Nick Plowman

Clinical manifestations of familial paraganglioma and phaeochromocytomas in succinate dehydrogenase B (SDH-B) gene mutation carriers

Objective  Phaeochromocytomas and paragangliomas are familial in up to 25% of cases and can result from succinate dehydrogenase (SDH) gene mutations. The aim of this study was to describe the clinical manifestations of subjects with SDH‐B gene mutations.

Contrasting clinical manifestations of SDHB and VHL associated chromaffin tumours

Mutations in succinate dehydrogense-B (SDHB) and the von Hippel-Lindau (VHL) genes result in an increased risk of developing chromaffin tumours via a common aetiological pathway. The aim of the present retrospective study was to compare the clinical phenotypes of disease in subjects developing chromaffin tumours as a result of SDHB mutations or VHL disease. Thirty-one subjects with chromaffin tumours were assessed; 16 subjects had SDHB gene mutations and 15 subjects had a diagnosis of VHL. VHL-related tumours were predominantly adrenal phaeochromocytomas (22/26; 84.6%), while SDHB-related tumours were predominantly extra-adrenal paragangliomas (19/25; 76%). Median age at onset of the first chromaffin tumour was similar in the two cohorts. Tumour size was significantly larger in the SDHB cohort in comparison with the VHL cohort (P=0.002). Multifocal disease was present in 9/15 (60%) of the VHL cohort (bilateral phaeochromocytomas) and only 3/16 (19%) of the SDHB cohort, while metastatic disease was found in 5/16 (31%) of the SDHB cohort but not in the VHL cohort to date. The frequency of symptoms, hypertension and the magnitude of catecholamine secretion appeared to be greater in the SDHB cohort. Renal cell carcinomas were a feature in 5/15 (33%) of the VHL cohort and 1/16 (6%) of the SDHB cohort. These data indicate that SDHB-related tumours are predominantly extra-adrenal in location and associated with higher catecholamine secretion and more malignant disease, in subjects who appear more symptomatic. VHL-related tumours tend to be adrenal phaeochromocytomas, frequently bilateral and associated with a milder phenotype.

Conjunctival Melanoma: The Role of Conservative Surgery and Radiotherapy in Regional Metastatic Disease

Objective: To evaluate prognostic factors and determine the role of conservative surgery and radiotherapy in managing metastatic conjunctival malignant melanoma (MM) involving preauricular/submandibular lymph nodes.

A Validation Study for the Use of ROS1 Immunohistochemical Staining in Screening for ROS1 Translocations in Lung Cancer.

Introduction: The presence of ROS proto‐oncogene 1, receptor tyrosine kinase gene (ROS1) rearrangements in lung cancers confers sensitivity to ROS kinase inhibitors, including crizotinib. However, they are rare abnormalities (in ˜1% of non–small cell lung carcinomas) that are typically identified by fluorescence in situ hybridization (FISH), and so screening using immunohistochemical (IHC) staining would be both cost‐ and time‐efficient. Methods: A cohort of lung tumors negative for other common mutations related to targeted therapies were screened to assess the sensitivity and specificity of IHC staining in detecting ROS1 gene rearrangements, enriched by four other cases first identified by FISH. A review of published data was also undertaken. Results: IHC staining was 100% sensitive (95% confidence interval: 48–100) and 83% specific (95% confidence interval: 86–100) overall when an h‐score higher than 100 was used. Patients with ROS1 gene rearrangements were younger and typically never‐smokers, with the tumors all being adenocarcinomas with higher‐grade architectural features and focal signet ring morphologic features (two of five). Four patients treated with crizotinib showed a partial response, with three also showing a partial response to pemetrexed. Three of four patients remain alive at 13, 27, and 31 months, respectively. Conclusion: IHC staining can be used to screen for ROS1 gene rearrangements, with patients herein showing a response to crizotinib. Patients with tumors that test positive according to IHC staining but negative according to FISH were also identified, which may have implications for treatment selection.

A “growing cause” of diabetic ketoacidosis

The progress of a young woman presenting with diabetic ketoacidosis is described. She was managed as for a new presentation of type 1 diabetes, but was subsequently diagnosed with acromegaly due to a large pituitary tumour. Following treatment for this, and relative normalisation of growth hormone levels, she was able to stop insulin completely. Subsequently, an oral glucose tolerance test showed no evidence of abnormal glucose tolerance and she remains non-diabetic.

Original ArticleTranslational OncologyA Validation Study for the Use of ROS1 Immunohistochemical Staining in Screening for ROS1 Translocations in Lung Cancer

Introduction: The presence of ROS proto‐oncogene 1, receptor tyrosine kinase gene (ROS1) rearrangements in lung cancers confers sensitivity to ROS kinase inhibitors, including crizotinib. However, they are rare abnormalities (in ˜1% of non–small cell lung carcinomas) that are typically identified by fluorescence in situ hybridization (FISH), and so screening using immunohistochemical (IHC) staining would be both cost‐ and time‐efficient. Methods: A cohort of lung tumors negative for other common mutations related to targeted therapies were screened to assess the sensitivity and specificity of IHC staining in detecting ROS1 gene rearrangements, enriched by four other cases first identified by FISH. A review of published data was also undertaken. Results: IHC staining was 100% sensitive (95% confidence interval: 48–100) and 83% specific (95% confidence interval: 86–100) overall when an h‐score higher than 100 was used. Patients with ROS1 gene rearrangements were younger and typically never‐smokers, with the tumors all being adenocarcinomas with higher‐grade architectural features and focal signet ring morphologic features (two of five). Four patients treated with crizotinib showed a partial response, with three also showing a partial response to pemetrexed. Three of four patients remain alive at 13, 27, and 31 months, respectively. Conclusion: IHC staining can be used to screen for ROS1 gene rearrangements, with patients herein showing a response to crizotinib. Patients with tumors that test positive according to IHC staining but negative according to FISH were also identified, which may have implications for treatment selection.

A validation study for the use of ROS-1 immunohistochemistry in screening for ROS-1 translocations in lung cancer

Introduction: The presence of ROS proto‐oncogene 1, receptor tyrosine kinase gene (ROS1) rearrangements in lung cancers confers sensitivity to ROS kinase inhibitors, including crizotinib. However, they are rare abnormalities (in ˜1% of non–small cell lung carcinomas) that are typically identified by fluorescence in situ hybridization (FISH), and so screening using immunohistochemical (IHC) staining would be both cost‐ and time‐efficient. Methods: A cohort of lung tumors negative for other common mutations related to targeted therapies were screened to assess the sensitivity and specificity of IHC staining in detecting ROS1 gene rearrangements, enriched by four other cases first identified by FISH. A review of published data was also undertaken. Results: IHC staining was 100% sensitive (95% confidence interval: 48–100) and 83% specific (95% confidence interval: 86–100) overall when an h‐score higher than 100 was used. Patients with ROS1 gene rearrangements were younger and typically never‐smokers, with the tumors all being adenocarcinomas with higher‐grade architectural features and focal signet ring morphologic features (two of five). Four patients treated with crizotinib showed a partial response, with three also showing a partial response to pemetrexed. Three of four patients remain alive at 13, 27, and 31 months, respectively. Conclusion: IHC staining can be used to screen for ROS1 gene rearrangements, with patients herein showing a response to crizotinib. Patients with tumors that test positive according to IHC staining but negative according to FISH were also identified, which may have implications for treatment selection.