Corticotroph hyperplasia and Cushing disease: diagnostic features and surgical management

View More View Less
  • 1 Department of Neurosurgery, Brigham and Women’s Hospital/Harvard Medical School, Boston, Massachusetts;
  • | 2 Department of Neurosurgery, University of North Carolina Hospitals, Chapel Hill, North Carolina;
  • | 3 Department of Pathology, Brigham and Women’s Hospital/Harvard Medical School, Boston;
  • | 4 Dana Farber Cancer Institute, Boston;
  • | 5 Harvard TH Chan School of Public Health, Boston; and
  • | 6 Division of Endocrinology, Brigham and Women’s Hospital/Harvard Medical School, Boston, Massachusetts
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00
Print or Print + Online

OBJECTIVE

This study was done to compare corticotroph hyperplasia and histopathologically proven adenomas in patients with Cushing disease by analyzing diagnostic features, surgical management, and clinical outcomes.

METHODS

Patients with suspected pituitary Cushing disease were included in a retrospective cohort study and were excluded if results of pathological analysis of the surgical specimen were nondiagnostic or normal. Cases were reviewed by two experienced neuropathologists. Total lesion removal was used as a dichotomized surgical variable; it was defined as an extracapsular resection (including a rim of normal gland) in patients with an adenoma, and for hyperplasia patients it was defined as removal of the presumed lesion plus a rim of surrounding normal gland. Bivariate and multivariate analyses were performed. Recurrence-free survival was compared between the two groups.

RESULTS

The final cohort consisted of 63 patients (15 with hyperplasia and 48 with adenoma). Normal pituitary acinar architecture was highly variable. Corticotroph hyperplasia was diagnosed based on the presence of expanded acini showing retained reticulin architecture and predominant staining for adrenocorticotropic hormone. Crooke’s hyaline change was seen in 46.7% of specimens, and its frequency was equal in nonlesional tissue of both groups. The two groups differed only by MRI findings (equivocal/diffuse lesion in 46% of hyperplasia and 17% of adenoma; p = 0.03). Diagnostic uncertainty in the hyperplasia group resulted in additional confirmatory testing by 24-hour urinary free cortisol. Total lesion removal was infrequent in patients with hyperplasia compared to those with adenoma (33% vs 65%; p = 0.03). Initial biochemical remission was similar (67% in hyperplasia and 85% in adenoma; p = 0.11). There was no difference in hypothalamic-pituitary-adrenal axis recovery or disease recurrence. The median follow-up was 1.9 years (IQR 0.7–7.6 years) for the hyperplasia group and 1.2 years (IQR 0.4–2.4 years) for the adenoma group. Lack of a discrete lesion and diagnostic uncertainty were the only significant predictors of hyperplasia (sensitivity 53.3%, specificity 97.7%, positive predictive value 88.9%, negative predictive value 85.7%). An adjusted Cox proportional hazards model showed similar recurrence-free survival in the two groups.

CONCLUSIONS

This study suggests an association between biochemically proven Cushing disease and histopathologically proven corticotroph hyperplasia. Imaging and operative findings can be ambiguous, and, compared to typical adenomas with a pseudocapsule, the surgical approach is more nuanced. Nevertheless, if treated appropriately, biochemical outcomes may be similar.

ABBREVIATIONS

ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone; HPA = hypothalamic-pituitary-adrenal; HR = hazard ratio; IPSS = inferior petrosal sinus sampling; ROC = receiver operating characteristic; UFC = urinary free cortisol.
Illustrations from Marx and Schroeder (pp 318–326). Copyright Henry W. S. Schroeder. Published with permission.

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00

Contributor Notes

Correspondence Michael P. Catalino: University of North Carolina Hospitals, Chapel Hill, NC. michael.catalino@unchealth.unc.edu.

INCLUDE WHEN CITING Published online September 4, 2020; DOI: 10.3171/2020.5.JNS201514.

Disclosures Dr. Min receives clinical or research support for the study described (includes equipment or material) from Corcept.

