Kurihara Masanori, Koda Hirotomo, Aono Hiromi, Sugimoto Izumi, Sakurai Yasuhisa, Sano Terunori, Saito Yuko, Murayama Shigeo, Mori Masaya
Department of Neurology, Mitsui Memorial Hospital, Tokyo, Japan.
Department of Pathology, Mitsui Memorial Hospital, Tokyo, Japan.
Neuropathology. 2019 Apr;39(2):147-155. doi: 10.1111/neup.12542. Epub 2019 Mar 13.
Miliary brain metastasis is a rare type of brain metastasis, in which carcinoma cells disseminate to numerous foci confined to Virchow-Robin/subpial spaces. Symptoms usually progress within several months, and magnetic resonance imaging (MRI) shows multiple small contrast-enhancing lesions. We report an autopsy case of a patient who rapidly deteriorated within a week due to miliary brain metastasis after epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) discontinuation, without contrast-enhancing lesions on MRI. A 74-year-old woman was diagnosed with stage IV lung adenocarcinoma with EGFR L868R mutation 2 years before presentation. Gefitinib, an EGFR-TKI was started. After 7 months, multiple new punctate contrast-enhancing lesions in the cerebral cortex appeared. After switching to another EGFR-TKI, erlotinib, these lesions disappeared. One year later, erlotinib was discontinued because of disease progression in the lung and docetaxel was initiated. Sixteen days later, cognitive decline appeared which rapidly progressed to bedridden state in 4 days. MRI showed multiple cortical small fluid-attenuated inversion recovery high intensity lesions which lacked contrast enhancement. The patient exhibited a state of akinetic mutism within a few days, and died 52 days after the appearance of neurological symptoms. The rapid progression indicated disease flare after EGFR-TKI discontinuation. Autopsy revealed numerous foci of metastasis in the cerebral cortex, basal ganglia, thalamus, and cerebellum, in which cancer cells were mostly confined to the Virchow-Robin/subpial spaces. These pathological findings were compatible with previous reports of miliary brain metastasis. Recent reports suggest that early disseminated cancer cells can survive for a long time and even remain after chemotherapy in supportive niches, and Virchow-Robin spaces are the niches in the brain. Our case suggests that these cancer cells may rapidly proliferate as a withdrawal burst after discontinuation of molecular targeted drugs, and show pathological findings of miliary brain metastasis.
粟粒性脑转移是一种罕见的脑转移类型，癌细胞扩散至局限于Virchow-Robin间隙/软脑膜下间隙的众多病灶。症状通常在数月内进展，磁共振成像（MRI）显示多个小的强化病灶。我们报告一例尸检病例，一名患者在停用表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）后因粟粒性脑转移在一周内迅速恶化，MRI上无强化病灶。一名74岁女性在就诊前2年被诊断为IV期肺腺癌伴EGFR L868R突变。开始使用吉非替尼，一种EGFR-TKI。7个月后，大脑皮质出现多个新的点状强化病灶。换用另一种EGFR-TKI厄洛替尼后，这些病灶消失。1年后，因肺部疾病进展停用厄洛替尼并开始使用多西他赛。16天后，出现认知功能下降，4天内迅速发展至卧床状态。MRI显示多个皮质小的液体衰减反转恢复序列高强度病灶，无强化。患者在数天内出现运动不能性缄默状态，神经症状出现后52天死亡。快速进展提示EGFR-TKI停用后疾病爆发。尸检显示大脑皮质、基底神经节、丘脑和小脑有大量转移灶，癌细胞大多局限于Virchow-Robin间隙/软脑膜下间隙。这些病理结果与先前关于粟粒性脑转移的报道相符。最近的报道表明，早期播散的癌细胞可以长期存活，甚至在化疗后仍留在支持性微环境中，而Virchow-Robin间隙是大脑中的微环境。我们的病例表明，这些癌细胞可能在分子靶向药物停用后作为撤退性爆发而迅速增殖，并表现出粟粒性脑转移的病理结果。
