Case summary

Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the second leading cause of oncological deaths worldwide. Defective DNA mismatch repair (MMR) occurs in approximately 15% of sporadic CRC, but represents only 3–6% of patients with advanced disease. Two immune-checkpoint inhibitors (ICI), pembrolizumab and nivolumab, have shown efficacy in patients with metastatic microsatellite instability-high CRC, providing durable responses and disease control. Although ICI are initially highly effective, disease progression rates are substantial and the optimal subsequent therapy for patients that progressed after ICI remains uncertain.

We report a case of a 58-year-old man, who presented at the emergency room with gastrointestinal bleeding in September 2016. Imaging studies showed a stenotic lesion in transverse colon (hepatic flexure). Extended right hemicolectomy was performed, with the diagnosis of a stage IIIB colorectal carcinoma. Immunohistochemistry for DNA MMR proteins showed loss of expression of MLH1 and PMS2. Twelve cycles of adjuvant FOLFOX were administered, but early local relapse was detected, two months later. Despite resection, hepatic and lymph node progression occurred after four months. After six months of first-line FOLFIRI plus bevacizumab, disease progression was confirmed. Second-line therapy with pembrolizumab 200 mg every 3 weeks was initiated. The patient experienced prolonged disease control of 16 months, with a lymph node oligo-progression at 10 months of immunotherapy controlled with radiotherapy. In October 2019, a new lymph node progression led to a third line treatment with nivolumab plus ipilimumab. After four cycles of the combination, nivolumab maintenance was initiated. Seven months later, liver and lymph nodes progression occurred, resulting in hepatic failure. The patient died after 23 months of sequential immunotherapy.

Although there is no strong evidence of subsequent treatment options for metastatic CRC patients with defective MMR, we present a case of clinical benefit and radiological response with sequential ICI. Further clinical trials are needed to evaluate this strategy in such patients.

Case summary

We report the case of a 46-years-old Caucasian woman who referred to our Institution following the diagnosis of breast cancer in 2010. The patient had also a personal history of epithelial ovarian cancer in 2006, and kidney cancer in 2008. Notably, no significant cancer diagnosis emerged in her family. Given the diagnosis of breast and ovarian cancers, the patient was tested for deleterious BRCA1/2 mutations. This analysis revealed a BRCA1 variant of unknown significance (VUS), thus a preventive Hereditary Breast and Ovarian Cancer syndrome (HBOC)-like clinical and instrumental screening was recommended. The detected BRCA1 VUS was reclassified as benign in 2015. From 2016 to 2018 the patient underwent surgical excisions of multiple skin lesions including sebaceous neoplasms (ranging from sebaceous adenoma to sebaceoma) and a squamous cell carcinoma in situ. In addition, she was diagnosed with high-grade urothelial bladder carcinoma in 2017. Given the fact that multiple diagnosed tumors were within the spectrum of Lynch syndrome, a next-generation sequencing multi-gene testing investigating hereditary non-polyposis colorectal cancer syndromes was recommended. The analyses identified a heterozygous MLH1 mutation c.250A>T (p.Lys84Ter), which was never reported in ClinVar and dbSNP databases. Bioinformatics analyses showed that this non-sense point mutation introduces a premature stop codon leading to a truncated and probably nonfunctional protein. Moreover, this mutation was classified as pathogenic by the Mutation Tester tool. Taken together, the personal history of more than one visceral carcinoma and the presence of multiple sebaceous neoplasms defined a Muir-Torre Syndrome presumably due to the c.250A>T MLH1 mutation detected. Therefore, the genetic counseling and MLH1 testing were extended to her offspring in 2019. Her son (28-years old) was found to be a carrier of the mutation and he was addressed to a personalized surveillance program. Notably, he was diagnosed with adenocarcinoma of the caecum, and undergone surgical treatment in June 2020. Our case supports the use of multigene or genome-scale sequencing and bioinformatics tools for the clinical management of patients with history of multiple cancers.

