Upper Gastrointestinal Tumors during Pregnancy: Diagnosis, Risk Factors, and Treatment Options – A Literature Review

The incidence of gastrointestinal cancers during pregnancy has been increasing in recent years, mainly due to the shift in maternal age at delivery [1]. Despite concerns for the well-being of the fetus, the survival of the mother is often the highest priority [2]. Oncologic surgery and perioperative chemotherapy can be applied in principle, whereas radiation is generally contraindicated. Iatrogenic preterm delivery is the most common pregnancy complication, while termination of pregnancy does not improve maternal outcomes for most non-gynecologic cancers. The long-term prognosis of pregnant women with tumors compared to non-pregnant patients with the same tumor stage and similar therapy is unclear due to a lack of data, but in principle is not considered significantly worse [3]. The current review discusses the available literature for several malignant upper gastrointestinal tumor entities focusing on esophageal cancer, gastric cancer, and pancreatic neoplasms.

While on average 1–2 out of every 1,000 pregnant women will develop cancer, the diagnosis of esophageal or gastric cancer during pregnancy or breastfeeding is even rarer, occurring in only 0.026–0.1% of all pregnancies [4]. It is often impossible to distinguish characteristic symptoms of esophageal cancer like dysphagia from pregnancy-related disorders or impairments (such as persistent nausea, bloating, dysphagia, recurrent (postprandial) vomiting, or refractory reflux). Therefore, we often experience a relevant delay in diagnosis and treatment resulting in a very poor prognosis [5].

As with all tumors during pregnancy, treatment depends on the gestational age of the pregnancy and the stage of the tumor. There are few case reports of esophageal cancer during pregnancy in the literature, and no specific guidelines exist so far [5‒7]. In their literature review, Bozkurt et al. analyzed 5 cases over a time span of 20 years [7] (see Table 1).

The majority were patients with advanced-stage squamous cell carcinoma of the esophagus. Gestational age at diagnosis ranged from 26 to 29 weeks. In most cases, only supportive or palliative therapy could be initiated. The alternative is radical oncologic surgery, possibly with stage-adjusted neoadjuvant or perioperative therapy, after induced premature birth from about the 28th week of pregnancy, depending on the degree of maturity and survival chances of the child [7].

In principle, the question arises whether in patients with confirmed risk factors for esophageal adeno- and squamous cell carcinoma (e.g., Barrett’s dysplasia, obesity, regular alcohol, and nicotine consumption etc.), and clinical symptoms (e.g., dysphagia or odynophagia, hematemesis, severe or untreated gastroesophageal reflux, and unintentional weight loss) an endoscopic examination of the upper gastrointestinal tract should be performed before planning a pregnancy. Looking at the international literature, so far there seems to be no clear evidence for such a strategy.

Gastric cancer diagnosed during pregnancy is a complex situation for both, the mother and fetus. Patients with newly diagnosed gastric cancer during pregnancy have an overall poor prognosis [11]. This is because the diagnosis of carcinoma not only is often delayed, but the hormonal situation during pregnancy may also be a growth-promoting factor for the tumor itself. However, except for a few case reports and smaller (mostly older) case series, data are scarce in the literature. As with esophageal cancer, the diagnosis is difficult, because possible warning signs of gastric cancer such as nausea, vomiting, and abdominal discomfort, are often overlooked or attributed to pregnancy [12]. The onset of nausea and vomiting usually occurs in the sixth week of pregnancy and can last up to 16–20 weeks. If nausea and vomiting due to hyperemesis continue beyond 20 weeks gestation, clinicians should pay special attention to the symptoms with consecutive forced diagnostic measures [13].

One of the most important risk factors for gastric cancer, an infection with Helicobacter pylori, is significantly higher in pregnant than in non-pregnant women (26.6% vs. 11%) [14]. In addition, the secretion of gastric acid decreases during pregnancy, while the production of gastric mucus increases. The histaminase produced by the placenta deactivates the histamine function. Therefore, patients seem not to show clinical worsening of symptoms, which can be caused by a malignant ulcer [15]. The pathogenesis of pregnancy-related gastric cancer is unclear. Furukawa et al. [16] suggest that pregnancy and/or childbirth may accelerate the growth of gastric cancer in young women, while Jaspers et al. [17] propose that the clinical features and prognosis of gastric cancer during pregnancy do not differ from those of other young patients. Isobe et al. [18] showed that the increase in estrogen during pregnancy promotes the growth of diffuse adenocarcinoma. The immunosuppressive effect of pregnancy may also be an additional factor in the development of a malignant process [19, 20]. Estrogen receptor b (ER-β) is expressed in gastric adenocarcinoma. The effect of estrogens on gastric cancer growth during pregnancy may be mediated through ER-β, particularly in signet ring cell adenocarcinoma. A recently published meta-analysis showed that ER-α overexpression predicted poor overall survival and worse tumor differentiation, whereas ER-β indicated favorable overall survival and better tumor differentiation in gastric carcinoma [21].

