Neuroendocrine Tumors of the Genitourinary Tracts
Mithra R. Baliga
Sudha R. Kini
This chapter covers neuroendocrine neoplasms of the genitourinary tracts, which occur only infrequently. Neuroendocrine neoplasms are more common in genital tracts and more common in the female than in the male genital tract as compared to the urinary tract. In females, the uterine cervix is the frequent site, followed by ovaries. Neuroendocrine tumors of the endometrium, vagina, and vulva also have been reported in the literature.
Male genital tract neuroendocrine tumors are of unusual occurrence. However, they involve prostate more frequently than the rest of the organs. Other neuroendocrine tumors include testicular carcinoids and small cell neuroendocrine carcinomas that occur rarely in the scrotum, penis, and penile urethra. Urinary tract neuroendocrine neoplasms are very uncommon.
The cytologic diagnosis of neuroendocrine tumors of the genitourinary tract is provided only from cervical smears in cases of poorly differentiated neuroendocrine carcinomas of the uterine cervix. Rarely small cell carcinomas of the urinary bladder may exfoliate in the urine and identified via cytologic examination. Except for these two sites, a primary cytologic diagnosis of genitourinary tract neuroendocrine tumors is not generally made. Most of these neoplasms are identified by either surgical biopsies or excision. Metastatic sites such as lymph nodes, liver, or lungs are occasionally subjected to fine needle biopsy procedures for the cytologic diagnosis. Body cavity fluids may also be examined for the cytologic diagnosis. Overall, the documentation of cytologic features, therefore, is very lean.
This chapter covers neuroendocrine neoplasms of the female genital tract, followed by male genital tract, prostate, and urinary tract.
NEUROENDOCRINE TUMORS OF THE FEMALEGENITAL TRACT
Neuroendocrine tumors of the female genital tract, although very rare, have been described in various sites such as endometrium, cervix, fallopian tubes, vagina, vulva, and ovaries. Of these, small cell carcinoma (poorly differentiated neuroendocrine carcinoma) of the uterine cervix and carcinoid tumors of the ovaries are more frequent and will be described in detail.
POORLY DIFFERENTIATED NEUROENDOCRINE (SMALL CELL) CARCINOMA OF THE UTERINE CERVIX
Small cell neuroendocrine carcinoma is a highly aggressive malignant neoplasm of the uterine cervix, accounting for 3% to 5% of all cervical cancers. The incidence is 0.5/100,000 in the United States. There is no racial predilection. Patient’s average age is 36 to 42 years, and the patients are typically younger than those with squamous carcinomas. Up to 80% of small cell carcinomas are associated with human papilloma virus (HPV), type 18. HPV type 16 has been detected in a minority of patients with small cell carcinomas.
The patients may be asymptomatic or clinically present with vaginal bleeding. Less frequently, they may present with paraneoplastic syndromes such as Cushing syndrome, carcinoid syndrome, and hypoglycemia. Small cell carcinomas are very aggressive tumors and metastasize widely. Greater than 75% of the patients are dead from the disease within 1 year. The tumors are detected less often on screening cervical smears than squamous cell carcinomas.
GROSS AND HISTOLOGIC FEATURES
The smaller lesions are inconspicuous on gross examination of the cervix. Larger lesions may present as ulcerated masses, often invading the deeper structures. Microscopic examination reveals a pattern similar to its pulmonary counterpart, characterized by large islands and masses of small, round, oval-to-short spindle cells with scant indiscernible cytoplasm and large nuclei and very high N/C ratios (Fig. 12.1; see Fig. 12.6). Palisading of the neoplastic cells at the periphery of the tumor islands is characteristic. The carcinoma also presents a trabecular pattern or a solid growth pattern. The nuclei demonstrate molding and are intensely hyperchromatic with a brisk mitotic activity. Karyorrhexis and large areas of tumor necrosis are frequent.
CYTOPATHOLOGIC FEATURES
The specimens for cytologic diagnosis mostly represent cervical/vaginal smears and occasionally aspiration biopsies of the metastatic sites or body cavity fluids. The cytopathologic features are similar to those seen in pulmonary small cell carcinomas (ref. Chapter 3; Table 3.7). The conventional cervical smears (Figs. 12.2 and 12.3) present excellent cytomorphology as compared to the liquid-based preparations (Figs. 12.4,12.5 and 12.6). The conventional smears show varying numbers of malignant cells, isolated, in loosely cohesive groups and in syncytial tissue fragments without any architectural patterns. The neoplastic cells are small with high N/C ratios. Their nuclei are round to oval, occasionally oblong to short spindle shaped, containing coarsely granular chromatin with either a salt-pepper appearance (Figs. 12.2 and 12.3) or deep-staining compact pattern. Nucleoli are not conspicuous, and nuclear molding is often noted. In the liquid-based preparations, the small cell carcinoma cells tend to aggregate in three-dimensional balls or present in a dispersed fashion (Figs. 12.4,12.5 and 12.6). These dispersed single cells can easily be overlooked or mistaken for endometrial cells. Within these three-dimensional balls, the nuclei of the small cell carcinoma cells in liquid-based
preparations are extremely crowded and overlapped and their morphology may not be well visualized.
preparations are extremely crowded and overlapped and their morphology may not be well visualized.
