An Unexpected Esophageal Lesion in a Patient With Muir-Torre Syndrome

Abstract

Question: In a 52-year-old female patient with a history of sebaceous gland neoplasms of the skin (carcinoma resected in 2017 and several subsequent adenomas) and positive family history for early-onset colorectal cancer (father at the age of 39 years), Muir-Torre syndrome was suspected. This is a rare variant of Lynch syndrome (LS; approximately 10% of individuals with LS) clinically defined by the typical LS tumor spectrum (colorectal cancer as well as extracolonic tumors, eg, endomtetrial/ovarian cancer, urinary tract cancer) and additional increased risk for characteristic skin neoplasms (especially sebaceous gland neoplasms and keratoacanthoma). DNA mismatch-repair (MMR) deficiency resulting in an accumulation of somatic mutations throughout the genome, also affecting genes involved in carcinogenesis, causes LS. Genetic testing identified a pathogenic germline mutation in MSH2 (mutS homolog 2) on chromosome 2p21 and confirmed the diagnosis in 2018. Compliant with current international guidelines, the patient was included in a specific tumor-screening program. In dermatologic follow-up examinations, basal cell carcinoma and squamous cell carcinoma of the skin were detected. By annual surveillance colonoscopies up to the present, 4 colorectal adenomas with sizes from 2 to 15 mm were resected. On an individual basis, and not covered by guidelines, we performed yearly surveillance esophagogastroduodenoscopy (EGD). Interestingly, at the age of 57 years, a small irregular and slightly elevated lesion (8 mm) with small central erosion (Figure A, arrow) was observed (Paris 0-IIa) in the mid-esophagus (25 cm from incisors). The central part of the lesion stained negative during chromoendoscopy with Lugol’s iodine (1%) (Figure B, arrow) and showed an irregular surface pattern with virtual chromoendoscopy (NBI mode; narrow band imaging) (Figure C). Therefore, malignancy was suspected, and the lesion was removed en bloc by means of rubber-band ligation assisted endoscopic mucosal resection (Figures D and E). Of note, the patient was never a smoker and only occasionally consumed alcohol. Endoscopies were performed with Olympus GIF-H190 endoscopes (Olympus, Hamburg, Germany). Which diagnosis do you suspect and is this lesion LS associated? Look on page 189 for the answer and see the Gastroenterology website (www.gastrojournal.org) for more information on submitting to Gastro Curbside Consult. Histopathologic and immunohistochemical examination of the resected tumor revealed poorly differentiated invasive squamous cell carcinoma (pT1a, Pn0, V0, R0, G3) (Figure F, hematoxylin and eosin [HE] stain, ×40) with focal invasion of the lamina muscularis mucosae (Figure G, HE, ×200, arrow). Molecular microsatellite instability testing discovered instability in 4/5 markers (BAT-26, NR-21, BAT-25, and NR-24; NR-27 was stable). When an LS-associated tumor was suspected, MMR protein immunohistochemistry showed a loss of MSH2 expression within the neoplastic cells (Figure H, ×200, red arrow) while surrounding tissue stained positive for MSH2 (Figure H, black arrow) and MLH1 expression was unaffected in neoplastic (Figure I, ×200, red arrow) and nonneoplastic (Figure I, black arrow) cells. Computed tomography and endoscopic ultrasound did not find any distant or lymph-node metastases, and there was no residual tumor in a follow-up endoscopy. Because of poor tumor differentiation and invasion of the lamina muscularis mucosae (m3), additive radiotherapy (50.4 Gy/59.92 Gy boost in 28 fractions) was recommended after discussion by the tumor board. This is the first description of an LS/Muir-Torre syndrome–associated squamous cell carcinoma of the esophagus in a patient without typical risk factors for this tumor entity. Moreover, we show in-depth molecular characterization to prove LS association. Only rarely have adenocarcinomas of the esophagus been reported1Sweetser S. Chandan V.S. Baron T.H. Dysphagia in Lynch syndrome.Gastroenterology. 2013; 145: 1167-1168Abstract Full Text Full Text PDF Scopus (6) Google Scholar in LS. Until recently, squamous cell carcinoma of the skin was not counted as typical skin manifestation of Muir-Torre syndrome, but an association has been demonstrated.2Ykema B.L.M. Adan F. Crijns M.B. et al.Cutaneous squamous cell carcinoma is associated with Lynch syndrome: widening the spectrum of Lynch syndrome-associated tumours.Br J Dermatol. 2021; 185: 462-463Crossref PubMed Scopus (7) Google Scholar Of note, our patient also suffered from squamous cell carcinoma of the skin. In conclusion, clinicians should carefully consider esophageal neoplasms as a rare manifestation of LS. Despite limited data supporting EGD surveillance in LS and in contrast to current guidelines, upper endoscopy could be easily performed along with routine colonoscopy in an effort to prevent morbidity and mortality from upper GI manifestations of LS (early-stage cancer observed in about 1.5% of asymptomatic patients3Farha N. Hrabe J. Sleiman J. Beard J. et al.Clinically actionable findings on surveillance EGD in asymptomatic patients with Lynch syndrome.Gastrointest Endosc. 2022; 95: 105-114Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar).