The clinical presentation and macroscopic appearance of adenosquamous carcinoma (ICD-O 8560/3) are not distinctive.

An admixture of malignant epithelial elements exhibiting both glandular and squamous architecture is the defining characteristic of adenosquamous carcinoma (Fig. 11.7). Scattered mucin-producing cells may occur in a squamous cell carcinoma [37], and this finding is not sufficient for a diagnosis of adenosquamous carcinomas. Routine staining for mucin in squamous carcinomas is not recommended since the identification of mucin has no clinical value [37]. Carcinomas having abundant mucin-producing cells without evidence of squamous differentiation (intercellular bridges, keratinization) should be diagnosed as poorly differentiated adenocarcinoma. A clear cell variant of adenosquamous carcinoma characterized by a clear appearance of the squamous component due to extensive glycogen has been described [38].

Mucoepidermoid carcinomas are a distinctive variant of adenosquamous carcinoma and characterized by a three cell types (epidermoid, mucin-producing, and intermediate).

Both cervical intraepithelial neoplasia (CIN)/squamous intraepithelial lesions (SILs) (see Chap. 6) and adenocarcinoma in situ (AIS) (see Chap. 8) are precursor lesions for adenosquamous carcinomas. Adenosquamous carcinomas likely are derived from epithelial reserve cells with subsequent bidirectional differentiation. Multiplex real-time polymerase chain reaction detects HPV in 80% of adenosquamous carcinomas, usually HPV 16/HPV 18; mixed HPV infection occurs in about a third of cases [39]. HPV 18 is the most prevalent HPV type in adenosquamous carcinoma, followed by HPV 16 [40]. The expression of adenine-thymine-rich interactive domain 1A (ARID1A) is downregulated in adenosquamous carcinoma as compared to squamous cell carcinoma, suggesting that this gene may have a role in the pathogenesis of adenosquamous carcinoma [41]. Consequently, the protein expression of ARID1A is frequently lost in adenosquamous carcinomas [42]. The t(11;19)-associated CRTC1-MAML2 gene fusion is identified in cervical mucoepidermoid, but not adenosquamous, carcinomas [43].

Whether adenosquamous differentiation is an independent predictor of poor outcome is unclear [44]. Some studies have indicated that adenosquamous carcinoma has a poorer outcome than adenocarcinoma and/or squamous carcinoma [44–47]. The balance of evidence suggests that adenosquamous carcinoma has a similar behavior and prognosis to squamous and adenocarcinomas [48–57]. Cervical carcinomas of an advanced-stage adenosquamous differentiation may be a predictor of poorer outcome [58]. HPV negativity in an adenosquamous carcinoma may be an indicator of poor prognosis [59].

Glassy cell carcinoma (ICD-O 8015/3) is a poorly differentiated variant of adenosquamous carcinoma and comprises no more than 2% of cervical carcinomas. Typically it occurs in young women, is characterized by a rapid course, and may have distant metastases. There are no distinctive gross features of glassy cell carcinoma.

The distinctive features of glassy cell carcinoma include sharp cytoplasmic margins, glassy eosinophilic cytoplasm, and large round to ovoid nuclei with prominent nucleoli [60]. A prominent eosinophilic infiltrate may be found in the adjacent stroma [61]. However, eosinophilic infiltrates may also be identified in invasive squamous carcinoma. The tumor cells lack estrogen and progesterone receptors [62].

Glassy cell carcinomas are associated with HPV 18 and probably originate from multipotential stem or reserve cells [63].

Some studies of glassy cell carcinomas have identified a poor prognosis and worse outcome than other cervical carcinomas [60]. Recent studies have not confirmed these prognostic findings [64, 65]. Surgery is the mainstay of treatment for early-stage glassy cell carcinoma; neoadjuvant radiochemotherapy has been recommended for more advanced disease [61, 66–68].

Adenoid basal carcinoma (ABC), also known as adenoid basal epithelioma (ICD-O 8098/3), is a rare tumor and usually occurs in women older than 50. Patients are usually asymptomatic and without detectable clinical or gross abnormality of the cervix unless associated with another carcinoma type. The tumor is usually discovered as an incidental microscopic finding [74].

ABC is composed solely of small well-differentiated rounded nests and cords of basaloid cells with scanty cytoplasm and focal gland or squamous formation (Figs. 11.8, 11.9, and 11.10). These nests infiltrate the cervical stroma and are often associated with CIN [74, 75]. The small cells are p16 positive on immunohistochemistry [76]. Invasive squamous carcinoma and small cell neuroendocrine carcinoma may be seen in association with ABC. The presence of such an invasive carcinoma excludes a case from categorization as ABC [77] and such cases should be labeled as “mixed carcinoma.” Consequently, a confident diagnosis of “pure” ABC cannot be rendered on a small biopsy, and definitive diagnosis requires the evaluation of the entire tumor [76, 77]. “Adenoid basal hyperplasia” has been described and is characterized by a proliferation of small basaloid HPV-negative nests extending less than 1 mm from the basement membrane [78]. Until additional descriptions are made, such lesions are better classified within adenoid basal carcinoma. The differential diagnosis of ABC includes adenoid cystic (ACC), squamous, and neuroendocrine carcinomas [79]. ABC and ACC share many immunohistochemical similarities [80]. ABC may be distinguished from ACC by its CD117 negativity [81]. A single report has suggested that p16 IHC can be used to distinguish low-grade, noninvasive ABC from invasive ABC [82].

