Liquid-based Cytological Features of Adenocarcinoma Not Otherwise Specified, Extrauterine Adenocarcinoma, and Other Malignant Neoplasms of The Uterine Cervix: A 5-year Single-institutional Experience With 30 Consecutive Patients

Abstract

Background/Aim

The adenocarcinoma (ADC) and other malignant neoplasm (OMN) terminologies of The Bethesda System represent various histological types of uterine and extrauterine malignancies. This study aimed to clarify the incidences of ADC not otherwise specified (ADC-NOS), ADC extrauterine (ADC-EXT), and OMN in our institution and describe their characteristic cytomorphological features.

Patients and Methods

We searched the database to identify all patients diagnosed with carcinoma, including those diagnosed through cervical liquid-based cytology (LBC), between January 2019 and December 2023. The electronic medical records and all available slides were reviewed.

Results

Overall, 30 of the 149,197 (0.02%) patients were diagnosed with ADC-NOS, ADC-EXT, and OMN. All three groups included various histological types of both gynecological and non-gynecological origin. More than two-thirds (23/30; 76.7%) were of uterine origin, but seven patients had metastatic carcinoma of extrauterine organ origin, including the ovary, lung, stomach, breast, colon, urethra, and pancreas. In all patients, the cytological features were concordant with the histological features.

Conclusion

In LBC, ADC-NOS does not only encompass uterine cervical tumors, but also various types of extrauterine malignancies. ADC-EXT and OMN also represent both extrauterine and uterine tumors. Awareness of the morphological features observed in LBC samples of non-gynecological malignancies may be helpful in obtaining the correct diagnosis.

Cervical cytology is the most well-established and successful screening test for cervical carcinoma (1). The introduction of conventional Papanicolaou smear into clinical practice in the 1940s has markedly reduced the incidence and mortality of cervical carcinoma (1). Cytological screening has resulted in not only an increased detection rate of early-stage cervical carcinoma, but also the detection and subsequent treatment of premalignant intraepithelial lesions. For instance, in the Korean cervical carcinoma screening program conducted between 1999 and 2017, the number of newly diagnosed cervical carcinoma cases and disease-related deaths significantly decreased (2,3). However, despite their significant success, conventional smears are not perfect. According to the 2020 Global Cancer Observatory estimates, cervical carcinoma remains as the fourth most common malignancy in women, both with respect to incidence (6.5%) and mortality (7.7%) (4).

Although the conventional smear is considered a primary screening test for cervical squamous lesions (2), it has suboptimal diagnostic accuracy for endocervical glandular lesions. Correspondingly, the incidence of endocervical adenocarcinoma (ADC) has not decreased to the same extent as that of cervical squamous cell carcinoma (SCC) in many countries (5). Compared to SCC, ADC of the endocervix often exhibits a more aggressive clinical behavior, worse prognosis, higher rates of recurrence and metastasis, and worse response to conventional treatment (6-9). As such, early detection of ADC or its precursor lesions would directly affect patient outcomes. Liquid-based cytology (LBC) has largely replaced the conventional smear owing to its better diagnostic performance for detecting intraepithelial lesions (1). However, the detection of endocervical glandular lesions is still challenging owing to the rarity of glandular lesions, difficulty in obtaining a sufficient quantity of cytological samples from the endocervix, pathologists’ lack of experience with their cytomorphological criteria, and interobserver variability (10,11).

Clinical management and surgical interventions depend heavily on the pathological information provided by cervical cytology and biopsy, along with clinical information obtained from physical examination and imaging studies. Although it is crucial to differentiate benign, premalignant, and malignant glandular lesions, the overlapping cytological features of different glandular lesions hinder the accurate subtyping of neoplasms. Furthermore, there is limited evidence on the use of cervical cytology to determine the locations of abnormal cells. Nevertheless, if accurate, cytology can potentially reduce the need for further invasive investigations. Cytology sampling is less invasive, more acceptable to patients, and offers a quicker turnaround of results than histological examinations.

