Gastric hepatoid adenocarcinoma during pregnancy



Anastasija Ranceva
Rokas Stulpinas
Rimvydas Norvilas
Consultant: Ugnius Mickys

A 38-year-old female was admitted to the hospital at the 20th week of her first pregnancy complaining of progressive abdominal pain, nausea, vomiting, diarrhea and weight loss. Laboratory findings revealed anemia (hemoglobin 102g/l) and elevated C-reactive protein (CRB-47,9mg/l). Ultrasonography (US) of the abdomen showed presence of ascites, right hydronephrosis (II°) and a small amount of fluid in the pleural cavities. Magnetic resonance imaging (MRI) revealed thickening of the gastric wall, perigastric lymph node enlargement and ascites (Fig.1). A sample taken during diagnostic paracentesis of ascites contained cells compatible with adenocarcinoma. Subsequently, esophagogastroduodenoscopy (EGD) was performed: a large ulcerated infiltrative tumour of the stomach was found and a biopsy was taken. Serum AFP level was elevated to 79,6 kU/l, another tumor marker CEA was elevated to 16,0 mkg/l.
HISTOLOGY (See Fig. 2-4)
Biopsy showed an ulcerated tumour, infiltrating lamina propria and the submucosal tissue. The tumor was composed of confluent cribriform (with scant AB+ intraluminal mucins), serpentine structures, solid nests and discohesive cells with a moderate amount of light eosinophilic, finely vacuolated cytoplasm and large, polymorphic nuclei containing eosinophilic macronucleoli. Sporadic giant cells, some larger pale intracytoplasmic vacuoles („pale bodies“) and intravascular invasion were noted.
Tumor stained positively for cytokeratins (PanCK 100% / CK7 80% / CK20 30%), CDX2 (50%), HepPar-1 (15%) and AFP (10%). Positivity for E-cadherin, SMAD4, PMS2/MSH6 was retained, scattered Synaptophysin positive cells were seen. WT1 and S100 reactions were negative and HER2 reaction was interpreted as ambiguous (2+).
No HER2 amplification on FISH was detected. NGS panel for solid tumors found mutations in CTNNB1 (c.97T>G (p.Ser33Ala)) and PIK3CA (c.1023_1024insTACT (p.Thr342TyrfsTer12) and c.1025_1026insTA (p.Tyr343ThrfsTer3)) genes.
Histologic pattern and immunophenotype were heterogenous, so a diagnosis was formulated as a poorly differentiated (G3 / MSS) gastric tubular adenocarcinoma with focal hepatoid differentiation (15%) and scattered neuroendocrine cells. Clinicians were notified that this tumor fulfills the criteria of a very aggressive subtype, a hepatoid adenocarcinoma of the stomach.
After all the investigations, the 21-week-pregnant patient was diagnosed with an aggressive, stage IV gastric cancer (cT4 N1 M1). The patient’s case was discussed during a tumor board meeting with surgeon, medical oncologist, gastroenterologist, gynecologist and obstetrics specialists. It was agreed that because of a metastatic disease, this patient could only be treated with palliative chemotherapy. The patient was informed about the situation and her prognosis: she decided to terminate the pregnancy and start treatment. After the abortion patient received 1st cycle of first line systemic chemotherapy with FOLFOX4 regimen (oxaliplatin, leucovorin, 5-fluorouracil), but for the second cycle she arrived with significant deterioration in clinical condition and performance status of ECOG-3. Radiologically a progression of disease was confirmed: new metastases in ovary, enlarged lymphadenopathy, progressing ascites and pleural effusion. The patient developed diffuse peritonitis, small bowel obstruction and in spite of the treatment she died 2 months since the initial disease presentation.
Pregnancy-associated gastric cancer is rare and difficult to diagnose as the symptoms can be confused with those of an ordinary pregnancy.  Pregnancy-associated hepatoid gastric adenocarcinoma (HAC) is not only very rare but also extremely aggressive as the above described case illustrates. HAC is a unique subtype of extrahepatic adenocarcinoma with clinicopathological presentation mimicking hepatocellular carcinoma (HCC). HAC is characterized by the histological resemblance to HCC (in a typical case solid sheets of large eosinophilic polygonal cells) and can be confirmed by several immunohistochemical markers such as AFP, Glypican-3, SALL4, and Hep-Par 1. The majority of patients (i.e., at least 70–80%) have elevated serum α-fetoprotein (AFP) levels.
Hepatoid adenocarcinoma (HAC) was first reported as an α fetoprotein (AFP)-producing tumor in 1970. However, the term “hepatoid carcinoma of the stomach” (HAC) was coined by Ishikura et al in 1985. HAC can originate in various organs such as the stomach, gallbladder, colon, lung, urinary bladder, pancreas.
The diagnosis of HAC is frequently delayed and at least half of patients have advanced disease at the time of diagnosis. Due to lack of evidence, treatment approaches have mostly followed principles for the treatment of common gastric cancer (CGC), including radical surgery in eligible patients with curative intent. Chemotherapy regimens including cisplatin-based chemotherapy are considered the most efficient first-line systemic treatment in advanced situations.
The scientific literature on this topic comprises mostly single case reports and some small single-institution patient series. Accordingly, scientific evidence for proper clinical decision-making and for the evaluation of various treatment outcomes is limited. The rarity of these patients and the scarce literature on this particular subgroup of GC make it difficult to provide any robust evidence for the clinical management of patients with HAC.


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