Hypothesis: HEG1 and claudin-4 staining will allow a diagnosis of epithelioid and biphasic mesothelioma versus non-small-cell lung carcinoma with only two stains in most cases

Histopathology. 2023 Feb;82(3):385-392. doi: 10.1111/his.14783. Epub 2022 Sep 5.


Separation of mesothelioma from metastatic carcinoma requires immunohistochemical support, with small batteries of stains recommended as a starting-point, but these numbers commonly expand to 10, 12 or more stains, a process that is not only expensive but frequently generates anomalous or confounding results, leading to even more stains. Here we review data on HEG1 clone SKM9-2, a new (now commercially available) mesothelioma marker and claudin-4, a broad-spectrum carcinoma marker, to ask whether these two stains are sufficient, by themselves, to separate mesotheliomas from non-small-cell lung (NSCLC) as well as other carcinomas. Data for HEG1, derived from four laboratories, showed membrane staining in 393 of 434 (91%) epithelioid/biphasic mesotheliomas and one of 360 (0.3%) NSCLC (sensitivity 91%, specificity 99.7%). Reports from seven laboratories evaluating claudin-4 in NSCLC showed positivity in 469 of 502 (93%) carcinomas and weak positivity in five of 463 (1.0%) epithelioid/biphasic mesotheliomas (sensitivity 93%, specificity 98.9%). Comparable results were found with carcinomas from other sites, except for serous and thyroid carcinomas, some of which react with HEG1 but are also positive for claudin-4. For sarcomatoid mesotheliomas, HEG1 sensitivity is modest and staining sometimes difficult to interpret. We hypothesise that the combination of HEG1 and claudin-4 immunostaining will potentially allow the separation of epithelioid/biphasic mesotheliomas from NSCLC carcinomas with high accuracy using only two immunostains in most cases. This combination will probably also work for carcinomas from most other sites, but more reports on HEG1 SKM9-2 staining of carcinomas other than NSCLC are needed. This approach would greatly simplify the diagnosis of mesothelioma.

Keywords: HEG1; claudin-4; mesothelioma; non-small-cell lung carcinoma.

Publication types

  • Review

MeSH terms

  • Biomarkers, Tumor
  • Carcinoma* / diagnosis
  • Carcinoma, Non-Small-Cell Lung* / diagnosis
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Claudin-4
  • Coloring Agents
  • Diagnosis, Differential
  • Humans
  • Immunohistochemistry
  • Lung Neoplasms* / diagnosis
  • Lung Neoplasms* / pathology
  • Membrane Proteins
  • Mesothelioma* / diagnosis
  • Mesothelioma* / pathology
  • Mesothelioma, Malignant* / diagnosis
  • Staining and Labeling


  • Claudin-4
  • Coloring Agents
  • Biomarkers, Tumor
  • HEG1 protein, human
  • Membrane Proteins