title: Genotype-Phenotype Correlation in Indian Patients with MEN2-Associated Pheochromocytoma and Comparison of Clinico-Pathological Attributes with Apparently Sporadic Adrenal Pheochromocytoma.
abstract: BACKGROUND
  Pheochromocytoma (PCC) manifests in up to 50% of MEN2 patients. We correlated the clinico-pathological features of MEN2-associated PCC (MEN-PCC) with RET mutations and compared them with non-MEN adrenal-PCCs.
  
  
  METHODS
  In this retrospective single institution study on a large PCC database (n = 208, 1997-2014) 24 MEN-PCC patients with known RET mutations were reviewed. Excluding 7 with incomplete data, the study cohort of 17 MEN-PCC patients from 11 kindreds (M:F::7:10) was identified. Clinical, biochemical, pathological attributes, and outcomes in the MEN-PCC group were correlated with the genotype, and further compared with non-MEN, apparently sporadic adrenal-PCCs (n = 132, excluding 37 extra-adrenal and 15 VHL/NF1/SDH-associated PCC).
  
  
  RESULTS
  Components of MEN2 encountered included MTC in 13(76.5%), Marfanoid habitus in 2, and PHPT, cutaneous lichen amyloidosis and mucosal neuromas in 1 patient each. In 11(64.7%), PCC was the first detected MEN2 component (Symptomatic:8, Incidentaloma:3). Four (23.5%) were normotensive; 8(47.1%) had bilateral PCC (7 synchronous, 1 metachronous). Surgery for PCC included laparoscopic adrenalectomy in 12; and cortical-sparing adrenalectomy in 2 of 8 bilateral PCC patients. Mean MEN-PCC tumor size was 6.9 ± 3.9 cm, and 6(35%) had additional adrenal medullary hyperplasia. Four different genotypes were encountered, commonest involving codon 634, others being 804 and 918. Mean age in MEN-PCC (27.7 ± 12.2 years) was lower than non-MEN PCC (39.4 ± 15.7, p = 0.018). Proportion of pediatric patients (35.3% in MEN-PCC vs. 12.9% in non-MEN-PCC, p = 0.007), bilateral tumors (47.1% in MEN-PCC, 4.5% in non-MEN-PCC, p < 0.001), and adrenal medullary hyperplasia (35.2% in MEN-PCC, 0.7% in non-MEN-PCC, p < 0.001) were different. Median 24-hour urinary metanephrines was significantly higher in index MEN-PCC patients, than non-MEN-PCC (634 vs. 214 mcg/24 h, p value = 0.006), but was non-significantly higher in non-index MEN-PCC patients. Mean tumor sizes were comparable in the two groups. None of MEN-PCC patients had malignant PCC, compared to 7(5.3%) in non-MEN-PCC.
  
  
  CONCLUSIONS
  In this cohort of MEN-PCC from India, the commonest causative RET mutations for MEN-PCC involved codon 634. MEN-PCC patients were younger, and more frequently had bilateral PCC than non-MEN disease. MEN-PCC patients in India are diagnosed with large tumors and extremely high catecholamine/metanephrine levels.
authors.affiliation: Department of Endocrine & Breast Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Rae Bareilly Road, Lucknow, 226014, Uttar Pradesh, India.
authors.forename: Sendhil
authors.initials: S
authors.lastname: Rajan
authors.affiliation: Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, Uttar Pradesh, India.
authors.forename: Ghazala
authors.initials: G
authors.lastname: Zaidi
authors.affiliation: Department of Endocrine & Breast Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Rae Bareilly Road, Lucknow, 226014, Uttar Pradesh, India. gaurav@sgpgi.ac.in.
authors.forename: Gaurav
authors.identifier: http://orcid.org/0000-0003-4194-2670
authors.initials: G
authors.lastname: Agarwal
authors.affiliation: Department of Endocrine & Breast Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Rae Bareilly Road, Lucknow, 226014, Uttar Pradesh, India.
authors.forename: Anjali
authors.initials: A
authors.lastname: Mishra
authors.affiliation: Department of Endocrine & Breast Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Rae Bareilly Road, Lucknow, 226014, Uttar Pradesh, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Department of Endocrine & Breast Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Rae Bareilly Road, Lucknow, 226014, Uttar Pradesh, India.
authors.forename: Saroj Kanta
authors.initials: SK
authors.lastname: Mishra
authors.affiliation: Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, Uttar Pradesh, India.
authors.forename: Eesh
authors.initials: E
authors.lastname: Bhatia
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D000311:Adrenal Glands / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D003062:Codon; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D015994:Incidence; D007194:India / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D008934:Mitogens; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D009154:Mutation; D010673:Pheochromocytoma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D003062:Codon; D004273:DNA, Neoplasm; D008934:Mitogens; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human