An unusual and potentially misleading phenotypic change in a primary gastrointestinal stromal tumour (GIST) under imatinib mesylate therapy

Abstract

We present a unique case of a 62-year-old female who was diagnosed with a huge gastric gastrointestinal stromal tumour (GIST). Core needle biopsy revealed a cellular spindle cell GIST with diffuse expression of CD117 and CD34. Four mitotic figures were counted in ten available HPFs, indicating a high-risk tumour. Computed tomography scan, performed after 8 months of neoadjuvant imatinib mesylate treatment (Glivec, 400 mg/day), revealed a partial response with reduction of tumour size from 20 × 15 × 15 cm to 13.3 × 8 × 7.6 cm. The patient underwent complete tumour resection. The tumour revealed extensive cystic changes and hyalinisation in 90% of the tumour mass. Multiple viable tumour clones, measuring up to 1 cm, showed highly anaplastic, large epithelioid cells with vesicular nuclei and prominent, centrally located nucleoli, strikingly mimicking the appearance of proximal-type epithelioid sarcoma, anaplastic carcinoma, melanoma or epithelioid angiosarcoma. These anaplastic tumour cells expressed pankeratin (KL-1) and vimentin, but they were completely negative for CD117, DOG-1, CD34, S100, desmin, α-smooth muscle actin, HMB45, CD30, CD45, CK7, CK20 and 34βE-12. Sufficient tissue for molecular analysis was available from the resected tumour. No mutations were detected in KIT exons 9, 11, 13, 17, PDGFRA exons 12, 14, 18, KRAS and BRAF. The patient was alive with no evidence of recurrence 28 months later. To our knowledge, this represents the first report on this unusual type of trans-differentiation in GIST under imatinib therapy. Awareness of this phenomenon would help to avoid diagnostic confusion when evaluating post-treatment resections from GISTs.

Targeting Disease Persistence in Gastrointestinal Stromal Tumors

“…Thus, both mechanisms may contribute to GIST persistence. Typically, the cells with low or no expression of KIT (KIT low/2 ) had epithelioid morphology [46,50,52], which also predominates in untreated KIT 2 GISTs [53]. Previously, we described a rare Kit low/2 cell type with nondescript epithelioid morphology in the tunica muscularis of postnatal mice and demonstrated their ability to self-renew and differentiate into ICCs in cell culture, in tissue explants, and following allogeneic transplantation in vivo [7,8,54].…”

“…Alternatively, a preexisting subset of cells not addicted to oncogenic RTK signaling, for example, due to lack of significant expression of the mutant receptor, could selectively survive the treatment. In six studies that investigated KIT expression in patients who underwent imatinib or sunitinib treatment prior to surgery, 15 of 131 samples lacked KIT expression detectable by conventional immunohistochemistry [46,[48][49][50][51][52] (further samples studied in [46] displayed reduced KIT expression [KIT low ]), whereas the remainder showed no obvious phenotypic change. Thus, both mechanisms may contribute to GIST persistence.…”

Pseudocystic dermatofibrosarcoma protuberans: report of two cases and demonstration of COL1A1‐PDGFB rearrangement

“…(This phenomenon is more accurately described as a pseudocystic change, because sarcomas, being mesenchymal in the origin, are very unlikely to have a true epithelial lining.) Extensive cystic change and hyalinization have been described in a case of gastric cellular spindle‐cell gastrointestinal stromal tumor (GIST) following 8 months of neoadjuvant treatment with imatinib mesylate 16 . Cystic/pseudocystic degeneration is sometimes encountered in untreated GIST as well.…”

Gastrointestinal stromal tumor of unusual phenotype after imatinib treatment

“…[ 3 ] In the clinical setting, diagnosis of GIST is based on the morphology and a group of IHC markers including DOG1, platelet-derived growth factor receptor-alpha (PDGFRα), CD34 as well as KIT. [ 3 – 5 ] A direct sequencing of KIT is sometimes necessary in diagnosis especially when KIT IHC staining is inconclusive. [ 6 , 7 ] It is important to understand that KIT IHC, a gold standard test, can be obscure after imatinib treatment.…”

“…In such cases, the diagnosis is largely based on histopathologic and molecular analyses. [ 5 , 8 – 10 ] Recently, in situ hybridization (ISH) of ETV1 mRNA was introduced as a useful technique in diagnosis of GIST, which showed similar specificity and slightly lower sensitivity to KIT IHC staining. [ 4 ] However, there has been no attempt to identify the expression of ETV1 mRNA in the GIST after imatinib therapy, to our knowledge.…”