Definition

Adenoid basal carcinoma (adenoid basal epithelioma) is composed of bland, uniform, basaloid cells arranged in nests with a variable amount of glandular and squamous differentiation. Based on their favorable outcome, there is a proposal to designate this tumor as ‘epithelioma,’ rather than carcinoma.

General Features

Adenoid basal carcinoma (epithelioma) accounts for less than 1% of cervical cancers and usually develops in postmenopausal women with a median age of 66.5 years and a wide age range, from 19 to 91 years. Most patients are asymptomatic and the tumor is frequently an incidental finding in a surgical specimen obtained after the diagnosis of high-grade squamous intraepithelial lesion on a Pap smear. In rare cases, patients can complain of vaginal bleeding, hematuria, or dysuria. The tumor appears to arise from reserve cells and is usually associated with human papillomavirus (HPV) 16.

Pathology

Grossly, the tumor is usually invisible; however, induration, erosion, ulceration, and abnormalities of the cervical mucosa have been described in rare cases. Adenoid basal carcinoma (epithelioma) is composed of multiple, small, round to oval nests of bland, uniform, basaloid cells with peripheral palisading ( Figures 13.1 and 13.2 ). The tumor nests are haphazardly distributed in the cervical stroma without eliciting a desmoplastic response although focal edema and mild chronic inflammation may be seen. The tumor typically does not reach the surface of the endocervical canal; however, occasionally it appears in continuity with an overlying dysplastic squamous epithelium. Clearing of the cytoplasm due to the accumulation of glycogen may be seen. There is a variable degree of glandular and squamous differentiation ( Figure 13.3 ). The former is characterized by the presence of columnar or cuboidal cells with bland nuclei surrounding a distinct lumen while the latter shows bland squamous cells in the center of the nests with preservation of a peripheral rim of basaloid cells. Occasionally, a cribriform pattern can be noted. The mitotic index is usually low, although it may vary from 0 to 9 mitoses per 10 high power fields (HPFs). There is no necrosis or lymphovascular or perineural invasion. Although the tumor is typically associated with a high-grade squamous intraepithelial lesion, rarely, it can be associated with a superficially or frankly invasive squamous carcinoma, adenoid cystic carcinoma, adenosquamous carcinoma, clear cell carcinoma, neuro­endocrine carcinoma, or carcinosarcoma.

Adenoid basal carcinoma (epithelioma) composed of round, oval, or slightly distorted nests.

Adenoid basal carcinoma (epithelioma) with bland cytology and peripheral palisading.

Adenoid basal carcinoma (epithelioma) with focal glandular formation.

Immunohistochemistry

Adenoid basal carcinoma (epithelioma) is usually immunoreactive for keratin AE1/AE3, CK902 (against cytokeratin 8 and 18), epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), CAM 5.2, p16, p53, and p63. S-100 can be positive in a few cases. A limited number of cases of adenoid basal carcinoma (epithelioma) has been tested for CD117 (c-kit) and found to be negative.

Differential Diagnosis

Adenoid basal hyperplasia is a superficial lesion with epithelial nests smaller than those seen in adenoid basal carcinoma (epithelioma). The nests reside within 0.5 mm of the basement membrane of the overlying or adjacent epithelium and are connected to it.

Adenoid cystic carcinoma tends to produce symptoms and a grossly visible mass. Microscopically, it contains tumor nests that are larger than those seen in adenoid basal carcinoma (epithelioma) and characteristically show a cribriform pattern containing either amorphous, hya­line, eosinophilic basement membrane-like material, or basophilic mucinous or eosinophilic secretion. Necrosis and stromal changes are often seen as well as lymphovascular invasion.

Squamous carcinoma can represent a diagnostic difficulty since adenoid basal carcinoma (epithelioma) can have florid squamous metaplasia with marked expansion of the tumor nests, thus mimicking an invasive squamous carcinoma. In addition, focal dysplastic changes can be noted in the areas of squamous metaplasia. Recognition of a residual rim of bland basaloid cells, which can be highlighted with the use of CAM 5.2 immunoreaction, will facilitate the proper identification of adenoid basal carcinoma (epithelioma) with extensive squamous metaplasia.

Basaloid squamous carcinoma, a rare type of cervical tumor, usually produces a symptomatic tumor mass. Microscopically, this tumor is composed of moderately pleomorphic, basaloid cells arranged in nests and cords. There is also peripheral palisading. Mitotic activity and necrosis are conspicuous. Larger cells with eosinophilic cytoplasm as well as a cribriform pattern can be seen. Hyalinization or myxoid change of the stroma is also common.

