Adrenal gland

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Adrenal gland is a little organ that hangs-out above the kidney. Pathologists rarely see it. It uncommonly is affected by tumours.

Anatomy & histology

Anatomy

  • Cortex.
  • Medulla.

Histology

It is composed of a cortex and a medulla.

Cortex

It has three layers - mnemonic: GFR (from superficial to deep):

  1. Zona glomerulosa - salt (e.g. aldosterone).
    • Eosinophilic cytoplasm. (???)
    • Layer normally discontinuous.
  2. Zona fasciculata - sugar (e.g. cortisol).
    • Clear cytoplasm - key feature.
    • Largest part of the cortex ~ 70%.
    • Cells in cords/nests. (???)
  3. Zona reticularis - steroid (e.g. dehydroepiandrosterone).
    • Marked eosinophilia of cytoplasm - key feature.
    • Granular/reticular cytoplasm.

Medulla

It consists of two cell types:[1]

  1. Chromaffin cells.
    • Arise of neural crest.
  2. Sustentacular cells (supporting cells).

Produce NED: norepinephrine, epinephrine, dopamine.

IHC

Adrenal cortex:

  • Chromogranin A -ve.
  • Synaptophysin +ve.
  • Alpha-inhibin +ve.

Clinical

Patients getting a bilateral adrenalectomy get pre-treatment with steroids.[2]

Adrenal insufficiency is an immediate danger post-op.[3]

Benign

The section covers non-neoplastic pathologies of the adrenal gland. These uncommonly come to the pathologist.

Stress response

Spironolactone bodies

General

Etiology:

  • Long-term use of spironolactone.

Microscopic

Features:[5]

  • Location: zona glomerulosa (where aldosterone is produced).
  • Appearance: eosinophilic spherical laminated whorls.

Images:

Hemorrhagic adrenalitis

  • AKA Waterhouse-Friderichsen syndrome.

General

  • Classically thought to be only due to Neisseria meningitidis; however, more recently also associated with Staphylococcus aureus,[6] and Streptococcus pneumoniae.[7]

Gross

Features:

  • Massive haemorrhage within the substance of the adrenal gland.

DDx (autopsy):

  • Post-mortem changes.

Microscopic

Features:

  • Massive haemorrhage within the substance of the adrenal gland.

Image: Haemorrhage in adrenal (nih.gov).

Adrenal cytomegaly

  • AKA adrenocortical cytomegaly.
  • AKA adrenal gland with cytomegaly.

General

May be associated with:[8]

Microscopic

Features:

  • Large cells in the adrenal cortex.[9]

Addison disease

General

  • Chronic adrenocortical insufficiency.

Clinical:

  • Brown skin - due POMC (a precursor of ACTH and melanocyte stimulating hormone (MSH)).[10]
  • Hypotension.
  • Nausea and vomiting.

DDx:[11]

Notes:

  • Secondary adrenocortical insufficiency (due to pituitary pathology):[12]
    • No hyperpigmentation (as no POMC).
    • Aldosterone usu. normal.

Microscopic

Features:[10]

  • Atrophy adrenal cortex - specifically zona fasciculata and zona reticularis.

Notes:

  • There is preservation of zona glomerulosa and medulla.

Benign neoplasms

Adrenal cortical adenoma

General

Epidemiology:

  • Often an incidental finding.

Pathologic/clinical:

  • May be hormonally active.
  • Radiologists are good at identifying adenomas, as they are usually lipid rich and have a characteristic low HU signal.[13]

Indications for excision:[14][15]

  • Lesions >30 mm.
  • Hormonally active.
  • Non-incidental finding. (???)

Microscopic

Classic features:

  • Well-defined cell borders.
  • Clear cytoplasm.
  • May have foci of necrosis/degeneration and nuclear atypia.

In aldosterone producing tumours:

  • May extend outside of the capsule (should not be diagnosed as adrenal cortical carcinoma).
  • No atrophy of non-hyperplastic cortex.

In cortisol producing tumours (Cushing syndrome):

  • Atrophy of the non-hyperplastic cortex (due to feedback inhibition from the pituitary gland).

