Anatomic pathology selected abstracts

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POU2F3: A marker for neuroendocrine-low/negative small cell lung cancer

POU2F3 (POU class 2 homeobox 3) is a novel transcription factor used to define the special molecular subtype of small cell lung cancer known as SCLC-P. However, the sensitivity and specificity of POU2F3 IHC staining has not been investigated fully. The authors conducted a study in which they explored the expression of POU2F3 by IHC in a large cohort of SCLC clinical samples (n=246), other common lung cancer types (n=2,207), and various other cancer types (n=194). The results showed that POU2F3 was strongly nuclear stained in 13.41 percent (33 of 246) of SCLC cases, with negative or minimal labeling for thyroid transcription factor-1 and neuroendocrine markers. Compared with POU2F3-negative SCLC, SCLC-P harbored fewer TP53 and RB1 mutations. POU2F3 was also expressed in 3.13 percent (eight of 256) of squamous cell carcinomas and 20 percent (two of 10) of large cell neuroendocrine carcinomas (LCNECs), whereas other lung cancer types were POU2F3 negative. Furthermore, POU2F3 was expressed in 22.2 percent (four of 18) of thymic tumors. All other tumors were POU2F3 negative, except for thymic carcinoma, although sparsely distributed weak nuclear staining was observed in lung adenocarcinoma, cervical squamous cell carcinoma, and colorectal carcinoma. The sensitivity and specificity of POU2F3 in neuroendocrine-low/negative SCLC were 82.1 percent and 99.4 percent, respectively. Notably, some rare unique patterns of POU2F3 expression were observed. One case of thymic squamous cell carcinoma was characterized by diffuse and uniform cytomembrane staining. One case of esophageal neuroendocrine tumor was nuclear positive, while the normal proliferating squamous epithelium was strongly membrane stained. The authors concluded that this is the largest cohort of clinical samples to confirm that POU2F3 is a highly sensitive and specific diagnostic marker for neuroendocrine-low/negative SCLC.

Wang Y, Jin Y, Shen X, et al. POU2F3: A sensitive and specific diagnostic marker for neuroendocrine-low/negative small cell lung cancer. Am J Surg Pathol. 2023;47(9):1059–1066.

Correspondence: Dr. Yuan Li at whliyuan@hotmail.com

Multi-society Delphi consensus statement on fatty liver disease nomenclature

The principal limitations of the terms nonalcoholic fatty liver disease and nonalcoholic steatohepatitis are their reliance on exclusionary confounder terms and the use of potentially stigmatizing language. The authors conducted a study to determine if content experts and patient advocates were in favor of changing the nomenclature or definition, or both. Three large pan-national liver associations led a modified Delphi process. Consensus was defined a priori as a supermajority (67 percent) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the names and diagnostic criteria. A total of 236 panelists from 56 countries participated in four online surveys and two hybrid meetings. Response rates across the four survey rounds were 87, 83, 83, and 78 percent, respectively. Seventy-four percent of respondents indicated that the current nomenclature was sufficiently flawed to consider a name change. The terms “non-alcoholic” and “fatty” were considered stigmatizing by 61 and 66 percent of respondents, respectively. Steatotic liver disease (SLD) was chosen as an overarching term to encompass the various etiologies of steatosis. The term steatohepatitis was thought to be an important pathophysiological concept that should be retained. Therefore, metabolic dysfunction-associated steatohepatitis (MASH) was selected to replace nonalcoholic steatohepatitis (NASH). Metabolic dysfunction-associated steatotic liver disease (MASLD) was chosen to replace nonalcoholic fatty liver disease (NAFLD). There was consensus to change the definition to include at least one of five cardiometabolic risk factors. Those cases with no metabolic parameters and no known cause were deemed cryptogenic SLD. A new category, termed MetALD, was created to describe those with MASLD who consume greater amounts of alcohol per week (140 to 350 g/week for females and 210 to 420 g/week for males). The authors concluded that the new nomenclature and diagnostic criteria are widely supported and non-stigmatizing and can increase disease awareness and accelerate the development of biomarkers for MASLD, MASH, and MetALD.

Rinella ME, Lazarus JV, Ratziu V, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023. doi: 10.1016/j.hep.2023.06.003

Correspondence: Dr. Philip N. Newsome at p.n.newsome@bham.ac.uk or Dr. Mary E. Rinella at mrinella@bsd.uchicago.edu