Gastric-type endocervical adenocarcinoma (GAS) is a diagnostic entity first described by Kojima et al1 in 2007 as a malignancy characterized by expression of gastric mucin and morphologically resembling pyloric glandular epithelium. Gastric mucin has also been identified in the long known entity of minimal deviation adenocarcinoma of mucinous type (adenoma malignum) which is now considered to be a well-differentiated form of gastric-type adenocarcinoma.1,2 GAS was added as a new category in the WHO tumor classification in 2014.3 The incidence of gastric-type adenocarcinoma and its geographical distribution is not yet well known as this tumor has been previously misclassified as usual, intestinal, or clear cell adenocarcinoma. Gastric adenocarcinoma has been reported to account for ~20% of all cervical adenocarcinomas in Japan,1,4 7.2% in China,5 and 10% in an international study, which also showed that GAS was the second most common subtype of endocervical adenocarcinoma, after usual type.6
The pathogenesis of GAS, unlike that of usual endocervical adenocarcinoma, is not related to human papilloma virus (HPV) infection.4–8 Understanding that HPV plays no part in maintaining this type of cervical adenocarcinoma has been complicated by the finding that sensitive polymerase chain reaction testing of cervical whole-tissue sections may detect presence of HPV in adjacent cervical epithelium which can produce false positive results. When such cases are investigated by laser-capture microdissection polymerase chain reaction, the tumor cells are invariably HPV negative.5
The underlying molecular genetic pathways in gastric-type adenocarcinoma are currently being investigated. Notably, an immunohistochemical study reported that 41% of the cases showed mutation-type p53 staining with either diffuse strong positivity (24%) or null pattern (17%).9 Next-generation sequencing has confirmed presence of p53 gene mutations in gastric-type adenocarcinomas.10,11 In addition, some patients with gastric-type adenocarcinoma have been reported to present with Peutz-Jeghers syndrome, an autosomal dominant disorder caused by germline mutation of STK11, a serine threonine kinase gene.12 This finding prompted a search for somatic mutations of STK11 gene, and such mutations were identified in over a half of sporadic cases.11,13 Postulated precursors of GAS include lobular endocervical gland hyperplasia (LEGH)2,14,15 and gastric-type adenocarcinoma in situ.16
The average age of the patients is between 49 and 51 which is similar to that of patients with usual endocervical adenocarcinoma.1,8,17 As many as 59% of patients present with stage II disease or higher,17 which is likely due to a combination of an aggressive tumor course and low yield from cytologic screening which has low sensitivity for minimal deviation adenocarcinoma.18,19 Cytologic features of less well-differentiated GAS were described only recently.20,21 In total 50% to 70% of patients with gastric adenocarcinoma present with profuse watery vaginal discharge,18,22 50% with abnormal bleeding,18 and 75% with cervix enlargement by diffuse growth (barrel-shaped cervix).18,19,22,23
The prognosis of patients with GAS, including that of minimal deviation adenocarcinoma, is significantly worse than that of patients with usual endocervical adenocarcinoma, even accounting for the stage at presentation.1,8,12,17 The tumor is notable for its propensity to metastasize to the ovaries, omentum, abdomen, and distant sites.17 In addition, gastric-type adenocarcinomas are typically resistant to conventional chemotherapy as compared with usual HPV-associated endocervical adenocarcinoma.24
The diagnostic accuracy in recognition of gastric-type adenocarcinoma is extremely important, as ovarian conservation in patients with GAS may not be recommended and the omentectomy should be considered as part of surgical treatment. The goal of this review is to illustrate the wide spectrum of histologic appearances of gastric-type adenocarcinoma of the cervix to aid in confident diagnosis.
TYPICAL HISTOLOGIC APPEARANCES OF GASTRIC-TYPE ADENOCARCINOMA
GASs described by Kojima et al1 is defined as a mucinous adenocarcinoma displaying 3 diagnostic criteria—(1) voluminous cytoplasm that is (2) clear or pale eosinophilic, with (3) cells showing distinct cell borders. The tumor is characterized by diffuse cervical infiltration frequently resulting in cervical enlargement and it typically extends deep within the cervical wall while also spreading axially in both directions, towards the ectocervix and towards the lower uterine segment. The axial span within the endocervical canal is usually more extensive than that seen in usual adenocarcinoma which typically invades close to the squamocolumnar junction.23 The invasive glands of GAS show marked variation in size and shape—from small cystic glands (Fig. 1A), crowded tubular glands (Fig. 1B), to cystically dilated lumina mimicking Nabothian cysts (Fig. 1C), and less frequently, cystic areas with complex intraluminal papillary infoldings (Fig. 1D).
A curious pattern of growth observed in some cases of GAS is invasion of the ectocervix with erosion through the ectocervical squamous mucosa (Figs. 2A–D). This pattern is not typically seen in usual endocervical adenocarcinoma which tends to invade locally within the stroma of the squamocolumnar junction.
