Adrenal gland

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.

Microscopic

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.

Note:

• Cortex may not be completely encapsulated.^{[citation needed]}

Medulla

It consists of two cell types:

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.

Adrenal insufficiency is an immediate danger post-op.

Benign

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

Stress response

• In fetuses - fat content increases due to stress -- see: Fetal_autopsy#Adrenal_fetal_fat_pattern.
• In newborns/children/adults - fat content decreases due to stress.

Spironolactone bodies

General

Etiology:

• Long-term use of spironolactone.

Microscopic

Features:

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

Images:

• SB - high mag. (WC).
• SB (circled) - cropped high mag. (WC).

Hemorrhagic adrenalitis

• AKA Waterhouse-Friderichsen syndrome.

General

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

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:

• Beckwith-Wiedemann syndrome.
• Prematurity.
• Rh-incompatibility.

Microscopic

Features:

• Large cells in the adrenal cortex.

Addison disease

General

• Chronic adrenocortical insufficiency.

Clinical:

• Brown skin - due POMC (a precursor of ACTH and melanocyte stimulating hormone (MSH)).
  • POMC presence implies the pituitary gland intact.
• Hypotension.
• Nausea and vomiting.

DDx:

• Autoimmune.
• Tuberculosis.
• AIDS.
• Malignancy.

Notes:

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

Microscopic

Features:

• 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.

Indications for excision:

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

Notes:

• Cushing disease is due to the ACTH over-production by the pituitary.
• In cortisol producing tumours (Cushing syndrome): atrophy of the non-hyperplastic cortex (due to feedback inhibition from the pituitary gland).

Microscopic

Classic features:

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

Note:

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

DDx:

• Adrenal cortical nodule.
• Adrenal cortical hyperplasia.
  • Hyperplasia is multifocal.
• Adrenal cortical carcinoma.

Pheochromocytoma

General

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

Memory device - the rule of 10s:

• 10% extra-adrenal (e.g. carotid body, organ of Zuckerkandl (neighourhood of aortic bifuration/IMA branch point)).
• 10% bilateral.
• 10% malignant.
• 10% no hypertension.
• 25% associated within a syndrome:
  1. Multiple endocrine neoplasia 2A and 2B.
  2. von Hippel-Lindau syndrome.
  3. Neurofibromatosis type 1.
  4. Familial paraganglioma syndromes - several.

Clinical

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

Laboratory findings (urine):

• Vanillylmandelic acid (VMA).
• Metanephrines.

Microscopic

Features:

• 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.

Images:

• Carotid body tumour - low mag. (WC).
• Carotid body tumour - high mag. (WC).

DDx:

• Adrenal cortical carcinoma - pheochromocytoma versus adrenal cortical carcinoma.

Pheochromocytoma versus adrenal cortical carcinoma

• Pheochromocytoma and adrenal cortical carcinoma overlap histologically.

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.
2. Thompson suggests one can differentiate benign from malignant with the aid of the following:
   • 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

• May be retroperitoneal.
• Multiple ganglioneuromas may be due to multiple endocrine neoplasia IIb.

Gross

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

DDx (gross):

• Leiomyoma.

Images:

• Adrenal ganglioneuroma (WC).
• Ganglioneuroma (webpathology.com).

Microscopic

Features:

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

Images:

• Ganglion - benign (WC).

Adrenal myelolipoma

Myelolipoma redirects here.

General

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

Treatment:

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

Microscopic

Features:

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

DDx:

• Angiomyolipoma of the kidney.
• Lipoma.
• Liposarcoma.
• Teratoma.

Images:

• Myelolipoma (WC).
• Myelolipoma (nih.gov).
• Adrenal myelolipoma (upmc.edu).

Adenomatoid tumour

See: Adenomatoid tumours (uterine tumours).

Malignant neoplasms

Adrenocortical carcinoma

• AKA adrenal cortical carcinoma.
• Abbreviated ACC.

General

• Prognosis sucks, esp. in adults.

Epidemiology:

• May be associated with a syndrome:
  • Li-Fraumeni syndrome.
  • Beckwith-Wiedemann syndrome.

Gross

• +/-Encapsulated.
• Necrotic-appearing.

Image:

• ACC - gross (WC).

Microscopic

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

Image:

• WC:
  • ACC - low mag. (WC).
  • ACC - high mag. (WC).
  • ACC with normal adrenal medulla - high mag. (WC).
  • ACC - cytology (AFIP/WC).
• www:
  • ACC (upmc.edu).

Notes:

• Tumour may contain fat.

Adult

Weiss criteria

Three of the following:

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:

• 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. and Dehner and Hill.

Dehner and Hill propose a very simple system:

• "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:

• Synaptophysin +ve/-ve.
• Chromogranin A -ve.
  • Pheochromocytoma +ve.
• EMA -ve.
  • Renal cell carcinoma +ve.
• S100 -ve.
  • Pheochromocytoma +ve (sustentacular cells).
• PAX-8 -ve.
• CD10 +ve/-ve -- cannot be used to differentiate from RCC.

Neuroblastoma

See also: olfactory neuroblastoma.

General

Epidemiology:

• Usually paediatric population.

Laboratory findings:

• Increased urine homovanillic acid.

Predictors of a poor prognosis:

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

Classification:

• In a grouping known as neuroblastic tumours which includes:
  • Ganglioneuroma (benign).
  • Ganglioneuroblastoma (intermediate).
  • Neuroblastoma (aggressive).

Gross

• Typically an abdominal mass.
  • ~40% arise in the adrenal gland.

Microscopic

Features:

• 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.
• 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:

• Small round cell tumours.
  • Wilms tumour.
  • Lymphoma.
  • Hepatoblastoma.

Images:

• Neuroblastoma (radiographics.rsna.org).
• Neuroblastoma (WC).
• Neuroblastoma (flickr.com).

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.
  • PGP = protein gene product.
• NB-84 +ve.
  • More sensitive that synaptophysin.
• Synaptophysin +ve.
• CD99 -ve.

EM

Distinctive EM appearance:

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

Pertinent negative:

• No glycogen.
  • Seen in EWS.

See also

• Small round cell tumours.