The proband has a history of various cancers. In 2001, at the age of 41 years, he was diagnosed with left kidney clear cell carcinoma; in 2008, with right lung clear cell carcinoma due to renal tumor metastasis; and in 2010, with bone metastases. In 2019, he had a rectal submucosal neuroendocrine tumor. He received the standard treatment each time.
In addition to the internal carcinomas, the proband also presented sequentially with multiple neoplasms located on the skin of the head and neck or upper chest, with faster growth starting in 2013 (Fig. 1). The pathology on excised skin lesions revealed primary benign and malignant tumors, including skin squamous cell carcinoma, keratoacanthoma, sebaceous adenoma, and sebaceous gland carcinoma (Additional file 1). Starting in May 2019, the proband had recurring appearance of skin tumors, at a rate of 15–17 per month. The tumors were removed and diagnosed as primary skin malignant tumors by pathological analysis.
Family history
One brother of the proband died of gastric cancer and three sisters were all diagnosed with endometrial cancer, with one case accompanied by metachronous rectal cancer. Only one brother was cancer-free. In addition, a daughter of one of his sisters was also diagnosed with endometrial cancer at the age of 47. Because of the family history of LS-like cancers and skin lesions, MTS, a subtype of LS, was considered as a diagnosis. Comprehensive genetic testing was performed, and genetic counseling was offered.
Laboratory tests
MMR protein expression in the proband’s visceral and reduplicative skin neoplasms (Additional file 2) was assessed by IHC using MaxVisionTM primary antibodies (anti-MLH1, MAB-0789; anti-PMS2, RMA-0775; anti-MSH2, MAB-0836; anti-MSH6, RMA-0770), which revealed the absence of MSH2 and MSH6 expression (Fig. 2). Microsatellite instability (MSI) analysis of genomic DNA with a 5-mononucleotide marker panel (BAT-25, BAT-26, NR-21, NR-24, and MONO-27), and PCR products analyzed by capillary electrophoresis using an ABI 3130xl Genetic Analyzer (Applied Biosystems, Forster City, CA) showed inconsistent results, with MSI-high for the chest squamous cell carcinoma (Additional file 2). Whole exon genetic tests of the proband’s multiple tumor tissues and peripheral blood were executed using next-generation sequencing (Additional file 2), which showed a germline heterozygous deletion (c.1024_1026 del) in exon 6 of MSH2 on chromosome 2, resulting in a deletion of the p.V342 amino acid. This autosomal dominant mutation excludes promoter methylation and has not been reported previously.
IHC tests of tumor tissues from the proband’s siblings and niece also showed the loss of MSH2 and MSH6 proteins, all with microsatellite stable results (Additional file 3). The same MSH2 mutation (c.1024_1026 del, p.V342del) was detected in samples from the affected siblings and niece, but not those from the cancer-free sibling (Additional file 3), supporting the pathogenic role of this MSH2 variant. Further analysis showed that the mutation had been inherited for three consecutive generations in the family (Fig. 3).
Clinical diagnosis
Consideration of the multi-primary cancers, the family history, and the genetic testing results led to the diagnosis of LS subtype MTS, based on the Amsterdam II criteria. The MSH2 mutation (c.1024_1026del) will be documented in the genetic database.
Clinical treatment
Based on the result of MMR gene defects and MSI-high, the proband was treated with sintilimab, an inhibitory antibody that binds to PD-1, at 200 mg per 3-week cycle. After 6 cycles, there were no new skin tumors for nearly 5 months, and the size of the largest skin tumor decreased from 0.9 × 0.6 to 0.2 × 0.1 cm (Fig. 1). The patient’s condition is stable, and the efficacy of immunotherapy is being monitored.