Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice

Summary Neurofibromatosis type 1 is a relatively common inherited disorder. Patients have a high predisposition to develop both benign and malignant tumours. Although many manifestations of neurofibromatosis type 1 affect the nervous system, other organs and tissues can also be affected. Because of the varying features and clinical heterogeneity inherent to this disorder, patients can present to different medical and surgical specialists and, therefore, the association of clinical symptoms with neurofibromatosis type 1 might not be appreciated. Thus, for prompt diagnosis and to provide optimum care for patients with neurofibromatosis type 1, clinicians must be aware of the diverse clinical features of this disorder. We advocate a multidisciplinary approach to care, entailing a dedicated team of specialists throughout the lifetime of the patient. As our understanding of this disorder deepens through basic laboratory and clinical investigations, swift implementation of new effective treatments becomes feasible.

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Neurofibromatosis type 1: a multidisciplinary approach to care.

A molecular biology–based taxonomy has been proposed for pheochromocytoma and paraganglioma (PPGL). Data from the Cancer Genome Atlas revealed clinically relevant prognostic and predictive biomarkers and stratified PPGLs into three main clusters. Each subgroup has a distinct molecular–biochemical–imaging signature. Concurrently, new methods for biochemical analysis, functional imaging, and medical therapies have also become available. The research community now strives to match the cluster biomarkers with the best intervention. The concept of precision medicine has been long awaited and holds great promise for improved care. Here, we review the current and future PPGL classifications, with a focus on hereditary syndromes. We discuss the current strengths and shortcomings of precision medicine and suggest a condensed manual for diagnosis and treatment of both adult and pediatric patients with PPGL. Finally, we consider the future direction of this field, with a particular focus on how advanced molecular characterization of PPGL can improve a patient’s outcome, including cures and, ultimately, disease prevention.

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New Perspectives on Pheochromocytoma and Paraganglioma: Toward a Molecular Classification.

Context: Pheochromocytomas and paragangliomas (PHEO/PGL) are neuroendocrine tumors that arise from sympathetic and parasympathetic paraganglia. Diagnosed rarely during childhood, PHEO/PGL are nonetheless important clinical entities, particularly given our evolving understanding of their pathophysiology. Evidence Acquisition: We identified articles through the U.S. National Library of Medicine by using the search terms pheochromocytoma and paraganglioma. Results were narrowed to manuscripts that included children and studies related to the genetics of PHEO/PGL. Web-based resources for genetic disorders were also used. For all articles, we performed subsequent reference searches and verification of source data. Evidence Synthesis: Up to 20% of PHEO/PGL are diagnosed in children. Most are functional tumors, and clinical presentation includes symptoms related to catecholamine hypersecretion and/or tumor mass effect. Increasingly, PHEO/PGL are identified during presymptomatic screening in children with genetic...

/pdf/a-current-review-of-the-etiology-diagnosis-and-treatment-of-4a2wxcxvwo.pdf

A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma.

Purpose: Patients with succinate dehydrogenase subunit B (SDHB) mutation-related pheochromocytoma/paraganglioma (PHEO/PGL) are at higher risk for metastatic disease than other hereditary PHEOs/PGLs. Current therapeutic approaches are limited but the best outcomes are based on the early and proper detection of as many lesions as possible. Because PHEOs/PGLs overexpress somatostatin receptor 2 (SSTR2), the goal of our study was to assess the clinical utility of [68Ga]-DOTA(0)-Tyr(3)-octreotate ([68Ga]-DOTATATE) positron emission tomography/computed tomography (PET/CT) and to evaluate its diagnostic utility in comparison to the currently recommended functional imaging modalities [18F]-fluorodopamine ([18F]-FDA), [18F]-fluorodihydroxyphenylalanine ([18F]-FDOPA), [18F]-fluoro-2-deoxy-D-glucose ([18F]-FDG) PET/CT as well as CT/magnetic resonance imaging (MRI). 

Experimental Design: [68Ga]-DOTATATE PET/CT was prospectively performed in 17 patients with SDHB-related metastatic PHEOs/PGLs. All patients also underwent [18F]-FDG PET/CT and CT/MRI with 16 of the 17 patients also receiving [18F]-FDOPA and [18F]-FDA PET/CT scans. Detection rates of metastatic lesions were compared between all these functional imaging studies. A composite synthesis of all used functional and anatomical imaging studies served as the imaging comparator. 

Results: [68Ga]-DOTATATE PET/CT demonstrated a lesion-based detection rate of 98.6% (95% confidence interval (CI) 96.5% to 99.5%), [18F]-FDG, [18F]-FDOPA, [18F]-FDA PET/CT, and CT/MRI showed detection rates of 85.8% (CI 81.3% to 89.4%) (p<0.01), 61.4% (CI 55.6% to 66.9%) (p<0.01), 51.9% (CI 46.1% to 57.7%) (p<0.01), and 84.8% (CI 80.0% to 88.5%) (p<0.01), respectively.

Conclusions: [68Ga]-DOTATATE PET/CT showed a significantly superior detection rate compared to all other functional and anatomical imaging modalities and may represent the preferred future imaging modality in the evaluation of SDHB-related metastatic PHEO/PGL.

https://clincancerres.aacrjournals.org/content/clincanres/21/17/3888.full.pdf

Superiority of [68Ga]-DOTATATE PET/CT to other functional imaging modalities in the localization of SDHB-associated metastatic pheochromocytoma and paraganglioma

BACKGROUND
A long-term follow-up was conducted of 18 patients with a diagnosis of pheochromocytoma/paraganglioma treated with a combination of cyclophosphamide, vincristine, and dacarbazine (CVD).

METHODS
The study design was a nonrandomized, single-arm trial conducted at a government medical referral center. Eighteen patients with metastatic malignant pheochromocytoma/paraganglioma were studied. After controlling symptoms of catecholamine excess, patients were treated with cyclophosphamide at 750 mg/m2, vincristine at 1.4 mg/m2, and dacarbazine at 600 mg/m2 on Day 1 and dacarbazine at 600 mg/m2 on Day 2, every 21 to 28 days.

RESULTS
Combination chemotherapy with CVD produced a complete response rate of 11% and a partial response rate of 44%. Median survival from a landmark was 3.8 years for patients whose tumors responded to therapy and 1.8 years for patients whose tumors did not respond (P = .65). All patients with tumors scored as responding reported improvement in their symptoms related to excessive catecholamine release and had objective improvements in blood pressure. CVD was well tolerated with only grade I/II toxicities.

CONCLUSIONS
Combination chemotherapy with CVD produced objective tumor responses in patients with advanced malignant pheochromocytoma/paraganglioma. In this 22-year follow-up there was no difference in overall survival between patients whose tumors objectively shrank and those with stable or progressive disease. However, patients reported improvement in symptoms, had objective improvements in blood pressure, and had tumor shrinkage that made surgical resection possible. The authors conclude that CVD therapy is not indicated in every patient with metastatic pheochromocytoma/paraganglioma, but should be considered in the management of patients with symptoms and where tumor shrinkage might be beneficial. Cancer 2008. © 2008 American Cancer Society.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.23812

Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients.

Elizabeth Hung

Papers

Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients.