Case Summary

Meningiomas are slow-growing benign neoplasms of the central nervous system and distant metastases are rare. Tumor-induced hypoglycemia is mainly due to insulin hypersecretion by pancreatic islet beta-cell tumors. Other mechanisms may cause hypoglycemia in non-pancreatic tumors, manifesting as non-islet-cell tumor hypoglycemia (NICTH). At present, limited reports are available for NICTH due to metastatic meningiomas.

This is a case of a 40-year-old lady who was diagnosed with right parasagittal anaplastic meningioma (WHO grade III) in 2015. She had tumour excision followed by radiotherapy to tumour bed 60Gy in 30 fractions. She remained well for 2 years until she developed progressive breathlessness in August 2017. CT scan showed presence of a large perihilar mass with multiple pulmonary metastases & biopsy confirmed histology of metastatic anaplastic meningioma.

She then had pleural effusion requiring admission for drainage & oxygen therapy, during which she developed recurrent symptomatic hypoglycaemia. Level of circulating insulin, C-peptide, and insulin-like growth factor-I (IGF-I) were low, and serum cortisol was normal. She was supported with corticosteroids and intravenous glucose. Her pulmonary metastases were deemed unresectable and patient did not manage to receive systemic therapy due to poor performance status.

Increased glucose metabolic rates of meningiomas have been known to be correlated with tumor growth & recurrence. In this case, there may be an excessive glucose utilization due to high volume of pulmonary metastases causing the NICTH. Paraneoplastic secretion of IGF-2-related substances producing NICTH also needs to be considered. Immediate correction of hypoglycemia, followed by systemic therapy or metasectomy when feasible, as well as prevention of recurrent hypoglycemia represents the ideal management of this situation.

Case Summary

A 68-year-old gentleman with no family history of cancer presented with reduced stool frequency for two months. Colonoscopy found a stenosing rectosigmoid lesion confirmed on biopsy as a moderately differentiated adenocarcinoma. Computed tomography (CT) revealed metastases to the lungs and indeterminate mesorectal and mediastinal lymph nodes. An anterior resection was performed with histology showing T3N1b colorectal cancer. Molecular profiling demonstrated proficient MMR. Polymerase chain reaction (PCR) testing by EntroGen KRAS/BRAF Mutation Analysis Kit did not detect mutations in BRAF V600E or KRAS exon 2, 3 or 4. Sanger sequencing was inconclusive for mutations in NRAS exons 2, 3 or 4.

He progressed after 8 cycles of 1^st line XELOX chemotherapy and 11 cycles of 2^nd line. He then received 3^rd line Capecitabine with Bevacizumab for 4 cycles before progression. Next generation sequencing (NGS) based plasma cell-free DNA (cfDNA) testing was done with Lucence Hallmark assay which found: KRAS p.A59T missense substitution with 0.08% allele frequency (AF); NRAS p.A59T missense substitution with 0.11% AF and APC p.S1465Wfs*3 frameshift deletion with 0.29% AF. As part of our IMPACT study, he has ongoing bi-weekly cycles of Panitumumab. Post 7 cycles, there was a confirmed partial response and CEA decrease from 116 to 10.3µg/L. Repeat plasma cfDNA testing showed resolution of KRAS, NRAS and APC mutations but emerging TP53 p.H214R missense substitution with 7.20% AF; SMAD4 p.W524* stop-gain mutation with 0.46% AF; SMAD4 p.F408_Y413del in-frame deletion with 1.85% AF and PTEN p.R335Q missense substitution with 0.14% AF.

Pathogenomic KRAS and NRAS mutations in exon 2,3,4 detected in tumour as well as cfDNA have been shown to be negative predictors of response to anti-EGFR antibodies in metastatic colorectal cancer. Both KRAS p.A59T and NRAS pA59T have been described in literature but their functional significance is undetermined. As far as the authors are aware, this is the first report of clinical response to anti-EGFR monotherapy. Further investigation is warranted to demonstrate presence of such mutations are not a contraindication to anti-EGFR treatment.

Case Summary

A 32-year-old man presented with gross hematuria. MRI showed heterogeneous enhancing mass at right kidney size 9.1×7.8×11.1 cm. involving perinephric fat, right adrenal gland with right renal vein thrombosis. In December 2015 he was treated with cytoreductive nephrectomy and adrenalectomy. The pathology reported papillary renal cell carcinoma type 2, Fuhrman grade 3, extended to right renal vein, free margin, positive malignancy in 1 regional lymph node and tumor metastasis to right adrenal gland; T3aN1M1 (Adrenal) with MSKCC score 1. He had no adjuvant treatment. In June 2015, CT scans showed multiple liver metastasis, Sunitinib was prescribed. The best response of Sunitinib was partial response, however he had progress of cancer on Nov 2017. Second line therapy with Nivolumab 200 mg every 2 weeks was prescribed, and he had developed thyroiditis, polyarthralgia and multiple left supraclavicular lymphadenopathy. After the completeness 4 cycles of Nivolumab, MRI scans showed rapidly progression of liver masses from 2.2 cm. in previous study to 5.3 cm. The laboratory showed marked increase in absolute eosinophil count (AEC) post first and second cycle of Nivolumab. He had fullness of abdomen and developed moderate amount of ascites; the cytology of ascites was positive for malignancy. The evaluation of treatment was hyperprogressive (HDP) disease, the treatment with nivolumab was stopped. Axitinib ware prescribed and he had well tolerated with Axitinib; the MRI scans showed stable response and decrease of ascites fluid. Although anti-PD-1/PD-L1 immunotherapy has greatly improved for the treatment of patients with metastatic clear cell RCC and is generally well-tolerated. some retrospective data showed benefit in treatment for non-clear cell RCC. However, immunotherapy doesn’t work for every patient, there are patients, who have no benefit form immunotherapy. HPD is defined as a Response Evaluation Criteria in Solid Tumors (RECIST) progression at the first evaluation and a 2-fold or greater increase in tumor growth rate from baseline. If HPD is evident, immunotherapy treatment should be stopped. Until now, no biological marker has been found to predict this accelerated tumor growth, there are some evidence of early hypereosinophilia as a marker of HPD.