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Dr Olearo (Gynecologic Oncology): Case Presentation
A patient in her 70s was referred to our center from her primary gynecologist with a diagnosis of advanced high grade endometriod adenocarcinoma of the endometrium. The patient was asymptomatic and disease was found during routine follow-up assessment, when transvaginal ultrasound revealed a bulky uterus with an enlarged uterine cavity, as evidenced by a 37×36 mm highly vascularized lesion, suspected myometrial invasion >50%, cervix enlarged, and a right adnexal solid mass measuring 71×46×35 mm. The primary gynecologist performed an endometrial biopsy. The pathology showed high grade endometrioid adenocarcinoma.
The patient had previous surgery for lobular breast carcinoma, followed by radiotherapy and maintenance therapy with anastrozole for 5 years. There was no family history of uterine or ovarian cancer but her daughter had been diagnosed with ductal carcinoma in situ of the breast. A CT scan showed an enlarged uterine cavity with solid components, right solid mass with small amount of free fluid in the cul-de-sac, and small, round shaped nodes in the perirectal fat. The upper abdomen was negative for any evidence of disease.
She was scheduled by her primary gynecologist for laparoscopic hysterectomy and salpingo-oophorectomy, eventually including nodal staging. However, at the time of intraoperative assessment there was evidence of abdominal carcinomatosis, both the right and left ovaries were enlarged and occupied by solid masses, and omental cake was found: these findings were not clearly described in the CT scan. The surgical plan changed and she underwent right adnexectomy, and biopsies of the omentum and peritoneum. Given the personal oncological history and the finding at laparoscopy, the patient was referred to our center.
Dr Fraternali Orcioni (Pathology): Please Describe the Findings From the Original Endometrial Biopsy as well as the Pathology From the Laparoscopic Surgery
A review of the specimen from the endometrial biopsy revealed that the component defined as high grade endometrioid cancer showed instead some typical features of what has now been defined as ‘gastric-gastrointestinal' type mucinous adenocarcinoma. The same pattern was found on the adnexal specimen and on the omentum, which showed clear signs of carcinomatosis.
The following immunohistochemistry features were reported on the specimens from endometrium and adnexa: positive CA 19.9, CDX-2, SATB2, negative estrogen and progesterone receptors, PGR, TTf1, p16, and PAX-8 ( Figure 1 ). Mismatch repair proteins were normally expressed.
Immunohistochemical features of gastric-gastrointestinal type mucinous adenocarcinoma: (A) CDX-2 positivity, (B) p16 negativity, and (C) SATB2 positivity.
On arrival of the patient at Azienda Ospedaliera Santa Croce e Carle Cuneo, the patient had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, she was fully recovered from the first laparoscopy, there was no vaginal bleeding, but she complained of bloating and tenesmus. Transvaginal ultrasound confirmed an enlarged uterine cavity with the previously described mass, solid left adnexa, and free fluid in the cul-de-sac.
Carcinoembryonic antigen was 1395 ng/mL while CA19.9 was >70 000 U/mL, CA-125 544 U/mL, and CA15.3 73 U/mL. The patient underwent a chest CT scan that was negative for any evidence of disease. Imaging from first CT scan was reviewed and the pelvic area, particularly the perirectal tissues, were found to be possible sites of carcinomatosis with rectal infiltration; the adnexa were both solid and enlarged. The uterus was bulky and filled with fluid and solid masses arising from the endometrial cavity and the cervix was also enlarged. The parametria were not easy to evaluate on the CT scan but there was no hydronephrosis. She underwent an esophagogastroduodenoscopy and colonoscopy that showed no evidence of primary gastrointestinal disease.
Dr Donato (Radiology): Can Imaging Provide Some Insight as to the Origin of this Tumor?
The attempt to define the primary site of advanced tumors strongly impact the choice of surgery and systemic treatment, which differs so much between extragenital and genital tumors, as well as between endometrial and cervical neoplasms. 1 While endoscopy and imaging studies (CT scan, positron emission tomography (PET) scan) can be used, they might not definitively pinpoint the exact origin, especially for gastric or ovarian tumors. 2 3 Distinguishing between an endometrial or cervical origin for this specific cancer is also arduous, if not impossible, particularly in advanced cases where the uterus is massively involved by the local spread of the disease ( Figure 2 ).
CT scan. (A) Uterine cavity and adnexal mass in coronal section (arrow on adnexal mass). (B) Longitudinal section of uterine cavity and cervix in sagittal section.
Current diagnostic tools have several limitations. Imaging techniques such as CT and PET/CT scans lack precision in identifying the exact source of the tumor 4 and might not identify precisely the extent of the disease, particularly in cases of miliary carcinomatosis. Although MRI offers some potential for detecting cervical involvement, data specific to gastric-gastrointestinal adenocarcinoma of the endometrium is scarce. 5 6
Dr Fraternali Orcioni (Pathology): Why was the Definition of a Primary Site of Tumor a Challenge in this Case?