  • 1

    Burke CW , Adams CBT , Esiri MM , et al. Transsphenoidal surgery for Cushing’s disease: does what is removed determine the endocrine outcome? Clin Endocrinol (Oxf) . 1990 ;33 (4 ):525 537 .

    • Search Google Scholar
    • Export Citation
  • 2

    Robert F , Hardy J . Cushing’s disease: a correlation of radiological, surgical and pathological findings with therapeutic results . Pathol Res Pract . 1991 ;187 (5 ):617 621 .

    • Search Google Scholar
    • Export Citation
  • 3

    Sheehan JM , Lopes MB , Sheehan JP , et al. Results of transsphenoidal surgery for Cushing’s disease in patients with no histologically confirmed tumor . Neurosurgery . 2000 ;47 (1 ):33 39 .

    • Search Google Scholar
    • Export Citation
  • 4

    Pouratian N , Prevedello DM , Jagannathan J , et al. Outcomes and management of patients with Cushing’s disease without pathological confirmation of tumor resection after transsphenoidal surgery . J Clin Endocrinol Metab . 2007 ;92 (9 ):3383 3388 .

    • Search Google Scholar
    • Export Citation
  • 5

    Lamberts SWJ , Stefanko SZ , de Lange SA , et al. Failure of clinical remission after transsphenoidal removal of a microadenoma in a patient with Cushing’s disease: multiple hyperplastic and adenomatous cell nets in surrounding pituitary tissue . J Clin Endocrinol Metab . 1980 ;50 (4 ):793 795 .

    • Search Google Scholar
    • Export Citation
  • 6

    Kovacs K , Horvath E , Coire C , et al. Pituitary corticotroph hyperplasia preceding adenoma in a patient with Nelson’s syndrome . Clin Neuropathol . 2006 ;25 (2 ):74 80 .

    • Search Google Scholar
    • Export Citation
  • 7

    Jagannathan J , Smith R , DeVroom HL , et al. Outcome of using the histological pseudocapsule as a surgical capsule in Cushing disease . J Neurosurg . 2009 ;111 (3 ):531 539 .

    • Search Google Scholar
    • Export Citation
  • 8

    Tyrrell JB , Brooks RM , Fitzgerald PA , et al. Cushing’s disease. Selective trans-sphenoidal resection of pituitary microadenomas . N Engl J Med . 1978 ;298 (14 ):753 758 .

    • Search Google Scholar
    • Export Citation
  • 9

    Salassa RM , Laws ER Jr , Carpenter PC , Northcutt RC . Transsphenoidal removal of pituitary microadenoma in Cushing’s disease . Mayo Clin Proc . 1978 ;53 (1 ):24 28 .

    • Search Google Scholar
    • Export Citation
  • 10

    Patil CG , Prevedello DM , Lad SP , et al. Late recurrences of Cushing’s disease after initial successful transsphenoidal surgery . J Clin Endocrinol Metab . 2008 ;93 (2 ):358 362 .

    • Search Google Scholar
    • Export Citation
  • 11

    Sheithauer BW , Horvath E , Lloyd RV , Kovacs K . Pituitary hyperplasia . Pathol Case Rev . 1998 ;3 (6 ):281 289 .

  • 12

    Lopes MBS . The 2017 World Health Organization classification of tumors of the pituitary gland: a summary . Acta Neuropathol . 2017 ;134 (4 ):521 535 .

    • Search Google Scholar
    • Export Citation
  • 13

    Carey RM , Varma SK , Drake CR Jr , et al. Ectopic secretion of corticotropin-releasing factor as a cause of Cushing’s syndrome. A clinical, morphologic, and biochemical study . N Engl J Med . 1984 ;311 (1 ):13 20 .

    • Search Google Scholar
    • Export Citation
  • 14

    Shahani S , Nudelman RJ , Nalini R , et al. Ectopic corticotropin-releasing hormone (CRH) syndrome from metastatic small cell carcinoma: a case report and review of the literature . Diagn Pathol . 2010 ;5 (56 ):56 .