Previous studies have consistently demonstrated that cervical cytology is associated with a significant error rate for squamous intraepithelial lesions and SCC. Despite the wealth of available information on the misinterpretation of squamous lesions, there is relatively little comparable information on the cytomorphological features of glandular lesions and ADC. Furthermore, the available data on ADC not otherwise specified (ADC-NOS), which includes all types of ADC regardless of subtype, are insufficient. Further, there are no analogous studies on the categories of ADC extrauterine (ADC-EXT) and other malignant neoplasms (OMNs). As such, this study aimed to compare the cytological features of ADC-NOS, ADC-EXT, and OMN in LBC. In addition, we retrospectively investigated the clinical and histological features of the patients to perform a cytohistological correlation and describe the characteristic cytomorphological features of these uncommon uterine and extrauterine tumors.

Patients and Methods

Study design and patient collection. This retrospective study was approved by the Institutional Review Board of Samsung Medical Center (protocol number: 2024-05-088; date of approval: May 22, 2024). The need to obtain signed informed consent from the patients or their guardians was waived by the Institutional Review Board owing to the retrospective nature of the study. We searched the database of the Department of Pathology and Translational Genomics at Samsung Medical Center between January 2019 and December 2023 to identify all reported cervical cytology patients diagnosed with carcinoma. Figure 1 shows a flowchart of the patient selection process. Among the 149,197 patients identified over the 5-year study period, 106 (0.07%) patients were diagnosed with carcinoma. Overall, 38, 14, 13, and 11 patients with cervical SCC, endocervical ADC, endocervical adenocarcinoma in situ (AIS), and endometrial ADC, respectively, were excluded. Finally, 17, six, and seven patients with ADC-NOS, ADC-EXT, and OMN, respectively, were included in the study. Patient information, including age, location and histological type of the lesions, and survival status, was obtained from electronic medical records and pathology reports.

Figure 1.

Flowchart of the patient selection process. During the 5-year study period, 106 of the 149,197 patients (0.07%) were diagnosed with carcinoma. Cervical squamous cell carcinoma (SCC; 38 patients), endometrial adenocarcinoma (ADC; 11 patients), endocervical ADC (14 patients), and endocervical adenocarcinoma in situ (AIS; 13 patients) are excluded. The 30 patients (0.02%) were divided into three groups by diagnosis as the ADC not otherwise specified (ADC-NOS; 17/30, 56.7%), ADC extrauterine (ADC-EXT; 6/30, 20.0%), and other malignant neoplasm (OMN; 7/30, 23.3%) groups. A cytohistological correlation revealed that each diagnosis type was further classified into gynecological and non-gynecological tumors. CCC: Clear cell carcinoma; EC: endometrioid carcinoma; EMPD: extramammary Paget disease; HGSC: high-grade serous carcinoma; HSIL: high-grade squamous intraepithelial lesion; PDAC: pancreatic ductal adenocarcinoma; SCNEC: small cell neuroendocrine carcinoma.

Slide review. Board-certified gynecological pathologists reviewed all available cytology slides using The Bethesda System (12). They also reviewed hematoxylin and eosin-stained slides obtained from the following tissue samples: cervical biopsies, endocervical curettages, endometrial curettages, cervical conizations, hysterectomies, and debulking surgeries. In case of discordance, cytohistological correlations were performed to evaluate the causes of the discrepancies.

Results

Baseline characteristics. The age at diagnosis ranged from 37 years to 83 years (mean=60.7 years). Table I summarizes the characteristics of the 30 patients cytologically diagnosed with ADC-NOS, ADC-EXT, or OMN. Subsequent histological diagnoses were made in 19 patients (63.3%). Diagnostic procedures included punch biopsy (n=8 patients, 26.7%), conization (n=2 patients, 6.7%), endometrial curettage (n=3 patients, 10.0%), endometrial polypectomy (n=1 patient, 3.3%), and vulvar excision (n=1 patient, 3.3%). Treatment information was available for 26 patients. Five, four, and one patient with cervical carcinoma underwent concurrent chemoradiation therapy (CCRT), surgery, and radiation therapy, respectively. One patient with cervical small cell neuroendocrine carcinoma (SCNEC) underwent CCRT followed by surgery. Three patients with endometrial endometrioid carcinoma (EEC) underwent surgery. Four patients with high-grade serous ovarian carcinoma (HGSC) received platinum-based chemotherapy. Five of the seven patients with metastatic carcinoma received chemotherapy, while the remaining two patients underwent surgery and postoperative chemotherapy. Eight patients, including one patient with cervical human papilloma virus-associated (HPVA)-SCC, one patient with endometrial EC, four patients with ovarian HGSC, and two patients with metastatic carcinoma, died of the disease.

