The revised WHO classification strictly defines mucinous carcinoma to include tumors composed of cells with intracytoplasmic mucin and includes gastric-type adenocarcinoma (GAS) in this group, as well as intestinal and signet-ring cell types.

The concept of GAS was first proposed by Kojima et al. in 2007 and included minimal deviation adenocarcinoma (MDA) (Fig. 9.1) in its morphological spectrum as an extremely well-differentiated variant, based on common gastric morphology and phenotype and aggressive clinical behavior [27]. Before the introduction of the concept and diagnostic criteria for GAS, the less-differentiated form was designated as endocervical-type mucinous adenocarcinoma [27, 28], which was in fact a wastebasket diagnostic category in the WHO 2003 classification. GAS is common in Japan, accounting for 20% to 25% of all endocervical adenocarcinomas [27], and limited data and personal communications indicate that it is less frequent in western countries [29, 30]. A European multinational epidemiological study demonstrated that GAS accounted for 1.5% (7/461) of all endocervical adenocarcinomas [22]. Microscopically, GAS is characterized by a proliferation of columnar cells with abundant pale or pale eosinophilic cytoplasm and distinct cell borders, arranged in glandular or cribriform patterns (Fig. 9.2) [27]. A recent study has described a foamy gland variant characterized by microvesicles in the cytoplasm [31], as seen in a variant of pancreatic adenocarcinoma with a deceptively benign appearance [32].

GAS characteristically has a gastric immunophenotype, as shown by positive staining with HIK1083 and/or anti-MUC6 antibody, two representative antibodies that recognize pyloric gland mucin of the stomach, and it is usually negative for p16^INK4a [27]. A comprehensive immunohistochemical study revealed that this tumor is frequently positive for p53 (mutation pattern), paired box gene-8 protein (PAX8), and carbonic anhydrase type IX [33]. HER2 expression is only rarely seen, in contrast to prototypical gastric adenocarcinoma [33]. In addition, p16^INK4a, a marker of HPV-driven neoplasms, is usually negative [21, 27], and subsequently Park et al. [6], Houghton et al. [7] and Kusanagi et al. [8] independently demonstrated the absence of high-risk HPV in cases of GAS.

Clinical presentation of GAS is similar to usual-type adenocarcinoma, but a notable finding is mucoid or watery discharge, as in cases of MDA. Magnetic resonance imaging features are distinctive and characterized by highly infiltrating and endophytic growth without forming well-demarcated masses associated with occasional cystic spaces, location in the upper cervix, and frequent vaginal or parametrial invasion in more than 60% of cases [34]. Importantly, Kojima et al. demonstrated that patients with GAS had significantly decreased overall survival of 30%, compared with 77% in those with usual-type tumors [27]. This aggressive nature was also demonstrated in a larger study. Based on a review of 40 cases of GAS, Karamurzin et al. reported frequent lymph node and distant metastasis with a 5-year-disease-specific survival of 42% compared with 91% in usual-type adenocarcinoma [35]. A subset of HPV-negative and TP53-mutated or p53-immunopositive endocervical adenocarcinomas, which show aggressive clinical behavior [14–16], might represent GAS. Omori et al. recently demonstrated that alteration of cyclin-dependent kinase inhibitors, including p16, p14, p27 and p21, and p53 overexpression, is closely related to frequent lymph node metastasis and worse prognosis in HPV-negative endocervical adenocarcinomas, including GAS [36].

A unique clinical presentation of GAS is an association with synchronous multifocal mucinous metaplasia and neoplasia of the female genital tract, involving the endometrium, fallopian tubes, ovaries, and uterine cervix. It may be associated with Peutz-Jeghers syndrome (PJS) [37–40]. Recently, a case of GAS arising in a patient with Lynch syndrome has been described [41].