Case summary

Gitelman syndrome is a rare, recessively-inherited disease characterized by chronic hypokalemia and hypomagnesemia as a result of defective electrolyte co-transport at the level of the distal convoluted tubule of the kidney. Here, we present the first report of a patient with Gitelman syndrome who developed multiple neoplasia including colorectal polyposis, synchronous colorectal cancers, recurrent breast fibroadenomata and a desmoid tumor. Whole exome sequencing and pedigree analysis confirmed germline compound heterozygous mutations of c.179C>T and c.1326C>G in SLC12A3, and in addition, identified a dominantly-inherited monoallelic c.934-2A>G splice site mutation in MUTYH. Germline mutations in other known cancer susceptibility genes, such as TP53 and APC, were not identified. In vitro, magnesium deficiency potentiated oxidative DNA damage in lymphoblastoid cell lines derived from the same patient, with elevated 8-hydroxy-2’-deoxyguanosine levels detected on ELISA and direct immunofluorescence. We postulate that monoallelic MUTYH mutations may manifest in the presence of cooperative non-genetic mechanisms, in this case possibly magnesium deficiency from Gitelman syndrome.

Case summary

Background

Urinary bladder paragangliomas are rare tumors which may present with symptoms due to mass effect, catecholamine release or be detected incidentally upon radiologic imaging or during screening in familial cases for hereditary tumors.

Case details

A 33 year old male patient presented with complaints of loose stools since the past one and a half months, associated with weight loss. The stools were non bloody. He did not complain of pain abdomen, fever or oral ulcers. There was no history of episodic headache, palpitations or sweating. There was no history of recent travel or consumption of frozen food or chinese food or history of consumption of water from a fresh water source. Physical examination was suggestive of pallor. A physical examination was unremarkable, except for the presence of pallor. An ultrasound abdomen was suggestive of a polypoid soft tissue lesion in urinary bladder, following which a conventional cystoscopy and transurethral resection of the bladder tumor was performed, during which a solid vascular broad based growth, 2*2 cm in size, on anterior wall was discovered and biopsied. Biopsy was reported as an Inflammatory myofibroblastic tumour. Immunohistochemistry showed the tumor to be synaptophysin, chromogranin and CD 56 positive, while the sustentacular cells were positive for S 100. Ki 67 index was 2 percent. Biopsy review was suggestive of urothelium covered tissue composed of organs of zellballen with an insular matrix of uniform polygonal cells, surrounded by prominent vascular network of thin walled blood vessels. Tumor cells were shown to have round to oval nuclei, with finely granular chromatin. Diagnosis of paraganglioma was made, based upon review of IHC and histopathological findings. CECT abdomen performed subsequently was suggestive of a mild plaque like thickening in antero-inferior wall of bladder with no obvious intraluminal mass like lesion. He was seeking a review, as he wanted to discuss the need for further management – including need for undergoing radical cystectomy,

Discussion

Type of surgical management and indications for adjuvant treatment of recurrent, non metastatic tumors need to be defined further.

Case summary

ROS1-rearrangement is a known oncogenic driver in non-small-cell lung cancer (NSCLC), present in 1-2% of cases. Crizotinib was the first drug approved for advanced-stage disease and remains the preferred approach in first-line therapy. However, the development of acquired resistance, usually within the ROS1 kinase domain, is inevitable and poses a clinical challenge in treating these patients. Some secondary resistance mutations have been described in preclinical models, such as G2032R, D2033N, L1951R and L2026M, though there are few reports in vivo to date. Likewise, the activity of new ROS1 inhibitors against those mutations has been restricted to in vitro analysis and scarce case reports. Nevertheless, Ceritnib, Brigatinib, Lorlatinib and Cabozantinib emerge as a strategy to overcome Crizotinib resistance in this setting. Here we report, for the first time, the clinical activity of Cabozantinib in a crizotinib-resistant NSCLC harboring CD74-ROS1 fusion and L2026M ROS1 mutation. After two lines of chemotherapy (cisplatin/pemetrexed and docetaxel) and exposure to immunotherapy (nivolumab), ROS1 rearrangement was identified in a lung biopsy by fluorescent in situ hybridization (FISH). The patient remained on partial response (RECIST 1.1) for 32 months with crizotinib. On progression, a lung re-biopsy detected by Next-Generation Sequencing (NGS) the gatekeeper L2026M mutation as the secondary resistance mechanism. Use of cabozantinib managed to restore disease control (stable disease by RECIST 1.1) with important clinical benefit (improvement of cough and dyspnea) for over 8 months.