Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Division of Pediatric Hematology and Oncology, Oregon Health & Science University/Doernbecher Children's Hospital, Portland, OR, USA.
Histopathology. 2022 Aug;81(2):215-227. doi: 10.1111/his.14680. Epub 2022 May 29.
Recurrent alterations involving receptor tyrosine or cytoplasmic kinase genes have been described in soft-tissue neoplasms such as infantile fibrosarcoma (IFS) and inflammatory myofibroblastic tumour (IMT). Recent trials and regulatory approvals for targeted inhibitors against the kinase domains of these oncoproteins have allowed for increased use of targeted therapies. We aimed to characterize the histologic features of paediatric mesenchymal neoplasms with kinase alterations treated with targeted inhibitors.
Eight patients with tyrosine kinase-altered mesenchymal neoplasms with pre- and posttreatment samples were identified. Tumours occurred in five females and three males with a median age at presentation of 6.5 years. Tumour sites were bone/somatic soft-tissue (n = 5) and viscera (n = 3). Pretreatment diagnoses were: IMT (n = 3), epithelioid inflammatory myofibroblastic sarcoma (n = 1), and descriptive diagnoses (n = 4) such as "kinase-driven spindle cell tumor." Fusions identified were ETV6::NTRK3 (n = 2), TPM3::NTRK1, SEPT7::BRAF, TFG::ROS1, KLC1::ALK, RANBP2::ALK, and MAP4::RAF1. Patients were treated with larotrectinib (n = 3), ALK or ALK/ROS1 inhibitors (n = 3), and MEK inhibitors (n = 2). Posttreatment tumours exhibited a striking decrease in cellularity (7/8) and the presence of collagenous stroma (7/8) with extensive glassy hyalinization (5/8). In two cases, abundant coarse or psammomatous calcifications were seen and in one case prominent perivascular hyalinization was noted. Residual viable tumour was seen in 3/8 cases (<5% in one case, and >75% in 2/8 cases).
Mesenchymal neoplasms with tyrosine kinase alterations treated with targeted inhibitors show a pathologic response, which includes decreased cellularity and stromal hyalinization. The presence of these features may be helpful in assessing tumour response after targeted therapy.
在软组织肿瘤中，如婴儿纤维肉瘤（IFS）和炎性肌纤维母细胞瘤（IMT），已经描述了涉及受体酪氨酸或细胞质激酶基因的复发性改变。针对这些癌蛋白激酶结构域的靶向抑制剂的最近临床试验和监管批准，允许更多地使用靶向治疗。我们旨在描述经靶向抑制剂治疗的具有激酶改变的儿科间叶性肿瘤的组织学特征。
鉴定了 8 例具有酪氨酸激酶改变的间叶性肿瘤患者，这些患者具有治疗前后的样本。肿瘤发生在 5 名女性和 3 名男性中，中位发病年龄为 6.5 岁。肿瘤部位为骨/体软组织（n=5）和内脏（n=3）。预处理诊断为：IMT（n=3），上皮样炎性肌纤维母细胞肉瘤（n=1）和描述性诊断（n=4），如“激酶驱动的梭形细胞肿瘤”。鉴定出的融合为 ETV6::NTRK3（n=2），TPM3::NTRK1，SEPT7::BRAF，TFG::ROS1，KLC1::ALK，RANBP2::ALK 和 MAP4::RAF1。患者接受拉罗替尼（n=3），ALK 或 ALK/ROS1 抑制剂（n=3）和 MEK 抑制剂（n=2）治疗。治疗后肿瘤表现出细胞减少（7/8）和胶原基质存在（7/8），伴有广泛的玻璃样透明化（5/8）。在 2 例中，可见大量粗或砂粒体样钙化，在 1 例中，可见明显的血管周围玻璃样变性。在 3/8 例中，残留的存活肿瘤可见（1 例<5%，2/8 例>75%）。
用靶向抑制剂治疗的具有酪氨酸激酶改变的间叶性肿瘤显示出病理反应，包括细胞减少和基质透明化。这些特征的存在可能有助于评估靶向治疗后的肿瘤反应。