Cytologically, the classic tumor appearance is that of malignant mucinous epithelium with voluminous, clear, foamy, or pale eosinophilic cytoplasm with distinct cellular borders (Figs. 3A, B). And though these tumors secrete gastric-type mucin, their morphologic appearance is most similar to pancreatobiliary tumors, often resembling pancreatic ductal adenocarcinoma or cholangiocarcinoma. In fact, out of context, these pancreatic-biliary tumors are morphologically indistinguishable from gastric-type adenocarcinoma of the cervix.
In contrast to the elongated and stratified nuclei of usual adenocarcinoma, the nuclei of GAS are rounded and present basally, most commonly in a single row. The nuclei have cleared or delicate, diffuse chromatin with distinct nucleolus and appear pale in comparison with hyperchromatic nuclei of usual endocervical adenocarcinoma which typically show coarse or granular chromatin. The atypia in GAS ranges from very uniform cells with bland appearing nuclei in tumor areas categorized as minimal deviation adenocarcinoma to moderate and marked atypia in less well-differentiated tumor areas which show irregularity of cellular shapes, nuclear enlargement, loss of nuclear basal alignment, variations of nuclear shapes, and presence of macronucleoli. Some GAS are composed entirely of well-differentiated component (minimal deviation adenocarcinoma), some show a spectrum from well to less-differentiated areas and some are composed entirely of markedly atypical glands without a well-differentiated counterpart. Mitotic figures are present but are less abundant than in usual adenocarcinoma and not easily visible at scanning magnification.6 Apoptotic activity can also be seen but is much rarer than in usual endocervical adenocarcinoma and is usually not as readily identified. Desmoplastic stromal response surrounding the invasive glands may be seen, especially at the invasive front in the deeper portion of the cervical wall.
The tumor may be seen in association with putative precursor lesion LEGH (Fig. 4A). LEGH is characterized by well-demarcated lobules of small, tubular mucinous glands arranged around a cystically dilated channel (Figs. 4A–D). The central channels may show variation in shape, including undulating contours and papillary infoldings. Both glands in the lobules and central cystic channels are lined by columnar cells with clear, mucin-filled cytoplasm and basally located, uniform, round to oval nuclei with indistinct nucleoli (Fig. 4D). Cases with architectural features of LEGH and cytologic atypia, but no evidence of invasion, are termed as atypical LEGH. In cases where LEGH accompanies invasive adenocarcinoma, LEGH is usually seen in the superficial parts of the mucosa, while carcinoma being present in the deeper portion of the cervical wall (Fig. 4A).
The recently described gastric-type adenocarcinoma in situ is an uncommon entity characterized by preserved, normal glandular architecture or intraluminal infoldings, and abundant clear, eosinophilic or foamy cytoplasm with occasional goblet cells. The nuclei are atypical and show enlargement, stratification, nuclear membrane irregularity, clumped or cleared chromatin and prominent nucleoli. Atypical LEGH as well as gastric-type adenocarcinoma in situ have been suggested to represent a spectrum of precursor lesions to GAS.2
SPECTRUM OF HISTOLOGIC FEATURES OF GASTRIC-TYPE ADENOCARCINOMA
Since the original description of GAS by Kojima et al there has been increasing recognition that these tumors may show diverse morphologic appearances beyond this description. As mentioned previously, GAS is morphologically indistinguishable from pancreatobiliary adenocarcinomas and like these gastrointestinal counterparts, GAS display a wide morphologic spectrum that may be diverging from the typical histologic features. The following examples illustrate cases in which the tumors had classic features at least focally, and in addition showed other morphologic characteristics.
One of the features not originally described but commonly seen in gastric-type adenocarcinoma is foamy change,25 as well as densely eosinophilic cytoplasm (Figs. 5A–D).
Occasional glands may show elongated and stratified nuclei reminiscent of usual adenocarcinoma (Figs. 6A, B), or show small tubular glands with cuboidal cells resembling mesonephric carcinoma (Figs. 6C, D).
The deep invasive tumor front may show infiltration with single cuboidal, densely eosinophilic cells (Figs. 7A, B), or invade with microcystic elongated and fragmented pattern (Figs. 8A, B). Both patterns may be reminiscent of endometrioid adenocarcinoma.
Presence of goblet cells in gastric-type adenocarcinoma may mimic HPV-positive intestinal-type adenocarcinoma of the cervix (Figs. 9A, B).
There are several appearances of GAS that may resemble clear cell carcinoma. These include glands with clear cytoplasm and atypical nuclei with various level of nuclear stratification (Figs. 10A, B), papillary areas with clear cytoplasm (Figs. 11A–D), tubular glands with cuboidal cells and depleted cytoplasm (Figs. 12A, B) or flattened cells with scant pale cytoplasm (Figs. 13A, B).