    • Search Google Scholar
    • Export Citation
  • 15

    Young WF Jr , Scheithauer BW , Gharib H , et al. Cushing’s syndrome due to primary multinodular corticotrope hyperplasia . Mayo Clin Proc . 1988 ;63 (3 ):256 262 .

    • Search Google Scholar
    • Export Citation
  • 16

    Biller B , Klibanski A , Koenig J , Martin JB . Diagnostic dilemmas in the management of hypothalmic-pituitary-adrenal disorders . Ann N Y Acad Sci . 1987 ;512 :338 350 .

    • Search Google Scholar
    • Export Citation
  • 17

    Asa SL . The role of hypothalamic hormones in the pathogenesis of pituitary adenomas . Pathol Res Pract . 1991 ;187 (5 ):581 583 .

    • Search Google Scholar
    • Export Citation
  • 18

    Nieman LK , Biller BMK , Findling JW , et al. The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline . J Clin Endocrinol Metab . 2008 ;93 (5 ):1526 1540 .

    • Search Google Scholar
    • Export Citation
  • 19

    Nieman LK , Biller BMK , Findling JW , et al. Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline . J Clin Endocrinol Metab . 2015 ;100 (8 ):2807 2831 .

    • Search Google Scholar
    • Export Citation
  • 20

    Bloodworth JMB Jr. Assessment of the pituitary hyperplasia/neoplasia interface . Pathol Res Pract . 1988 ;183 (5 ):626 630 .

  • 21

    Al-Gahtany M , Horvath E , Kovacs K . Pituitary hyperplasia . Hormones (Athens) . 2003 ;2 (3 ):149 158 .

  • 22

    Semple PL , Vance ML , Findling J , Laws ER Jr . Transsphenoidal surgery for Cushing’s disease: outcome in patients with a normal magnetic resonance imaging scan . Neurosurgery . 2000 ;46 (3 ):553 559 .

    • Search Google Scholar
    • Export Citation
  • 23

    Horvath E , Kovacs K , Scheithauer BW . Pituitary hyperplasia . Pituitary . 1999 ;1 (3-4 ):169 179 .

  • 24

    Mete O , Asa SL . Precursor lesions of endocrine system neoplasms . Pathology . 2013 ;45 (3 ):316 330 .

  • 25

    Oldfield EH , Vance ML , Louis RG , et al. Crooke’s changes in Cushing’s syndrome depends on degree of hypercortisolism and individual susceptibility . J Clin Endocrinol Metab . 2015 ;100 (8 ):3165 3171 .

    • Search Google Scholar
    • Export Citation
  • 26

    Patil CG , Veeravagu A , Prevedello DM , et al. Outcomes after repeat transsphenoidal surgery for recurrent Cushing’s disease . Neurosurgery . 2008 ;63 (2 ):266 271 .

    • Search Google Scholar
    • Export Citation
  • 27

    Simmons NE , Alden TD , Thorner MO , Laws ER Jr . Serum cortisol response to transsphenoidal surgery for Cushing disease . J Neurosurg . 2001 ;95 (1 ):1 8 .

    • Search Google Scholar
    • Export Citation
  • 28

    Srinivasan L , Laws ER , Dodd RL , et al. The dynamics of post-operative plasma ACTH values following transsphenoidal surgery for Cushing’s disease . Pituitary . 2011 ;14 (4 ):312 317 .

    • Search Google Scholar
    • Export Citation
  • 29

    Kovacs K , Stefaneanu L , Horvath E , et al. Pituitary corticotroph adenoma in a woman with long-standing Addison’s disease: a histologic, immunocytochemical, electron microscopic, and in situ hybridization study . Endocr Pathol . 1996 ;7 (1 ):91 97 .

    • Search Google Scholar
    • Export Citation
  • 30

    Zhou J , Ruan L , Li H , et al. Addison’s disease with pituitary hyperplasia: a case report and review of the literature . Endocrine . 2009 ;35 (3 ):285 289 .

