Robert J. Tomsich Pathology and Laboratory Medicine Institute, Anatomic Pathology, Cleveland Clinic, Cleveland, OH, 44195, USA.
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35249, USA.
Hum Pathol. 2020 Apr;98:81-88. doi: 10.1016/j.humpath.2020.02.008. Epub 2020 Mar 3.
Flat urothelial lesions with atypia may pose significant diagnostic challenges. Given frequent increased proliferation rates in florid reactive urothelial atypia and limited studies on the interpretation of p53 stains in the urothelium (following current standard guidelines for correlation with P53 mutation status), we sought to further study the discriminatory value of Ki-67 and p53 for florid reactive urothelial atypia versus urothelial carcinoma in situ (CIS). Bladder specimens diagnosed as reactive urothelial atypia (n = 40) and CIS (n = 40) were assessed by immunohistochemical staining with antibodies for Ki-67, p53, CD44, and CK20. Immunoreactivity was scored based on percent cells positive for Ki-67 and pattern of reactivity with p53 (aberrant: diffuse strong positive or negative; normal: patchy/wild type). CD44 and CK20 reactivity patterns served as adjunctive internal validation controls for reactive urothelial atypia and CIS, as previously described. In reactive urothelial atypia, Ki-67 ranged from 0% to 90% (mean, 34% ± 26) with 30 cases (75%) having >10%. In CIS, Ki-67 ranged from 5% to 95% (mean, 50% ± 25) with 17 cases (43%) having >50%. In all 40 cases (100%) of reactive urothelial atypia, p53 expression had a wild-type pattern. In CIS, aberrant p53 expression was identified in 15 cases (37%): 3 cases (7%) were p53 negative (i.e. null phenotype) and 12 cases (30%) showed strong and diffuse nuclear reactivity (in >85% of cells). The remaining 25 cases (63%) of CIS had a p53 wild-type pattern of expression. Cytoplasmic CK20 immunoreactivity in umbrella cells was seen in 34 cases (85%) of reactive urothelial atypia, and 6 cases (15%) were negative. In addition, 35 cases (88%) of reactive urothelial atypia demonstrated full-thickness CD44 expression, while 5 cases (12%) had expression confined to the basal/parabasal layers of the urothelium. Strong and diffuse CK20 positivity was present in 39 cases (98%) of CIS, and patchy positivity was detected in 1 case (2%). None of the CIS cases overexpressed CD44: 16 cases (40%) showed focal expression in the nonneoplastic basal cell layer; 24 cases (60%) demonstrated no staining. In summary, Ki-67 has poor discriminatory value for reactive urothelial atypia versus CIS and adds little to the classic CK20/CD44 immunophenotype. While p53 sensitivity for CIS is relatively low (30%) and interpretation as either wild type or negative may be challenging in a small subset of cases, strong and diffuse nuclear reactivity was 100% specific in the distinction from florid reactive urothelial atypia in this cohort.
具有非典型性的扁平尿路上皮病变可能具有重大的诊断挑战。鉴于在明显的反应性尿路上皮非典型性中经常存在增殖率增加，以及在尿路上皮中 p53 染色的解释（遵循当前与 P53 突变状态相关的标准指南）的研究有限，我们试图进一步研究 Ki-67 和 p53 对明显的反应性尿路上皮非典型性与原位尿路上皮癌（CIS）的鉴别价值。通过免疫组织化学染色用 Ki-67、p53、CD44 和 CK20 的抗体评估诊断为反应性尿路上皮非典型性（n=40）和 CIS（n=40）的膀胱标本。根据 Ki-67 阳性细胞百分比和 p53 反应模式（异常：弥漫强阳性或阴性；正常：斑片状/野生型）对免疫反应性进行评分。CD44 和 CK20 反应模式如前所述，用作反应性尿路上皮非典型性和 CIS 的辅助内部验证对照。在反应性尿路上皮非典型性中，Ki-67 的范围为 0%至 90%（平均值为 34%±26%），其中 30 例（75%）>10%。在 CIS 中，Ki-67 的范围为 5%至 95%（平均值为 50%±25%），其中 17 例（43%）>50%。在所有 40 例（100%）反应性尿路上皮非典型性中，p53 表达呈野生型模式。在 CIS 中，15 例（37%）中发现异常 p53 表达：3 例（7%）为 p53 阴性（即空表型），12 例（30%）显示强且弥漫的核反应性（>85%的细胞）。CIS 的其余 25 例（63%）具有 p53 野生型表达模式。在 34 例（85%）反应性尿路上皮非典型性中可见伞细胞中的细胞质 CK20 免疫反应性，6 例（15%）为阴性。此外，35 例（88%）反应性尿路上皮非典型性表现为全层 CD44 表达，而 5 例（12%）的表达局限于尿路上皮的基底/副基底层。39 例（98%）CIS 表现出强烈和弥漫的 CK20 阳性，1 例（2%）表现出斑片状阳性。没有 CIS 病例过度表达 CD44：16 例（40%）在非肿瘤性基底细胞层中表现为局灶性表达；24 例（60%）无染色。总之，Ki-67 对反应性尿路上皮非典型性与 CIS 的鉴别价值较差，并且对经典的 CK20/CD44 免疫表型几乎没有补充。虽然 p53 对 CIS 的敏感性相对较低（30%），并且在一小部分病例中可能难以解释为野生型或阴性，但在本队列中，强而弥漫的核反应性 100%特异性地与明显的反应性尿路上皮非典型性区分开来。
