RETRACTED ARTICLE: Cervical adenosquamous carcinoma: detailed analysis of morphology, immunohistochemical profile, and clinical outcomes in 59 cases

Abstract

Although 2014 World Health Organization criteria require unequivocal glandular and squamous differentiation for a diagnosis of cervical adenosquamous carcinoma, in practice, adenosquamous carcinoma diagnoses are often made in tumors that lack unequivocal squamous and/or glandular differentiation. Considering the ambiguous etiologic, morphological, and clinical features and outcomes associated with adenosquamous carcinomas, we sought to redefine these tumors. We reviewed slides from 59 initially diagnosed adenosquamous carcinomas (including glassy cell carcinoma and related lesions) to confirm an adenosquamous carcinoma diagnosis only in the presence of unequivocal malignant glandular and squamous differentiation. Select cases underwent immunohistochemical profiling as well as human papillomavirus (HPV) testing by in situ hybridization. Of the 59 cases originally classified as adenosquamous carcinomas, 34 retained their adenosquamous carcinoma diagnosis, 9 were reclassified as pure invasive stratified mucin-producing carcinomas, 10 as invasive stratified mucin-producing carcinomas with other components (such as HPV-associated mucinous, usual-type, or adenosquamous carcinomas), and 4 as HPV-associated usual or mucinous adenocarcinomas with benign-appearing squamous metaplasia. Two glassy cell carcinomas were reclassified as poorly differentiated usual-type carcinomas based on morphology and immunophenotype. There were significant immunophenotypic differences between adenosquamous carcinomas and pure invasive stratified mucin-producing carcinomas with regard to HPV (p<0.0001), PAX8 (p=0.038; more in adenosquamous carcinoma), p40 (p<0.0001; more in adenosquamous carcinoma), p63 (p=0.0018; more in adenosquamous carcinoma) and MUC6 (p<0.0001; less in adenosquamous carcinoma), HNF1beta (p=0.0023), vimentin (p=0.0003), p53 (p=0.0004), and CK7 (p=0.0002) expression. Survival outcomes were similar between all groups. adenosquamous carcinomas should be diagnosed only in the presence of unequivocal malignant glandular and squamous differentiation. The two putative glassy cell carcinomas studied did not meet our criteria for adenosquamous carcinoma, and categorizing them as such should be reconsidered.

Clinical Outcomes of HPV-associated and Unassociated Endocervical Adenocarcinomas Categorized by the International Endocervical Adenocarcinoma Criteria and Classification (IECC)

“…MUC6, CDX2, p53, vimentin and ER expression differ among these types, especially when comparing intestinal-type mucinous HPVA and usual-type HPVA [14]. We previously reported that iSMILE frequently express MUC6 (evidence of glandular differentiation), but they are less frequently positive for PAX8 (possibly indicating reserve cell origin), with more frequent p53 overexpression compared to usual-type ECAs [4]. The current study demonstrates that mucinous HPVAs portend a worse PFS than usual-type HPVAs, but a better (although non-significant) OS compared to gastric-type NHPVAs, indicating that mucinous HPVAs should be separated from both non-mucinous HPVAs and NHPVAs if confirmed in other studies.…”

“…As both usual and mucinous HPVassociated adenocarcinomas can exhibit cytoplasmic mucin, we diagnosed usual-type HPVA when a tumor demonstrated fewer than 50% of neoplastic cells with obvious intracytoplasmic mucin, as seen on H&E sections; mucinous HPVA, not otherwise specified (NOS) had features similar to usual-type adenocarcinoma, but had more than 50% of neoplastic cells with appreciable intracytoplasmic mucin. HPV-associated mucinous carcinomas were further subclassified into: intestinal-type mucinous carcinoma, in which more than 50% of glands contained goblet cells; and invasive stratified mucin-producing carcinoma (iSMILE), in which a lesion was composed almost entirely (> 90%) [4] of invasive nests of stratified columnar cells with peripheral palisading and variable amounts of intracytoplasmic mucin [5], resembling its in-situ counterpart (SMILE) [6]. Gastric-type NHPVAs were diagnosed according to existing criteria [7].…”

A combination of cytokeratin 5/6, P63, P40 and MUC5AC are useful for distinguishing squamous cell carcinoma from adenocarcinoma of the cervix

“…are only found in a few adenocarcinomas [10,16]. Kriegsmann et al suggested the use of either CK5/6 or P40 over P63 in the routine diagnostic setting [17]. CK7 is expressed in many ductal and glandular epithelial cells (mainly gallbladder, hepatic ducts, and pancreatic ducts), in tissues of the female genital tract (ovary, endometrium, fallopian tube, and cervix), and in the breast, lung, and urinary tract tissues [18].…”

A combination of cytokeratin 5/6, p63, p40 and MUC5AC are useful for distinguishing squamous cell carcinoma from adenocarcinoma of the cervix

“…However, the positive expression of CK5/6, p63, and p40 are only found in a few adenocarcinomas [10,16]. Kriegsmann et al suggested the use of either CK5/6 or p40 over p63 in the routine diagnostic setting [17]. CK7 is expressed in many ductal and glandular epithelial cells (mainly gallbladder, hepatic ducts, and pancreatic ducts), in tissues of the female genital tract (ovary, endometrium, fallopian tube, and cervix), and in the breast, lung, and urinary tract tissues [18].…”