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Abstract：
BACKGROUND: Despite major advancements, effective treatment for patients with SMARCB1-deficient cancers has remained elusive. Here, we report the first case of a SMARCB1-deficient undifferentiated carcinoma in the rectum expressing high PD-L1 and responding to a PD-1 inhibitor, as well as with low tumor mutation burden (TMB), proficient mismatch repair (MMR) and BRAF V600E mutation.
METHODS: A 35-year-old man visited our hospital complaining of increased defecation frequency, bloody stools and weight loss of 3 kg for one month. Colonoscopy revealed an ulcerated and irregular mass approximately 8-12 cm from the anus. Surgical resection was performed. Histopathological findings revealed that the tumor cells had poor connectivity with each other; each cell had eosinophilic cytoplasm and a polymorphic nucleus. Brisk mitotic activity and necrosis were frequently observed in the tumor cells. Immunohistochemical examination showed that the tumor cells were negative for SMARCB1. The tumor proportion score (TPS) of PD-L1 (22C3) expression was 95%, and the combined positive score (CPS) was 100; the tumor was mismatch repair (MMR) proficient. Next-generation sequencing showed a low tumor mutation burden (TMB), as well as the BRAF V600E mutation. The final diagnosis was SMARCB1-deficient undifferentiated carcinoma. Chemotherapy was useless in this case. His tumor recurred during chemotherapy, and he then received targeted therapy with tirelizumab, an inhibitor of PD-1. At present, his general condition is good. A recent computed tomography (CT) scan showed that the tumor had disappeared, indicating that the immunotherapy was effective. Astonishingly, his most recent follow-up was in August, and his condition continued to improve with the tumor has disappeared.
CONCLUSIONS: SMARCB1‑deficient undifferentiated carcinoma in the rectum is extremely rare, and it has aggressive histological malignancy and poor progression. The observed response to PD-1 inhibitors suggests a role for prospective use of SMARCB1 alterations as a predictive marker for immune checkpoint blockade.
METHODS: A 35-year-old man visited our hospital complaining of increased defecation frequency, bloody stools and weight loss of 3 kg for one month. Colonoscopy revealed an ulcerated and irregular mass approximately 8-12 cm from the anus. Surgical resection was performed. Histopathological findings revealed that the tumor cells had poor connectivity with each other; each cell had eosinophilic cytoplasm and a polymorphic nucleus. Brisk mitotic activity and necrosis were frequently observed in the tumor cells. Immunohistochemical examination showed that the tumor cells were negative for SMARCB1. The tumor proportion score (TPS) of PD-L1 (22C3) expression was 95%, and the combined positive score (CPS) was 100; the tumor was mismatch repair (MMR) proficient. Next-generation sequencing showed a low tumor mutation burden (TMB), as well as the BRAF V600E mutation. The final diagnosis was SMARCB1-deficient undifferentiated carcinoma. Chemotherapy was useless in this case. His tumor recurred during chemotherapy, and he then received targeted therapy with tirelizumab, an inhibitor of PD-1. At present, his general condition is good. A recent computed tomography (CT) scan showed that the tumor had disappeared, indicating that the immunotherapy was effective. Astonishingly, his most recent follow-up was in August, and his condition continued to improve with the tumor has disappeared.
CONCLUSIONS: SMARCB1‑deficient undifferentiated carcinoma in the rectum is extremely rare, and it has aggressive histological malignancy and poor progression. The observed response to PD-1 inhibitors suggests a role for prospective use of SMARCB1 alterations as a predictive marker for immune checkpoint blockade.
摘要：
背景：尽管取得了重大进步，对SMARCB1缺陷型癌症患者的有效治疗仍然难以实现.这里,我们报道了第一例直肠中SMARCB1缺陷的未分化癌表达高PD-L1并对PD-1抑制剂有反应，以及低肿瘤突变负荷（TMB），精通错配修复（MMR）和BRAFV600E突变。
方法：一名35岁的男子到我院就诊，抱怨排便次数增加，血便和体重减轻3公斤一个月。结肠镜检查显示距肛门约8-12厘米的溃疡和不规则肿块。进行手术切除。组织病理学发现，肿瘤细胞彼此之间的连通性差；每个细胞都有嗜酸性粒细胞的细胞质和多态性的细胞核。在肿瘤细胞中经常观察到活跃的有丝分裂活性和坏死。免疫组织化学检查显示肿瘤细胞SMARCB1阴性。PD-L1(22C3)表达的肿瘤比例评分(TPS)为95%,合并阳性评分（CPS）为100分；肿瘤错配修复（MMR）精通。下一代测序显示低肿瘤突变负荷（TMB），以及BRAFV600E突变。最终诊断为SMARCB1缺陷型未分化癌。化疗在这种情况下是无用的。他的肿瘤在化疗期间复发了,然后他接受了替利单抗的靶向治疗，PD-1的抑制剂。目前,他的总体状况很好。最近的计算机断层扫描（CT）扫描显示肿瘤已经消失，表明免疫疗法是有效的。令人惊讶的是，他最近的随访是在8月份，随着肿瘤消失，他的病情继续好转。
结论：直肠SMARCB1缺陷型未分化癌极为罕见，它具有侵袭性组织学恶性肿瘤和不良进展。观察到的对PD-1抑制剂的反应表明SMARCB1改变作为免疫检查点阻断的预测标志物的前瞻性用途的作用。
方法：一名35岁的男子到我院就诊，抱怨排便次数增加，血便和体重减轻3公斤一个月。结肠镜检查显示距肛门约8-12厘米的溃疡和不规则肿块。进行手术切除。组织病理学发现，肿瘤细胞彼此之间的连通性差；每个细胞都有嗜酸性粒细胞的细胞质和多态性的细胞核。在肿瘤细胞中经常观察到活跃的有丝分裂活性和坏死。免疫组织化学检查显示肿瘤细胞SMARCB1阴性。PD-L1(22C3)表达的肿瘤比例评分(TPS)为95%,合并阳性评分（CPS）为100分；肿瘤错配修复（MMR）精通。下一代测序显示低肿瘤突变负荷（TMB），以及BRAFV600E突变。最终诊断为SMARCB1缺陷型未分化癌。化疗在这种情况下是无用的。他的肿瘤在化疗期间复发了,然后他接受了替利单抗的靶向治疗，PD-1的抑制剂。目前,他的总体状况很好。最近的计算机断层扫描（CT）扫描显示肿瘤已经消失，表明免疫疗法是有效的。令人惊讶的是，他最近的随访是在8月份，随着肿瘤消失，他的病情继续好转。
结论：直肠SMARCB1缺陷型未分化癌极为罕见，它具有侵袭性组织学恶性肿瘤和不良进展。观察到的对PD-1抑制剂的反应表明SMARCB1改变作为免疫检查点阻断的预测标志物的前瞻性用途的作用。
