A 37-year-old woman, gravida 2, para 0, with a suspicious tumor at the liver hilum at 21 weeks 5 days of gestation was admitted to the department of obstetrics and gynecology of our hospital. Physical examination revealed a very sick and suffering patient. The patient presented with dyspnoea, jaundice, epigastric pain, ascites, and abdominal tenderness. Orange urine and white stool were reported. There was no previous or family history of any cancer. No regular medication was reported. The patient was a former light smoker; she did not smoke during pregnancy. Magnetic resonance imaging (MRI) had been performed eight days before the patient's admission; it revealed an enlarged liver with a centrally located tumor at the liver hilum and disseminated hepatic and abdominal lymph node metastases. MRI also displayed mechanical cholestasis with dilated biliary ducts and ascites (Figure 1).
On obstetrical ultrasonography at the time of admission, the estimated fetal weight was 470 g (59th percentile), a Doppler measurement of blood flow through the uterine arteries was performed, and the median PI (pulsatile index) was below 1.5. Fetal movements, fetal anatomy, placenta, amniotic-fluid volume, and the length of the cervix (40.0 mm) were normal.
At the time of the patient's initial presentation, laboratory results showed severe normocytic normochromic anemia with haemoglobin level 6.7 g/dl and hematocrit 20.2%, leukocytosis with a white blood cell count of 14.47 G/l, and a normal platelet count. Liver function parameters were elevated as follows: total bilirubin 16.64 mg/dl, glutamate oxaloacetate transaminase (GOT) 70 U/l, glutamate pyruvate transaminase (GPT) 42 U/l, and gamma-glutamyl transferase (GGT) 90 U/l. Cholinesterase was <1 kU/l; both alkaline phosphatase (843 U/l) and lactate dehydrogenase (LDH) (635 U/l) were elevated. Total protein and albumin levels were reduced (52.5 g/l, 28.0 g/l, respectively). Blood coagulation analysis resulted in a prothrombin time of 34%; an activated partial thromboplastin time (APTT) was 45.1 s. Fibrinogen (279 mg/dl) was normal. A high level of C-reactive protein (CRP) (8.23 mg/dl) was detected. Common kidney function parameters and serum electrolytes were normal. These laboratory findings are shown in Table 1. Tests for viral hepatitis B and hepatitis C and HIV were all negative.
Acute hepatic failure was diagnosed. According to the findings, the patient underwent a percutaneous transhepatic biliary drainage (PTBD) (Figure 2). Pathological examination of the liver-biopsy specimens, obtained at PTBD, revealed a poorly differentiated, diffusely infiltrating SRCC, grade 3 (Figure 3). By immunohistochemistry, the tumor was positive for cytokeratin (CK) 7 (Figure 4(a)). Tumor cells were negative for CK20, caudal-type homeobox transcription factor 2 (CDX2), estrogen receptor (ER), progesterone receptor (PR), PAX8, and human epidermal growth factor receptor 2 (HER2). Positive expression of programmed death-ligand 1 (PD-L1) was found in 30% of the tumor cells. Immunohistochemistry of phosphatase and tensin homolog (PTEN) was weak and not conclusive. In conclusion, histomorphology and immunohistochemical findings argued for a primary tumor of the upper gastrointestinal tract. DNA repair proteins like MLH1, MSH2, MSH6, and PMS2 were positively expressed. Thus, these findings argued against microsatellite instability. Next generation sequencing-based analysis of common targetable cancer mutations was ordered. The Ion AmpliSeq  Cancer Hotspot Panel v2 (Ion Torrent ) and the Ion AmpliSeq  BRCA1 and BRCA2 Panel (Thermo Fisher Scientific Inc., Waltham, MA, USA) were used for mutational analyses.
The following day, recurrence of ascites was observed. Therefore ultrasound-guided paracentesis was performed.
Two days after admission, regular labour started spontaneously at 6 am; therefore the patient was transferred to the delivery room. Immediately, the patient had rupture of membranes and delivered a female infant in pelvic presentation, by spontaneous vaginal delivery, at full 22 weeks of gestation. The baby weighed 427 g; the Apgar scores at 1, 5, and 10 minutes were all 1. The placenta seemed cleft; thus ultrasonography of the uterine cavum was performed, and no placental residues were detected. In general, loss of blood and involution of uterus were normal.
