Primary Small Bowel Adenocarcinoma with Metastatic Ovarian Tumor in a Pregnant Woman

Small bowel cancer accounts for only 0.6% of all malignant tumors and 3.0% of all gastrointestinal malignant tumors [1]. According to one study, the histological types of small bowel cancer were carcinoid in 37.3% of cases, adenocarcinoma in 36.9%, and malignant lymphoma in 17.3% [2]. In addition, 1 in 1,000 pregnant women are estimated to have malignant tumors. Thus, pregnancies complicated by small bowel cancer are very rare, and only a few English-language case reports have been published to date [3‒5].

The diagnosis of small bowel cancer is extremely difficult because of its rarity, lack of specific clinical symptoms, and particular anatomical features. We herein report the first case of small bowel adenocarcinoma with metastasis to the ovary during pregnancy. The diagnosis was extremely challenging during pregnancy; the small bowel was not found to be the primary site until a detailed intra-abdominal examination was performed during cesarean delivery at 37 weeks.

A 32-year-old primigravida developed abdominal pain and was referred to our hospital at 29 weeks 4 days of gestation. She had no specific medical history or family history of cancer. Her hemoglobin level was 11.5 g/dL. Ultrasound examination revealed a large multilocular cystic mass on the right side of the uterus. Magnetic resonance imaging showed that the multilocular cyst was 17 cm in diameter and exhibited diffusion restriction, with a mixture of low and high signal areas on T2-weighted imaging; thus, right ovarian cancer was suspected (Fig. 1a). Computed tomography (CT) showed no lymph node enlargement or distant metastasis, and there were no findings suggestive of a primary site other than the right ovary (Fig. 1b). Esophagogastroduodenoscopy (EGD) showed no abnormal findings. Tumor marker concentrations were as follows: carcinoembryonic antigen (CEA), 37.3 ng/mL; cancer antigen 125, 733 U/mL; and cancer antigen 19-9 (CA19-9), 1,613 U/mL. The patient underwent laparotomy to remove the right adnexa at 30 weeks 6 days of gestation under a preoperative diagnosis of primary ovarian cancer (Fig. 1c). Pathologically, atypical columnar epithelial cells proliferating in a papillary or ductal pattern were observed in the ovary, and immunostaining was partially positive for cytokeratin-7, positive for cytokeratin-20, and negative for estrogen receptor (Fig. 2a–d). Although these histological findings were atypical for primary adenocarcinoma of the ovary, no other site was suggestive of the primary site, and the patient was diagnosed with ovarian mucinous carcinoma (TNM stage IC1). The postoperative tumor marker concentrations were as follows: CEA, 7.1 ng/mL; cancer antigen 125, 346 U/mL; and CA19-9, 668 U/mL. Although these concentrations were lower than those before surgery, all were still high. Because the histological type was mucinous carcinoma, colonoscopy was performed at 34 weeks to rule out other primary sites, and no abnormalities were found. Based on the initial diagnosis (primary mucinous carcinoma of the ovary [TNM stage T1c1 N0 M0]), we scheduled cesarean delivery and staging laparotomy at term. The fetal well-being was assessed by cardiotocography and ultrasound during pregnancy, revealing no problems. Following an elective cesarean delivery at 37 weeks 5 days, we performed hysterectomy, left adnexectomy, omentectomy, and appendectomy. A healthy female infant weighing 2,590 g was delivered with an Apgar score of 5/9. After delivery, we performed a detailed intra-abdominal examination and palpated a 2-cm tumor in the jejunum 20 cm anorectally from the ligament of Treitz. The small bowel was partially resected by gastrointestinal surgeons (Fig. 3a, b). A nodular lesion was also biopsied in the peritoneum of the ileocecal region. Pathologic examination revealed adenocarcinoma with a highly differentiated component in the mucosal layer of the jejunum and decreased differentiation through the lamina propria and subserosal layers, suggesting primary carcinoma of the small bowel. The lesion was morphologically and immunohistochemically similar to the ovarian tumor (Fig. 4a–e), and the margin was negative. We found that the ovarian and peritoneal nodules were metastatic lesions, and the patient was diagnosed with TNM stage IV small bowel cancer (TNM; pT4NXM1). Although no residual tumor was grossly visible, FOLFOX was continued for seven cycles as adjuvant therapy from day 34 of the postpartum period. Oxaliplatin was discontinued because of peripheral neuropathy, and simplified LV5FU2 was continued thereafter. At 3 months postpartum, a cancer genome profiling test (FoundationOne^® CDx gene profiling test; Chugai Pharmaceutical Co., Ltd., Tokyo, Japan) was performed to find additional therapeutic options. The test detected several gene alterations, including pathogenic mutations in KRAS (p.G12V) and TP53 (p.R213*); however, no genome-matched therapies were applicable to the patient. KRAS and TP53 mutations are commonly seen in adenocarcinoma of the colon and small bowel. At 11 months postpartum, the disease recurred in the abdominal wall and peritoneum. Treatment with FOLFOX was resumed, but peritoneal dissemination increased without a response. Although third-line treatment with CPT-11 was begun at 14 months postpartum, the patient died at 18 months postpartum without a clinical response.

This case report describes a pregnancy complicated by small bowel cancer with metastatic ovarian cancer, and the pregnancy continued to 37 weeks. The only symptom was abdominal pain, and the pregnancy made the diagnosis extremely difficult. To date, only three such cases have been reported in English, and the initial symptoms in all three cases were nausea and vomiting caused by small bowel obstruction (Table 1).

