Malignant gastrointestinal neuroectodermal tumour arising in the extrahepatic bile ducts; a rare neoplasm in an unusual anatomic location
- 1 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- 2 Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- 3 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Correspondence to Chen Zhang; chenzhan@iupui.edu
Abstract
Malignant gastrointestinal neuroectodermal tumour (GNET) is a rare, aggressive neoplasm with fewer than 100 cases reported in the literature. Most cases arise in the tubular gastrointestinal tract. We reported a unique case of GNET arising in the extrahepatic bile ducts and reviewed the literature of GNETs. The patient is a female in her mid-30s who presented with painless jaundice and diarrhoea several months after cholecystectomy for biliary dyskinesia. Workup revealed a tumour arising from the peripheral 4B bile ducts involving the left hepatic duct and bifurcation. Histologic examination of the lesion showed a malignant spindled and epithelioid neoplasm which strongly expressed S100 and SOX-10. Neoplastic cells were negative for various cytokeratins and melanoma markers. FISH testing using EWSR1 break-apart probes showed rearrangement of the EWSR1 gene region. The immunohistochemical and molecular findings are consistent with a diagnosis of GNET arising in the extrahepatic bile ducts.
Background
Gastrointestinal neuroectodermal tumour (GNET), also referred to as clear cell sarcoma-like tumour of the gastrointestinal tract, is a rare malignant entity which generally arises within the gastrointestinal tract of young adults.1–4 The tumour is characterised by an EWSR1 rearrangement, most often an EWSR1-ATF1 or EWSR1-CREB1 fusion. Microscopically, tumour cells appear epithelioid to spindled with a nested, solid or pseudopapillary architecture and stain strongly positive for S100 and SOX-10 and negative for melanocytic markers such as Melan A and HMB45. The most often reported primary sites include the small bowel and less frequently the stomach and colon. There have been rare reports in the literature of GNETs arising in the oral cavity,5 6 oesophagus7 and liver.8 Here we present a case of GNET arising in the extrahepatic bile ducts of a woman in her mid-30s and discuss the clinical findings along with the histologic and molecular features.
Case presentation
The patient is a female in her mid-30s who initially presented with right upper quadrant pain for the past 6 months. Cholescintigraphy revealed a gallbladder with normal anatomy and an ejection fraction of 0%. Cholecystectomy for biliary dyskinesia was performed. Fifteen months after the cholecystectomy, the patient presented to the emergency department with complaints of diarrhoea along with a 2-week history of skin itching, dark urine and scleral icterus. Laboratory studies were remarkable for elevated bilirubin (total bilirubin=4.1 mg/dL, direct bilirubin=2.7 mg/dL) and abnormal liver function tests (ALT=345 U/L, AST=180 U/L, alkaline phosphatase=262 U/L). Serologic tests for hepatitis A, B and C were negative.
Investigations
Clinical concern for cholestatic jaundice was raised and the patient underwent magnetic resonance cholangiopancreatography which revealed intrahepatic biliary tract dilation and a possible bile duct stricture. Endoscopic retrograde cholangiopancreatography confirmed the presence of a severe, complex biliary stricture of indeterminate aetiology located at the hepatic duct bifurcation. Biopsies and brushings were taken, and the stricture was dilated and stented. The biopsy of the hepatic duct revealed a malignant epithelioid neoplasm that was positive for S100 and SOX-10 and was favoured to be metastatic melanoma. The patient underwent a full-body dermatologic examination which revealed no skin lesions of concern. Whole body PET/CT showed an FDG-avid central hepatic hilar lesion consistent with the primary malignancy and an FDG-avid low-density lesion in the left hepatic lobe suspicious for metastasis.
Twenty days after the emergency admission, surgical resection of the tumour was performed and consisted of complete extrahepatic bile duct resection and left hepatectomy with portal lymph node dissection. Staging laparoscopy found no evidence of occult metastatic disease of the abdominal cavity and organs. Reconstructive Roux-en-Y cholangiojejunostomy was performed.
Differential diagnosis
Pathologic findings
Gross examination of the resection specimen was remarkable for a 2.3×2.1 x 2.0 cm poorly circumscribed heterogeneous mass involving the common bile and hepatic ducts and abutting the liver. No hepatic lesions were identified.
Microscopic examination showed spindled and epithelioid tumour cells forming solid sheets and nests, diffusely infiltrating the wall of the bile duct and extending into adjacent hepatic parenchyma (figure 1A–D). The tumour cells showed vesicular chromatin, occasionally prominent nucleoli and abundant eosinophilic to clear cytoplasm. Scattered osteoclast-like giant cells were seen. Focal tumour necrosis was present (2%) and a mitotic rate of 2 per 10 high-power fields was identified. Immunohistochemical study showed tumour cells were positive for S100 and SOX-10 and were negative for pan-cytokeratin AE1/AE3, cytokeratin Cam5.2, EMA, CD138, CD45RB (LCA), CD68, ERG, tyrosinase, Melan A, HMB45, MiTF and PRAME. INI-1 expression was retained. Twelve lymph nodes were submitted, and all were negative for metastatic disease.
