The clinical case data of patients who were pathologically diagnosed with GAS from September 2019 to April 2021 at the second West China University Hospital of Sichuan University were retrieved. A total of 16 patients were eligible for the study.

Pathological diagnostic criteria were based on the WHO classification of tumors, female genital tumors, 5th edition [5]. Essential: abundant pale eosinophilic to clear cytoplasm and distinct cell borders (gastric phenotype) or well-formed glands with a random distribution and minimal atypia (minimal deviation); destructive invasion and moderate to severe nuclear atypia (gastric-type); negative ER/PR. Desirable: negative or patchy p16 and/or negative HPV testing; neutral-type mucin (pinkish-red on Alcian blue/PAS staining); abnormal p53 staining in ~50% [5].

The results of all pathological tests were reviewed and verified by two pathologists.

The clinical manifestations, diagnosis, treatment, and other case data of the 16 patients with GAS were retrospectively analyzed. All patients were followed up by telephone or outpatient visits for 11.23 $\pm$ 5.23 (range, 3–21) months before June 1, 2021. The clinical data of the patients with 16 GAS are presented in Table 1.

The mean age of the 16 patients was 52.94 $\pm$ 10.23 (range, 34–68) years. The main clinical manifestations were irregular vaginal bleeding (8 cases), heavy and transparent vaginal discharge with no peculiar smell (6 cases), physical examination (1 case), and abdominal mass (1 case) caused by ovary metastasis. Postoperative pathology was as follows: 15 cases were of GAS, and 1 case was of MDA.

Before surgeries, cervical exfoliated cells of the 16 patients were examined, and the thin-prep cytology test (TCT) was indicated in 6 abnormal cases (37.5%) and 2 HPV-positive cases (case 4 and case 5). Consistent with previous findings [6, 7], tumor marker levels were abnormal in 9 out of 10 examined cases in the present study, suggesting tumor markers such as CA 125 and CA 19–9 are valuable for GAS diagnosis. Moreover, similar to other pelvic tumors in women [8], GAS may show the first symptom of a giant abdominal mass, as shown by case 3 in this study. According to pathological diagnosis, 9 cases that had been considered as cervical adenocarcinoma by cervical biopsy were confirmed as GAS by postoperative pathology. Two cases were diagnosed as GAS by preoperative cervical biopsy and another one by preoperative fractional curettage. Two adenocarcinoma cases were diagnosed as GAS after surgery, whereas one case that had been considered as the case of an ovarian malignant tumor previously was corrected as GAS (stage IIIC2) after surgery. One case was identified as MDA after a total hysterectomy for adenomyosis.

In terms of treatment, 8 patients underwent a transabdominal extensive hysterectomy, 7 patients underwent a laparoscopic extensive hysterectomy, and one patient with adenomyosis underwent a laparoscopic total hysterectomy and bilateral salpingectomy, followed by a laparoscopic hysterectomy, bilateral oophorectomy, and pelvic lymph node dissection with para-aortic lymph node dissection after the surgery. All patients received concurrent chemoradiotherapy (CCRT) after the operation; 14 patients received it at our hospital, and 2 patients received it at their local medical institutions. The patients were followed-up postoperatively, and all patients survived. However, GAS recurred in 3 patients 3 to 6 months after the treatment. These 3 patients are currently undergoing radiotherapy or chemotherapy.

Based on the International Federation of Gynecology and Obstetrics (FIGO) 2018 Clinical Staging Standard for cervical cancer, 4 cases were of IB (25%), 4 cases of II (25%), and 8 cases of III (50%) stages. The 3 recurrent cases with no medical control were all defined as stage III.

The pathological data of the 16 patients with GAS are presented in Table 2. The pathology of 15 patients with GAS showed that in all highly differentiated cervical mucinous adenocarcinoma (gastric patterns), the cervical stroma and tumor thrombi were found in vessels, indicating significant local infiltration. One patient with MDA showed the tumor, infiltrating the whole layer of the cervical stroma and invading the lower segment of the corpus uteri. Besides, lymph-node metastasis was detected in 8 patients. MDA is the best-differentiated type of gastric adenocarcinoma, which is now uniformly called GAS. In this study, patients with GAS tended to be in an advanced stage at the time of visit with a high incidence of deep cervical interstitial infiltration, lymphatic vessel infiltration, and lymph node metastasis, accounting for 87.5% (14/16), 100% (16/16), and 50% (8/16), respectively. The immunohistochemical detection of histopathological sections from patients with GAS showed that the samples were 100% positive for molecular markers such as cytokeratin (CK)7 (11/11), mucin (muc)-6 (11/11), muc-5 (8/8), Kiel (Ki)67 (14/14), and tumor protein P53 (p53) (3/3). The positive rate of carcinoembryonic antigen (CEA) (7/10) was as high as 70%, whereas those of other common molecular markers were relatively low, as shown in Table 3 and Fig. 1.

Fig. 1.

Histologic characteristics of gastric-type endocervical adenocarcinoma.