Table I. Characteristics of the 30 patients.

ADC: Adenocarcinoma; AIS: adenocarcinoma in situ; ASC: adenosquamous carcinoma; CCC: clear cell carcinoma; EC: endometrioid carcinoma; EMPD: extramammary Paget disease; HGSC: high-grade serous carcinoma; HPVA: human papillomavirus-associated; HPVI: human papillomavirus-independent; HSIL: high-grade squamous intraepithelial lesion; IDC: invasive ductal carcinoma; ILC: invasive lobular carcinoma; PCC: poorly cohesive carcinoma; PDAC: pancreatic ductal adenocarcinoma; SCNEC: small cell neuroendocrine carcinoma.

Cytological features of cervical tumors. Human papilloma virus infection (HPVI) gastric-type endocervical ADC revealed crowded clusters of glandular epithelial cells characterized by densely packed hyperchromatic nuclei (Figure 2A). These cellular clusters were organized into honeycomb-like sheets exhibiting foamy or vacuolated cytoplasm, well-defined cytoplasmic borders, and moderate nuclear atypia (Figure 2B). Tumor cell nuclei were significantly larger than those found in non-neoplastic intermediate squamous cells (Figure 2C). They often displayed coarse chromatin and prominent nucleoli. Histologically, gastric-type ADC showed intraluminal papillary growth, hyperchromatic nuclei, and abundant intracytoplasmic mucin (Figure 2D). The pleomorphic, round to oval nuclei of the tumor cells were consistent with the cytological features observed in LBC (Figure 2E). The HPVI mesonephric-type endocervical ADC displayed varying sizes of three-dimensional cellular clusters or sheets of hyperchromatic tumor cells (Figure 2F). These irregularly shaped, densely packed tumor cell clusters and sheets occasionally showed small glandular lumina, which sometimes had a slit-like appearance (Figure 2G-H). The tumor cells possessed hyperchromatic nuclei with small, indistinct nucleoli and occasional intranuclear cytoplasmic pseudo-inclusions (Figure 2I-J). Histologically, mesonephric-type ADC were characterized by various architectural patterns, including compactly aggregated small tubules containing hyaline-like eosinophilic intraluminal secretions (Figure 2K), endometrioid-like glands, solid sheets, and cystically dilated ducts. In one patient with cervical SCNEC, the tumor cells formed large cellular aggregates or were dispersed as single cells. They exhibited stippled chromatin, inconspicuous nucleoli, scant cytoplasm, and a high nuclear-to-cytoplasmic ratio. Positive immunoreactivity for chromogranin and synaptophysin in the biopsy samples confirmed the diagnosis of SCNEC.

Figure 2.

Cytological and histological features of cervical tumors, including cervical human papillomavirus-independent (A-E) gastric-type adenocarcinoma (ADC) and (F-K) mesonephric-type ADC. (A) Cytologically, gastric-type ADC exhibit small, papillary clusters of neoplastic glandular cells possessing tight, hyperchromatic nuclei. (B) Honeycomb-like cellular sheets showing vacuolated cytoplasm, distinct cell borders, and nuclear atypia. (C) The atypical nuclei are much larger than those of normal intermediate squamous cells (green arrows). They possess coarse chromatin and conspicuous nucleoli. (D) Histologically, gastric-type ADC exhibit intraluminal papillary growth, hyperchromatic nuclei, and abundant intracytoplasmic mucin. (E) The presence of enlarged pleomorphic nuclei is concordant with the cytological features observed in image C. (F) Cytologically, mesonephric-type ADC exhibit variable-sized, tight clusters and sheets of hyperchromatic tumor cells. (G) The crowded sheets of tumor cells possess small glandular lumina (yellow arrows). (H) A small, irregular-shaped cellular cluster with slit-like glandular lumen (yellow arrow). (I) The tumor cells display nuclear hyperchromasia and small, inconspicuous nucleoli. (J) The intranuclear cytoplasmic pseudoinclusions (blue arrow) are occasionally identified. (K) Histologically, mesonephric-type ADC exhibit inter-anastomosing cellular sheets and nests and compactly aggregated tubules and glands, of which small glandular lumina contained densely eosinophilic intraluminal secretions. Original magnification, A: 200×; B: 600×; C: 600×; D: 100×; E: 200×; F: 20×; G: 100×; H: 400×; I: 400×; J: 800×; K: 100×.