Gastrointestinal neuroectodermal tumour. (A) Low magnification view of the tumour invading extensively the wall of the extrahepatic bile duct. The lumen of the bile duct (upper right) is compressed. (B) Tumour appears invading the hepatic parenchyma (lower right) in a nodular and pushing fashion. (C) The area of tumour with a spindled cell morphology. (D) The area of the tumour with epithelioid morphology, showing pleomorphic vesicular nuclei and abundant clear cytoplasm. Osteoclast-like giant cells are seen. Magnification: 20× (A and B), 200× (C and D). H&E stain.
Molecular findings
The fluorescence in situ hybridisation probe set for EWSR1 (22q12.2; dual-colour, break-apart) demonstrated a red/green/fusion fluorescence pattern of EWSR1 rearrangement in tumour cells (figure 2). PCR analysis of BRAF and NRAS showed no mutation. MSI-high was not detected. Genetic evaluation of the tumour via next-generation sequencing (FoundationOne CDx) revealed a microsatellite-stable tumour with an EWSR1-ATF1 fusion. No actionable therapeutic targets were identified.
The fluorescence in situ hybridisation probe set for EWSR1 (22q12.2; dual-colour, break-apart) demonstrates a split red/green fluorescence pattern of EWSR1 rearrangement in a tumour cell. A normal cell (below the tumour cell) with fused (unrearranged) red/green (yellow) fluorescence is shown for comparison.
Final pathologic diagnosis
GNET, arising from the extrahepatic bile duct, pathological staging pT3N0MX (pTNM, AJCC eighth edition, 2018).
Treatment
The patient did not receive postsurgical chemotherapy or radiation, and is followed by active surveillance.
Outcome and follow-up
Ninety days after the surgery, a PET/CT showed two concerning hypermetabolic foci along the liver resection bed. Fine needle aspiration of these lesions showed granulomatous inflammation with no evidence of malignancy. The patient continues to be followed by active surveillance with no evidence of local recurrence or distant metastasis, presently at 13 months postresection.
Discussion
GNETs are rare aggressive tumours that may present a diagnostic challenge. GNETs typically present in young to middle-aged adults and female predominance was demonstrated in some studies.2 Initial symptoms include weight loss, abdominal pain and gastrointestinal obstruction related to tumour site. The tubular gut is predominantly involved with the small intestine being the most often-reported primary site, although rare cases of GNETs arising in other locations such as the liver and oral cavity have been reported.1 5 6 Our case is the first report of GNET arising in extrahepatic bile ducts. Obstruction of the extrahepatic bile ducts was likely responsible for the painless jaundice witnessed in our case.
Our case shows typical histologic features as previously reported cases of GNET, with spindled to polygonal tumour cells arranged in solid sheets and nests. The CD68 positive osteoclast-like giant cells admixed with tumour cells have been reported in about half of GNET cases1 and are also identified in our current case. The immunohistochemical studies are very useful and usually sufficient differentiating GNET from other mimics (table 1). GNETs typically show strong, diffuse expression of S100 and SOX-10, with variable expression of neuroendocrine markers such as synaptophysin and neuron-specific enolase. Tumour cells are negative for CD117, DOG-1, α-smooth muscle actin, desmin, CD99 and melanocytic markers such as HMB45 and melan A. In equivocal cases, molecular profiling and ultrastructural studies may be needed for the differential diagnosis.
Immunohistochemical staining patterns of GNET and mimics
| GNET | CCS-ST | Melanoma | GIST | Epithelioid MPNST | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CCS-ST, clear cell sarcoma of soft tissue; GIST, gastrointestinal stromal tumour; GNET, gastrointestinal neuroectodermal tumour; MPNST, malignant peripheral nerve shealth tumor. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| S100 | + | + | + | – | + | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SOX-10 | + | + | + | – | + | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HMB45 | – | + | + | – | – | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Melan A | – | + | + | – | – | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| MITF | – | + | + | – | – | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DOG1 | – | – | – | + | – | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| CD117 | – | – | ± | + | – | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| INI1/SMARCB1 | Retained | Retained | Retained | Retained | Lost in >50% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Ethics statements
Patient consent for publication
Acknowledgments
We are thankful to Dr Omer Saeed for his help in the data collection and image preparation.
Footnotes
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Contributors CZ is the guarantor of the content of the manuscript. CZ and CQM performed microscopic examinations. AA-H provided patients’ clinical data. GHV performed FISH analysis. All authors contributed to manuscript preparation.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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