TRAF7 mutations and immunohistochemical study of uterine adenomatoid tumor compared with malignant mesothelioma

Our plain-English summary of TRAF7 mutations and immunohistochemical study of uterine adenomatoid tumor compared with malignant mesothelioma, by H. Itami, T. Fujii, T. Nakai, et al (Human Pathology, 2021).

The study

• Authors: H. Itami, T. Fujii, T. Nakai, M. Takeda, Y. Kishi, F. Taniguchi, C. Terada, F. Okada, Y. Nitta, M. Matsuoka, S. Sasaki, S. Sugimoto, T. Uchiyama, K. Morita, T. Kasai, R. Kawaguchi, C. Ohbayashi
• Journal: Human Pathology
• Published: 2021;111:59-66
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Adenomatoid tumors (ATs) are benign mesothelial tumors with a good prognosis and usually occur in female and male genital tracts, including in the uterus. ATs are genetically defined by tumor necrosis factor receptor-associated factor (TRAF) 7 mutations, and a high number of AT cases show immunosuppression. On the other hand, malignant mesotheliomas (MMs) are malignant mesothelial tumors with a very poor prognosis. Genetic alterations in TRAF, methylthioadenosine phosphorylase(MTAP), and BRCA-associated nuclear protein 1 (BAP1) in ATs derived from the uterus and MMs of pleural or peritoneal origin were compared by gene sequence analysis or immunohistochemical approaches. Formalin-fixed paraffin-embedded tissues derived from patients were used for immunohistochemical staining of L1 cell adhesion molecule (L1CAM), BAP1, MTAP, and sialylated protein HEG homolog 1 (HEG1) in 51 uterine AT cases and 34 pleural or peritoneal MM cases and for next-generation sequencing of the TRAF7 gene in 44 AT cases and 21 MM cases. ATs had a significantly higher rate of L1CAM expression than MMs, whereas MMs had a significantly higher rate of loss of MTAP and BAP1 expression than ATs. There was no difference in the rate of HEG1 expression between the tumor types. Most of the ATs (37/44; 84%) had somatic mutations in TRAF7, but none of the MMs had somatic mutations in TRAF7 (0/21; 0%). In addition, a low number of AT cases were associated with a history of immunosuppression (9/51; 17.6%). TRAF7 mutation is one of the major factors distinguishing the development of AT from MM, and immunosuppression might not be associated with most AT cases.

Copyright © 2021 Elsevier Inc. All rights reserved.