Clinical Behavior and Management

Morphologically pure adenoid basal carcinomas (epitheliomas) behave in a benign fashion without metastases to lymph nodes or other sites, local recurrences, or death. Microscopic examination of the entire tumor is necessary to exclude the presence of an associated neoplasm that could have an adverse impact on the prognosis. Cases of morphologically pure adenoid basal carcinoma (epithelioma) are treated with a loop electrosurgical excision procedure or cold knife cone with negative margins. In cases where the neoplasm extends to the margins, a comment should be included in the report about the possible association with another tumor type that could affect the prognosis.

Definition

Cervical adenoid cystic carcinoma is a neoplasm with histologic features mimicking those of similar tumors of the salivary glands and upper respiratory tract.

General Features

This tumor is rare and mostly seen in postmenopausal women (mean age, 72 years), but it is occasionally detected in younger women in the third or fourth decades of life. Uterine bleeding is the most common presentation with a rare case diagnosed incidentally. This neoplasm appears to originate from reserve cells and is usually associated with HPV 16.

Pathology Features

The tumor has a variable appearance from small polypoid lesions to large exophytic, friable masses or deeply invasive endophytic tumors. Microscopically, it is composed of mildly pleomorphic basaloid cells arranged in nests, sheets, cords, and trabeculae. Clear cell changes may be present. A distinct cribriform pattern containing either an amorphous hyaline eosinophilic basement membrane-like material or basophilic mucinous or eosinophilic secretion is usually seen ( Figure 13.4 ). Mitotic activity is variable, ranging from scanty to very high. Necrosis is often present and extensive. Stromal changes are typically prominent, ranging from hyalinization to myxoid or fibroblastic change. The solid variant lacks the typical cribriform pattern, but the tumor is recognized by the presence of abundant periodic acid–Schiff (PAS)-positive basement membrane material around the tumor cells that grow in solid nests, cords, and trabeculae. Small foci of squamous differentiation may be seen. Adenoid cystic carcinoma can be associated with adenoid basal carcinoma (epithelioma), in situ or invasive squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma. Adenoid cystic carcinoma tends to involve lymphovascular spaces and develops lymph node metastasis early.

Adenoid cystic carcinoma.

Immunohistochemistry

Tumor cells are reactive for wide spectrum cytokeratin (CK), CAM 5.2, and EMA. S-100 protein reactivity occurs in some cases while others are unreactive or just focally and weakly reactive. A rare case of cervical adenoid cystic carcinoma has been tested for CD117 (c-kit) and was found to be strongly reactive in approximately 5% of the cells. This finding does not compare with the common expression of CD117 (c-kit) in adenoid cystic carcinoma of the salivary glands, which is seen in 80–100% of cases.

Clinical Behavior and Management

Adenoid cystic carcinoma is an aggressive tumor. In one series, nearly half of the patients died of local recurrence or metastatic disease within 8 months to 8 years of diagnosis. Treatment options include radiotherapy, surgery, surgery and adjuvant radiotherapy, or chemotherapy.

Definition

This tumor is composed of uniform small cells with a high nuclear to cytoplasmic ratio, similar to small cell carcinoma of the lung.

General Features

This tumor accounts for less than 5% of the cervical carcinomas; however, it represents the most frequent neuroendocrine neoplasm of the uterine cervix. Patients’ ages range from 20 to 87 years (mean, 45 years). Vaginal bleeding is the most common symptom followed by pain. A rare case has been detected in an abnormal Pap smear. Occasionally, patients have developed paraneoplastic syndromes, including Cushing’s syndrome, hypoglycemia, inappropriate antidiuretic hormone production, carcinoid syndrome, and Eaton–Lambert syndrome. Most tumors are International Federation of Gynecology and Obstetrics (FIGO) stage I or II.

Pathology

Tumors range in size from 1 to 10 cm. A rare case has presented in a normal-appearing cervix. Microscopically, small cell carcinoma is composed of oval or spindled cells with scanty cytoplasm, dark nuclei, and no apparent nucleoli. The cells are arranged in nests, trabeculae, and cords ( Figures 13.8 and 13.9 ). Focal gland formation can be noted. There are numerous mitoses and apoptotic bodies. Molding of the nuclei, crush artifact, and necrosis are common. Occasionally, deposition of hematoxylin-stained material around vessels walls (Azzopardi phenomenon) is seen. Lymphovascular invasion is commonly seen. Associated large cell neuroendocrine carcinoma, in situ or invasive squamous cell carcinoma, or adenocarcinoma may be found.

Neuroendocrine carcinoma, small cell type. Nests and trabeculae of tumor cells.

Neuroendocrine carcinoma, small cell type.

Immunohistochemical Studies

In most cases, the tumor cells express at least one neuroendocrine marker, such as synaptophysin, chromogranin, NSE, or CD56 ( Figure 13.10A and B ). The tumor cells are diffusely positive for p16. Up to 87% of the cases are reactive for TTF-1. In addition, the tumor cells may react for keratin 20, neurofilament, and CD99. There are conflicting reports on the expression of c-kit in these tumors. Whereas in one study up to 43% of the tumors expressed c-kit, only one tumor of another series expressed c-kit diffusely.

