May 2022 – Gastroenterology Case One

Gastrointestinal stromal tumor with chondroid differentiation.

The patient is a 67-year-old man with a biopsy-proven gastrointestinal stromal tumor status post-treatment who underwent a partial gastrectomy for resection of a persistent mass.

Microscopically, sections of the gastric mass showed two distinct morphologic components. Spindle cells with high nuclear to cytoplasmic ratio, vesicular chromatin, and rare mitoses (Image 2). The second component was composed of mixed spindled and epithelioid cells with chondroid differentiation (Image 3). The second component also showed nuclear pleomorphism, vesicular chromatin, and numerous mitotic figures (greater than 10 mitoses per 5 mm²).

Immunohistochemical stains were performed at the referring institution and Mayo Clinic. The spindle cells were positive for CD34, vimentin, CD117 (patchy), DOG1 (patchy), desmin (patchy), and SMA (patchy). S100 was positive in areas of chondroid differentiation. Immunostains performed at Mayo Clinic showed diffuse positive staining for CD117 and DOG1 in both spindle and epithelioid cells including the area of chondroid differentiation. There was no loss of succinate dehydrogenase B (SDHB) expression.

The morphology and immunohistochemical profile supported the diagnosis of GIST with chondroid differentiation. In light of the patient's history of prior treatment with imatinib, it is inappropriate to use the conventional GIST risk stratification scheme to assess the aggressiveness of the current tumor. Nonetheless, the presence of abundant mitotic figures certainly is indicative of a high-grade sarcoma. Molecular studies were also performed and no mutations were detected in both c-Kit and PDFGR genes.

GISTs with chondroid differentiation have been reported, more often in treated tumors, but rarely seen in treatment-naïve tumors as well. In a similar clinical setting, GISTs can also show other unusual morphology, suggesting differentiation patterns including osseous, muscular, rhabdoid, vascular and undifferentiated/pleomorphic sarcoma types. It is generally believed that the morphologic variance represents a “trans-differentiation” or “dedifferentiation” process. Strictly speaking, dedifferentiation describes the regression of a lineage-specific tumor to a primitive, less specialized state of development and loss of typical immunohistochemical stains. In other words, classic KIT-positive GIST to anaplastic/pleomorphic-type KIT negative tumors. In contrast, trans-differentiation described the conversion of tumor cells to another specialized cell type. Currently, in the GIST literature, the two terms are used variably without a clear distinction by different authors.

Regardless of terminology, the morphologic variance of GISTs poses a real diagnostic challenge in clinical practice. Pathologists must become aware of the process of “trans-” or “de-”differentiation in GISTs given their unusual morphology and often associated aggressive biological behavior, such as metastasis, recurrence and resistance to kinase inhibitor therapy.

GISTs are the most common mesenchymal neoplasm of the gastrointestinal tract, with three classic morphologic types, namely spindle cell predominant, epithelioid cell predominant, and mixed type. Usually, tumor cells show minimal cytological atypia, low proliferation index, and diffuse CD117 and DOG1 expression. In cases with trans-differentiation or dedifferentiation, searching for areas of classical GIST morphology will support your diagnosis. The trans- or de-differentiated component can show different morphological patterns, often with loss of CD117 and DOG1 expression and aberrant immunostaining positivity for other epithelial or mesenchymal differentiation markers like cytokeratin, desmin, etc. Interestingly, CD34 expression may be preserved in the dedifferentiated component in some cases. In this case, the patient’s prior history of GIST and preserved CD117 and DOG1 expression in the tumor cells are helpful to confirm the diagnosis. 

It has been hypothesized that trans- or dedifferentiation may be triggered by alternative escape mechanisms besides the activation mutation in GISTs. Therefore, molecular studies are currently advised in cases of these unusual tumors because they might provide critical diagnostic clue and/or therapeutic insights, especially in cases where classic-GIST is not identified. It will likely help to further understand potential alterations of oncogenic pathways related to this phenomenon. 

Finally, in practice, to exclude a possibility of GIST with dedifferentiation or trans-differentiation, it is important to adequately sample tumor specimens and search for areas of classic-GIST even if the initial tumor morphology suggests an undifferentiated sarcoma or sarcoma with heterologous elements.

References

1. Karakas C, Christensen P, Baek D, Jung M, Ro JY. Dedifferentiated gastrointestinal stromal tumor: Recent advances. Ann Diagn Pathol. 2019 Apr;39:118-124. doi: 10.1016/j.anndiagpath. 2018.12.005. Epub 2018 Dec 18. PMID: 30661742.
2. Pulcini G, Villanacci V, Rossi E, Gheza F, Cervi E, Ferrari AB, Cervi G, Bassotti G. Gastrointestinal stromal tumor with chondroid differentiation. Anticancer Res. 2009 Jul;29(7):2761-5. PMID: 19596958.
3. Yu G, Yang P, Ran W, Xing X, Wang T, Wu S, Pan X, Qu G, Gai P, Ding W. Chondroid gastrointestinal stromal tumor in the stomach with early adenocarcinoma. Int J Clin Exp Pathol. 2019 May 1;12(5):1642-1648. PMID: 31933982; PMCID: PMC6947111.
4. Pulvers J, Guminski A, Chou A, Gill AJ, Ahadi M. Decoding a mysterious morphology with molecular pathology: chondroid metaplasia in a metastatic gastrointestinal stromal tumour after imatinib therapy. Pathology. 2020 Apr;52(3):396-398. doi:10.1016/j.pathol.2019.12.007. Epub 2020 Feb 26. PMID: 32111397.