RESUMEN
BACKGROUND: Papillary thyroid carcinoma rarely undergoes anaplastic transformation. Some risk factors for anaplastic transformation of thyroid cancer are known, but such transformation is difficult to predict in practice. We report a case demonstrating elevations of neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) over time as a precursor to anaplastic transformation of thyroid carcinoma. CASE PRESENTATION: The patient was an 89 year-old woman with a history of chronic aortic dissection. She was referred to our department after her local doctor detected thyroid nodules. She had previously been found to have multinodular goiter and enlarged left cervical lymph nodes on computed tomography. Her chief complaint was cervical discomfort and hoarseness. Blood tests revealed: white blood cells (WBCs), 4900 /µL; CRP, 0.29 mg/dL; neutrophils, 64.4%; and lymphocytes, 25.4%. A 21 mm mass was identified in the upper left lobe. Left III (16 mm) and left VI (16 mm) lymph node were enlarged on ultrasonography. Fine-needle aspiration cytology diagnosed malignant papillary carcinoma. However, due to the advanced age and medical history of the patient, a non-surgical policy was implemented. The primary tumor grew to 4 cm in diameter by 9 months after diagnosis, and blood tests showed: WBC, 7700 /µL; CRP, 0.18 mg/dL; neutrophils, 65.3%; and lymphocytes, 22.3%. By 10 months after diagnosis, the tumor had increased rapidly in diameter to 8 cm, with blood tests showing: WBC, 6500 /µL; CRP, 1.01 mg/dL; neutrophils, 68.2%; and lymphocytes, 19.3%. Anaplastic transformation of papillary thyroid carcinoma was diagnosed, and the patient was placed on treatment under a policy of best supportive care. Multiple lung metastases appeared 11 months after diagnosis, and blood test results showed: WBC, 13,300 /µL; CRP, 11.28 mg/dL; neutrophils, 93.6%; and lymphocytes, 2.3%. Unfortunately, the patient died of disease progression 63 days after identification of undifferentiated metastasis. CONCLUSIONS: Chances to see the natural history of anaplastic transformation of thyroid cancer are rare. Elevations in NLR and CRP over time may be precursors to anaplastic transformation.
RESUMEN
A subset of thyroid cancers present at advanced stage or with dedifferentiated histology and have limited response to standard therapy. Tumors harboring the BRAF V600E mutation may be treated with BRAF inhibitors; however, tumor response is often short lived due to multiple compensatory resistance mechanisms. One mode of resistance is the transition to an alternative cell state, which on rare occasions can correspond to tumor dedifferentiation. DNA sequencing and RNA expression profiling show that thyroid tumors that dedifferentiate after BRAF inhibition are enriched in known genetic alterations that mediate resistance to BRAF blockade, and may also drive tumor dedifferentiation, including mutations in the PI3K/AKT/MTOR (PIK3CA, MTOR), MAP/ERK (MET, NF2, NRAS, RASA1), SWI/SNF chromatin remodeling complex (ARID2, PBRM1), and JAK/STAT pathways (JAK1). Given these findings, recent investigations have evaluated the efficacy of dual-target therapies; however, continued lack of long-term tumor control illustrates the complex and multifactorial nature of these compensatory mechanisms. Transition to an immune-suppressed state is another correlate of BRAF inhibitor resistance and tumor dedifferentiation, suggesting a possible role for concurrent targeted therapy with immunotherapy. Investigations into combined targeted and immunotherapy are ongoing, but early results with checkpoint inhibitors, viral therapies, and CAR T-cells suggest enhanced anti-tumor immune activity with these combinations.
