Stomach

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2022, Case 04, and is gastrointestinal stromal tumor of the stomach. The information provided in this case was accurate and correct at the time of publication in 2022. Any changes in terminology since the time of publication may not be reflected in this case.   

The histological sections demonstrate a moderately cellular neoplasm with uniform monomorphic spindle cells. There is abundant pale eosinophilic cytoplasm and bland elongated nuclei, with some nuclear palisading. Nucleoli are inconspicuous, with occasional perinuclear vacuoles and rare mitotic figures. Some sections show hyalinized vessels and myxoid stroma. The clinical, histologic, and immunohistochemical findings are most consistent with gastrointestinal stromal tumor (GIST) with spindle cell morphology, arising in the stomach.

GISTs are commonly encountered mesenchymal neoplasms of the gastrointestinal tract (GIT), arising from the interstitial cells of Cajal. They arise most frequently in the stomach (60%), jejunum and ileum (30%), duodenum (5%), and colon and rectum (<5%); they rarely involve the esophagus, appendix, and gallbladder. Rarely, “extra-gastrointestinal GIST,” involving the omentum, mesentery, or retroperitoneum with no apparent connection to the GIT, has been described. Most GISTs are asymptomatic, discovered incidentally on imaging or surgery. When symptomatic, patients present with GI bleeding, anemia, or abdominal fullness.

GISTs are typically solitary, well-circumscribed, and centered in the muscularis propria. Microscopically, they have spindle or epithelioid cells, usually in fascicular, palisaded, storiform, or sheet-like growth patterns. Stroma is usually scant, but fibrous septa can sometimes delineate the tumor cells in an organoid pattern. Myxoid change, hyalinization, and variable lymphoplasmacytic inflammatory infiltrate may be seen. As in this case, the spindle cells are relatively short and uniform, with eosinophilic, slightly fibrillary cytoplasm. The epithelioid cells have a more abundant cytoplasm, usually with peri-nuclear halos and well-defined cell borders. Clear cell, oncocytic, and plasmacytoid variants are less common. Truly pleomorphic tumors are rare; however, both pleomorphism and unusual differentiation (eg, skeletal muscle) can be seen in lesions that have been treated with tyrosine kinase inhibitors (TKI). Nuclear palisading in a GIT mesenchymal tumor often indicates a GIST, despite its traditional association with neural neoplasms. Skeinoid fibers, which are amorphous periodic acid-Schiff-positive modified collagen fibers, are usually seen in small intestinal tumors. Multifocality is more common in pediatric patients and in syndromic situations like neurofibromatosis type 1, Carney triad, Carney–Stratakis syndrome, and a familial syndrome with germline mutations of KIT.

Immunohistochemistry has become imperative to distinguish GIST from its histologic mimics. Roughly 95% of GIST are strongly and diffusely immunoreactive for CD117 (KIT); however, staining can be more focal in unusual cases, exhibiting dot-like, peri-nuclear, or membranous staining. These staining patterns do not correlate with mutation type or response to therapy. Nearly all GIST are immunoreactive for DOG1 (ANO1). Most KIT-negative/DOG1-positive GIST are gastric or extra-visceral and almost invariably harbor a PDGFRA mutation. However, DOG1 expression is not related to mutational status and is a useful marker to identify a subset of patients with CD117-negative GIST, who might benefit from TKI. Therefore, DOG1 should be part of a panel when evaluating these lesions. About 70% of GIST are positive for CD34, 30% to 40% are positive for smooth muscle actin (SMA), and up to 5% are focally positive for S100, desmin, and/or keratin.  

GIST demonstrate variable behavior, ranging from benign to malignant. The risk of progressive disease is divided into four categories – none, low, moderate, or high. Currently, the Armed Forces Institute of Pathology criteria, recommended by the College of American Pathologists, shown in table 1 below, recognize anatomic location, size, and mitotic rate as the most important parameters for grading and assessing behavior for conventional GIST. These criteria should only be applied to primary, unifocal GIST that have not been treated with neoadjuvant or TKI therapy. These criteria are also not entirely applicable to succinate dehydrogenase (SDH) deficient GISTs due to their unpredictable behavior. Tumor rupture and true mucosal invasion are other important risk factors associated with aggressive clinical behavior and adverse prognosis. GIST can metastasize to the liver or disseminate throughout the peritoneal cavity as numerous metastatic nodules. In general, they very rarely metastasize to lymph nodes. However, ~50% of SDH-deficient GIST metastasize to lymph nodes. 

