Poorly differentiated squamous carcinoma with small cells morphologically resembles a high-grade squamous intraepithelial lesion of small cell size and may also be confused with true small cell (neuroendocrine) carcinoma [6] (see below). The cells have more cytoplasm, greater cytoplasmic density, better definition of cell borders, coarsely granular chromatin, and less crush artifact than do those of small cell carcinoma [3]. The lack of definitive nuclear molding and background necrosis and the identification of a squamous component favor squamous cell carcinoma [4]. Ancillary studies (see below) can be helpful in arriving at the correct interpretation. While neuroendocrine markers are negative in squamous carcinoma, p63 and p40 will show some positvity.

These uncommon tumors may occur over a wide age range and account for 1–5 % of cervical malignancies. Neuroendocrine tumors are classified in the 2014 World Health Organization terminology as low-grade neuroendocrine tumors (carcinoid and atypical carcinoid) and high-grade neuroendocrine carcinomas (small cell neuroendocrine carcinoma and large cell neuroendocrine carcinoma) [8].

Glassy cell carcinoma of the cervix is a rare variant of poorly differentiated adenosquamous carcinoma that affects younger patients [4, 17] and is associated with HPV types 18 and 16 [18]. Characteristically, tumor cells are arranged in sheets and clusters with large abundant granular (ground glass-like) cytoplasm and large pleomorphic nuclei. The nuclei have coarse irregular chromatin and distinctive prominent nucleoli [17] that may be mistaken for inclusions of herpes virus or Reed-Sternberg cells in Hodgkin disease. Cytoplasmic vacuolization and bizarre cells with multinucleation can be seen. The tumor may be associated with an eosinophilic lymphoplasmacytic infiltrate in the background. Dyskeratosis and intracellular glycogen may not be appreciated. The differential diagnosis is with other poorly differentiated neoplasms involving the cervix including nonkeratinizing squamous cell carcinoma, poorly differentiated adenocarcinoma, and clear cell carcinoma, or a metastasis/extension from the colon, endometrium, vagina, or urethra where glassy cell carcinomas have been reported.

This tumor comprises about 1 % of endocervical carcinomas, although higher prevalence rates have been reported in the Japanese literature [19]. It is, for the most part, hrHPV DNA negative [20–22]. Cervical cytology specimens show a large number of glandular cells that closely resemble benign endocervical cells arranged in clusters, strips, and isolated cells. Pseudostratified glandular strips, loss of polarity within clusters, a disorganized “drunken” honeycomb sheet arrangement, and a spectrum of atypical nuclear changes are the key diagnostic features. The individual cells are cuboidal to columnar and have abundant lacy, golden-yellow vacuolated cytoplasm containing neutral gastric/pyloric type mucin [23]. Marked nuclear enlargement (two to three times the size of intermediate squamous nuclei), nuclear pleomorphism, and visible nucleoli are seen only in a minority of these cell groups. This tumor is also positive for CEA, Ki67 (>50 % of tumor nuclei), and p53 while it is negative for estrogen and progesterone receptors.

The differential diagnostic considerations include benign endocervical glands, atypical glandular cells, adenocarcinoma in situ (AIS), and endometrial adenocarcinoma [20]. AIS shows loss of mucin and lacks abnormal single cells, which are both present in mucinous carcinomas. Tightly crowded sheets of glandular cells with overlapping nuclei, “ragged edged” borders, and feathering are distinctive features of AIS which are not present in mucinous carcinoma. Endometrial adenocarcinoma displays three-dimensional groupings with nuclear overlap or papillary architecture, pleomorphic hyperchromatic nuclei with irregularly distributed chromatin, and scant vacuolated cytoplasm containing intracytoplasmic neutrophils (see Figs. 6.​46, 6.​47, and 6.​48).

MMMT is an uncommon and highly aggressive carcinosarcoma (<5 % of malignant neoplasms of the uterine corpus) that arises in the endometrium, but which may extend as a fungating mass into the cervical os. By definition, the tumor is biphasic, being composed of malignant epithelial and mesenchymal components. The malignant epithelial component morphologically most often resembles poorly differentiated endometrioid adenocarcinoma; clear cell and serous differentiation are less frequent. Mesenchymal (sarcomatous) elements are usually endometrial stromal, fibroblastic, or leiomyosarcomatous. Occasional heterologous elements may include rhabdomyosarcoma, chondrosarcoma, or osteosarcoma. Recent clinicopathologic, immunohistochemical, and molecular genetic studies have provided strong evidence that MMMTs are best classified as variants of carcinoma.

Exfoliated malignant cells from the endometrium or direct sampling of extension of an MMMT to the cervix/vagina may yield malignant cells in a cervical cytology sample. Morphologic presentations of MMMT on cytologic preparations are usually hypercellular and show high‑grade malignant tumor cells. The presence of both malignant epithelial (Fig. 7.7) and sarcomatous components (Fig. 7.8) suggests the possibility of MMMT. However, degeneration or limited sampling of poorly differentiated malignant cells may lead to interpretive difficulties [24, 25]. The differential diagnosis includes endometrial adenocarcinoma, pure sarcoma, botryoid rhabdomyosarcoma (seen in children/adolescents), and other poorly differentiated or undifferentiated tumors.

Clear cell adenocarcinoma of the cervix or the vagina is a rare tumor of Müllerian origin that [26] occurs most commonly in daughters of women who received diethylstilbestrol (DES), a nonsteroidal estrogen, during pregnancy. The peak age for DES-associated clear cell carcinoma is between 14 and 22 years and for non-DES-associated cases it ranges between 13 and 80 years. Cervical cytology specimens show cells that are arranged in sheets, clusters, or papillae [27]. The tumors contain cells with delicate, vacuolated, glycogen-rich cytoplasm, naked nuclei and a “tigroid” background similar to that seen in other glycogen-rich tumors. The nuclei are large, pale, and round with prominent nucleoli. HPV has been detected only in 40 % of clear cell carcinomas in both DES- and non-DES-associated cases [28].

Primary sarcomas of the female genital tract are rare; these can originate from the vagina, cervix, uterus, fallopian tubes, or ovaries, but most commonly arise in the uterine corpus. Sarcomas may be pure or mixed with epithelial components and usually present with degenerated, sparse, or isolated tumor cells in the cervical sample [1–3].

Pure sarcomas include leiomyosarcoma, rhabdomyosarcoma, fibrosarcoma [29], endometrial stromal sarcoma [30], Ewing/primitive neuroectodermal tumors (PNET) [13, 14], and myeloid sarcoma [15]. Most pure sarcomas present with undifferentiated, pleomorphic, multinucleated, and/or bizarre cells and cannot be further subtyped. If present, characteristic cytologic features such as spindle or strap cells or round blue cell cytomorphology may suggest the specific type of sarcoma [1–3, 8]. When sufficient cytologic material is available, immunohistochemistry may help further subcategorize the sarcoma.