Over expression of CDK4 and MDM2 in a patient with recurrent ALK-negative mediastinal inflammatory myofibroblastic tumor

Abstract

Rationale: The diagnosis of anaplastic lymphoma kinase (ALK)-negative inflammatory myofibroblastic tumors (IMT) remains challenging because of their morphological resemblance with spindle cell sarcoma with myofibroblastic characteristics. Patient concerns: A 69-year-old female patient presented with loco-regional recurrent IMT several times within 8 years after primary treatment and neck lymph node metastasis 3.5 years after last recurrence. Diagnosis: The primary, recurrence, and lymph node metastasis lesions were diagnosed as ALK-negative IMTs based on the histopathological features. Interventions: Biopsy samples were obtained during repeated surgeries and evaluated for genomic alterations during first and recurrent presentations. The evaluation was done using pathway-driven massive parallel sequencing, and genomic alterations between primary and recurrent tumors were compared. Outcomes: Copy number gains and overexpression of mouse double minute 2 homolog (MDM2) and cyclin dependent kinase 4 (CDK4) were observed in the primary lesion, and additional gene amplification of Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), Succinate Dehydrogenase Complex II subunit C (SDHC), and thyroid stimulating hormone receptor (TSHR) Q720H were found in the recurrent tumors. Metastases to the neck lymph node were observed 3.5 years after recurrence. Lessons: Our results indicated genetic evolution in a microscopically benign condition and highlighted the importance of molecular characterization of fibro-inflammatory lesions of uncertain malignant potential.

Treatment, pathological characteristics, and prognosis of pulmonary inflammatory myofibroblastic tumor–a retrospective study of 8 cases

“…Some researchers have found the existence of cancer stem cells in PIMT tissues ( 24 ), and some studies have reported that the lymph nodes removed during surgery in patients with PIMT were positive ( 23 ). In addition, cervical lymph node metastasis has occurred 3.5 years post-operation ( 25 ). Moreover, the WHO points out that IMT is a borderline tumor with the potential for recurrence and rare metastasis.…”

“…( 23 ). Some patients with IMT who have tumor tissue removed still experience relapse and distant metastasis ( 25 – 27 ). In one study, researchers followed up 23 patients after PIMT excision for 2–127 months; in those cases, recurrence only occurred twice after operation, and there was no recurrence after reoperation ( 28 ).…”

“…One study has confirmed that Anthracycline-based and methotrexate plus/minus vinorelbine/vinblastine (MTX-V) regimens are very effective in IMT ( 17 ). Studies have reported the cases of using radiotherapy for recurrence of surgical resection ( 25 ), but currently there is no sufficient evidence to prove the efficacy of radiotherapy. There are reports that gene-targeted drugs are used to treat IMT ( 32 – 40 ).…”

Uterine Inflammatory Myofibroblastic Tumors

“…Proposed high-risk clinicopathologic features in uterine IMTs include older patient age, larger tumor size, infiltrative borders, predominance of myxoid morphology, severe cytologic atypia, necrosis, and increased mitotic activity 6,7,29. Proposed IHC and molecular high-risk features from prior studies including IMTs from other anatomic sites have included ALK-negativity, RANPB2::ALK gene fusions in the so-called epithelioid inflammatory myofibroblastic sarcoma, p53 expression, and MDM2 overexpression/amplification 28–35. There is currently a gap in the literature regarding whether molecular alterations drive clinical behavior, perhaps due to the narrow focus on gene fusions that drive IMTs.…”

“…6,7,29 Proposed IHC and molecular high-risk features from prior studies including IMTs from other anatomic sites have included ALK-negativity, RANPB2::ALK gene fusions in the so-called epithelioid inflammatory myofibroblastic sarcoma, p53 expression, and MDM2 overexpression/amplification. [28][29][30][31][32][33][34][35] There is currently a gap in the literature regarding whether molecular alterations drive clinical behavior, perhaps due to the narrow focus on gene fusions that drive IMTs. To our knowledge, no comprehensive molecular characterization of aggressive IMTs from any site has been reported in the literature.…”