Myxofibrosarcoma harboring an <i>MLH1</i> pathogenic germline variant associated with Muir-Torre syndrome: a case report

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Abstract

Background

Muir–Torre syndrome (MTS), which accounts for a small subset (1–3 %) of Lynch syndrome (LS), is an autosomal dominant genetic disorder characterized by sebaceous gland or keratoacanthoma associated with visceral malignancies. Most families with MTS have pathogenic germline variants (PGV) in MSH2. Sarcomas are not common on the LS tumor spectrum, and sarcomas associated with MTS are extremely rare.

Case presentation

Here we report a myxofibrosarcoma of the abdominal wall in a 73-year-old man with a sebaceoma that occurred synchronically, leading to a diagnosis of MTS. The loss of MLH1 and PMS2 protein expression was detected in immunohistochemistry, and high-frequency microsatellite instability (MSI-H) was also confirmed. A germline genetic analysis revealed that he harbored the MLH1 PGV.

Conclusions

This is the first case of MSI-H myxofibrosarcoma with MTS in an MLH1 PGV carrier. Although rare, we should recognize that sarcomas can be part of the spectrum of LS and MTS.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13053-021-00192-z.

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Most cited references 25

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PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.

Dung Le, Jennifer Uram, Hao Wang … (2015)

Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.

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Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Dung Le, Jennifer N. Durham, Kellie N Smith … (2017)

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.

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Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results From the Phase II KEYNOTE-158 Study

Aurélien Marabelle, Dung Le, Paolo Ascierto … (2019)

Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti‒programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer. Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review. Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events. Our study demonstrates the clinical benefit of anti–programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.

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Author and article information

Contributors

Eisuke Kobayashi: ekobayas@ncc.go.jp

Journal

Journal ID (nlm-ta): Hered Cancer Clin Pract

Journal ID (iso-abbrev): Hered Cancer Clin Pract

Title: Hereditary Cancer in Clinical Practice

Publisher: BioMed Central (London )

ISSN (Print): 1731-2302

ISSN (Electronic): 1897-4287

Publication date (Electronic): 21 August 2021

Publication date PMC-release: 21 August 2021

Publication date Collection: 2021

Volume: 19

Electronic Location Identifier: 34

Affiliations

[1 ]GRID grid.272242.3, ISNI 0000 0001 2168 5385, Department of Musculoskeletal Oncology and Rehabilitation, , National Cancer Center Hospital, ; 5-1-1 Tsukiji, Chuo-ku, 104-0045 Tokyo, Japan

[2 ]GRID grid.177174.3, ISNI 0000 0001 2242 4849, Department of Orthopaedic Surgery, Graduate School of Medical Sciences, , Kyushu University, ; Fukuoka, Japan

[3 ]GRID grid.272242.3, ISNI 0000 0001 2168 5385, Endoscopy Division, , National Cancer Center Hospital, ; Tokyo, Japan

[4 ]GRID grid.272242.3, ISNI 0000 0001 2168 5385, Department of Genetic Medicine and Services, , National Cancer Center Hospital, ; Tokyo, Japan

[5 ]GRID grid.272242.3, ISNI 0000 0001 2168 5385, Department of Clinical Genomics, , National Cancer Center Research Institute, ; Tokyo, Japan

[6 ]GRID grid.272242.3, ISNI 0000 0001 2168 5385, Department of Diagnostic Pathology, , National Cancer Center Hospital, ; Tokyo, Japan

[7 ]GRID grid.420115.3, ISNI 0000 0004 0378 8729, Oncogene Research Unit/ Cancer Prevention Unit, , Tochigi Cancer Center Research Institute, ; Tochigi, Japan

Article

Publisher ID: 192

DOI: 10.1186/s13053-021-00192-z

PMC ID: 8379813

PubMed ID: 34419117

SO-VID: 981c5772-4ce8-460c-9f5d-6f0ed6f213df

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 11 May 2021

Date accepted : 13 August 2021

Funding

Funded by: National Cancer Center Research and Development Fund

Award ID: 31-A-2

Funded by: FundRef http://dx.doi.org/10.13039/100009619, Japan Agency for Medical Research and Development;

Award ID: JP19ck0106268

Award ID: JP20ck0106554

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: myxofibrosarcoma,muir-torre syndrome,lynch syndrome,mismatch repair (mmr),microsatellite instability (msi)

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: myxofibrosarcoma, muir-torre syndrome, lynch syndrome, mismatch repair (mmr), microsatellite instability (msi)

Myxofibrosarcoma harboring an MLH1 pathogenic germline variant associated with Muir-Torre syndrome: a case report

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Abstract

Background

Case presentation

Conclusions

Supplementary Information

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Karger: Oncology

Most cited references 25

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results From the Phase II KEYNOTE-158 Study

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