Notes:

Pheochromocytoma

General

  • Considered to be a paraganglioma.[17]
  • Literally means "dusky" (pheo) "colour" (chromo) - dull appearance on gross.
  • Tumour arises from adrenal medulla - chromaffin cells.[18]

Memory device - the rule of 10s:[18]

Clinical

  • Classic finding: hypertension.
  • Paroxysms (i.e. episodes) of tachycardia, headache, anxiety, hypertension.

Laboratory findings (urine):

  • Vanillylmandelic acid (VMA).
  • Metanephrines.

Microscopic

Features:[19]

  • Chief cells:
    • Usu. polygonal cells, may be spindled.
    • Arranged in cell nests - "Zellballen" (literally cell balls) - key feature.
    • Stippled chromatin (AKA salt and pepper chromatin) - coarsely granular chromatin.
    • Granular cytoplasm, often basophilic - important.
  • Sustentacular cells (structural support cell).
  • Often haemorrhagic - highly vascular.
  • +/-Nuclear pleomorphism.

Notes:

  • The nested architecture (Zellballen) is useful for differentiating from ACC.
  • Metastasis sole criteria of malignancy.[18]

Images:

DDx:

Pheochromocytoma versus adrenal cortical carcinoma
  • Pheochromocytoma and adrenal cortical carcinoma overlap histologically.[20]

Favour pheochromocytoma:

  • Small chickenwire-pattern blood vessels, nests, salt-and-pepper chromatin, red blood cell extravasation.

Favour adrenal cortical carcinoma:

  • Nucleolus, sheeting.

Malignant pheochromoctyoma

  1. Robbins says metastases are the sole criteria of malignancy.[18]
  2. Thompson suggests one can differentiate benign from malignant with the aid of the following:[21]
    • Marked nuclear atypia.
    • Invasion:
      • Capsular.
      • Vascular.
    • Necrosis.
    • Cellular monotony.
    • Mitoses:
      • Rate.
      • Atypical mitosis.

IHC

  • Chief cells:
    • Chromogranin A +ve.
    • Synaptophysin +ve.
  • Sustentacular cells:
    • S100 +ve.

Electron microscopy

  • Membrane-bound secretory granules.

Sign out

ADRENAL MASS, RIGHT, ADRENALECTOMY:
- PHEOCHROMOCYTOMA.
- SURGICAL MARGIN NEGATIVE FOR PHEOCHROMOCYTOMA.

COMMENT:
The tumour cells stains for chromogranin and synaptophysin. S-100 marks the sustentacular cells.
Inhibin is negative in the tumour cells. The immunostaining pattern is consistent with a 
pheochromocytoma.

Micro

The sections shows a partially hemorrhagic lesion in the medulla of the adrenal gland that is arranged in nests (Zellballen). The tumour cells have abundant grey/blue granular cytoplasm, and nuclei with granular chromatin (salt and pepper chromatin). The lesion is surrounded by a compressed rim of adrenal cortex and fibrosis tissue. The core of the lesion is fibrotic and has clusters of hemosiderin-laden macrophages.

There is no capsular invasion. Vascular invasion is not identified. There is no necrosis. Mitotic activity is not appreciated.

The adrenal cortex is unremarkable.

Adrenal ganglioneuroma

Main article: Ganglioneuroma

General

Gross

  • Solid.
  • White.
  • Firm.
  • Well-circumscribed.
  • May be nodular.

DDx (gross):

Images:

Microscopic

Features:

  • Ganglion cells - key feature.
    • Large cells with large nucleus.
      • Prominent nucleolus.
  • Disordered fibrinous material.

Images:

Adrenal myelolipoma

General

  • Benign and rare.
  • Typically asymptomatic and hormonally inactive.[22]
    • Symptoms: back or abdominal pain.
  • Diagnosis - usu. by abdominal CT.

Treatment:

  • Watchful waiting if small (<=7 cm) and asymptomatic.[22]

Microscopic

Features:[23]

  • Adipose tissue.
  • Hematopoietic elements from all three lineages:
    1. Erythroid.
    2. Myeloid.
    3. Megakaryocytic.
  • +/-Calcification.[22]

DDx:

Images:

Adenomatoid tumour

See: Adenomatoid tumours (uterine tumours).