If gastric cancer is suspected in a pregnant woman, upper endoscopy with biopsy and histopathologic confirmation is recommended. Computed tomography is usually not indicated because of the severe radiation damage, especially in the first trimester. Magnetic resonance imaging is considered relatively safe as it does not expose the mother or fetus to ionizing radiation and often does not require intravenous contrast during pregnancy [13].

As in the case of esophageal cancer during pregnancy, the treatment plan for gastric cancer is also determined on a multidisciplinary basis according to the gestational age of the pregnancy and the stage of the tumor. If the diagnosis of gastric cancer is confirmed and the tumor is at an early stage, surgical treatment is the optimal and only potentially curative treatment [13].

Until the 22nd week of pregnancy, endoscopic resection according to the recommendations of the Japanese classification of gastric cancer, which is identical to the 8th edition of the Union International Contre le Cancer (UICC)/TNM classification, is the optimal solution for cases with mucosal tumors (pT1a), which also preserves pregnancy [22].

Non-obstetric surgery during pregnancy should not be postponed, if it will affect the health and outcome of the mother. The American College of Obstetrics and Gynecology recommends that a pregnant woman should never be denied indicated surgery, regardless of the trimester [23]. Other case reports also suggest that minimally invasive resection with oncologically adequate lymphadenectomy is a safe procedure for both, mother and child [24]. According to a systematic literature review from Japan, if potentially resectable gastric cancer is diagnosed before 22 weeks gestation, surgery is recommended after termination of pregnancy by induced abortion. At 22–27 weeks gestation, induced preterm delivery or careful monitoring should be performed, followed by surgery; at 28 weeks gestation, surgery after delivery may be recommended [4] (see Tables 2, 3).

According to Constatin et al. [22], the following points should be considered [22]. Between 22 and 28 weeks of gestation, the anesthetic and surgical risks of surgery under general anesthesia are lower as organogenesis is already complete. If the diagnosis is made at the beginning of this interval, resection can be considered after induction of labor. If possible, resection can also be performed while pregnancy is maintained [22]. Neoadjuvant chemotherapy can be considered to reach fetal maturity, taking possible complications such as growth restriction, preterm delivery, and hematopoietic suppression at birth into account [25]. If the diagnosis is made at the end of the interval, the optimal choice is to wait and ensure fetal surveillance, until the fetal risk is reduced. This is usually the case at 32–34 weeks, followed by delivery and resection. In emergencies, such as complications of neoplasia with perforation or hemorrhage, the mother’s survival is always the predominant goal [22].

Beyond 28 weeks of gestation, delivery can safely take place within a few weeks. For this reason, it is recommended that the patient and fetus should be monitored until delivery. Delivery may be spontaneous or by cesarean section followed by gastrectomy 10–14 days later. Gastrectomy during cesarean section is not recommended because of the significant risk of hemorrhage and thromboembolism. For complicated tumors requiring emergency surgery, induction of labor is mandatory because at the abovementioned time of gestation the fetus has a high chance of survival [22, 26].

Regarding the surgical approach, the options of open and laparoscopic (or robotic) D2-gastrectomy with corresponding reconstruction of the food passage are available. For distal gastric cancer (antrum or pylorus), subtotal resections with systematic lymph node dissection are the standard, if oncologically adequate safety margins can be achieved.

Although the minimally invasive approach reduces the need for postoperative analgesia and possible manipulation of the uterus during surgery, it is associated with technical difficulties due to the size of the uterus and – despite the reduced surgical trauma – an additional potential risk, namely, that of CO₂ absorption [27]. Conventional open gastrectomy is associated with larger surgical trauma and intra-abdominal blood loss but is usually associated with shorter surgical procedure times [28]. The technical procedures do not differ in other oncologic parameters, such as the number of lymph nodes resected, the occurrence of postoperative complications, or hospital mortality. Although there is a lack of evidence from prospective randomized trials for surgical treatment of gastric cancer during pregnancy, anesthesia is safe for both, open and minimally invasive procedures in this setting. Laparoscopic or open gastrectomy with systematic D2-lymphadenectomy and subsequent chemotherapy according to the current guidelines and clinically and histopathologically verified tumor stage might be a safe option for gastric cancer in pregnancy, although the long-term prognosis of this approach is still largely unexplored due to the limited data available. However, the quality and expertise of the multidisciplinary team, consisting of surgeons experienced in upper gastrointestinal surgery and with a correspondingly high volume of cases in the center, competent oncologists, obstetricians, and neonatologists, are crucial for the optimal therapy and long-term prognosis. At the same time, the wishes of the mother should always be at the forefront, and ethical considerations should also be taken into account.

