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Uterine Neurotrophic Tyrosine Receptor Kinase Rearranged Spindle Cell Neoplasms: Three Cases of an Emerging Entity
Abstract:
Uterine sarcomas are rare; most are either smooth muscle or endometrial stromal in origin. Recent molecular advances have identified several, genetically defined entities with specific morphologic, clinicopathological associations, and therapeutic options. We report 3 cases of uterine neurotrophic tyrosine receptor kinase ( NTRK )-rearranged spindle cell neoplasms," currently classified as "emerging entities" in the WHO Classification of Female Genital Tract Tumors, 2020, Fifth Edition. The affected patients were 32, 34, and 42 years of age. Two patients presented with vaginal bleeding; the third presented with a cervical mass found incidentally during laparoscopy for an ectopic gestation. All 3 tumors were polypoid masses that distorted the cervix. Microscopically, they comprised cellular, fascicular, and storiform, plump spindle cells, with occasional rounded cells, and frequent mitoses (4-48/10 high power fields) in a myxoid stroma. All 3 cases showed entrapment of benign cervical glands. Inflammatory cell infiltrates, including plasma cells, were noted in all 3 tumors. One case had tumor cell necrosis, osteoid-like material, and osteoclast-like giant cells and showed lymphovascular invasion. Immunohistochemically, our cases showed patchy S100 (2/3) and CD34 (3/3) positivity. CD10 was positive in 2/3 cases. 3/3 cases showed pan-tropomyosin receptor kinase positivity (cytoplasmic). The NTRK -translocations demonstrated were: NTRK1::TMP3, NTRK1::TPR, and NTRK3::SPECC1L . Two of the patients had extensive disease and underwent chemotherapy. Larotrectinib was approved for one patient who demonstrated a striking reduction in tumor volume upon initiation of this treatment.
Insights
This study details three rare uterine neurotrophic tyrosine receptor kinase (NTRK)-rearranged spindle cell neoplasms. Targeted therapy with Larotrectinib showed significant tumor reduction in one patient, highlighting a promising treatment option.
Area of Science:
- Gynecologic Pathology
- Oncology
- Molecular Pathology
Background:
- Uterine sarcomas are rare, with diverse origins and emerging molecular classifications.
- Recent advances identify genetically defined entities with distinct clinical and therapeutic profiles.
- Neurotrophic tyrosine receptor kinase (NTRK)-rearranged spindle cell neoplasms are emerging entities in female genital tract tumors.
Purpose of the Study:
- To report and characterize three cases of uterine NTRK-rearranged spindle cell neoplasms.
- To describe their morphologic, immunohistochemical, and molecular features.
- To discuss potential therapeutic implications, including targeted therapy.
Main Methods:
- Case series analysis of three patients with uterine NTRK-rearranged spindle cell neoplasms.
- Histopathological examination including morphology, mitotic count, and stromal characteristics.
- Immunohistochemical staining for S100, CD34, CD10, and pan-tropomyosin receptor kinase (TRK).
- Molecular analysis to identify specific NTRK gene fusions (NTRK1::TMP3, NTRK1::TPR, NTRK3::SPECC1L).
Main Results:
- Patients aged 32, 34, and 42 presented with vaginal bleeding or incidental cervical masses.
- Tumors were polypoid, spindle cell neoplasms with high mitotic activity, myxoid stroma, and inflammatory infiltrates.
- Immunohistochemistry showed variable S100/CD10 positivity and consistent pan-TRK positivity.
- NTRK gene fusions were identified in all three cases.
- One patient with extensive disease showed significant tumor regression with Larotrectinib treatment.
Conclusions:
- Uterine NTRK-rearranged spindle cell neoplasms represent a distinct emerging entity.
- Morphological and immunohistochemical features aid in diagnosis.
- Identification of NTRK fusions is crucial for potential targeted therapy with TRK inhibitors like Larotrectinib.
- Larotrectinib demonstrated efficacy in a patient with advanced disease.
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