Clear cell carcinoma of the endometrium: an immunohistochemical and molecular analysis of 45 cases

Gian Franco Zannoni, Angela Santoro, Giuseppe Angelico, Saveria Spadola, Damiano Arciuolo, Marianna Valente, Frediano Inzani, Angela Pettinato, Annarita Pettinato, Simona Vatrano, Francesco Fanfani, Giovanni Scambia, Filippo Fraggetta

Risultato della ricerca: Contributo in rivistaArticolo in rivista

11 Citazioni (Scopus)


The aim of the present paper is to study a cohort of pure selected endometrial clear cell carcinomas (ECCCs) from an immunohistochemical and molecular perspective to provide new data about the molecular profile of this disease. In detail, 45 consecutive patients with a proven diagnosis of pure ECCC, according to World Health Organization criteria, were included into the study. We determined the incidence of KRAS, BRAF, and PIK3CA mutations as well as the immunohistochemical expression of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, PMS2), estrogen, progesterone receptors, p16, and p53. Immunohistochemical analyses for α-methylacyl-coenzyme-A racemase and Napsin A were performed to support the diagnosis of ECC. All cases were positive for at least 1 of the 2 markers. In detail, 34 of 45 (75.5%) cases were positive for α-methylacyl-coenzyme-A racemase, and 40 of 45 (88.8%) cases showed positive staining for Napsin A. All selected cases exhibited negative immunostain for estrogen receptor and progesterone receptor, a “patchy” immunostain for p16, and a “wild-type” staining pattern for p53. Fifteen patients (15/45; 33.3%) showed loss of 1 or more MMR proteins by immunohistochemistry. Seven patients showed dual loss of MSH2 and MSH6, 4 patients (8.8%) showed isolated loss of MSH6, and the remaining 4 patients showed isolated loss of PMS2, respectively. Pyrosequencing analysis revealed the presence of 5 of 45 mutations (11%) at codon 12 in exon 2 of KRAS (3/5 p.G12D, 60%; 2/5 p. G12V, 40%) and 5 of 45 (11%) mutations in PIK3CA gene, of which 3 of 5 (60%) were in exon 9 of PIK3CA (2 p.E542K and 1 p.Q546K) and 2 of 5 (40%) were in exon 20 (p.H1047R). Two synchronous mutations affecting exon 9 of PIK3CA (p.Q546K) and exon 2, codon 12 of KRAS (p.G12D) were found. No mutations were detected in the hot spot region of BRAF. In conclusion, we provided detailed immunohistochemical and molecular data in a series of ECC, demonstrating a high incidence (33%) of MMR deficiencies detected by immunohistochemistry as well as a synchronous mutation affecting PIK3CA and KRAS genes. A more extensive interrogation of the genomic features of a much larger series of clear cell carcinomas will be required to define the genomic landscape of this subtype and to determine whether there are molecular alterations that are unique to, or significantly enriched in, clear cell tumors compared to other subtypes.
Lingua originaleEnglish
pagine (da-a)10-17
Numero di pagine8
RivistaHuman Pathology
Stato di pubblicazionePubblicato - 2019


  • Adenocarcinoma, Clear Cell
  • Adult
  • Aged
  • Aged, 80 and over
  • BRAF
  • Biomarkers, Tumor
  • Class I Phosphatidylinositol 3-Kinases
  • Clear cell endometrial carcinoma
  • DNA Mismatch Repair
  • Endometrial Neoplasms
  • Endometrium
  • Female
  • Hot spot mutations
  • Humans
  • Immunohistochemistry
  • KRAS
  • Microsatellite Instability
  • Microsatellite instability
  • Middle Aged
  • Mutation
  • PIK3CA
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins p21(ras)


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