title: Disentangling of Malignancy from Benign Pheochromocytomas/Paragangliomas.
abstract: OBJECTIVE
  Many malignant tumors initially appear benign but subsequently exhibit extensive metastases. Early identification of malignant pheochromocytomas and paragangliomas (PPGLs) before metastasis is important for improved prognosis. However, there are no robust prognostic indices of recurrence and malignancy. The aim of this study was to identify the clinical and histopathological factors that predict malignant PPGLs.
  
  
  METHODS
  Retrospective follow-up study.
  
  
  METHODS
  In this study, we included 223 patients with pathologically confirmed PPGLs who were treated between 2000 and 2015 at the Seoul National University Hospital in South Korea.
  
  
  RESULTS
  Of these patients, 29 were diagnosed with malignancy, 12 of whom presented with metastatic lesions at the initial diagnosis while 17 developed metastases during follow-up. Nineteen patients with recurrent PPGLs consisted of ones with malignant PPGLs (n = 17) and multifocal PPGLs (n = 2) who had VHL and RET mutations. The mean age at presentation for malignant PPGLs was significantly younger than that for benign PPGLs (43.0 vs. 49.0 years, respectively; p = 0.023). Tumor size was not a distinguishing factor between malignant and benign PPGLs (5.0 vs. 4.5 cm, respectively; p = 0.316) nor did it predict recurrence. Of 119 patients with available pheochromocytoma of adrenal gland scaled score (PASS) data, those with malignant PPGLs presented PASS values ≥4. Of 12 parameters of PASS, necrosis, capsular invasion, vascular invasion, cellular monotony, high mitosis, atypical mitotic figures, and nuclear hyperchromasia were significant predictors of malignancy.
  
  
  CONCLUSIONS
  Tumor size did not predict malignancy or recurrence of PPGLs. PPGL patients with characteristic pathologic findings and PASS ≥4 or germline mutations require close follow-up.
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.|Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon-si, South Korea.
authors.forename: Kyong Young
authors.initials: KY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Jung Hee
authors.identifier: http://orcid.org/0000-0003-1932-0234
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: A Ram
authors.initials: AR
authors.lastname: Hong
authors.affiliation: Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Moon-Woo
authors.initials: MW
authors.lastname: Seong
authors.affiliation: Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Kyu Eun
authors.initials: KE
authors.lastname: Lee
authors.affiliation: Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University, Seoul Metropolitan Government Boramae Medical Center, Seoul, South Korea.
authors.forename: Sang Wan
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Chan Soo
authors.initials: CS
authors.lastname: Shin
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.|Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon-si, South Korea.
authors.forename: Seong Yeon
authors.initials: SY
authors.lastname: Kim
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000453:epidemiology* / Q000235:genetics; D000328:Adult; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology; D010235:Paraganglioma / Q000453:epidemiology* / Q000235:genetics; D010673:Pheochromocytoma / Q000453:epidemiology* / Q000235:genetics; D011379:Prognosis; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D012189:Retrospective Studies; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C497446:VHL protein, human