First case report of malignant peritoneal mesothelioma and oral verrucous carcinoma in a patient with a germline PTEN mutation: a combination of extremely rare diseases with probable further implications

Our plain-English summary of First case report of malignant peritoneal mesothelioma and oral verrucous carcinoma in a patient with a germline PTEN mutation: a combination of extremely rare diseases with probable further implications, by M.W. Löffler, J. Steinhilber, F.J. Hilke, et al (BMC Medical Genetics, 2018).

The study

• Authors: M.W. Löffler, J. Steinhilber, F.J. Hilke, S.P. Haen, H. Bösmüller, I.A. Montes-Mojarro, I. Bonzheim, A. Stäbler, U. Faust, U. Grasshoff, I. Königsrainer, H.G. Rammensee, L. Kanz, A. Königsrainer, S. Beckert, O. Riess, C. Schroeder
• Journal: BMC Medical Genetics
• Published: 2018;19(1):144
• Type of article: Case report
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The PTEN-hamartoma-tumor-syndrome (PHTS) is caused by germline mutations in Phosphatase and Tensin homolog (PTEN) and predisposes to the development of several typical malignancies. Whereas PTEN mutations have been implicated in the occurrence of malignant mesotheliomas, the genetic landscape of verrucous carcinomas (VC) is largely uncharted. Both VC and malignant peritoneal mesotheliomas (MPM) are exceedingly rare and a potential link between these malignancies and PHTS has never been reported.

Case Presentation: We here describe the clinical course of a PHTS patient who, in addition to a typical thyroid carcinoma at the age of 36 years, developed a highly-differentiated oral VC and an epithelioid MPM six years later. The patient with a history of occupational asbestos exposure underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for MPM. The clinical diagnosis of PHTS was consequently corroborated by a germline PTEN deletion. Sequencing of tumor tissue revealed a second hit in PTEN in the thyroid carcinoma and VC, confirmed by a PTEN loss and activation of the PI3K/AKT pathway in immunohistochemistry. Furthermore, additional somatic mutations in the thyroid carcinoma as well as in the VC were detected, whereas the genetics of MPM remained unrevealing.

Discussion And Conclusions: We here report the very unusual clinical course of a patient with rare tumors that have a germline mutation first hit in PTEN in common. Since this patient was exposed to asbestos and current evidence suggests molecular mechanisms that might render PHTS patients particularly susceptible to mesothelioma, we strongly recommend PHTS patients to avoid even minimal exposure.

In plain English

This case report described one Caucasian man, a carpenter, with PTEN-hamartoma-tumor-syndrome (PHTS), an inherited cancer-predisposition condition. He met the diagnostic criteria for Cowden syndrome. Genetic testing found a germline deletion of one copy of the whole PTEN gene. He had a thyroid carcinoma removed at age 36. At 42 he was diagnosed with a verrucous carcinoma of the lower lip and an epithelioid malignant peritoneal mesothelioma. He reported about seven years of frequent work with fibre cement roofing containing mainly chrysotile asbestos, starting 25 years before the mesothelioma diagnosis, followed by exposure to asbestos-containing flooring. After surgery and heated chemotherapy inside the abdomen, scans showed no recurrence over two years. Tumor testing found a second PTEN defect in the thyroid and lip tumors but not in the mesothelioma, where no somatic oncogene mutations were found. The authors noted that a case report cannot establish causality. They concluded that a greatly increased vulnerability to asbestos in PHTS is plausible, and recommended that people with PHTS avoid even minimal asbestos exposure.

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: Case report (single patient), including genetic sequencing and immunohistochemistry of three tumors
• Who was studied: One Caucasian male patient with PTEN-hamartoma-tumor-syndrome (Cowden syndrome), a carpenter. He had a papillary thyroid carcinoma at age 36, then a verrucous carcinoma of the lower lip and a malignant peritoneal mesothelioma at age 42. The patient's location is not stated; the authors are at the University of Tübingen, Germany.
• Exposure: Occupational asbestos exposure as a carpenter. He had frequent exposure to fibre cement roofing containing mainly chrysotile asbestos for about seven years, starting 25 years before the mesothelioma diagnosis. This was followed by a subsequent 5-year period of exposure to asbestos-containing industrial flooring during building renovations.
• Main results:
  • Laparoscopy showed nodular lesions spread over the small bowel, transverse colon and liver. These were diagnosed as a differentiated epithelioid mesothelioma with papillary growth type.
  • The patient met enough criteria for a diagnosis of Cowden syndrome. Genetic testing confirmed a heterozygous germline deletion of the complete PTEN gene. The article does not state whether the deletion was inherited from a parent, and further segregation analysis was recommended.
  • After cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, repeated abdominal and thoracic CT scans showed no signs of recurrence during two years of follow-up.
  • A thoracic CT scan showed diffuse thickening in both lungs, appearing as milky spots and nodules of constant size over time, and emphysema-type changes. No lesions suspicious of malignancy were seen.
  • A second PTEN defect (a 'second hit') was found in two of the three tumors: a truncating variant in the verrucous carcinoma, and loss of the second PTEN copy in the thyroid carcinoma.
  • In the peritoneal mesothelioma, no somatic oncogene mutations were identified and no loss of the second PTEN copy was detected.
  • PTEN protein staining was weak but focally positive in the mesothelioma and negative in the other two tumors. Phospho-mTOR staining was strong in the mesothelioma.
• The authors' conclusion: The authors concluded that, although there is no conclusive evidence yet, a highly increased vulnerability to asbestos as a contributing factor to peritoneal mesothelioma in PHTS is plausible and supported by molecular mechanisms. They stated that persons with PHTS should avoid any, even minimal, exposure to asbestos.
• Limitations the authors state:
  • The authors stated that a case report cannot establish conclusive evidence or causality.
  • The authors stated that, because the cancers are so rare, there is no conclusive evidence available yet.
  • The authors described a link between PHTS and verrucous carcinoma, and likewise between PHTS and peritoneal mesothelioma, as never previously reported and purely speculative.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Carcinoma, Germline Mutation, Malignant Mesothelioma, Epithelioid, Asbestos Exposure, Cytoreductive Surgery, HIPEC.

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