Table 1. Guidelines for Risk Assessment of Primary Gastrointestinal Stromal Tumor (GIST)

# Defined as metastasis or tumor-related death  
## Denotes small number of cases
Source: https://documents.cap.org/protocols/cp-other-gist-resection-19-4100.pdf

First-line therapy for GIST is complete resection. However, adjuvant therapy based on targeting the mutant KIT or PDGFRA proteins is common, since approximately 40% of GISTs recur or metastasize after complete resection. Approximately 75% of GISTs possess activating mutations in the KIT gene, and 10% have activating mutations in the PDGFRA gene. These are mutually exclusive mutations and excellent targets for small molecule TKI therapy, like imatinib mesylate and sunitinib malate. Histologic features seen following TKI therapy include hypocellularity, myxoid stroma, fibrosis, and necrosis, with nests of viable tumor cells. Secondary or acquired mutations can be associated with development of tumor resistance in the setting of long-term TKI therapy. These post treatment secondary mutations may lead to rhabdomyoblastic, cartilaginous, and osseous differentiation; rare GISTs can also show dedifferentiation prior to treatment.

Recently, two major subgroups of GIST were recognized based on molecular classification: SDH-competent and SDH-deficient GIST. SDH-competent GIST include tumors with mutations of KIT or PDGFRA, and a subset of GIST with mutations in NF1 or BRAF. SDH-deficient GIST include tumors with a genetic alteration in any of the SDH subunit genes, leading to SDH dysfunction. Although rare, SDH-deficient GIST have specific implications, and it is recommended in the CAP GIST Protocol that all gastric GIST should be screened for loss of SDHB by immunohistochemistry. These comprise the majority of pediatric GIST, as well as those in patients with Carney triad or Carney–Stratakis syndrome. SDH-deficient GIST arise almost exclusively in the stomach, predominantly in females, at a younger age, with multinodular or plexiform growth, epithelioid morphology, lymphovascular invasion, nodal involvement, and metastasis to the liver and peritoneum.

The differential diagnosis of spindled mesenchymal neoplasms in the GIT is quite broad. Immunohistochemical workup and specific anatomic layer of origin are useful clues in their evaluation.  

Desmoid fibromatosis usually arises extrinsic to the GIT, demonstrates nuclear labeling for β-catenin, and shows negativity for DOG1 and CD117.  

Inflammatory myofibroblastic tumor also arises extrinsic to the GIT but appears to arise in the serosa or muscularis propria if involved through local extension. They are positive for SMA, desmin, and variably keratin and ALK1, and negative for CD117, DOG1, and S100. Approximately half of these tumors have an ALK gene rearrangement.

Inflammatory fibroid polyp arises in the submucosa and is diffusely positive for CD34 and variably positive for SMA, but negative for CD117, desmin, and S100. Like GIST, it can harbor a PDGFRA mutation.

Schwannoma also arises in the submucosa. It often has peri-tumoral or intratumoral lymphoid aggregates, variable hyalinized vessels, and it strongly and diffusely expresses S100 protein, lacking reactivity for CD117, DOG1, SMA, and desmin.

Lastly, leiomyoma shows diffuse staining for desmin and SMA, and usually has absent staining for CD117 and DOG1. A commonly encountered pitfall is that mast cells and/or entrapped interstitial cells of Cajal within a leiomyoma stain with CD117.

1. A 64-year-old man presents with a stomach mass and is diagnosed with a gastrointestinal stromal tumor (GIST). Which of the following is the most commonly mutated gene in GIST? 
    
   1. EGFR
   2. FMS
   3. KIT
   4. PDGFRA
   5. RET 
       
2. Which of the following statements about GIST is true? 
    
   1. They arise from mast cells.
   2. They commonly metastasize to lymph nodes.
   3. They commonly show oncocytic and clear cells.
   4. They commonly stain for DOG1.
   5. They most commonly arise in the ileum.  
       
3. Which of the following is most likely to correlate with a succinate dehydrogenase (SDH)-deficient GIST?
    
   1. Gastric location
   2. Male sex of the patient
   3. Older age group
   4. Presence of skeinoid fibers
   5. Spindled morphology 

1. Dei Tos AP, Hornick JL, Miettinen M. Gastrorintestinal stromal tumor In: WHO Classification of Tumours Editorial Board. WHO Classification of Tumors: Digestive System Tumours. 5th ed. International Agency for Research on Cancer; 2019:439-443.
2. Downs-Kelly E. Chapter 30 - mesenchymal tumors of the gastrointestinal tract. In: Odze RD, Goldblum JR, eds. Surgical Pathology of the GI Tract, Liver, Biliary Tree and Pancreas. Third ed.: Saunders; 2015:822.
3. Fletcher CDM, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol. 2002;33(5):459-465.
4. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Path. 2006;23(2):70-83.
5. Miettinen M, Lasota J. Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) – A review. Intl J Biochem Cell Biol. 2014;53:514-519.
6. Protocol for the examination of resection specimens from patients with gastrointestinal stromal tumor (GIST) v4.1.0.0. Accessed January 29, 2021. https://documents.cap.org/protocols/cp-other-gist-resection-19-4100.pdf.
7. Rubin BP. Gastrointestinal Stromal Tumor (GIST) and Extragastrointestinal GIST In: Goldblum JR, Folpe AL, Weiss SW, eds. Enzinger & Weiss’s Soft Tissue Tumors.: Elsevier; 2020:614-638. 

1. KIT (C)
2. They commonly stain for DOG1. (D)
3. Gastric location (A)