Cytological features of endometrial tumors. Grade 3 EECs were cytologically characterized by cellular clusters of varying sizes, singly scattered isolated cells, and occasional tumor diathesis. The nuclear size of tumor cells was more than three-fold larger than that of inflammatory cells (Figure 3A-B). The tumor cells possessed large round nuclei with mild-to-moderate pleomorphism and prominent nucleoli. Mitotic figures, including atypical figures, were occasionally identified (Figure 3C-D). Low-power magnification of the endometrial curettage specimen revealed solid tumor cell growth associated with extensive necrosis (Figure 3E). High-power magnification revealed pleomorphic nuclei with large nucleoli and increased mitotic activity, similar to cytological features (Figure 3F). LBC of grade 1 EEC showed irregularly shaped, variably sized clusters of glandular epithelial cells. Some exhibited peripheral nuclear palisading and cytoplasmic feathering, resembling endocervical AIS (Figure 3G-H). The tumor cells possessed hyperchromatic nuclei, similar to or slightly larger than those of normal intermediate squamous cells (Figure 3I-J). Histologically, grade 1 EEC exhibited a back-to-back arrangement of neoplastic glands, with little or no intervening stroma. The hyperchromatic, elongated nuclei of the stratified columnar cells were consistent with the cytological features mentioned above (Figure 3K-L).

Figure 3.

Cytological and histological features of (A-F) high-grade and (G-L) low-grade endometrial endometrioid carcinomas (EECs). (A) Cytologically, high-grade EEC exhibit some variable-sized cellular clusters, singly dispersed tumor cells, and tumor diathesis. (B) The tumor cell nuclei are quite larger than those of lymphocytes and neutrophils. (C) Irregular-shaped cellular clusters display nuclear enlargement and pleomorphism, as well as a few mitotic figures (green arrow). Note an atypical mitotic figure (yellow arrow). (D) The pleomorphic nuclei showed single or multiple conspicuous nucleoli. (E) Histologically, high-grade EEC showing large solid sheets of tumor cells and areas of tumor cell necrosis (blue arrows). (F) The presence of nuclear pleomorphism, conspicuous nucleoli, and mitotic figures is concordant with the cytological features observed in images C and D. (G) Cytologically, low-grade EEC exhibit scattered clusters and sheets of glandular cells. (H) These three-dimensional clusters display foci of peripheral nuclear palisading with cytoplasmic tags protruding from the periphery (purple arrows), closely resembling endocervical adenocarcinoma in situ. (I and J) Note the nuclear feathering-like foci (purple arrows). The hyperchromatic nuclei of the tumor cells are nearly the same as or slightly larger than those of normal intermediate squamous cells (white arrows). (K) Histologically, low-grade EEC exhibit confluent glandular proliferation with back-to-back arrangement. (L) The amount of intervening stroma is little or almost absent. The neoplastic glands are lined with stratified columnar cells possessing enlarged nuclei, which are concordant with the cytological features observed in images I and J. Original magnification, A: 60×; B: 100×; C: 600×; D: 800×; E: 20×; F: 200×; G: 20×; H: 40×; I: 200×; J: 200×; K: 40×; L: 150×.

Cytological features of extrauterine gynecological tumors. Cytological examination of ovarian HGSC revealed variable-sized papillary clusters of hyperchromatic tumor cells (Figure 4A). The tightly packed papillary clusters of the tumor cells exhibited nuclear overlap and slit-like spaces (Figure 4B). Tumor diathesis (Figure 4C) and mitotic figures (Figure 4D) were readily identifiable. Histological examination revealed high-grade tumors with papillary and micropapillary architectures, slit-like glandular lumens, and frequent intraluminal necrotic debris, which aligned with the cytological features (Figure 4E-F). The cytological features of vulvar extramammary Paget disease (EMPD) included the formation of two to three small clusters or nests, in which the polygonal tumor cells showed enlarged, hyperchromatic nuclei, and distinct cherry-red macronucleoli. These nuclei were three- to four-fold larger than those of normal squamous epithelium (Figure 5A-B). In some foci, the tumor cells were arranged in larger, irregularly shaped clusters, exhibiting severe nuclear pleomorphism (Figure 5C-D). A wide vulvar excision specimen showed singly dispersed or nested large tumor cells with abundant pale vacuolated cytoplasm. These were located immediately above the basal layer of the epidermis (Figure 5E).