 Fig. 12.1: Histologic Sections of Poorly Differentiated Neuroendocrine (Small Cell) Carcinoma of the Uterine Cervix. A, B: Mediumpower view showing a solid and trabecular growth pattern (H&E). C: Higher magnification showing peripheral palisading of nuclei. The cells are short spindle shaped with high N/C ratios (H&E). |
 Fig. 12.2: Conventional Cervical Smear from the Same Case as Figure 12.1. A: Medium-power view, showing a large population of malignant cells in varying-sized syncytial tissue fragments. B: Higher magnification demonstrating the large population of small malignant cells, with mildly pleomorphic nuclei containing compact chromatin. Nucleoli are not seen. Nuclear molding can be appreciated. The cell borders are poorly defined, and the cytoplasm is indistinct with high N/C ratios. |
 Fig. 12.3: A-C: Another example of histologically proven small cell neuroendocrine carcinoma of the uterine cervix. The malignant cells are discrete and loosely cohesive, small with poorly defined cell borders, scant, indiscernible cytoplasm, and high N/C ratios. Note single cells are difficult to type as malignant. Note the classic salt-pepper chromatin in B (conventional smear). |
 Fig. 12.4: Liquid-Based Preparation of a Cervical Smear, Depicting Small Cell Carcinoma Cells. Note the number of malignant cells is very small and they are present isolated or in small groups. They resemble lymphoid cells as no features suggestive of small cell carcinoma are readily appreciated. (Courtesy of Ms. Karen Atkinson, MPA, CT (ASCP), CMIAC, Director of Education and Training, and Mr. Tim Collins, BS, CT (ASCP), Senior Scientist, Research and Development, BD Diagnostics-Women’s Health and Cancer, Burlington, North Carolina.) |
IMMUNOPROFILE
The small cell carcinoma cells are immunoreactive to neuroendocrine markers such as chromogranin, synaptophysin, neuron-specific enolase, TTF-1, CD56, and cytokeratin.
ULTRASTRUCTURE
Ultrastructurally, cells of small cell carcinomas demonstrate dense-core neurosecretory granules.
DIAGNOSTIC DIFFICULTIES AND DIFFERENTIAL DIAGNOSES
Recognition of malignant cells originating from small cell neuroendocrine carcinoma may be compromised because of small number of cells, poor cytologic details, or misinterpretation. The differential diagnoses of small cell carcinomas of the cervix include diagnostic entities that are composed of cells with a small size, namely endometrial cells, endometrial adenocarcinoma, high-grade squamous intraepithelial lesion, and poorly differentiated squamous carcinoma, florid follicular cervicitis, and malignant lymphoma. The differential diagnostic features are listed in Table 12.1 and illustrated in Figures 12.7,12.8,12.9,12.10,12.11,12.12 and 12.13.
 Fig. 12.5: A-C: Liquid-based preparation of a cervical smear, depicting small cell carcinoma cells from a case of histologically confirmed small cell neuroendocrine carcinoma. Note that these cells are in tight three-dimensional groups and their cytomorphology is not readily apparent. Cervical biopsy revealed a small cell neuroendocrine carcinoma. |
 Fig. 12.6: A 38-year-old woman with a history of multiple abnormal pap smears complained of right lower quadrant pain. Pelvic examination revealed a large cervical mass. A pap smear was obtained and multiple cervical biopsies were done. A-D: Liquid-based preparation of a cervical smear showing syncytial tissue fragments of small cells with poorly defined cell borders, very high N/C ratios, and indistinct cytoplasm. The nuclear chromatin is compact and deep staining. A few discrete cells are present in the background. The smear was interpreted as high-grade squamous intraepithelial lesion. The cervical biopsies revealed a widely invasive small cell carcinoma. E: This low-power view of the cervical biopsy shows a small cell carcinoma in subepithelial location and diffusely infiltrating the cervical stroma (H&E). F: Higher magnification highlighting the small cell carcinoma. (Courtesy of Dr. Mithra Baliga, University of Mississippi, Jackson, Mississippi.) |
TABLE 12.1. DIFFERENTIAL DIAGNOSES OF SMALL CELL CARCINOMA OF THE UTERINE CERVIX | ||||||||||||||||||||
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Differential Diagnoses of Cervical Poorly Differentiated Neuroendocrine (Small Cell) Carcinoma (Figs. 12.7,12.8,12.9,12.10,12.11 and 12.12)
 Fig. 12.7: A: Conventional cervical smear showing a polymorphic lymphoid cell population consistent with lymphofollicular cervicitis. B: Liquid-based preparation showing a tight aggregate of lymphoid cells that can be mistaken for a small cell carcinoma. |
 Fig. 12.8: Endometrial Cells and Endometrial Adenocarcinoma. A, B: These two different conventional smears contain well-preserved endometrial cells, which morphologically resemble small cell carcinoma cells. C: Liquid-based preparation showing endometrial cells. D: Conventional cervical smear showing cells of well-differentiated endometrial adenocarcinoma.
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