Major abdominal surgery is associated with an increased risk of fetal death and spontaneous abortion in the range of 8–11% but is not associated with a risk of fetal malformations. However, several intra- and postoperative complications (e.g., hemorrhage) may endanger the fetus through consequences of hypoperfusion, hypoxia, and hypotension [26].

Benign and malignant pancreatic neoplasms are extremely rare during pregnancy, and the number of cases in the literature is even lower than for the aforementioned esophageal and gastric cancers [29‒31]. Pancreatic ductal adenocarcinoma (PDAC), neuroendocrine tumors, and cystic neoplasms of the pancreas in pregnant women always pose a challenge in terms of diagnosis and therapeutic management, as well as the appropriate timing of oncologic, medical, and surgical therapy. Mucinous cystic neoplasms (MCNs) of the pancreas are the most reported pancreatic neoplasms during pregnancy [30]. It appears that MCNs, which develop during pregnancy, have a different growth pattern and tend to be large. MCNs are already relatively rare, accounting for about 8% of all surgically resected pancreatic cystic neoplasms. The vast majority of MCNs (95%) occur in women. The female-to-male ratio is 20:1 [32]. Because most MCNs are localized in the body or tail of the pancreas, they can be treated surgically with a left pancreatic resection or left subtotal pancreatectomy. This was the treatment of choice in the two case reports presented by Revoredo et al. [30] in which a patient underwent emergency laparotomy for a ruptured MCN [30]. Surgery in the second trimester of pregnancy should be preferred, if possible. The prognosis in the absence of invasive carcinoma is favorable, with a 5-year survival rate of 100%. No complications have been reported with distal pancreatectomy during pregnancy.

PDAC in pregnant women is extremely rare and only very few cases have been described in the literature that were diagnosed and treated before birth [33]. Its prognosis during pregnancy, especially in resectable cases, is unknown, because most patients have advanced inoperable disease. Nevertheless, radical surgical oncologic therapy at the latest possible stage of pregnancy is the only potentially curative treatment option [33]. This should always be performed by a highly specialized, multidisciplinary team of experts in a designated center.

Cancer of the upper gastrointestinal tract during pregnancy is very rare, but important to be treated adequately. Diagnosis and treatment are complex and require individualized approaches based on gestational age and tumor stage. The timely and correct diagnosis is often difficult, as symptoms of tumor disease (dysphagia, reflux, bloating, or recurrent vomiting) can easily be misinterpreted as pregnancy-related symptoms, such as hyperemesis. Therefore, if these symptoms persist, an appropriate diagnostic work-up is always indicated.

When looking at the abovementioned and analyzed literature available, it must be stated that the data on esophageal and pancreatic cancer is very limited and mostly consists of single case reports. Furthermore, when looking at the available studies about gastric cancer in pregnant patients there are literature reviews from, e.g., Japan with at least considerable patient numbers, however, the big limitation seems to be the heterogenous data especially with regard to the time of treatment (1960s–2007) and, hence, significantly different therapeutic options in oncology, surgery, and obstetrics. In conclusion, radical oncologically correct therapy at the latest possible stage of pregnancy is often the only potentially curative treatment option. Multimodal perioperative concepts are possible in principle, but every single therapeutic step must be carefully considered. The therapy should always be coordinated by a highly specialized, multidisciplinary team of experts in a designated center. The needs of the mother and ethical considerations regarding the fetus play an important role.

Patrick S. Plum, Robert Nowotny, René Thieme, Nicole Kreuser, and Ines Gockel declare that they have no conflicts of interest.

This study was not supported by any sponsor or funder.

Idea and conception: P.S.P. and I.G. Literature research: P.S.P., R.N., R.T., N.K., and I.G. Manuscript writing: P.S.P., R.N., and I.G. Editing manuscript: R.T., R.N., and N.K. Graphics: P.S.P., R.N., and N.K. All the authors have read and agreed to the published version of this manuscript.

Patrick S. Plum and Robert Nowotny contributed equally to this work.