About the Program
Next opening: 2027-2028
Number of positions: 1
Length: 1 year
This ACGME-accredited fellowship provides robust training in disorders of the luminal GI tract, pancreas and hepatic pathology (medical liver including liver transplantation), preparing trainees for a career in an academic or private practice setting. Five GI pathologists provide clinical service, contribute to the research program of the GI section, and support the GI Pathology training program across four distinct hospital and outpatient settings.
The GI pathology fellow will get exposure to a comprehensive spectrum of gastrointestinal surgical specimens, ranging from small biopsies to complex procedures, as well as hepatobiliary specimens. Training also includes reviewing consult digital slides from community practices in Texas. The fellow will have graduated responsibility in performing operating room consultations (frozen sections and gross examination). The fellow is expected to closely interact with surgeons/clinicians and pathology colleagues from community practice, actively participate in tumor boards, IBD/liver conferences, participate in research projects and will have the opportunity to attend and contribute to numerous didactic and clinical conferences.
Rotations
The fellow will rotate across two institutions: Baylor St. Luke’s Medical Center and Texas Children’s Hospital, with a one-month rotation at MD Anderson Cancer Center. Program strengths include extensive experience in routine and complex gastrointestinal pathology, pancreatic pathology, medical liver biopsies, liver transplantation, and pediatric pathology.
A one-week rotation in clinical gastroenterology is included, during which the fellow may observe advanced endoscopic procedures such as EMR/ESD and EUS-guided FNA/FNB performed by experienced gastroenterologists.
Stipends and Benefits
Visit the Graduate School of Biomedical Sciences page on stipends and benefits for fellows.
Admissions
Candidates must be board certified or eligible for certification in anatomic pathology or AP/CP.
All application materials, including recommendation letters, must be submitted online, and include the following:
- Completed online House Staff Application
- Current Curriculum Vitae
- Personal Statement
- Transcript from Medical School(s)
- Three Recommendation Letters
Applications are accepted from mid-April to July 31 for positions beginning July 1 two years later. Interviews are conducted starting in July or August and are completed by the end of August of the application year.
Case of the Month
Dr. Hong Yu, PGY-3
Mentor: Shaimaa Elzamly, M.D., Ph.D., Assistant Professor
Case History
A 69-year-old man presented with exertional dyspnea, cough, and dysphagia. Imaging raised concern for an esophagotracheal mass, and he was admitted to the intensive care unit for airway monitoring.
CT Findings
A circumferential mass involved the entire thoracic esophagus. The largest component, immediately superior to the carina, measured 5.0 × 5.2 cm. The mass invaded the lower trachea, producing partial stenosis, and occluded the lower esophagus. A 3.3-cm left adrenal mass was suspicious of metastatic disease.
Pathology
Biopsy of the esophageal mass revealed an invasive adenocarcinoma, predominantly arranged in a tubulopapillary architecture. Focally, the carcinoma cells demonstrated strikingly clear cytoplasm with occasional subnuclear vacuolization. A separate fragment of esophageal squamous mucosa showed mild reactive changes.
Immunohistochemistry
Tumor cells were strongly positive for CDX2, positive for SALL4, patchy positive for TTF-1 (moderate intensity), and focally positive glypican-3, AFP, and CK20, while negative for CK7, Napsin A, PAX8, and p40. HER2 was negative. Nuclear expression of MLH1, PMS2, MSH2, and MSH6 was intact, indicating a low likelihood of mismatch repair deficiency or microsatellite instability–high status.
Final Diagnosis
Invasive, moderately differentiated adenocarcinoma with enteroblastic differentiation.
Discussion
We are presenting a very interesting case of a rare esophageal adenocarcinoma showing enteroblastic differentiation, supported by both the tumor morphology and immunohistochemical profile. Morphologically, the tumor demonstrates a tubulopapillary architecture with occasional clear cytoplasm and subnuclear vacuolization, resembling primitive intestinal-like structures. Immunohistochemically, the tumor expresses fetal gastrointestinal epithelial markers (SALL4, AFP, and glypican 3), further supporting the diagnosis (1,2).
The prevalence of adenocarcinoma with enteroblastic differentiation in the distal esophagus and esophagogastric junction is currently unclear. However, one large cohort study reported a prevalence of 0.7% (6 of 826 cases) among patients with esophageal adenocarcinoma (1). In this study, a possible association with the loss of SWI/SNF marker expression and consistent express of claudin-6 has also been reported. In the current case, BRG1 (SMARCA4) expression was retained by immunohistochemistry, providing no evidence of SMARCA4 protein loss. No additional SWI/SNF immunostains were available. Gastrointestinal adenocarcinomas with enteroblastic differentiation are associated with aggressive biology, frequent lymphovascular and venous invasion, and higher rates of nodal and hepatic metastasis than conventional adenocarcinoma (2).