Figure 4.

Cytological and histological features of ovarian high-grade serous carcinoma. (A) Cytologically, three-dimensional papillary clusters of hyperchromatic tumor cells are admixed with tumor diathesis. (B) Large cohesive groups of atypical glandular cells showing nuclear crowding, small glandular lumina and slit-like spaces (blue arrows), and true papillary configuration. (C) Note the tumor diathesis (green arrow). (D) Note the mitotic figure (yellow arrow). (E) Histologically, the tumor exhibits papillary and micropapillary architecture with slit-like glandular spaces, concordant with the cytological features observed in image B. (F) The presence of intraluminal tumor cell necrosis is concordant with the cytological features observed in image C. Original magnification, A: 20×; B: 400×; C: 400×; D: 600×; E: 20×; F: 100×.

Figure 5.

Cytological and histological features of vulvar extramammary Paget disease (EMPD). (A) Cytologically, the tumor cells are arranged into clusters and nests (yellow arrows). They possessed large, polygonal, hyperchromatic nuclei, of which the size is markedly larger than that of normal squamous epithelium (green arrow). Some tumor cells with crescent-shaped nuclei that resembled those of signet-ring cell carcinoma. (B) The cytoplasm is abundant, with an irregular border (yellow arrow). The tumor cells display prominent macronucleoli. (C) An irregular-shaped, three-dimensional cellular aggregate consisting of loosely clustered tumor cells with hyperchromatic nuclei. (D) Note severe nuclear pleomorphism and anisonucleosis. (E) Histologically, large EMPD cells contain abundant pale cytoplasm and are located immediately above the basal layer of the epidermis. They were singly dispersed within the epidermis or arranged in clusters and nests near the basement membrane. Original magnification, A: 600×; B: 800×; C: 400×; D: 600×; E: 200×.

Cytological features of metastatic tumors. Cytologically, metastatic invasive lobular carcinoma (ILC) of the breast showed small clusters or sheets of monotonous small-to-medium-sized tumor cells with mild- to intermediate-grade nuclear atypia (Figure 6A-B). The biopsy sample revealed relatively uniform, round tumor cells arranged in single files, cords, and nests (Figure 6C). In metastatic colonic carcinoma patients, variable-sized tumor cell clusters contained small glandular lumina. High-grade nuclear atypia was observed in the necrotic background (Figure 6D-E). High-power magnification of the resected specimen showed well-differentiated glandular structures with basally located elongated nuclei and brisk mitotic activity (Figure 6F). Cytological examination of the metastatic pancreatic ductal adenocarcinoma (PDAC) revealed a hypercellular smear showing loosely cohesive tumor cells with marked nuclear enlargement, hyperchromasia, and severe anisonucleosis. Some demonstrated orangeophilic and squamoid morphologies (Figure 6G-H). The biopsy sample of the metastatic PDAC showed poorly formed, fragmented glands, consistent with the cytological findings (Figure 6I). Metastatic urethral ADC consisted predominantly of pseudostratified columnar epithelium with a mucin-containing cytoplasm and basally located hyperchromatic nuclei. The tumor diathesis was easily identifiable. The cytological features of metastatic urethral ADC were similar to those of endocervical or colonic ADC, but the lack of immunoreactivity for p16 and caudal-type homeobox 2 in the biopsy sample ruled out the possibility of endocervical or colorectal origin.

Figure 6.