This patient has a history of breast cancer, and therefore it was mandatory to exclude recurrence and peritoneal dissemination from her first tumor because the clinical presentation was abdominal carcinomatosis. This was excluded due to the morphology and immunohistochemistry features of the specimen. The negativity of p16 at immunohistochemistry excluded a potential human papillomavirus related origin of the disease. Taking into account the challenges and limitation of imaging, pathology examination has a crucial role in refining the diagnosis, even with some major limitations.
The fact that the disease presented the same features on endometrial biopsy, peritoneal carcinomatosis, and adnexa made it easier to determine a uterine origin. However, the involvement of both the endometrial cavity with myometrial invasion and cervical stroma and glands made it impossible to establish the exact site of origin of the uterine disease ( Figure 3 ). Moreover, this is a rare entity: gastric-gastrointestinal type mucinous adenocarcinoma accounts for 10–15% of all cervical adenocarcinomas worldwide, and the largest case series of endometrial gastric or gastrointestinal type of endometrium was only recently published by Wong et al 7 and accounted for nine cases (including also benign diseases) and included in the WHO classification. 8 In this case, the definition of tumor origin cannot rely only on the pathology analysis and it would be more appropriate to define it as a ‘uterine’ gastric-gastrointestinal type mucinous adenocarcinoma. However, the in-depth analysis of macroscopic presentation, microscopic pattern, and immunohistochemistry may help guide clinical management.
Aspect of the neoplasm (A) on the adnexa, (B) on the uterine cavity, and (C) on the cervix (there is abundance of mucin and the glands are columnar (tall and slender) and show features of intestinal or gastric differentiation on all the specimens). On the cervical sample (C), there is a small amount of normal epithelium preserved at the level of the exocervix.
The multidisciplinary tumor board, considering the massive amount of disease involving the endometrial cavity, involvement of the adnexa, and carcinomatosis, decided that the presentation was more consistent with advanced cancer of endometrial origin.
Dr Fraternali Orcioni (Pathology): What are the Main Histological Features of Gastric-like Tumors and why are they a Challenge for the Pathologist?
Histologically, gastric-gastrointestinal type mucinous adenocarcinoma recapitulates pyloric gastric epithelium or pancreaticobiliary epithelium. Gastric-gastrointestinal type mucinous adenocarcinoma presents specific histological features that can be both characteristic and diagnostically challenging for pathologists. Here is a breakdown of the main histological features as well as the main diagnostic challenges:
Mucin production: These tumors are composed of abnormal glands that produce excessive mucin.
Epithelial cells: The tumor cells lining the glands are often columnar (tall and slender) and may show features of intestinal or gastric differentiation. This can be helpful in some cases, but not always definitive for pinpointing the origin.
Mucinous predominance : The abundance of mucin can obscure underlying architectural details that would be crucial for differentiating between a primary gastric or a primary müllerian (endometrial or cervical) origin.4
Immunohistochemistry : While immunohistochemistry can be a valuable tool, a specific panel for gastric-gastrointestinal type mucinous adenocarcinoma is not yet established. Markers such as CA 19–9, CDX-2, and SATB2, used in this case (Figure 1), can be helpful but may not be entirely specific for gastric-gastrointestinal type mucinous adenocarcinoma and might be expressed in other malignancies, such as colorectal cancer. 9
Dr Olearo (Gynecologic Oncology): Based on the Limited Amount of Available Data, can we Consider the Presentation in this Patient Consistent with Those of Other Reported Patients?
Both gastric type adenocarcinoma of the cervix and endometrial adenocarcinomas with gastric differentiation in general exhibit aggressive clinical behavior. In the series by Wong et al, 7 visceral metastases were present in three of four cases: two patients were dead of disease at follow-up at 7 months to 3 years, one was alive with progression at 9 months, and one was alive without disease at 7 months. Similarly, both cases reported by Hino et al 10 were advanced at diagnosis and the patients died from disease, one with lung metastases and the other with peritoneal carcinomatosis. This highlights the importance of separating these neoplasms from conventional müllerian type mucinous or endometrioid adenocarcinomas, and they should likely be managed as real high grade neoplasms.
Dr Puppo (Gynecologic Oncology): What is the Best Surgical Approach for this Type of Tumor?