The difficulty in diagnosis of GAS is reported by a limited number of published research studies and epidemiological data. Women between the age of 30 and 80 can suffer from GAS. Patients show a range of major clinical symptoms such as heavy mucinous, watery vaginal secretions, or irregular vaginal bleeding [11]. Nevertheless, many patients without any specific clinical symptoms were pathologically diagnosed with GAS [12]. GAS is mostly located in the upper part of the cervix and deep inside the cervical glands, unlike ordinary cervical adenocarcinomas. It is highly invasive and spreads to the peritoneum. It invades the ovaries and the greater omentum. The affected tissues can be thickened and hardened, and the cervix becomes barrel-shaped without the presence of any distinct huge mass. Because the mode of growth is endogenous and not exogenous, GAS presents a smooth cervix in the gynecological examination and cannot be discovered via cytology or cervical scraping [13].

Ordinary cervical adenocarcinoma is usually associated with a high risk of HPV18 infection, whereas GAS is not associated with HPV infection, according to present studies. A previous study reported that HPV does not promote this specific subtype of cervical adenocarcinoma. Because HPV is found in the adjacent cervical upper skin in the sensitive polymerase chain reaction (PCR) test of the cervical whole tissue section, false-positive results can occur. When these patients were diagnosed using laser capture microdissection PCR, the HPV detection of tumor cells was always negative [14]. Therefore, we speculated that the 2 HPV-positive patients in this study can be false positives. GAS is associated with lobar endocervical glandular hyperplasia (LEGH) and Peutz-Jeghers syndrome [15]. Cervical gastric adenocarcinoma in situ and atypical LEGH share common molecular genetic alterations, such as deficiency of 1p and acquisition of 3q, and both of them are precancerous lesions of GAS.

GAS is usually discovered accidentally [16]. The low diagnostic rate by routine cytological screening can be due to the difficulty in obtaining material, the nuance of cytology in gastric mucinous adenocarcinoma, and the lack of knowledge about the disease. In the present study, only 6 patients (37.5%) presented abnormalities in TCT, and 3 patients were diagnosed with GAS (18.8%) by preoperative pathological examination, which was significantly lower than that of other types of cervical cancers. Therefore, a deep biopsy of cervical tissues and colposcopic cervical curettage should be performed when GAS is highly suspected clinically. Many of the 12 patients (75%) in stage II or later stages were diagnosed with advanced cancer during their follow-ups. A patient who was admitted to the hospital with a pelvic mass was suspected of having an ovarian malignant tumor. The patient had abnormalities during routine cervical screening and was diagnosed with gastric mucinous adenocarcinoma through cervical biopsy and by examining the frozen section of the ovarian tumor during surgery. Another patient who underwent hysterectomy for adenomyosis had repeated negative results of cervical cytology screening and fractional curettage before surgery; however, the diagnosis was MDA based on the postoperative pathology. Well-differentiated GAS appears to be normal during colposcopy, cervical cytology, and even during the routine histopathological examination. To confirm the diagnosis of GAS, deeper tissues should be collected, or cervical conization should be performed. Because of occult lesions and inaccurate materials, the biopsy diagnosis can be diversified, which includes chronic cervicitis, cervical polyps, atypical hyperplasia of cervical glandular epithelium, and endometrioid adenocarcinoma. These are also the reasons for missed diagnosis. Therefore, for patients with cervical hypertrophy along with vaginal fluid, contact bleeding, or irregular vaginal bleeding, when biopsy results do not match the clinical results, multiple deep biopsies, cervical curettage, hysteroscopy, and even cervical conization should be performed to avoid the missed diagnosis of early GAS.

In histopathological morphology, GAS seems to be “kind”, but it is indeed aggressive. The biggest paradox and challenge of the diagnosis and treatment of dedifferentiated endometrioid adenocarcinoma (DEAC) lies in its biological behaviors. Routine screening and examination for cervical cancer may not fulfill the present requirements of diagnosis. Therefore, pathologists and clinicians should have more understanding and vigilance toward GAS to increase the accuracy of diagnosis and reduce the risk of missed diagnosis or misdiagnosis. Kojima et al. [1] proposed the following three morphological criteria: (1) abundant mucinous cytoplasm, (2) transparent or lightly eosinophilic cytoplasm, and (3) a clear cell boundary. In 2019, these criteria were extended by Pirog et al. [17] with a pathomorphological description that the glands of DEAC can be composed of small cubic or flat cells, papillary glands, goblet cells in glands, and thick eosinophilic cells characterized by distinct cytoplasmic vacuoles, namely foam-like cytoplasm. Gastric differentiated glands are usually simple in structure, single tubular, and widely distributed in the cervical stroma. Most of its glands differ in size, and most of its glandular cavities are dilated or angular. The cell boundary of the gland is clear; the cytoplasm is rich, transparent, or lightly eosinophilic. The nucleus is light to moderate atypia, and small nucleoli can appear, with few pathological mitotic images or necrosis. The degree of fibrogenic reaction in the surrounding cervical stroma differs. The above characteristics are also the pathological reasons for the complexity in differentiating normal cervical glands from neoplastic gastric glands during cervical biopsy and the higher risk of missed diagnosis. When the cervical gland is more than, or equal to 7 mm below the surface of the cervix and slightly abnormal glands are close to the thick-wall blood vessels, the pathologists should be alerted to the possibility of GAS, and a timely discussion with the gynecologists is necessary. The pathologists and gynecologists can completely avoid misdiagnosis or missed diagnosis with further knowledge of the clinical manifestations, signs, and auxiliary examinations of the patient by appropriately combining the application of immunohistochemical markers.