    • Search Google Scholar
    • Export Citation
  • 31

    Mustila T , Keskinen P , Terho M , et al. Pediatric Cushing’s disease due to pituitary hyperplasia . J Pediatr Endocrinol Metab . 2011 ;24 (3–4 ):191 192 .

    • Search Google Scholar
    • Export Citation
  • 32

    Noctor E . Paediatric cyclical Cushing’s disease due to corticotroph cell hyperplasia . BMC Endocr Disord . 2015 ;15 :27 .

  • 33

    Kuebber S , Ropte S , Hori A . Proliferation of adenohypophyseal cells into posterior lobe. Their normal anatomical condition and possible neoplastic potentiality . Acta Neurochir (Wien) . 1990 ;104 (1–2 ):21 26 .

    • Search Google Scholar
    • Export Citation
  • 34

    Starke RM , Reames DL , Chen CJ , et al. Endoscopic transsphenoidal surgery for Cushing disease: techniques, outcomes, and predictors of remission . Neurosurgery . 2013 ;72 (2 ):240 247 .

    • Search Google Scholar
    • Export Citation
  • 35

    Smith TR , Hulou MM , Huang KT , et al. Complications after transsphenoidal surgery for patients with Cushing’s disease and silent corticotroph adenomas . Neurosurg Focus . 2015 ;38 (2 ):E12 E11 .

    • Search Google Scholar
    • Export Citation
  • 36

    Zaidi HA , Penn DL , Cote DJ , Laws ER Jr . Root cause analysis of diagnostic and surgical failures in the treatment of suspected Cushing’s disease . J Clin Neurosci . 2018 ;53 :153 159 .

    • Search Google Scholar
    • Export Citation
  • 37

    Prevedello DM , Pouratian N , Sherman J , et al. Management of Cushing’s disease: outcome in patients with microadenoma detected on pituitary magnetic resonance imaging . J Neurosurg . 2008 ;109 (4 ):751 759 .

    • Search Google Scholar
    • Export Citation
  • 38

    Meij BP , Lopes MB , Vance ML , et al. Double pituitary lesions in three patients with Cushing’s disease . Pituitary . 2000 ;3 (3 ):159 168 .

    • Search Google Scholar
    • Export Citation
  • 39

    Trouillas J , Guigard M-P , Fonlupt P , et al. Mapping of corticotropic cells in the normal human pituitary . J Histochem Cytochem . 1996 ;44 (5 ):473 479 .

    • Search Google Scholar
    • Export Citation
  • 40

    Horvath E , Kovacs K , Lloyd RV . Pars intermedia of the human pituitary revisited: morphologic aspects and frequency of hyperplasia of POMC-peptide immunoreactive cells . Endocr Pathol . 1999 ;10 (1 ):55 64 .

    • Search Google Scholar
    • Export Citation
  • 41

    Bunevicius A , Laws ER , Vance ML , et al. Surgical and radiosurgical treatment strategies for Cushing’s disease . J Neurooncol . 2019 ;145 (3 ):403 413 .

    • Search Google Scholar
    • Export Citation
  • 42

    Hinojosa-Amaya JM , Cuevas-Ramos D , Fleseriu M . Medical management of Cushing’s syndrome: current and emerging treatments . Drugs . 2019 ;79 (9 ):935 956 .

    • Search Google Scholar
    • Export Citation
  • 43

    Melmed S . Pathogenesis of pituitary tumors . Nat Rev Endocrinol . 2011 ;7 (5 ):257 266 .

  • 44

    Reincke M , Sbiera S , Hayakawa A , et al. Mutations in the deubiquitinase gene USP8 cause Cushing’s disease . Nat Genet . 2015 ;47 (1 ):31 38 .

    • Search Google Scholar
    • Export Citation
  • 45

    Bi WL , Horowitz P , Greenwald NF , et al. Landscape of genomic alterations in pituitary adenomas . Clin Cancer Res . 2017 ;23 (7 ):1841 1851 .

    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 141 141 102
Full Text Views 47 47 31
PDF Downloads 78 78 51
EPUB Downloads 0 0 0