Afterwards, an abdominal CT (computed tomography) scan detected metastatic disease, a large mass located at the liver hilum (6 cm at maximum) next to the gastric cardia, hepatic metastasis, cholangiectasis, and enlarged locoregional lymph nodes, and bone metastases in the whole axial skeletal system. Additionally, the CT showed signs of a paralytic ileus; therefore a stomach tube has been inserted. A chest CT scan demonstrated a large right upper lobe mass (5 cm in diameter), appearing malignant, and bilateral pleural effusions (Figure 5).
In conjecture, histopathologic and imaging findings were most consistent with a primary signet cell carcinoma of gastric origin.
Despite antibiotic coverage with ampicillin after PTBD, the patient developed clinical signs of sepsis including tachycardia, fever, dyspnoea, and low blood pressure, along with significantly elevated procalcitonin (PCT) levels (5.12 ng/ml). PCT is used as a biomarker for the diagnosis of sepsis, and PCT is used to guide antibiotic therapy. Initially, no specific focus of sepsis was found. Accordingly, antibiotic therapy was changed by replacing ampicillin with piperacillin/tazobactam.
Blood cultures later grew Candida albicans and streptococci. Teicoplanin and fluconazole were thus added to the piperacillin/tazobactam regimen. Moreover, polymerase chain reaction (PCR) for DNA quantification of CMV revealed 1.63 x 102 c/ml. Thus, valganciclovir was administered.
Seven days after admission, an ultrasound examination of the liver demonstrated minimal intrahepatic cholangiectasis and gallbladder wall thickening. Decompression effect and clinical improvement were observed, but there was no improvement in laboratory parameters of cholestasis with bilirubin levels plateauing at 26.87 mg/dl.
Antitumor therapy was discussed: Because of her poor performance status (ECOG 3) and cholestasis, the patient was not a candidate for chemotherapy, and beyond PD-L1, no drugable targets were discovered in immunohistochemical analyses. After careful discussion with the patient and her family and after obtaining informed consent experimental therapy with pembrolizumab (200 mg as intravenous infusion) was initiated and well tolerated. Pembrolizumab represents a monoclonal antibody which binds to PD-1, blocking the interaction between PD-1 and its ligands (e. g. PD-L1). In tumor tissues, binding of PD-1 on T-cells to PD-L1 expressed by tumor cells inhibits the antitumor immune response of T-cells, thus enabling immune escape of tumor cells and neoplastic growth.
A few days later, the results from sequencing analyses were available: Sequencing results revealed a deletion in exon 19 of the epidermal growth factor receptor (EGFR) [p.(E746_A750del)], which represents a prototypical mutation characterizing as subset of adenocarcinomas of the lung. In addition, mutations of RB1 (exon 22) and TP53 (exon4) were detected. The patient did not have a BRCA1/2 mutation. Additional immunohistochemical stains ordered based on sequencing results revealed that the tumor cells were highly positive for thyroid transcription factor-1 (TTF1), which represents a useful marker in the diagnosis of tumors of thyroid or lung origin (Figure 4(b)).
Based on the mutational profile, treatment with afatinib was recommended. Afatinib shuts down the signalling activity of receptor tyrosine kinases of the ErbB family by binding to three members of the family, namely, EGFR, HER2 and HER4, and by inhibiting the transphorylation of a fourth member, HER3. Owing to her rapidly deteriorating health status, the patient was not able to commence afatinib. Despite supportive measures the patient died on the 14th day of admission.
Taken together, this pregnant woman was diagnosed with signet ring cell carcinoma which was primary assumed to originate from the upper gastrointestinal tract. In addition, liver and bone metastasis and a malignant-appearing lung lesion were observed. According to the histopathological (CK7 positive, CK20 negative, TTF1 positive) and genetic findings (mutation of EGFR, exon 19), primary SRCC of the lung was the final diagnosis.