The consistent expression of claudin-6 in this subgroup may have important therapeutic implications. Claudin-6 is a tight junction protein that has emerged as a potential therapeutic target. Claudin-6–directed therapies, including chimeric antigen receptor T-cell (CAR-T) therapy, are currently being investigated in early-phase clinical trials, including the BioNTech BNT-211-01 trial (1,3).
The different diagnosis of our case is fetal adenocarcinoma of the lung. High-grade fetal adenocarcinoma of the lung is an important mimic because it may show TTF-1, SALL4, AFP, or glypican-3. Low-grade fetal adenocarcinoma characteristically shows fetal lung–like glands, morules, and nuclear/cytoplasmic β-catenin; high-grade fetal adenocarcinoma shows greater atypia, usually lacks morules, and often retains membranous β-catenin with diffuse p53 (4). Here, the dominant circumferential esophageal mass, esophageal occlusion, secondary tracheal invasion, and negative Napsin A favor an esophageal primary; patchy TTF-1 alone is insufficient for lung origin.
Another less likely differential diagnosis based on morphology is metastatic clear cell renal cell carcinoma may show clear cytoplasm and present as metastatic disease, but it is typically PAX8 and CAIX positive. PAX8 negativity, strong CDX2 expression, SALL4/glypican-3 expression, tubulopapillary enteroblastic morphology, and the absence of a renal mass argue against this diagnosis.
Finally, in esophageal adenocarcinoma, the presence of enteroblastic differentiation, strikingly clear tumor cell cytoplasm, or loss/marked reduction of CK7 expression should prompt consideration of fetal gut-like differentiation and appropriate immunohistochemical staining. Identifying this subgroup may have important clinical implications, as these patients could potentially benefit from emerging targeted therapies (1,3).
Question
1. Which combination of morphologic and immunohistochemical findings most strongly supports a diagnosis of adenocarcinoma with enteroblastic differentiation?
A. Solid growth pattern with p40 positivity
B. Tubulopapillary architecture with clear cytoplasm and positivity for SALL4 and glypican-3
C. Lepidic growth pattern with diffuse Napsin A and TTF-1 positivity
D. Clear cell morphology with PAX8 and CAIX positivity
Correct answer: B. Tubulopapillary architecture, clear cytoplasm, subnuclear vacuolization, and expression of fetal gastrointestinal markers such as SALL4 and glypican-3 support enteroblastic differentiation.
Explanation of the other options:
- A is incorrect: A solid growth pattern with p40 positivity supports squamous differentiation rather than adenocarcinoma with enteroblastic differentiation.
- C is incorrect: Lepidic growth with diffuse Napsin A and TTF-1 expression favors a primary pulmonary adenocarcinoma.
- D is incorrect: Clear cell morphology with PAX8 and CAIX expression favors clear cell renal cell carcinoma.
2. Which emerging therapeutic target may have particular relevance in adenocarcinomas with enteroblastic differentiation?
A. SALL4
B. Claudin-6
C. CDX2
D. AFP
Correct answer: B. Claudin-6 expression has been reported in this subgroup and may represent a potential therapeutic target, including through emerging claudin-6–directed therapies such as CAR-T cell approaches.
Explanation of the other options:
- A is incorrect: SALL4 is an oncofetal nuclear marker that supports enteroblastic differentiation, but it is not the principal emerging therapeutic target in this setting.
- C is incorrect: CDX2 is a nuclear transcription factor used as a marker of intestinal differentiation rather than as a therapeutic target.
- D is incorrect: AFP may support fetal gastrointestinal, hepatoid, or enteroblastic differentiation and can serve as a serum biomarker, but it is not the emerging therapeutic target highlighted in this tumor subgroup.
References
Kraemer M, Zander T, Alakus H, Buettner R, Lyu SI, Simon AG, Schroeder W, Bruns CJ, Quaas A. Fetal gut cell-like differentiation in esophageal adenocarcinoma defines a rare tumor subtype with therapeutically relevant claudin-6 positivity and SWI/SNF gene alteration. Sci Rep. 2024 Jun 12;14(1):13474. doi: 10.1038/s41598-024-64116-2.
Murakami T, Yao T, Mitomi H, et al. Clinicopathologic and immunohistochemical characteristics of gastric adenocarcinoma with enteroblastic differentiation: a study of 29 cases. Gastric Cancer. 2016;19:498–507.
Mackensen A, Haanen JBAG, Koenecke C, et al. CLDN6-specific CAR-T cells plus amplifying RNA vaccine in relapsed or refractory solid tumors: the phase 1 BNT211-01 trial. Nat Med. 2023;29(11):2844–2853. doi:10.1038/s41591-023-02612-0.
Li Y, Xi SY, Yong JJ, et al. Morphologic, immunohistochemical, and genetic differences between high- and low-grade fetal adenocarcinomas of the lung. Am J Surg Pathol. 2021;45:1464–1475.