Occasionally the tumor may infiltrate in the form of miniature glands with very scant eosinophilic cytoplasm and large angulated, hyperchromatic nuclei, reminiscent of serous carcinoma (Figs. 14A, B).
Some tumors may demonstrate extensive mucin extravasation within the cervical wall (Figs. 15A, B). One report showed that such tumors could extend to the pelvis and present as pseudomyxoma peritonei,26 in which case the possibility of a metastasis from a primary ovarian or gastrointestinal primary tumor must be excluded.
Presence of these various morphologic patterns may pose a significant diagnostic dilemma, and make examination of a single cervical biopsy difficult and uncertain. Examination of multiple tumor sections in a cone biopsy or hysterectomy specimen more likely uncovers area of unequivocal gastric differentiation with classic criteria. The problem arises in scant samples such as biopsies and curettages where diagnosis may require help of special stains and sensitive HPV detection in tumor sample. Still, careful examination of the cytologic features of tumor cells can inform the diagnosis as the same histologic features are identifiable in small specimens.10
Gastric-type adenocarcinoma shows characteristic immunohistochemical positivity for gastric mucin markers MUC6 and HIK1083.1,2,8,9 Unfortunately HIK1083 may not be routinely available for diagnostic purposes and MUC6 is not entirely specific. Kojima et al1 reported positive staining for HIK1083 and MUC6 in 75% and 31% of gastric adenocarcinomas, respectively. In comparison, these markers were positive in only 10% of usual adenocarcinomas, each.1 Mikami et al found HIK1083 and MUC6 positivity in 75% and 65% of GAS, respectively, whereas Carleton et al9 reported MUC6 positivity in 80% of GAS Benign endocervical epithelium was reported to be positive for HIK1083 in 2% of cases and for MUC6 in 8% of cases.2 Similar to usual endocervical adenocarcinoma, gastric-type adenocarcinoma is generally negative for estrogen receptor (ER) and progesterone receptor (PR) immunostaining (though focal weak ER positivity has been reported),8,9 and shows cytoplasmic carcinoembryonic antigen positivity.8,9,12 The staining for p16 in GAS is characteristically negative, reflecting negative HPV status, however, recent studies reported rare cases with strong, diffuse p16 positivity (Figs. 16A, B),9 which may confound the differential diagnosis with usual endocervical adenocarcinoma.
Sixty eight to 88% of GAS has been reported to be positive for PAX8,9,27 while CK7, CK20, and CDX2 positivity has been reported in 100%, 50%, and 51% of cases, respectively.9 Approximately half of GAS cases studied thus far show aberrant p53 immunostaining with either diffuse strong positivity or null pattern.8,9,27 Interestingly, gastric-type adenocarcinoma expresses markers typically present in clear cell carcinomas, HNF-1 beta and napsin A.8,9,28 The tumor has been reported to be negative for PAX2 staining.9,29
LEGH shows mostly similar immunohistochemical profile as GAS, with positive expression of gastric mucin markers MUC6 and HIK10832,15 and negative staining for hormone receptors.15 Unlike GAS, they are typically positive for PAX229 and thus far have only shown wild-type p53 staining pattern.30
Because of the wide morphologic spectrum of gastric-type adenocarcinoma, depending on the predominant feature, the differential diagnosis can include both benign and malignant conditions. Gastric minimal deviation adenocarcinoma must be differentiated from LEGH, deep Nabothian cysts, diffuse laminar endocervical glandular hyperplasia, and adenomyomas of endocervical type. Lack of ER and PR immunostaining distinguishes minimal deviation adenocarcinoma from all of the above benign conditions except LEGH. Differentiation of minimal deviation adenocarcinoma from LEGH is usually based on architectural findings of haphazard gland architecture and deep extension within cervical stroma in cases of adenocarcinoma. LEGH should maintain well-defined lobular architecture with minimal cytologic atypia, while minimal deviation adenocarcinoma shows at least focal areas of unequivocal malignancy either in the form of severe nuclear atypia or destructive stromal invasion. In equivocal cases, 3 immunostains may be helpful in differential diagnosis—smooth muscle actin, p53 and PAX2. Positive smooth muscle actin staining may be seen in cervical stromal cells immediately adjacent to invasive glands of minimal deviation adenocarcinoma (Fig. 17), highlighting desmoplastic stromal response, but the staining is not seen around LEGH.31 In addition, half of minimal deviation adenocarcinoma cases may show aberrant p53 immunohistochemical staining (diffusely positive or null), while LEGH exhibits wild-type p53 staining.9 In a single publication, PAX2 staining was reported to be positive in all cases of LEGH and negative in minimal deviation adenocarcinoma.29
