Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: a report of new cases and review of the literature

Our plain-English summary of Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: a report of new cases and review of the literature, by Y. Karamurzin, Z. Zeng, Z.K. Stadler, et al (Human Pathology, 2012).

The study

• Authors: Y. Karamurzin, Z. Zeng, Z.K. Stadler, L. Zhang, I. Ouansafi, H.A. Al-Ahmadie, C. Sempoux, L.B. Saltz, R.A. Soslow, E.M. O'Reilly, P.B. Paty, D.G. Coit, J. Shia, D.S. Klimstra
• Journal: Human Pathology
• Published: 2012;43(10):1677-87
• Type of article: Case report, Review
• Cited by: 88 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Immunohistochemical detection of DNA mismatch repair proteins and polymerase chain reaction detection of microsatellite instability have enhanced the recognition of mismatch repair-deficient neoplasms in patients with Lynch syndrome and, consequently, led to the identification of tumors that have not been included in the currently known Lynch syndrome tumor spectrum. Here, we report 4 such unusual tumors. Three of the 4, a peritoneal mesothelioma, a pancreatic acinar cell carcinoma, and a pancreatic well-differentiated neuroendocrine tumor, represented tumor types that, to the best of our knowledge, have not been previously reported in Lynch syndrome. The fourth tumor was an adrenocortical carcinoma, which has rarely been reported previously in Lynch syndrome. Three of our 4 patients carried a pathogenic germ-line mutation in a mismatch repair gene. The unusual tumor in each of the 3 patients showed loss of the mismatch repair protein corresponding to the mutation. The fourth patient did not have mutation information but had a history of colonic and endometrial carcinomas; both lacked MSH2 and MSH6 proteins. Interestingly, none of the 4 unusual tumors revealed microsatellite instability on polymerase chain reaction testing, whereas an appendiceal carcinoma from 1 of the study patients who was tested simultaneously did. The recognition of such tumors expands the repertoire of usable test samples for the workup of high-risk families. As yet, however, there are no data to support the inclusion of these tumors into general screening guidelines for detecting Lynch syndrome, nor are there data to warrant surveillance for these tumors in patients with Lynch syndrome.

Copyright © 2012 Elsevier Inc. All rights reserved.

In plain English

This article reported four patients linked to Lynch syndrome and reviewed earlier reports. Lynch syndrome is an inherited condition caused by faults in DNA mismatch repair genes. Three patients carried such a fault; the fourth had no mutation information, but her earlier endometrial cancer lacked two mismatch repair proteins. Patients came from hospitals in New York and Brussels. Each had an unusual tumor type: a peritoneal mesothelioma in a 56-year-old man with an MLH1 mutation, a pancreatic acinar cell carcinoma, a pancreatic well-differentiated neuroendocrine tumor and an adrenocortical carcinoma. All four tumors showed abnormal mismatch repair proteins on staining, and the mesothelioma lacked MLH1 and PMS2. None of the four showed microsatellite instability on testing; an appendix cancer from one patient did. Asbestos was not mentioned; the authors said it was unclear whether such tumors were part of the syndrome or coincidental. The authors concluded that such tumors can serve as test samples when working up high-risk families. They added that there is as yet no evidence to recommend surveillance for these tumors, or routine testing of them to detect the syndrome.

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 series (report of 4 patients) with a review of the literature
• Who was studied: 4 patients identified from pathology and clinical genetics databases at Memorial Sloan-Kettering Cancer Center (New York) and Cliniques Universitaires Saint-Luc (Brussels). Three carried a pathogenic germ-line mismatch repair gene mutation; the fourth had no mutation information. The mesothelioma patient was a 56-year-old man of European ancestry.
• Exposure: Inherited (germ-line) mutations in DNA mismatch repair genes: MLH1 in patient 1, MSH6 in patient 2, MSH2 in patient 4, and unknown in patient 3. The article does not mention asbestos or any other environmental exposure.
• Main results:
  • Patient 1's tumor (the peritoneal mesothelioma) had features of epithelioid malignant mesothelioma.
  • The mesothelioma lacked the mismatch repair proteins MLH1 and PMS2 on staining, matching the patient's MLH1 mutation.
  • The unusual tumors in all 4 patients showed mismatch repair protein abnormalities on immunohistochemistry.
  • In patient 3, whose germ-line mutation status was unknown, the prior endometrial carcinoma had lost MSH2 and MSH6 staining. The pancreatic endocrine tumor had also lost these two proteins.
  • Testing with 5 mononucleotide markers found stable microsatellites (no microsatellite instability) in the unusual tumors of all 4 patients.
  • The appendix cancer from patient 4, tested at the same time, showed high-frequency microsatellite instability.
  • The authors stated that their report added peritoneal mesothelioma, pancreatic acinar cell carcinoma and pancreatic well-differentiated neuroendocrine tumor to the list of unusual mismatch repair-deficient tumors in Lynch syndrome.
  • In a separate series of 40 pancreatic acinar cell carcinomas at the authors' center, this case was the only one associated with hereditary nonpolyposis colorectal cancer syndrome.
• The authors' conclusion: The authors concluded that these unusual tumors can serve as test samples in working up high-risk families. They also concluded that there is as yet no evidence to recommend general surveillance for these tumors in Lynch syndrome, or routine testing of them to detect Lynch syndrome.
• Limitations the authors state:
  • The germ-line mutation status of patient 3 was unknown.
  • Data on how often unusual tumors other than breast cancer occur in Lynch syndrome are essentially lacking.
  • Whether these unusual tumors are coincidental or part of the inherited syndrome remains to be clarified.
  • The mismatch repair deficiency in these tumors may be a secondary event rather than the cause of the tumor.
  • Normal mismatch repair protein staining in such unusual tumors does not rule out Lynch syndrome.

Topics

Medical terms in this study, explained in our Lexicon: Microsatellite Instability (MSI-H), Neoplasm, Peritoneal Mesothelioma, Acinar, Carcinoma, Well-Differentiated.

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