Cytological and histological features of non-gynecological metastatic tumors, including (A-C) metastatic invasive lobular carcinoma (ILC) of the breast, (D-F), metastatic colonic adenocarcinoma, and (G-I) metastatic pancreatic ductal adenocarcinoma (PDAC). (A and B) Small-to-medium-sized tumor cells exhibit low-to-intermediate-grade nuclear atypia. The tumor cell nuclei occasionally exhibit intranuclear grooves and small nucleoli. (C) Metastatic ILC cells are arranged in single files, cords, and nests. (D) Metastatic colonic adenocarcinoma showing variable-sized cellular clusters with small glandular lumina. (E) Small fragments of atypical glandular epithelium are admixed with large amounts of tumor diathesis. (F) Well-formed glands and tubules showing basally oriented, elongated nuclei with hyperchromasia and frequent mitoses. (G) In the fine-needle aspiration cytology sample of metastatic PDAC, hypercellular smear showing large discohesive tumor cells, some of which have orangeophilic cytoplasm, resembling superficial squamous epithelium of the normal uterine cervix. (H) Note nuclear enlargement, hyperchromasia, and severe anisonucleosis. (I) The histological features of metastatic PDAC are concordant with the cytological features observed in image G. Most of the metastatic PDAC cells are singly dispersed, and some of them display poorly formed small glands with intracytoplasmic mucin. Original magnification, A: 400×; B: 400×; C: 100×; D: 100×; E: 200×; F: 200×; G: 100×; H: 400×; I: 100×.

Discussion

In this study, although 10 patients had HPVA tumors of uterine cervical origin, including SCC (2/10), HSIL (1/10), ASC (2/10), ADC (3/10), AIS (1/10), and SCNEC (1/10), the remaining 20 patients had cervical HPVI ADC (3/20), endometrial EC (3/20), CCC (1/20), ovarian HGSC (5/20), vulvar EMPD (1/20), and metastatic carcinoma of the extragenital origin (7/20). Table II summarizes the cytological features of uncommon uterine and extrauterine tumors in which LBC cytology can be interpreted as ADC-NOS, ADC-EXT, or OMN. A brief description of the cytological features is provided below.

Table II. Cytological features of uncommon uterine and extrauterine tumors.

ADC: Adenocarcinoma; EEC: endometrial endometrioid carcinoma; EMPD: extramammary Paget disease; HGSC: high-grade serous carcinoma; HPVI: human papillomavirus-independent; ILC: invasive lobular carcinoma; N/C: nuclear-to-cytoplasmic.

Cervical HPVI gastric-type ADC. Neoplastic glandular epithelial cells resemble benign endocervical cells and are arranged in clusters, strips, or isolated cells. The characteristic features include pseudostratified epithelial strips, loss of polarity within the clusters, disorganized (“drunken”) honeycomb-like cellular sheets, and a variable degree of atypical nuclear changes. Cuboidal-to-columnar epithelial cells possess distinct cell borders and an abundant lacy, golden-yellow vacuolated cytoplasm containing gastric-type neutral mucin (13,14). Marked nuclear enlargement, pleomorphism, and conspicuous nucleoli have been observed in only a small proportion of patients (12).

Cervical HPVI mesonephric-type ADC. Tumor cells typically form small tubules, tight clusters, and sheets with a relatively clean background. Singly dispersed tumor cells are occasionally observed. They possess small- to medium-sized, round- to-oval nuclei with an increased nuclear-to-cytoplasmic (N/C) ratio (15,16). The hyperchromatic nuclei exhibit relatively smooth nuclear contours (17,18).

EEC. Cytology specimens obtained from endometrial carcinoma generally show fewer abnormal cells than those obtained from endocervical tumors because the lesional cells need to be exfoliated from the endometrium. Tumor cells usually occur singly or in small compact clusters. For low-grade EECs, the nuclei are slightly larger than those of nonneoplastic endometrial cells and are larger in size with higher histological grades. Variations in nuclear size and the loss of nuclear polarity are noted. In high-grade tumors, nuclei exhibit moderate hyperchromasia, irregular chromatin distribution, and chromatin clearing. The nucleoli are generally less prominent but become larger with higher grades. The cytoplasm is scant, basophilic, and frequently vacuolated. Isolated cells or small clusters may contain intracytoplasmic neutrophils, often described as a “bag of polys.” A finely granular or “watery” tumor diathesis is variably present (12).

Ovarian HGSC. Although tumor cells are usually observed within a clean background, tissue destruction can produce tumor diathesis when there is direct tumor extension to the cervix (12). Tumor cells often form three-dimensional clusters and papillary or micropapillary tufts. Tumor cells frequently contain enlarged, highly pleomorphic nuclei with a high N/C ratio, coarse chromatin, conspicuous nucleoli, and vacuolated cytoplasm. Psammomatous calcifications are also frequently observed (18,19).

