ×200). O-CCC, clear cell carcinoma of ovary; H-E, hematoxylin-eosin.

  • Fig. 2 ARID1A expressions in O-CCC. (A) In endometriosis, nuclear staining occurs along the epithelial lining (inlet), but CCC shows complete loss of ARID1A (DAB, ×40). (B) Total loss of ARID1A in a branched tubular pattern (DAB, ×100). (C) Focal expression (nearly total loss) in an alveolar pattern (DAB, ×200). (D) Moderate preservation of AR1D1A expression in a cystic papillary pattern (DAB, ×200). ARID1A, AT-rich DNA-interacting domain 1A; O-CCC, clear cell carcinoma of ovary; DAB, 3'-3' diaminobenzidine.

  • Fig. 3 HNF1β and ERβ expressions in O-CCC. (A and B) HNF1β expression. (A) Complete loss of HNF1-β is rarely found in CCC. However, negative expression of p53 or ER with loss of ARID1A is common (DAB, ×100). (B) Luminal hobnail cells express HNF1-β. More HNF1-β expression occurs in cells closer to the luminal side (DAB, ×200). (C and D) ERβ expression. (C) complete loss of ERβ is common (DAB, ×100). (D) Luminal protruding hobnail cells express ERβ (DAB, ×100). ERβ, estrogen receptor beta; O-CCC, clear cell carcinoma of ovary; ARID1A, AT-rich DNA-interacting domain 1A; DAB, 3'-3' diaminobenzidine.

  • Fig. 4 E-cadherin expressions in O-CCC. Loss of CDH1, or E-cadherin was manifested variably. (A) Complete loss of CDH1 (DAB, ×10). (B) Partial and weak staining (DAB, ×100). (C) Aberrant CDH1 expression. Aberrant cytoplasmic expression with fragmented or broken linear forms instead of membrane staining is an indicator of E-cadherin disruption (DAB, ×100). (D) Within the same tumor, CDH1 loss is heterogeneous. The solid arrow points to a region of partial CDH1 loss as seen by weak staining along the membrane. The broken arrow points to disrupted fragments in the membrane (DAB, ×200). (E) Images taken at a higher magnification show aberrant staining, such as and non-continuous, fragmented membrane, or cytoplasmic staining (DAB, ×200). O-CCC, clear cell carcinoma of ovary; DAB, 3'-3' diaminobenzidine.

  • Fig. 5 Kaplan-Meier curve of cancer-specific survival for O-CCC, stratified by ARID1A expression status. O-CCC, clear cell carcinoma of ovary; ARID1A, AT-rich DNA-interacting domain 1A.


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