Recent advances in invasive adenocarcinoma of the cervix

Abstract

Endocervical adenocarcinomas (ECAs) are currently classified according to the 2014 World Health Organization (WHO) system, which is predominantly based on descriptive morphologic characteristics, considers factors bearing minimal etiological, clinical, or therapeutic relevance, and lacks sufficient reproducibility. The 2017 International Endocervical Adenocarcinoma Criteria and Classification (IECC) system was developed by a group of international collaborators to address these limitations. The IECC system separates ECAs into two major groups-those that are human papillomavirus-associated (HPVA) and those that are non-HPV-associated (NHPVA)-based on morphology (linked to etiology) alone, precluding the need for an expensive panel of immunohistochemical markers for most cases. The major types of HPVA ECA include the usual (with villoglandular and micropapillary architectural variants) and mucinous types (not otherwise specified [NOS], intestinal, signet-ring, and invasive stratified mucin-producing carcinoma). Invasive adenocarcinoma NOS is morphologically uninformative, yet considered part of this group when HPV positive. NHPVA ECAs include gastric, clear cell, endometrioid, and mesonephric types. The IECC system is supported by demographic and clinical features (HPVA ECAs develop in younger patients, are smaller, and are diagnosed at an earlier stage), p16/HPV status (almost all HPVA ECAs are p16 and/or HPV positive), prognostic parameters (NHPVA ECAs more often have lymphovascular invasion, lymph node metastases, and are Silva pattern C), and survival data (NHPVA ECAs are associated with worse survival). A move from the morphology-based WHO system to the IECC system will likely provide clinicians with an improved means to diagnose and classify ECAs, and ultimately, to better personalize treatment for these patients.

Keywords: Classification; Endocervical adenocarcinoma; HPV; International Endocervical Adenocarcinoma Criteria and Classification.

Figure 1.

Endocervical adenocarcinoma classification systems: The 2014 World Health Organization system and the International Endocervical Adenocarcinoma Criteria and Classification (IECC, 2018) system. The WHO classification system categorizes tumors based primarily on morphology, while the IECC system divides tumors into those that are human papillomavirus associated (HPVA) and those that are not (NHPVA) based on more detailed diagnostic criteria, resulting in the reclassification of many WHO-defined tumors.

Figure 2.

Major International Endocervical Adenocarcinoma Criteria and Classification (IECC) HPV-associated types: (A) Usual-type endocervical adenocarcinoma (ECA) exhibiting mucin depletion (<50% of cells) and (B) apical “floating” mitoses and apoptotic debris, (C) mucinous not otherwise specified (NOS)-type ECA exhibiting abundant intracytoplasmic mucin (≥50% of cells), (D) mucinous intestinal-type ECA (goblet cells in ≥50% of cells), (E) mucinous signet-ring type ECA (signet-ring morphology in ≥50% of tumor cells), (F) invasive stratified mucin-producing adenocarcinoma (iSMILE), (G) villoglandular-type ECA and (H) micropapillary-type ECA.

Figure 3.

p16 and HPV. (A) p16 was considered positive if strong, diffuse block-like staining was present. p16 was considered negative if there was non–block-like patchy staining (B) or focal/weak staining (C). (D) HPV RNA-based in situ hybridization showing the presence of high-risk HPV.

Figure 4.

Differential diagnostic considerations for usual-type HPVA. (A) Usual-type endocervical adenocarcinoma can exhibit pseudoendometrioid morphology, mimicking the appearance of (B) endometrioid endometrial adenocarcinoma, but will also have floating mitoses, apoptotic debris, and will be negative for estrogen receptor. Usual-type endocervical adenocarcinoma can also exhibit slit-like spaces (C), thin/fine papillary archiecture (D) or broad papillary architecture (E), mimicking the appearance of endometrial serous adenocarcinoma (F), but it will be negative for p53 and HPV.

Figure 5.

Major International Endocervical Adenocarcinoma Criteria and Classification (IECC) non–HPV-associated (NHPVA) types: (A) Gastric-type adenocarcinoma, which can be associated with gastric-type adenocarcinoma in situ colonizing normal glands (B), signet-ring cell morphology (C) lobular endocervical glandular hyperplasia (LEGH), E) clear cell, and F) mesonephric types.