Vulvar EMPD. Tumor cells are grouped into clusters or dispersed individually. They are typically large, with abundant pale cytoplasm and a high N/C ratio. The round-to-oval nuclei are located either centrally or eccentrically. Nuclear chromatin is finely granular or reticular with prominent nucleoli (20,21).

ILC. The diagnosis of metastatic breast carcinoma based on cervical cytology can be challenging, especially in patients with an atrophic background. The specimens typically exhibited a clean background without a definite tumor diathesis. Tumor cells are arranged in single files, nests, or dispersed as individual cells. They are slightly larger than the benign endocervical cells and have a high N/C ratio. Some show intracytoplasmic mucin vacuoles that push their nuclei to the periphery of the cells (22,23). Immunostaining for gross cystic disease fluid protein 15, estrogen receptor, and GATA-binding protein 3 helps pathologists confirm the diagnosis of metastatic carcinoma of mammary origin in cervical cytology specimens (12).

Colonic ADC. Tumor cells are typically present in groups that occasionally form glandular structures. Individual tumor cells are tall and columnar. They usually exhibit nuclear pleomorphism, hyperchromasia, nuclear overlap, and loss of nuclear polarity. The distinctive cytological features of colonic ADC include a columnar cell shape, palisading cigar-shaped nuclei, and scattered goblet cells containing distended mucin vacuoles. Additionally, “dirty necrosis” is characteristic of colonic ADC (24-26). Immunostaining for cytokeratin 20 and caudal-type homeobox 2 helps pathologists identify metastatic tumor cells of colorectal origin because these cells typically exhibit strong positive staining for both markers (12).

There are several possible explanations why common cervical HPVA tumors, such as SCC, HSIL, ASC, ADC, and AIS, are interpreted as ADC-NOS, ADC-EXT, or OMN in the cytology specimens. First, these tumors have overlapping cytomorphological features, making it challenging to accurately determine the type of lesion. Second, when the number of sampled tumor cells is low, the characteristic morphological features of common HPVA tumors may not be observed. This suboptimal performance often leads to broader categorizations, such as ADC-NOS and OMN, rather than a more specific diagnosis. Third, cervical metastases from extragenital malignancies are unusual. Uterine or cervical metastasis of extragenital malignancies generally manifests as the systemic involvement of advanced-stage tumors. Owing to pathologists lacking experience regarding the cytomorphological criteria specific to these cervical lesions, they may be more likely to interpret them as ADC-NOS or OMN rather than ADC-EXT, as they will have difficulty in making a definitive classification.

Study limitations. First, we enrolled patients who were diagnosed and treated at a single institution, limiting the reproducibility of the results. Patient demographics, clinical manifestations, and management strategies may vary among institutions and regions. Second, the selection of patients from an East Asian population, specifically from South Korea, could have introduced biases related to ethnicity and variations in the characteristics of practicing pathologists. Finally, the retrospective nature of this study may have introduced intrinsic biases related to data collection and patient selection. Future investigations with larger multi-institutional cohorts of patients diagnosed with ADC-NOS, ADC-EXT, or OMN are warranted to validate our findings and encompass the full spectrum of pathological features of uncommon cytological diagnoses.

Conclusion

We demonstrated the incidence of ADC-NOS, ADC-EXT, and OMN at our institution. During the 5-year study period, 106 (0.07%) of the 149,197 patients were diagnosed with carcinoma, and 30 (0.02%) patients were diagnosed with either ADC-NOS (17 patients), ADC-EXT (six patients), or OMN (seven patients). In LBC, ADC-NOS, ADC-EXT, and OMN did not only encompass uterine cervical tumors, but also represented various types of extrauterine malignancies. We comprehensively described the cytological features of these tumors, which were concordant with their histological features. Awareness of the LBC features of uterine tumors, as well as those of non-gynecological malignancies, may be helpful in making the correct diagnosis.

Conflicts of Interest

None of the Authors have any conflicts of interest or financial ties to declare regarding this study.

Authors’ Contributions

All Authors made substantial contributions to the conception of this study, analysis and interpretation of the data, drafting and critical revision of the manuscript, and approval of the final version for publication.

Acknowledgements

This work was supported by the Samsung Medical Center Grant (SMO1240641) and a National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIT) (2023R1A2C2006223).