GAS shows highly malignant biological behavior, strong invasiveness, and rapid metastasis. Most patients with GAS are found to have metastasis to fallopian tubes, ovaries, or the greater omentum when diagnosed, which makes the treatment more difficult and leads to a poor prognosis. Furthermore, metastasis lesions could be infiltrated with a considerate quantity of neutrophils. In some patients, endometrial involvement and nerve infiltration can occur, and the tumor glands that spread to fallopian tubes and endometrium resemble the benign mucous-metaplasia glands. Advanced techniques and diagnostic markers, such as immunohistochemical markers, should be fully used for the pathological examination, thereby aiming to improve the diagnosis and differential diagnosis of GAS. CK7, CK20, CEA, MUC6, p16, ER, and p53 are common immunohistochemical markers in the diagnosis of gastric adenocarcinoma [18, 19, 20]. Patients with GAS are usually positive for HIK1083, CK7, CEA, and MUC6. Among them, HIK1083 is a relatively specific marker for gastric adenocarcinoma; however, its sensitivity is only about 75% [21]. Even though the positive rate of MUC6 is as high as 45.8% to 81.0%, its specificity was reported to be quite low, which can be due to its expression in normal glands (8%) [22, 23, 24]. The positive rate of p53 mutant expression ranged between 41.0% and 51.9%. Besides, ER and PR are negative in general. It was reported that 61.7% of 47 patients with gastric adenocarcinoma were p16 negative, with 29.7% showing focal expression and 4.3% showing cytoplasmic expression [25]. Similarly, p16 has a high negative rate (86.7%, 13/15) and a low positive rate in the present study. Even though GAS is irrelevant in HPV infection, its pathogenesis and molecular genetic characteristics should be studied further.

Most of the guidelines for the treatment of cervical cancers are based on the treatments for cervical squamous cell carcinoma and common cervical adenocarcinoma. HPV-I cervical adenocarcinoma has different biological behavior and clinical outcomes. Because of low morbidity and insufficient studies with large sample data, GAS lacks specialized standards for its screening, diagnosis, and treatment. Therefore, the treatment regimen for GAS is that of squamous cell carcinoma at the same stage, which is still controversial. Because GAS can spread to the abdominal cavity along the peritoneum, patients with early-stage GAS should receive surgeries similar to the comprehensive staging surgery for early ovarian carcinomas, such as extensive hysterectomy, bilateral salpingo-oophorectomy, pelvic lymph node dissection, omentectomy, and appendix resection, supplemented by platinum-based CCRT or radiotherapy. In the present study, 14 patients underwent an extensive hysterectomy. One patient was diagnosed with endometrial gastric adenocarcinoma and received laparoscopic panhysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection. Another patient was diagnosed with MDA after a total hysterectomy and, thus, underwent bilateral oophorectomy and pelvic and abdominal para-aortic lymph nodes dissection. The 2 patients were supplemented with CCRT after the surgery. The follow-up of the patient with MDA who underwent a series of medical interventions, such as total hysterectomy, bilateral salpingo-oophorectomy, lymph node dissection, and postoperative CCRT rather than extensive hysterectomy, showed an ideal prognosis [26]. A total of 18 patients with MDA were once classified into the early stage (FIGO IB1/IB2, 88.8%) and advanced stage (FIGO III/IV, 11.1%), which indicated that despite the difficulty in diagnosing timely and precisely, the majority of the patients can be detected in their early stages [27]. This was also verified in our study. Although preoperatively, only 3 of 16 patients were confirmed as GAS by biopsy. A total of 14 patients were correctly diagnosed with cervical adenocarcinoma by pathological examination, which supported the possibility of early discovery through preoperative biopsy or sectional curettage. Li et al. [28] summarized and reported that the mean survival time for patients in stages I, II, III, and IV were 5 years, 38.1 months, 22.8 months, and 5.4 months, respectively. For early-staged patients who underwent an extensive hysterectomy, the multidisciplinary treatment strategies of cis-platinum-based CCRT and molecular-targeted therapy should be determined for improving the local progress and prognosis of gastric adenocarcinoma. Compared with patients in the early stages, the patients in the middle and advanced stages showed an inferior prognosis. Patients with one stage-IB followed up in our study had no recurrence (18 months after therapies), whereas the patients with 3 stage-IIIC suffered from recurrence within 3 to 6 months after treatment, so they underwent radiotherapy and chemotherapy, and their conditions had been constantly followed up.