Among malignant lesions, GAS may be difficult to distinguish from usual endocervical adenocarcinoma, especially if the tumor demonstrates glands with elongated and stratified nuclei. The newly described classification system validated morphologic discrimination of HPV associated from non–HPV-associated endocervical adenocarcinomas by the presence of easily identifiable mitoses and apoptoses at scanning magnification in HPV-associated adenocarcinoma.6 Gastric-type adenocarcinomas are, however, not devoid of mitoses and apoptoses, they are just not as readily identifiable as in usual endocervical adenocarcinoma. In addition, identification of the precursor lesion may also be helpful. Usual endocervical adenocarcinoma may be seen in association with adenocarcinoma in-situ and high-grade squamous intraepithelial lesion (HSIL), whereas GAS can be seen in association with LEGH or gastric adenocarcinoma in situ, though they are not always present. However, it should be noted that the presence of HSIL and GAS are not mutually exclusive as there could be 2 true-true and unrelated neoplastic processes occurring simultaneously.6 Usual adenocarcinoma is reported to be p16 positive in 81% of cases.6 Negative p16 staining is in favor of gastric differentiation. When available, positive staining for HIK1083 and negative HPV testing are also in support of gastric differentiation. In cases that show morphologic features of gastric-type adenocarcinoma which are p16 diffusely positive, sensitive HPV testing of tumor tissue only should be performed as lack of HPV detection will be confirmatory for gastric differentiation. A recent paper examining tumors with mixed usual/gastric features concluded that such tumors can be definitely categorized as either usual or gastric-type based on the results of special stains, and that there is no intermediate category of mixed usual gastric adenocarcinoma.32
Tumors with goblet cell morphology can be subclassified into intestinal-type or gastric-type adenocarcinoma using the same algorithm as for usual type adenocarcinoma described above. Intestinal-type adenocarcinoma may be accompanied by adenocarcinoma in situ and HSIL, shows diffuse p16 positivity and positive HPV detection.
Another subtype of endocervical carcinoma that may be confused with gastric-type adenocarcinoma is clear cell carcinoma, a tumor that may show various characteristic architectural patterns—tubulocystic, papillary, and solid and is composed of cells that are either cuboidal or flat. Clear cell carcinoma only rarely shows tall, columnar cell shaped cells. Clear cell carcinoma shows positivity for HNF-1 beta in 78% of cervical tumors and Napsin A in 100% of cervical tumors.8,28 p16 positivity was reported as focal to diffuse in 100% of cases, despite lack of HPV detection (the underlying mechanism is currently unknown).8 Gastric adenocarcinoma may display tubulocystic and papillary patterns but not solid growth, and usually has glands lined by tall columnar cells. Among tumor markers, gastric adenocarcinoma shows positivity for clear cell carcinoma markers HNF-1 beta and Napsin-A8,9,28 and, therefore, these are not helpful in the differential diagnosis. However, in contrast to gastric-type adenocarcinoma, clear cell carcinoma is negative for cytoplasmic carcinoembryonic antigen and positive for p16.8
Gastric-type adenocarcinoma involving the lower uterine segment and displaying eosinophilic cytoplasm and/or microcystic elongated and fragmented pattern of infiltration may be difficult to differentiate from endometrioid adenocarcinoma. In such case, positive immunostaining for ER and PR is in favor of endometrioid adenocarcinoma. In addition, immunohistochemistry for DNA mismatch repair proteins can be helpful if lost, since this is indicative of microsatellite unstable endometrial endometrioid adenocarcinoma. In tumors with scant eosinophilic cytoplasm and markedly atypical nuclei, serous carcinoma may be in the differential. In contrast to GAS, serous carcinoma shows diffuse and strong p16 positivity, not related to HPV. Tumors with mucin extravasation and intraperitoneal spread raise the possibility of metastatic gastrointestinal or pancreatobiliary primary adenocarcinomas. In such instances PAX8 positivity is in favor of primary cervical adenocarcinoma, however, since not all cervical gastric-type adenocarcinomas are PAX8 positive,9 a negative result should be correlated with the imaging studies.
In conclusion, GAS has a wide morphologic spectrum from extremely well differentiated and therefore, mimicking a benign process, to poorly differentiated such that the origin and/or subtype of the tumor cannot be determined by morphology alone. They are characterized by clear, eosinophilic, and/or foamy cytoplasm containing gastric-type mucin but morphologically closely resembling pancreatobiliary adenocarcinomas. These are aggressive, chemotherapy-refractory, non–HPV-associated neoplasms that may be difficult to recognize, especially if unfamiliar with the morphologic variations that can be seen. GAS should be considered in the differential diagnosis of any adenocarcinoma of the gynecologic tract that has unusual morphology and/or immunohistochemical profile from what might be expected.
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
cervical gastric adenocarcinoma; gastric-type endocervical adenocarcinoma; cervical minimal deviation adenocarcinoma; lobular endocervical glandular hyperplasia