Malignant neoplasms

Adrenocortical carcinoma

  • AKA adrenal cortical carcinoma.
  • Abbreviated ACC.

General

  • Prognosis sucks, esp. in adults.

Epidemiology:

Gross

  • +/-Encapsulated.
  • Necrotic-appearing.

Image:

Microscopic

Various criteria exist for this diagnosis. The most widely used is the Weiss criteria, which is a big long clunker.

Image:

Notes:

  • Tumour may contain fat.[24]

Adult

Weiss criteria

Three of the following:[25]

  1. High nuclear grade.
  2. High mitotic rate; >5/50 HPF (@ 40X obj.) - definition suffers from HPFitis.
  3. Atypical mitoses.
  4. Cleared cytoplasm in >= 25% of tumour cells.
  5. Sheeting (diffuse architecture) in >= 1/3 of tumour cells.
  6. Necrosis in nests.
  7. Venous invasion.
  8. Adrenal sinusoid invasion; lymphovascular space invasion within the adrenal gland.
  9. Capsular invasion.
Volante criteria

There is a simplified set of criteria by Volante et al. - that is not widely used:[26]

  • Reticular network disruption (with reticulin staining).
  • One of the three following:
    1. Abundant mitoses >5/50 high-power fields - definition suffers from HPFitis.
    2. Necrosis.
    3. Vascular invasion.

Pediatric

The criteria in the pediatric setting are somewhat different. This is discussed by Wieneke et al.[27] and Dehner and Hill.[28]

Dehner and Hill propose a very simple system:[28]

  • "Low risk" < 200 g & confined to the adrenal.
  • "Intermediate risk" 200-400 g, no mets, +/-microscopic disease outside adrenal.
  • "High risk" >400 g, or mets, or gross invasion of adjacent structures.

IHC

  • Vimentin +ve.
  • Melan A +ve.
  • Inhibin-alpha +ve.
  • Cytokeratins +ve/-ve.

Others:

Neuroblastoma

See also: olfactory neuroblastoma.

General

Epidemiology:

  • Usually paediatric population.

Laboratory findings:

  • Increased urine homovanillic acid.

Predictors of a poor prognosis:[30]

  • High mitotic-karyorrhectic index.
  • Lack of schwannian stroma.
  • >18 months.
  • Near ploidy.
  • N-MYC amplification.
  • Lymph node spread.
  • Distant spread.

Classification:

Gross

Microscopic

Features:[33]

  • Small round blue cells separated by thin (pink) fibrous septa.
  • Homer-Wright rosettes.
    • Rosette with a small (~100 micrometers - diameter) meshwork of fibers (neuropil) at the centre.[34]
  • Neuropil-like stroma = paucicellular stroma with a cotton candy-like appearance; see comparison below.
    • >50% neuropil-like stroma -- otherwise it's a ganglioneurona or ganglioblastoma.

Notes:

  • The fibrous septa are especially useful for differentiation from lymphoma.

DDx:

Images:

Schwannian vs. neuropil

Feature Schwannian Neuropil
Cellularity high ~ spacing of cells < 30 µm low ~ spacing of cells > 100 µm
Fibrillary yes, long fine strands no
Associations ganglion cells neuroblasts
Cytoplasmic vacuolation yes ?

Classification/grading

Commonly grouped by the Shimada classification, which depends on the presence a number of things including:

  • Mitoses/karyorrhectic cells.
  • Molecular abnormalities.

IHC

  • PGP 9.5 +ve.[36]
    • PGP = protein gene product.
  • NB-84 +ve.[37]
    • More sensitive that synaptophysin.
  • Synaptophysin +ve.
  • CD99 -ve.

EM

Distinctive EM appearance:[38]

  • Dendritic processes with longitudinally oriented microtubules.
  • Membrane bound electron-dense granules (contain catecholamines).
  • Desmosomes
    • Not seen in EWS, RMS, lymphomas.
  • Membrane densities.

Pertinent negative:[38]

  • No glycogen.