Some studies have shown that endometrioid carcinoma is an HPV-driven neoplasm. However, the detection rate of high-risk HPV, as well as the incidence of this particular subtype of endocervical adenocarcinoma, varies significantly, ranging from 12.9% to 100%, with a total of 31.3% (20/64) in the English-language literature [1, 2, 9, 22, 23]. Endometrioid carcinoma is defined as showing features similar to endometrioid carcinoma of the uterine corpus. With strict criteria of the absence or paucity of intracytoplasmic mucin, and existence of ciliated cells, squamous differentiation, or morules (Fig. 9.3) and exclusion of extension from an endometrial carcinoma, endometrioid carcinoma of the cervix appears to be a rare neoplasm, with an incidence of less than 10% of all endocervical adenocarcinomas [42], and most cases are considered to be HPV negative. A significant number of HPV-related, usual-type endocervical adenocarcinomas may have been regarded as endometrioid carcinoma because of the paucity of intracytoplasmic mucin, resulting in a higher incidence of up to 30% in some series [42, 43].

Diagnosis of serous carcinoma of the uterine cervix should be established by diligent imaging studies and microscopic examination to eliminate secondary cervical involvement by serous carcinoma of other sites including the endometrium, fallopian tubes, ovaries, or peritoneum. Serous carcinoma shows proliferation of highly anaplastic cells arranged in papillary, micropapillary, or solid growth with occasional slit-like spaces (Fig. 9.4). Strictly defined primary serous carcinoma of the cervix is rare and accounts for less than 1% of all endocervical adenocarcinomas. It should be kept in mind that usual-type endocervical adenocarcinoma occasionally shows a micropapillary pattern of growth and nuclear anaplasia, imparting a close resemblance to serous carcinoma (Fig. 9.5) [44]. Such tumors arising in young patients may have been designated as HPV-positive serous carcinomas of the cervix in the English-language literature [7, 10]. In addition, serous carcinoma shows immunoreactivity for p16^INK4a as a result of non-HPV-related mechanisms [45]. Some investigators have suggested that serous carcinoma is HPV driven, although the detection rate of high-risk HPV ranges from 0% to 100%, with a total of 28.2% (20/71) in the literature [1, 7, 9, 21–23, 26].

Clear cell carcinoma is characterized by neoplastic cells with abundant clear cytoplasm caused by accumulation of glycogen, arranged in tubular, tubulocystic, papillary, micropapillary, and solid patterns, as well as a hobnail appearance of cells (Fig. 9.6). Stromal hyalinization resulting from deposition of basement membrane material is a common finding. As in serous carcinoma, diagnosis of clear cell carcinoma is made after excluding secondary involvement by endometrial or ovarian tumors. It is well known that this particular tumor was commonly found among young women who had a history of in utero exposure to diethylstilbestrol (DES), a synthetic estrogenic agent that was approved by the US Food and Drug Administration in 1941 [46]. However, patients are now mostly postmenopausal, and clear cell carcinoma appears to be independent of exposure to DES. Recent studies have shown that clear cell carcinoma is mostly unrelated to HPV [1, 7, 21, 24], although three studies detected HPV in 13% [23], 20% [9], and 27.3% [22] of cases. Clear cell carcinoma frequently shows increased epidermal growth factor receptor (EGFR) or HER2 expression or activation of AKT or mammalian target of rapamycin (mTOR). Therefore, tyrosine kinase inhibitor blockade of the AKT-mTOR pathway might be an effective treatment strategy for this tumor [24].

Mesonephric duct remnants and hyperplasia are the putative origins of mesonephric carcinoma, because of morphology, topographic relationship, and immunophenotype. Mesonephric carcinoma is characterized by proliferation of cuboidal or columnar cells with pale eosinophilic cytoplasm, arranged in tubular, trabecular, papillary, reticular, or solid patterns, and diastase-resistant periodic acid-Schiff (PAS)-positive luminal secretion (Fig. 9.7). Well-differentiated mesonephric carcinoma can be misinterpreted as endometrioid carcinoma. Immunohistochemically, it is positive for CD10, inhibin, and calretinin and negative for estrogen receptor and p16^INK4a. More recent studies have shown that it is positive for HMGA2 [25], PAX8 [25, 47], and GATA3 [48] and occasionally can be positive for hepatocyte nuclear factor 1-β (beta) and thyroid transcription factor 1 (TTF-1) [25]. Detection of high-risk HPV has not hitherto been reported in cases of this subtype of endocervical adenocarcinomas [1, 7, 21, 25].