CLEAR CELL ADENOCARCINOMA – CERVIX

CLEAR CELL ADENOCARCINOMA – CERVIX

• Clear cell adenocarcinoma of cervix is malignant epithelial neoplasm composed of flat or cuboidal cells having clear to eosinophilic cytoplasm and are arranged in one or more patterns like papillary, tubulocystic or solid pattern

• Accounts for 3-4% of cervical adenocarcinoma

• Age – bimodal age distribution with 1st peak occurring in 17 – 37 years ( rarely in children) and second peak in 44 – 88 years of age

• Pathogenesis:

  • Not clearly understood

  • Proposed that these tumors arise from either adenosis of ectocervix, cervical tubulo endometrioid metaplasia or cervical endometriosis

  • These tumors are HPV negative

• They arise in two clinical settings

  • Sporadic tumors occur in endocervix

  •  In association with Di Ethyl stilbesterol exposure and were in younger patients developing in ectocervix rather than endocervical canal

• Morphology

• Gross :

  • Tumors present as

    • endophytic growth with diffuse enlargement of cervix

    • exophytic with a protruding mass

    • without clinically evident mass

• Microscopy :

  • Three major patterns seen in this tumor are 

    • Papillary 

    • Tubulo cystic

    • Solid

  • Tumor cells are flattened to cuboidal having clear cytoplasm due to accumulation of glycogen or granular eosinophilic cytoplasm.

  • Hobnail cells with hyperchromatic nuclei projecting into lumen of the cysts or tubules can also be seen

  • Tubules and cysts are usually lined by flattened epithelium with bland nuclei giving the benign appearance

  • Papillae lined by tumor cells and with hyalinized cores can also be present

  • Large nucleoli, intranuclear pseudo inclusions and hyaline globules can also be seen

  • Mitotic count is usually low

  • Stroma shows hyalinization

• Immunohistochemistry 

  • tumor cells are positive for 

    • Hepatocyte Nuclear factor – 1β

    • Napsin A

    • P 16 (diffuse or focal) – though it is negative for HPV

    •  AMACR

  • Tumor cells are negative for 

    • ER

    • PR

    • CEA

  • P53 – non -aberrant (wild type)

• Prognosis : Better overall survival and low recurrence rate in patients with early stage of disease

• Differential diagnosis 

  • Clear cell adeno squamous carcinoma– solid sheets of clear cells in addition to glandular spaces lined by columnar cells which are positive for mucicarmine

  • Clear cell squamous cell carcinoma (HPV related) – shows diffuse solid pattern without spectrum of architectural patterns seen in adenocarcinoma

  • Gastric adenocarcinoma – clear cell adenocarcinoma with tall columnar cells can be similar to gastric adenocarcinoma as P16, HNF -1β and Napsin A can be expressed in gastric adenocarcinoma but are CEA shows variable expression in which is negative in clear cell adenocarcinoma of cervix

  • Mesonephric adenocarcinoma– this should be differentiated with clear cell adenocarcinoma having tubulocystic pattern. GATA 3 is usually positive in mesonephric adenocarcinoma  

  • Other benign conditions like atypical oxyphilic metaplasia, florid Aria stella reaction, solid micro glandular adenosis and radiation induced atypia can mimic clear cell adenocarcinoma in small biopsy. but all these conditions express hormone receptors and lack proliferative activity