Introduction

Gastric type Adenocarcinoma (GAS) is a rare subtype of cervical endocervical adenocarcinoma, classified as a variant of mucinous endocervical adenocarcinoma in the 2014 World Health Organisation (WHO) Classification of Tumours of Female Reproductive Organs. Unlike the more common Usual Endocervical Adenocarcinoma (UEA), GAS is not related to human papilloma virus (HPV), demonstrates more aggressive behaviour, presents at a higher stage, shows unusual patterns of metastasis and has poorer survival outcome as compared to UEA [1]. GAS exhibits a spectrum of differentiation, with Minimal Deviation Adenocarcinoma (MDA) as an extremely well differentiated form.

Emerging evidence suggests that GAS and MDA are malignant entities on a wider spectrum of endocervical glandular lesions exhibiting gastric differentiation (Table 1) [2,3].

In particular, over the last decade, a possible in-situ or pre-malignant category has been postulated, namely atypical Lobular Endocervical Glandular Hyperplasia (LEGH) and Gastric-Type Adenocarcinoma In-Situ (GAIS). These potential precursors were recognised due to their occurrence in association with MDA and similar immunohistochemically profile for markers of gastric differentiation.

Histologic Features

Atypical LEGH has been used to describe cases of LEGH exhibiting a degree of architectural and/or cytologic atypia without evidence of stromal invasion. These atypical features include (1) nuclear enlargement; (2) irregular nuclear contour; (3) distinct nucleoli; (4) coarse chromatin texture; (5) loss of polarity; (6) occasional mitotic figures; (7) apoptotic bodies and/or nuclear debris in the lumen and (8) infolding of epithelium or papillary projections with fine fibro vascular stroma [2].

In contrast, GAIS has been used to refer to a lesion in which endocervical glands are replaced by columnar cells showing atypical cytological features similar to atypical LEGH. These include columnar cells with abundant lightly eosinophilic, foamy or bubbly cytoplasm and nuclear atypia that is generally low grade. Goblet cells have also been described (Figure 1A-1C).

Unlike atypical LEGH, GAIS retains pre-existing normal glandular architecture, which is different from the lobular architecture of clusters of small glands surrounding a dilated duct typical of LEGH. GAIS sometimes shows intraglandular architectural complexity with small luminal papillary infoldings that may form bridges and cribriform structures. GAIS also shows a distinct topographical location, often arising at the cervical transformation zone in contrast to a high endocervical location as for LEGH [3]. Nonetheless, some authorities have recommended subsuming both atypical LEGH and GAIS under a common umbrella term of “GAIS”.

Both atypical LEGH and GAIS demonstrate gastric differentiation histologically, as evidenced by pale cytoplasm that stains red with Alcian blue/periodic Acid‐Schiff due to neutral mucins as compared to the purple‐violet of acid and neutral mucins in normal endocervical glands (Figure 1D).

Gastric differentiation is also evidenced by positive staining with HIK1083 and/or MUC6 immunostains. Atypical LEGH, GAIS and GAS are also reported to be positive for CK7 and negative for ER and PR. Being unrelated to HPV, p16 is generally negative or exhibits non block‐type staining [4].

Cytologic Features

The characteristic cytologic features of GAS on Papanicolaou (Pap) smears are different from usual adenocarcinoma in-situ/ Usual Endocervical Adenocarcinoma (UEA). Characteristic cytological features of GAS include (a) monolayered and honeycomb sheets; (b) vacuolar and/or foamy cytoplasm, with intracytoplasmic golden-yellow mucin; (c) intracytoplasmic neutrophil entrapment and (d) vesicular nuclei with distinct nucleoli [5]. In comparison, the cytological features of AIS/UEA are well described: (a) crowded hyperchromatic groups with pseudostratified columnar cells and rosette formation; (b) cytoplasmic and nuclear feathering; (c) enlarged nuclei with coarsely granular hyperchromatic chromatin and inconspicuous nucleoli; and (d) mitotic figures and apoptotic bodies. Macronucleoli and tumour diathesis will be seen in UEA.

The cytologic features of gastric-type pre-malignant lesions are not as well described in literature (Table 2).

These lesions are subtler and present a diagnostic challenge on Pap smears. A search on PubMed using the keywords “Gastric-type adenocarcinoma in-situ of the cervix” identified only three case reports and one small series in which the cytological features on Pap smear were detailed. In these cases, the diagnoses on Pap smear were that of atypical glandular cells, ranging from not otherwise specified to favour neoplasia/suggestive of AIS [6-9]. In these reports, monolayered and honeycomb sheets predominate, although overlapping, complicated branching clusters; acinar pattern; pseudostratified strips and peripheral palisading were also present in some. Common to all cases were glandular cells with mucinous cytoplasm, either as golden-yellow mucin or foamy cytoplasm. Goblet cells were present in two cases. Intracytoplasmic neutrophils were not described. Nuclear atypia was present but often low grade or focal, mostly described as vesicular nuclei with conspicuous nucleoli (Figure 2).

Discussion & Conclusion

GAS and its precursors are an uncommon but increasingly recognised subtype of endocervical glandular neoplasia. Lesions within this spectrum falling within the category of GAIS are rare and only recently beginning to be characterised. The findings on cytologic smears are subtle and are often classified as atypical glandular cells. Currently, high risk HPV testing may be used to triage smears with borderline endocervical cells, with the implication that these lesions, being non-HPV related, may be missed. Furthermore, moving into the era of HPV vaccination and primary HPV based cervical screening, these lesions are likely to increase in relative incidence and importance. However, as HPV negative cases would not be subject to morphologic analysis, the opportunity to detect GAIS before progression to GAS may be missed. It is hence important for cytotechnologists, cytopathologists, histopathologists as well as clinicians to be aware of the unique etiologic, cytologic and histologic features of these lesions.

Conflict of Interest

The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Acknowledgement

Cytology and Histology staff KK Hospital, Singapore.

Figure 1: (A) - Abnormal gland showing mild intraglandular complexity (magnification x200). (B) - Areas showing nuclear atypia, with stratified hyperchromatic enlarged nuclei (magnification x400). (C) - Foci of goblet cells (magnification x400).

Figure 1: D)- Red cytoplasmic staining contrasting with purple-violet staining of adjacent normal endocervical glands (Alcian blue/PAS stain, magnification x200).

Figure 2: (A) Pap smear shows monolayered sheets of endocervical cells with vesicular nuclei and conspicuous nucleoli (magnification x 400). (B) - The cells showed abundant foamy cytoplasm (magnification x 600). (C) - Pseudostratified palisaded groups of cells and (D) - focal goblet cells were present (magnification x 400). Okuyama et al presented sequential Pap smears in two cases of GAIS, which revealed an interesting finding of localisation of golden-yellow mucin to the surface of glandular clusters preceding development of nuclear atypia. They proposed that this may prove a sensitive finding for early detection of adenocarcinoma arising in LEGH [9].

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