Gastrointestinal stromal tumor (with mixed epithelioid and spindled morphology)
Histopathology:
- Submucosal well-circumscribed highly cellular tumor with predominant fascicular arrangement of spindle cells
- Many areas exhibiting large polygonal cells with vesicular nuclei, abundant clear cytoplasm, and peripheral nuclear placement, give signet ring-like appearance.
- Signet ring-like cells merge with more typical spindled and epithelioid cells.
- Very occasional palisading is appreciated. But vacuolation and necrosis are not seen.
- Occasional atypical mitoses are seen.
- Areas of oedematous-myxoid changes and hyaline degeneration are also seen.
- Few areas show the perivascular arrangement of tumor cells.
Practical Points of Pathoclinics:
- Most GISTs (70-80%) are spindle cell tumors with moderate-high cellularity and low-grade cytologic atypia. Cells are arranged in fascicular, storiform or whorls pattern with variable areas of palisading. Tumor cells have mostly blunt-ended nuclei with evenly dispersed fine chromatin, small nucleoli, and ill-defined cell borders with a syncytial appearance. Paranuclear vacuoles and dense eosinophilic collagen fibrils/skeinoid fibers can be seen.
- Epithelioid morphology (10-20%) is uncommon and shows multi-nodular plexiform architecture. Epithelioid cells are seen in solid sheets or nesting pattern. Cells have vesicular nuclei and abundant clear to pale eosinophilic cytoplasm. Peripheral placement of nuclei and abundant clear cytoplasm gives signet ring-like appearance. Epithelioid GISTs may be misinterpreted as an epithelial neoplasm in a small biopsy.
- GISTs with mixed morphology (10%) are composed of spindle and epithelioid cells.
- The uncommon features of GISTs are pseudoglandular architecture, multinucleated cells, rhabdoid cells, inflammation, myxoid changes, sclerotic changes, collagenous background, cystic changes, and tumor necrosis. Pleomorphic cells and dedifferentiated areas are rare in de novo GISTs but are common with long-term tyrosine kinase inhibitor treatment.
- CD117/c-kit and DOG-1 immunohistochemistry are the marker of choice for diagnosing GISTs as most GISTs harbor mutually exclusive C-KIT or PDGFRA gain-of-function mutations.
- In cases of weak positive or negative CD117/c-kit and negative DOG-1, differentials of spindle cell GISTs are leiomyoma/leiomyosarcoma (Desmin, SMA and H-caldesmon), schwannoma (S-100 and SOX10), fibromatosis (beta-catenin), solitary fibrous tumor (STAT6), inflammatory myofibroblastic tumor (ALK), Inflammatory fibroid
polyp (CD34). - In cases of negative CD117/c-kit and negative DOG-1, differentials of epithelioid cell GISTs are carcinoma (AE1/AE3), metastatic melanoma (HMB-45, S100, SOX10, Melan A, Mart-1), PECOMA (SMA, HMB45, Melan A, Desmin, TFE3), glomus tumor (SMA, H-caldesmon), neuroendocrine neoplasms (cytokeratin, synaptophysin,
chromogranin A). - The majority of pediatric GISTs (80-85%) and few adult GISTs (10-15%), especially young female, lack C-kit/PDGFRA mutations and are referred to as wild-type GISTs (wt-GIST). These wild-type GISTshave SDH-mutation and are detected by loss of immunohistochemical staining for SDH subunit B. However, all negative cases of SDHB immune do not harbor SDH gene mutation. Both SDH mutation and KIT or PDGFR-α mutations are mutually exclusive in most cases. SDH-mutated GISTs are also positive for DOG1 and CD117 immunohistochemistry. SDH negative cases can be sporadic or syndromic (Carney Triad: pulmonary chondroma and paraganglioma or Carney-Stratakis Syndrome: paraganglioma). Tyrosine kinase inhibitors are not much effective in cases of SDH-deficient GISTs, so surgery is the recommended treatment. Molecular characterization of GIST is necessary before initiating tyrosine kinase inhibitors therapy.
- SDH-deficient GISTs are multiple, with multinodular and plexiform growth pattern. SDH-deficient GISTs have predilection for stomach (antrum) involvement and have epithelioid or mixed morphology. Cellularity is usually high without significant pleomorphism. Atypical mitoses are not common. Palisading, vacuolation, and coagulative necrosis are usually not seen. Prognostic categorization based on site, size, and mitoses are not applicable in SDH-deficient GISTs in contrast to C-kit or PDGFRA mutated spindle cell GISTs. Lymphovascular invasion and lymph node metastasis are common. The overall behavior is indolent with low mortality, but disease progression and recurrence occur frequently.
- Pathologist’s takeaway point: In cases with epithelioid or mixed morphology GISTs, SDHB immunohistochemistry should be added in addition to CD117/C-kit and DOG-1, as such cases are clinically, prognostically, and therapeutically different.
References:
- Brčić I, Argyropoulos A, Liegl-Atzwanger B. Update on Molecular Genetics of Gastrointestinal Stromal Tumors. Diagnostics (Basel). 2021 Jan 28;11(2):194. doi: 10.3390/diagnostics11020194. PMID: 33525726; PMCID: PMC7912114.
- Ibrahim A, Chopra S. Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors. Arch Pathol Lab Med. 2020 May;144(5):655-660. doi: 10.5858/arpa.2018-0370-RS. Epub 2019 Jun 6. PMID: 31169996.