In plain English

This laboratory study from Japan compared a benign tumor of the uterus, called adenomatoid tumor, with malignant mesothelioma of the pleura or peritoneum. The authors examined stored tissue from 51 uterine adenomatoid tumor cases and 34 mesothelioma cases (30 pleural, 4 peritoneal). They stained the tissue for several markers and sequenced the TRAF7 gene where the DNA was usable (44 adenomatoid tumor cases, 21 mesothelioma cases). All 51 adenomatoid tumors stained for L1CAM, compared with 18 of 34 mesotheliomas (52.9%). Loss of MTAP was seen in 50.0% of mesotheliomas and loss of BAP1 in 55.9%, but neither loss was seen in any adenomatoid tumor. HEG1 and the standard mesothelial markers did not differ significantly between the two tumor types. TRAF7 mutations in a gene region called the WD40 repeats were found in 37 of 44 adenomatoid tumors (84%) and in none of the mesotheliomas. Nine of 51 adenomatoid tumor patients (17.6%) had a history of immunosuppression. The study did not examine asbestos exposure. The authors concluded that TRAF7 mutation is one of the major factors distinguishing adenomatoid tumor from mesothelioma, and that immunosuppression might not be associated with most adenomatoid tumor cases.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Comparative pathology and genetic study of archived (formalin-fixed, paraffin-embedded) tumor tissue, using immunohistochemistry and next-generation sequencing of the TRAF7 gene
• Who was studied: 51 uterine adenomatoid tumor cases (Nara Medical University 2003 to 2017; Takanohara Central Hospital 2014 to 2018) and 34 malignant mesothelioma cases, 30 pleural and 4 peritoneal (Nara Medical University 2010 to 2018; National Hospital Organization Kinki-chuo Chest Medical Center 2015 to 2018), Japan
• Exposure: The study did not assess asbestos or any other exposure. It compared tissue markers (L1CAM, MTAP, BAP1, HEG1, calretinin, WT-1, D2-40) and TRAF7 gene mutations between the two tumor types.
• Main results:
  • L1CAM staining was positive in 51 of 51 adenomatoid tumors (100%) and in 18 of 34 mesotheliomas (52.9%), P less than 0.001
  • MTAP loss was found in 0% of adenomatoid tumors and 50.0% (17 of 34) of mesotheliomas. BAP1 loss was found in 0% of adenomatoid tumors and 55.9% (19 of 34) of mesotheliomas. Both differences had P less than 0.001.
  • HEG1 was positive in 100% of both tumor types. Calretinin, WT-1 and D2-40 also showed no significant differences between adenomatoid tumors and mesotheliomas.
  • 37 of 44 adenomatoid tumors (84%) had TRAF7 missense mutations at the carboxy-terminal WD40 repeats. None of the 21 analyzed mesotheliomas had mutations there. DNA could not be analyzed in 7 adenomatoid tumor cases and 13 mesothelioma cases.
  • A TRAF7 change called del 111E was found in 36 of 44 adenomatoid tumors, 15 of 21 mesotheliomas, and 4 of 8 non-tumor tissue samples. The authors suggested it is a germline (inherited) change rather than a tumor (somatic) mutation.
  • 9 of 51 adenomatoid tumor patients (17.6%) had a history of immunosuppression. This was compared with 9 of 50 patients without adenomatoid tumor (18%) who had a hysterectomy at Nara Medical University in 2017. 31 of 37 adenomatoid tumor cases with somatic TRAF7 mutations (83.8%) had no such history.
  • Adenomatoid tumors were found in 1.4% (51 of 3648) of uterine surgeries
• The authors' conclusion: The authors concluded that TRAF7 mutation is one of the major factors distinguishing the development of adenomatoid tumor from malignant mesothelioma, and that immunosuppression might not be associated with most adenomatoid tumor cases.
• Limitations the authors state:
  • The newly found TRAF7 mutations P16L, G27E and R29G need confirmation in studies with more adenomatoid tumor cases
  • Further studies are needed to understand adenomatoid tumors with TRAF7 mutations outside the WD40 repeats and adenomatoid tumors without TRAF7 mutations

Topics

Medical terms in this study, explained in our Lexicon: Adenomatoid Tumor, Malignant Mesothelioma, Prognosis, Necrosis, MTAP, BAP1, Immunohistochemistry, HEG1.

Related studies

• Adenomatoid tumors of the male and female genital tract are defined by TRAF7 mutations that drive aberrant NF-kB pathway activation — B. Goode, N.M. Joseph, et al. (2018)
• Uterine adenomatoid tumors confirmed by immunohistochemical staining — M. Irikoma, K. Takahashi, et al. (2001)
• Immunohistochemical evidence of the mesothelial histogenesis of a uterine adenomatoid tumor — Y. Satoh, M. Hiraguchi, et al. (1998)
• Well-differentiated papillary mesothelioma of the peritoneum is genetically defined by mutually exclusive mutations in TRAF7 and CDC42 — M. Stevers, J.T. Rabban, et al. (2019)
• Synchronous occurrence of benign mesothelioma and adenomatoid tumor of uterus: A case report and review of literature — P.R. Shen, J. Cen, et al. (2019)
• Composite multicystic mesothelioma and adenomatoid tumour of the uterus: different morphological manifestations of the same process? — J.K. Chan, M.H. Fong (1996)

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