Neuroendocrine carcinoma, small cell type, reactive for chromogranin ( A ) and synaptophysin ( B ).

Differential Diagnosis

Poorly differentiated squamous cell carcinomas can be composed of small cells with scanty cytoplasm resembling a small cell neuroendocrine carcinoma. However, squamous carcinoma typically lacks the abundant apoptotic bodies, nuclear molding, and crush artifact that are commonly seen in small cell neuroendocrine carcinoma. The use of neuroendocrine markers such as synaptophysin, chromo­granin, and CD56 will facilitate the correct diagnosis as small cell carcinoma should be positive for at least one of these markers. It should be noted that markers traditionally used to prove squamous differentiation (i.e., p63 and CK 5/6) can be positive in neuroendocrine carcinomas.

Lymphoma and melanoma require standard immuno­histochemical studies to distinguish them from small cell neuroendocrine carcinoma.

Primitive neuroectodermal tumor can share histologic and immunohistochemical features with small cell neuroendocrine carcinoma. Molecular studies for HPV together with CD99, keratin, and neuroendocrine marker immunoreactions are required to ascertain the correct diagnosis as cervical neuroendocrine carcinomas are HPV associated whereas primitive neuroectodermal tumors are not.

Clinical Behavior and Management

Small cell carcinoma is an aggressive neoplasm that tends to develop widespread metastases (i.e., bone, liver, lung, lymph nodes, and soft tissue) and has an overall 5 year survival rate of only 29%. Patients with early stage disease are treated with radical hysterectomy. In addition, adjuvant cisplatinum and etoposide-based chemotherapy and radiotherapy are used for distant and local control of the disease. Patients with advanced stage disease are treated with radiotherapy and chemotherapy.

Definition

This high-grade tumor is composed of cells with a moderate or abundant cytoplasm, visible nucleoli, and neuroendocrine differentiation.

General Features

Large cell neuroendocrine carcinoma is the second most common type of neuroendocrine tumor of the uterine cervix and accounts for 0.6% of the invasive cervical carcinomas. The mean age of patients is 37 years (age range, 21–75 years). The most common symptom is vaginal bleeding, but some tumors are detected as a result of an abnormal Pap smear. The tumors are usually FIGO stage I or II.

Pathology

The tumor is usually polypoid or exophytic, although it may be ill defined and not even grossly visible. The tumor can be up to 6 cm in greatest dimension and shows a variable cut surface, ranging from tan-brown to yellow-gray or white, with areas of hemorrhage or necrosis. Microscopically, the tumor cells have a moderate or abundant amount of cytoplasm, moderately or markedly atypical nuclei with vesicular or finely granular chromatin, and visible nucleoli ( Figure 13.11 ). They are arranged in nests, trabeculae, or solid sheets. Glandular formation can be seen ( Figure 13.12 ). The mitotic index is high (more than 10 mitoses per 10 HPFs). Geographic necrosis and lymphovascular invasion are typically present ( Figure 13.13 ). The tumor can be associated with adenocarcinoma in situ , invasive adenocarcinoma (mucinous or endometrioid type), and small cell carcinoma.

Neuroendocrine carcinoma, large cell type.

Neuroendocrine carcinoma, large cell type. Focal glandular differentiation.

Neuroendocrine carcinoma, large cell type, showing geographic necrosis.

Immunohistochemistry

All tumors express at least one neuroendocrine marker, such as synaptophysin, chromogranin, or CD56. All cases are reactive for p16. The tumor cells can also express TTF-1, p63, keratin 20, neurofilament, and CD99.

Differential Diagnosis

Small cell neuroendocrine carcinoma has cells with scanty cytoplasm, hyperchromatic nuclei, and no nucleoli.

Adenocarcinoma may be erroneously diagnosed due to the presence of focal glandular differentiation in large cell neuroendocrine carcinoma, or the association with either an adenocarcinoma in situ or invasive adenocarcinoma. Attention to the architectural patterns (i.e., insular or trabecular) and the presence of geographic necrosis as well as the use of neuroendocrine markers will allow the proper diagnosis. It is important to bear in mind that focal expression of neuroendocrine markers can be seen in an otherwise typical adenocarcinoma or adenosquamous carcinoma of the uterine cervix.

Poorly differentiated squamous cell carcinoma shows at least focal evidence of keratin production or intercellular bridges.

Melanoma requires standard immunohistochemical studies to be distinguished from large cell neuroendocrine carcinoma.

Clinical Behavior and Management

The outcome for patients with large cell neuroendocrine carcinoma is poor. Survival across all stages is dismal with 67% of patients dying of disease. Intra-abdominal/intra­pelvic and distant metastasis, including liver, kidney, adrenal gland, lymph nodes, lung, bone, and brain, are usually seen. Treatment includes surgery with adjuvant radiotherapy and chemotherapy.