Is a biopsy necessary for submucosal lesions?

Biopsy of Submucosal Lesions: A Risk-Stratified Approach

Biopsy is not universally necessary for all submucosal lesions, but is essential for lesions >2 cm, those arising from the muscularis propria, symptomatic lesions, or when malignancy cannot be excluded—with the specific biopsy technique determined by lesion size, layer of origin, and clinical context.

Initial Characterization: When to Pursue Tissue Diagnosis

Small Asymptomatic Lesions (<2 cm)

• Submucosal lesions <2 cm in the upper GI tract and small intestine may be managed with EUS surveillance annually without immediate biopsy, particularly if they demonstrate benign features 1
• Lesions with characteristic endoscopic appearance of lipomas (pillow sign) or pancreatic rests (central umbilication, 6-10 mm, antral location) with normal overlying mucosa do not require further evaluation or surveillance 1
• Large retrospective studies demonstrate that routine surveillance for small asymptomatic lesions is unnecessary 1

Larger Lesions (≥2 cm) and High-Risk Features

• For lesions ≥2 cm, histological diagnosis is necessary before definitive management 1
• Gastric GISTs >2 cm should be considered for resection, making preoperative diagnosis critical 1
• Ulcerated, bleeding, or symptomatic subepithelial lesions require tissue diagnosis and consideration for resection regardless of size 1

Selecting the Appropriate Biopsy Technique

EUS-Guided Tissue Acquisition (Preferred for Muscularis Propria Lesions)

• EUS is the modality of choice to evaluate indeterminate subepithelial lesions and determine layer of origin, which guides biopsy strategy 1
• For lesions arising from the muscularis propria (fourth layer), EUS-guided fine-needle biopsy (FNB) or fine-needle aspiration (FNA) is preferred to differentiate GISTs from leiomyomas 1
• EUS-guided FNA with immunohistochemical staining (CD117/c-kit, CD34, smooth muscle actin, S100) significantly improves diagnostic yield for hypoechoic fourth-layer masses like GISTs 1
• EUS-guided core needle biopsy using 19-gauge Trucut needle provides tissue architecture for histologic evaluation, with initial studies showing correct diagnosis in 80% (4/5) of cases versus 20% (1/5) with FNA alone 1

Forceps Biopsy Techniques (For Submucosal Layer Lesions)

• Bite-on-bite "tunneling" biopsies using jumbo forceps can establish diagnosis for lesions arising from the submucosa (third layer) with diagnostic yield of 42-65% 1
• Standard forceps biopsies are designed for mucosa and are often non-diagnostic for submucosal lesions 1
• Jumbo forceps biopsy has comparable diagnostic yield to EUS-FNA for third-layer lesions (55-65% vs similar rates) but lower yield (40%) for muscularis propria lesions 1
• Bleeding complications occur in approximately 2.8-33% of cases with stacked forceps techniques 1
• Novel jumbo biopsy "unroofing" technique demonstrates 92% diagnostic yield for gastric submucosal masses without significant complications 2

Endoscopic Resection Techniques (Diagnostic and Therapeutic)

• Endoscopic submucosal resection (ESMR) or dissection (ESD) provides both diagnosis and treatment with significantly higher diagnostic yield (87%) compared to forceps biopsy (17%) for submucosal lesions 1, 3
• ESMR/ESD should be reserved for lesions confined to submucosal or deep mucosal layers due to 2-3% perforation risk 1
• Endoscopic resection of muscularis propria lesions carries higher perforation risk and should be limited to endoscopists skilled in advanced resection techniques 1
• Aspiration lumpectomy provides adequate histologic diagnosis in 95% of cases versus 77% with strip biopsy for submucosal lesions 4

Critical Clinical Scenarios Requiring Preoperative Diagnosis

Complex or Potentially Morbid Resections

• For tumors requiring multi-visceral resection or major surgery (e.g., total gastrectomy), every effort must be made to obtain preoperative diagnosis via EUS or image-guided percutaneous biopsy 1
• Preoperative biopsy is preferable even for easily resectable tumors to exclude differential diagnoses (leiomyosarcoma, lymphoma, neurogenic tumors, desmoid tumors) that require different treatment strategies 1
• If the diagnosis is GIST, mutational analysis is mandatory to exclude imatinib-resistant disease before initiating systemic therapy 1
• When performed appropriately, preoperative biopsy is safe with minimal side effects and without oncological compromise 1

Metastatic Disease

• When obvious metastatic disease is present, biopsy an easily accessible metastatic focus rather than performing laparotomy/laparoscopy for diagnostic purposes 1
• CT- or ultrasound-guided biopsy may be considered for very large tumors (>10 cm) 1

Common Pitfalls and How to Avoid Them

Technical Considerations

• Standard mucosal biopsies using conventional forceps are inadequate because subepithelial lesions have normal overlying mucosa and the forceps cannot reach deep enough 1
• EUS-guided FNA alone has limited diagnostic yield for intramural lesions; immunohistochemical analysis is essential for accurate diagnosis 1
• The inability of EUS-FNA to predict malignant potential in GISTs (particularly Ki-67 proliferation index) remains a major limitation 1

Safety Concerns

• Concern about peritoneal seeding from biopsy of cystic masses is often overstated; EUS-guided biopsy is preferable but transcutaneous biopsy targeting solid components appears safe 1
• Bleeding risk with endoscopic resection techniques is significant both during and after the procedure 1

Avoiding Unnecessary Procedures

• Do not perform laparotomy or laparoscopy solely for diagnosis when less invasive tissue acquisition methods are available 1
• Excision biopsy should be reserved for circumstances where other biopsy methods are impossible (e.g., some small intestinal GISTs) or for symptomatic bleeding lesions 1
• If a suspected GIST requires resection, it must be performed as oncologic surgery by appropriately trained surgeons in or linked to a sarcoma specialist center 1