See also

References

  1. ↑ Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009). Robbins and Cotran pathologic basis of disease (8th ed.). Elsevier Saunders. pp. 1159. ISBN 978-1416031215.
  2. ↑ URL: http://www3.interscience.wiley.com/cgi-bin/fulltext/119909358/PDFSTART. Accessed on: 21 August 2010.
  3. ↑ URL: http://ats.ctsnetjournals.org/cgi/content/full/62/5/1516. Accessed on: 21 August 2010.
  4. ↑ Becker MJ, Becker AE (September 1976). "Fat distribution in the adrenal cortex as an indication of the mode of intrauterine death". Hum. Pathol. 7 (5): 495–504. PMID 964978.
  5. ↑ Kovacs K, Horvath E, Singer W (December 1973). "Fine structure and morphogenesis of spironolactone bodies in the zona glomerulosa of the human adrenal cortex". J. Clin. Pathol. 26 (12): 949-57. PMC 477936. PMID 4131694. http://jcp.bmj.com/cgi/pmidlookup?view=long&pmid=4131694.
  6. ↑ Adem PV, Montgomery CP, Husain AN, et al. (September 2005). "Staphylococcus aureus sepsis and the Waterhouse-Friderichsen syndrome in children". N. Engl. J. Med. 353 (12): 1245–51. doi:10.1056/NEJMoa044194. PMID 16177250.
  7. ↑ Hamilton D, Harris MD, Foweraker J, Gresham GA (February 2004). "Waterhouse-Friderichsen syndrome as a result of non-meningococcal infection". J. Clin. Pathol. 57 (2): 208–9. PMC 1770213. PMID 14747454. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770213/.
  8. ↑ URL: http://www.humpath.com/?adrenal-cytomegaly. Accessed on: 3 January 2012.
  9. ↑ 9.0 9.1 Aterman, K.; Kerenyi, N.; Lee, M. (1972). "Adrenal cytomegaly.". Virchows Arch A Pathol Pathol Anat 355 (2): 105-22. PMID 4336262.
  10. ↑ 10.0 10.1 10.2 Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009). Robbins and Cotran pathologic basis of disease (8th ed.). Elsevier Saunders. pp. 1157. ISBN 978-1416031215.
  11. ↑ Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009). Robbins and Cotran pathologic basis of disease (8th ed.). Elsevier Saunders. pp. 1155. ISBN 978-1416031215.
  12. ↑ Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 585. ISBN 978-1416054542.
  13. ↑ URL: http://emedicine.medscape.com/article/376240-overview.
  14. ↑ Luton, JP.; Martinez, M.; Coste, J.; Bertherat, J. (Jul 2000). "Outcome in patients with adrenal incidentaloma selected for surgery: an analysis of 88 cases investigated in a single clinical center.". Eur J Endocrinol 143 (1): 111-7. PMID 10870039.
  15. ↑ Liu, XK.; Liu, XJ.; Dong, X.; Kong, CZ. (Jun 2008). "[Clinical research about treatment for adrenal incidentalomas]". Zhonghua Wai Ke Za Zhi 46 (11): 832-4. PMID 19035218.
  16. ↑ IAV. 18 February 2009.
  17. ↑ Thompson, Lester D. R. (2006). Endocrine Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 327. ISBN 978-0443066856.
  18. ↑ 18.0 18.1 18.2 18.3 Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 586. ISBN 978-1416054542.
  19. ↑ Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009). Robbins and Cotran pathologic basis of disease (8th ed.). Elsevier Saunders. pp. 1161. ISBN 978-1416031215.
  20. ↑ Sangoi, AR.; McKenney, JK. (Mar 2010). "A tissue microarray-based comparative analysis of novel and traditional immunohistochemical markers in the distinction between adrenal cortical lesions and pheochromocytoma.". Am J Surg Pathol 34 (3): 423-32. doi:10.1097/PAS.0b013e3181cfb506. PMID 20154585.
  21. ↑ Thompson, Lester D. R. (2006). Endocrine Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 259. ISBN 978-0443066856.