Because treatments for endometrial and cervical advanced cancers differ, establishing the origin of the disease was extremely relevant but very complex in this case. Given the rarity of uterine gastric-gastrointestinal type mucinous adenocarcinoma, there is no established specific consensus treatment algorithm. In advanced cases, the treatment response among patients has not been systematically assessed and even with therapy, advanced stage lesions tend to have a poor response, both for cervical and endometrial cancers. In this specific case, there was a relevant tumor burden and possible risk of bowel occlusion, and therefore surgical debulking seemed the best option to both reduce the risk of bowel occlusion and offer the best chance of accessing systemic treatment.
Dr Destefanis (Medical Oncology): What Type of Systemic Therapy Could be Offered to this Patient and What Would be the Anticipated Response?
Given that this is an extremely rare histological neoplasm, aggressive clinical behavior may present at diagnosis as a disease spread to locoregional organs, peritoneum, and often with distant metastases, and still pose the challenge of uncertain primary site of origin. Uterine gastric-gastrointestinal type mucinous adenocarcinoma does not currently fit into any known molecular group of the Cancer Genome Atlas (TCGA). It seems, however, appropriate to consider these neoplasms in the non-endometrioid carcinomas group, 11 and in the FIGO 2023 classification 12 they are included in the ‘aggressive histological type’ group. The first line therapeutic approach involves systemic therapy based on platinum, and the combination with carboplatin AUC 5 and paclitaxel 175 mg/m2 every 3 weeks may be considered initially. Absence of expression for estrogen and progesterone indicates lack of sensitivity to hormonal therapy with progestins or aromatase inhibitors.
Usually, these are lesions with microsatellite stability, and in rare cases of microsatellite instability, they still present a low mutational burden. Therefore, the therapeutic approach to be considered after progression with first line platinum based chemotherapy may include the combination of pembrolizumab plus lenvatinib. 13 In the case of further progression or unacceptable toxicity during combination therapy with immune checkpoint inhibitors and tyrosine kinase inhibitors, with documented HER2 expression, therapy with trastuzumab deruxtecan can be proposed based on drug availability (off-label use, compassionate use, or expanded access program). 14 HER2 has not been included in the molecular classification of endometrial tumors, but since it can represent a possible therapeutic target, its determination is desirable when patients have exhausted standard therapeutic approaches. In the PORTEC-3 study, HER2 status was evaluated in 407 high risk patients with different histological types, and 24 cases (5.9%) of HER2 positivity were identified: nine (37.5%) serous histology, six endometrioid (25%), five (20.8%) clear cell, and four mixed histology (16.7%). 15
The rarity, aggressiveness, and importance of correct histopathological diagnosis and subsequent therapeutic assistance pathway require evaluation in a multidisciplinary team in reference centers for gynecological oncology. All cases of uterine gastric-gastrointestinal type mucinous adenocarcinoma should be included in registries for rare tumors to have more consistent data for diagnostic and therapeutic purposes.
The Tumor Board decided that surgical debulking was feasible with the intent of radical treatment followed by chemotherapy; the plan was discussed with the patient who accepted. She underwent laparotomy 14 days after her first laparoscopy with abdominal washing, posterior pelvic exenteration with Hudson-Delle Piane radical retrograde hysterectomy, end-to-end rectal anastomosis, left oophorectomy, radical omentectomy, and removal of carcinosis from the small bowel, mesorectum, and pelvic peritoneum. There was no gross residual disease at the end of the surgical procedure. She recovered well and was discharged home on day 7 after the procedure.
The patient had an uneventful postoperative course, allowing the beginning of chemotherapy treatment with carboplatin–paclitaxel 25 days after the surgical approach. She completed the planned six cycles of chemotherapy, during which she did not experience grade 3–4 toxicity, maintained dose intensity, and there was no treatment discontinuation. On April 2024, she was free from tumor related symptoms and was awaiting restaging CT scan and subsequent onco-gynecological evaluation.
Closing Summary
Gastric-gastrointestinal type mucinous uterine adenocarcinoma is a rare form of adenocarcinoma that is commonly misdiagnosed on imaging and pathology; advanced cases pose the challenge of diagnosis of its origin. Compared with other cervical or endometrial cancers, this tumor type has an aggressive course and poor prognosis. Diagnostic workup is critical to improve patient outcomes. However, imaging shows several limitations and the final extension of the disease can be confirmed mainly at surgery. The final pathology analysis plays a crucial part in defining the origin of the disease and its biological features. Due to the rarity of gastric-gastrointestinal type uterine adenocarcinoma, tailored medical therapy is lacking. At present, standard platinum based chemotherapy is the best option for advanced disease, in combination with immunotherapy. While specific prospective studies might be extremely difficult due to the small number of cases, these cases should be treated in referral centers, and national and international registries of rare tumors should be encourage to share more knowledge of these rare entities.
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Footnotes
X @ElenaOlearo
Contributors EO in the corresponding and presenting author. AP is the guarantor. All authors contributed to the paper because the case was discussed during a Tumor Board regular session.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.