It is postulated that ABC has its origin from a reserve cell [80, 83]. ACC is another tumor within this morphological spectrum. ABC is a high-risk HPV-related tumor with HPV types 16 and 33 being identified [76, 84, 85].

Pure ABC is a low-grade tumor, has an excellent prognosis, and rarely metastasizes [74]. Although the term “adenoid basal epithelioma” has been suggested to reflect this benign behavior, ABC is a well-known and accepted entity. The outcome of mixed carcinomas and ABC is largely dependent upon prognostic features of the non-ABC component. The detection of an invasive component of usual type in an excisional biopsy showing ABC, that is a “mixed carcinoma,” should direct appropriate management.

Adenoid cystic carcinoma (ACC, ICD-O 8200/3) of the cervix is very rare, representing fewer than 1% of all cervical carcinomas [86]. Cervical ACC is clinically aggressive, often presenting as a prominent mass and showing signs of deep invasion including bloody, watery, or purulent discharge [87–90]. ACC most frequently occurs in postmenopausal black women [80, 91, 92], although cases in Hispanic, Asian, and white patients have also been reported [81, 92].

ACC of the cervix is characterized by morphological features resembling ACC of the salivary gland [93, 94]. The tumors are poorly circumscribed; perineural and vascular invasion are frequent. Tumor cells grow in both large and small nests, within which cribriform, trabecular, solid, and cord-like patterns can be seen. In most cases, there is at least focal formation of round pseudoglandular spaces filled with globules of hyaline basement membrane material or mucin. The stromal areas between tumor nests have a predominantly hyaline appearance, although desmoplastic or myxoid changes can be seen. Tumor necrosis is common, and focal calcifications may also be present [87, 92].

Both at the periphery of tumor nests and surrounding the pseudoglandular spaces, the cells tend to palisade in a more compact formation. These palisading cells usually have very scant cytoplasm, dark compact nuclei, and a more bland basaloid appearance. By contrast, the cells found throughout the tumor can have a range of nuclear atypia, and mitotic figures may be abundant, although bizarre pleomorphic cells are generally not present. The palisading (“abluminal”) cells represent a distinct cell population having a predominantly myoepithelial phenotype and can be highlighted with p63 immunohistochemistry [89]. The remaining (“adluminal”) cells have a more heterogeneous epithelial phenotype, without clear squamous or glandular appearance, and are variably positive for CD117 [81]. The hyaline/mucinous globules are strongly highlighted by a PAS stain. The diagnosis of cervical ACC can also be made on a Papanicolaou smear, when basaloid cells surrounding hyaline globules are seen [95].

In the cervix, the presence of a solid undifferentiated component is not unusual in ACC and may be generally underappreciated [96]. Unlike ACC of the salivary gland, the prognostic significance of an undifferentiated component (“solid ACC”) is unclear for cervical ACC, given that the latter is already treated as an aggressive clinical entity [88]. Cervical ACC can also be seen as a component of a mixed carcinoma having conventional squamous or other divergent epithelial differentiation [79, 89]. These variant patterns may be more closely associated with high-risk HPV compared to pure ACC [97].

The most important differential diagnosis is adenoid basal carcinoma (ABC, previous section), which in its pure form carries a favorable prognosis. Unlike ACC, ABC is a tumor with a single cell population that is characteristically CD117 negative. ABC also lacks the stromal changes and nuclear variability seen in ACC [79].

ACC is part of a spectrum of cervical carcinomas with basaloid features, postulated to arise from the reserve cells [79]. Unlike other basaloid tumors, ACC arising in numerous sites is associated with a distinct t(6:9) resulting in a MYB-NFIB fusion gene [98]. Overexpression of the MYB protein has been reported in three cases of cervical ACC with mixed squamous differentiation—in all three cases, high-risk HPV DNA was also detected [89]. However, another study of both mixed-type ACC and pure ACC showed that these two patterns are distinct with respect to HPV status. Whereas cervical carcinomas of mixed differentiation have high-risk HPV in its ACC component, pure cervical ACC is not associated with high-risk HPV and does not demonstrate p16 overexpression [97].

ACC shows a high propensity for perineural and vascular invasion and for distant metastasis in the long term, especially to the lung [99, 100]. Even when presenting at Stage I, the 5-year survival is as low as 56% based on a review of early cases [91]. ACC is considered radiosensitive, and some authors recommend a low threshold for radiation therapy following hysterectomy [88, 101].

Melanoma of the cervix (ICD-O 8720/3) is a very rare cervical malignancy. The usual presentation is the onset of vaginal bleeding in a woman in her sixth decade [107]. On examination an exophytic ulcerating lesion is often seen on the cervix. Blackish hue or discoloration may serve to distinguish melanoma from cervical carcinoma.