  22. ↑ 22.0 22.1 22.2 Daneshmand, S.; Quek, ML. (2006). "Adrenal myelolipoma: diagnosis and management.". Urol J 3 (2): 71-4. PMID 17590837.
  23. ↑ 23.0 23.1 Cha, JS.; Shin, YS.; Kim, MK.; Kim, HJ. (Aug 2011). "Myelolipomas of both adrenal glands.". Korean J Urol 52 (8): 582-5. doi:10.4111/kju.2011.52.8.582. PMC 3162227. PMID 21927708. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3162227/.
  24. ↑ Heye S, Woestenborghs H, Van Kerkhove F, Oyen R (2005). "Adrenocortical carcinoma with fat inclusion: case report". Abdom Imaging 30 (5): 641–3. doi:10.1007/s00261-004-0281-5. PMID 15688105.
  25. ↑ Jain M, Kapoor S, Mishra A, Gupta S, Agarwal A (2010). "Weiss criteria in large adrenocortical tumors: a validation study". Indian J Pathol Microbiol 53 (2): 222–6. doi:10.4103/0377-4929.64325. PMID 20551521.
  26. ↑ Volante M, Bollito E, Sperone P, et al. (November 2009). "Clinicopathological study of a series of 92 adrenocortical carcinomas: from a proposal of simplified diagnostic algorithm to prognostic stratification". Histopathology 55 (5): 535–43. doi:10.1111/j.1365-2559.2009.03423.x. PMID 19912359.
  27. ↑ Wieneke JA, Thompson LD, Heffess CS (July 2003). "Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients". Am. J. Surg. Pathol. 27 (7): 867–81. PMID 12826878.
  28. ↑ 28.0 28.1 Dehner LP, Hill DA (2009). "Adrenal cortical neoplasms in children: why so many carcinomas and yet so many survivors?". Pediatr. Dev. Pathol. 12 (4): 284–91. doi:10.2350/08-06-0489.1. PMID 19326954.
  29. ↑ Unger P, Hoffman K, Pertsemlidis D, Thung S, Wolfe D, Kaneko M (May 1991). "S100 protein-positive sustentacular cells in malignant and locally aggressive adrenal pheochromocytomas". Arch. Pathol. Lab. Med. 115 (5): 484–7. PMID 1673596.
  30. ↑ Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 254. ISBN 978-1416054542.
  31. ↑ Shimada H, Ambros IM, Dehner LP, Hata J, Joshi VV, Roald B (July 1999). "Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee". Cancer 86 (2): 349–63. PMID 10421272.
  32. ↑ Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 253. ISBN 978-1416054542.
  33. ↑ Chung EM, Murphey MD, Specht CS, Cube R, Smirniotopoulos JG (2008). "From the Archives of the AFIP. Pediatric orbit tumors and tumorlike lesions: osseous lesions of the orbit". Radiographics 28 (4): 1193–214. doi:10.1148/rg.284085013. PMID 18635637.
  34. ↑ Wippold FJ, Perry A (March 2006). "Neuropathology for the neuroradiologist: rosettes and pseudorosettes". AJNR Am J Neuroradiol 27 (3): 488–92. PMID 16551982.
  35. ↑ URL: http://radiographics.rsna.org/content/28/4/1193.full. Accessed on: 12 January 2011.
  36. ↑ Ootsuka, S.; Asami, S.; Sasaki, T.; Yoshida, Y.; Nemoto, N.; Shichino, H.; Chin, M.; Mugishima, H. et al. (Jun 2008). "Useful markers for detecting minimal residual disease in cases of neuroblastoma.". Biol Pharm Bull 31 (6): 1071-4. PMID 18520032.
  37. ↑ Miettinen, M.; Chatten, J.; Paetau, A.; Stevenson, A. (Mar 1998). "Monoclonal antibody NB84 in the differential diagnosis of neuroblastoma and other small round cell tumors.". Am J Surg Pathol 22 (3): 327-32. PMID 9500774.
  38. ↑ 38.0 38.1 Mackay, B.; Masse, SR.; King, OY.; Butler, J. (Dec 1975). "Diagnosis of neuroblastoma by electron microscopy of bone marrow aspirates.". Pediatrics 56 (6): 1045-9. PMID 1196755.
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