The clinical symptoms of small bowel adenocarcinoma are nonspecific. In a single-institution report of 491 cases of small bowel adenocarcinoma, abdominal pain occurred in 43% of cases, nausea and vomiting in 16%, anemia in 15%, and no symptoms in <9% [6]. Because jejunal and ileal cancers are difficult to detect by EGD or colonoscopy, they are often found as advanced-stage cancers. In our case, the patient presented with abdominal pain at 29 weeks of gestation. After resection of the right ovarian tumor, her symptoms became mild, and she developed no symptoms secondary to the small bowel lesion. Although it was necessary to exclude primary carcinoma of the gastrointestinal tract from the histopathology of the ovarian tumor, there were no abnormal findings on EGD and colonoscopy. No further surveillance was added.

If the patient had not been pregnant, positron emission tomography (PET)-CT or small bowel endoscopy might have been considered. PET-CT is useful for detecting adenocarcinoma of the small bowel because of wall thickening due to fluorodeoxyglucose uptake [7]. Fetal 18-fluorodeoxyglucose uptake has been reported after PET-CT during pregnancy [8]; thus, PET-CT can be performed even during pregnancy, but only if the benefits to the mother outweigh the risks to the fetus [9]. Video capsule endoscopy and double-balloon endoscopy are useful for identification of small bowel tumors. Generally, these gastrointestinal endoscopy techniques are not recommended during pregnancy because of the compression of the gastrointestinal tract by the gravid uterus and the decrease in gastrointestinal peristalsis. However, they are not absolutely contraindicated during pregnancy, and there is a possibility that the small bowel tumor could have been found by endoscopy in this case.

The elevated tumor marker concentrations may have suggested the existence of other remaining lesions after surgery in the present case. In a blood sample taken 2 weeks after right adnexectomy, the tumor marker concentrations were still high, although they were lower than before surgery. Maternal serum levels of CEA and CA19-9 are not affected by pregnancy [10]. The half-lives of CEA and CA19-9 are a few days long, and the postoperative levels of these tumor markers might be helpful in the consideration of other primary sites such as the small bowel or appendix.

Intraperitoneal inspection and palpation during surgery are important for the diagnosis of small bowel cancer. In a retrospective study of localized adenocarcinoma of the small bowel, diagnosis was made by endoscopy (38%), surgery (35%), radiographic imaging (21%), and capsule endoscopy (6%) among 197 patients [11]. In our case, the diagnosis of small bowel cancer was made by careful palpation of the abdominal cavity during cesarean delivery and staging laparotomy. When metastatic ovarian cancer is suspected, it is important to consider the possibility of the small bowel as the primary site.

Although chemotherapy was not administered during pregnancy in this case, FOLFOX could be considered as a treatment option for small bowel cancer during pregnancy. In pregnancies complicated by colorectal cancer, FOLFOX is typically chosen if the decision is made to continue the pregnancy [12]. Regardless of the presence of pregnancy, the first-line chemotherapy regimen for small bowel cancer in general is FOLFOX ± bevacizumab, CAPOX ± bevacizumab, or FOLFIRI ± bevacizumab [13]. The use of bevacizumab during pregnancy is not recommended [14]. Systemic chemotherapy is an option for TNM stage IV small bowel cancer, but there are no reports of chemotherapy during pregnancy.

For rare cancers with few treatment options, cancer genomic profiling tests can help identify additional treatments. Regarding genomic profiling of small intestinal adenocarcinoma, DNA mismatch repair deficiency was reported in 7.6% of cases in one study [15]. Pembrolizumab and nivolumab with or without ipilimumab are treatment options for DNA mismatch repair deficiency/microsatellite instability-high tumors [13]. In this case, we performed the FoundationOne^® CDx gene profiling test, which is a tumor-only panel used to analyze mutations of 324 genes and recombination of 36 genes. We found that the tumor had a microsatellite-stable status with KRAS and TP53 mutations, but no genome-matched therapy was available for the patient; therefore, standard therapy was recommended.

Small bowel adenocarcinoma may be the primary site of ovarian cancer in patients without EGD or colonoscopy findings. A detailed bowel examination is important during surgery for suspected ovarian cancer in pregnancy. Persistently high tumor marker concentrations or irregular symptoms after oophorectomy should prompt further exploration by PET-CT, video capsule endoscopy, and double-balloon endoscopy. Although these tests are sometimes avoided during pregnancy, they are not absolutely contraindicated. When the primary site is unknown, as in this case, it is important to perform such investigations without hesitation to achieve an accurate diagnosis. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000540524).

We thank Angela Morben, DVM, ELS, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient and her husband for publication of the details of their medical case and any accompanying images.

The authors declare that they have no conflicts of interest to disclose.

The authors received no financial support for this article’s publication.

Yutaro Takahashi contributed to the first draft and finalization of the manuscript. Takayoshi Iijima contributed to the writing of the manuscript and finalization of the manuscript. Yumi Ishidera performed the surgery, participated in the patient’s care, and supervised the case report. Taichi Mizushima supervised the case report. Yuichi Imai performed the surgery and participated in the patient’s care. Daisuke Utsunomiya contributed to the diagnosis of the ovarian tumor. Noritoshi Kobayashi and Yasushi Ichikawa determined the course of treatment and performed the chemotherapy. Shingo Kato performed the cancer genome profiling test. Jotaro Harada obtained the pathological diagnosis of the tumor. Etsuko Miyagi supervised the case report. All the authors read and approved the final manuscript.

All data relevant to the case are available as part of the article and its online supplementary material. Further inquiries can be directed to the corresponding author.