CHAPTER 24

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THE ENDOCRINE SYSTEM

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THE THYROID GLAND
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Congenital
o Lingual thyroid
o Thyroglossal duct cyst
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Hyperthyroidism
o Primary – independently functioning gland
o Graves – thyroid stimulating antibodies
o Toxic MNG – Plummer syndrome
o Toxic adenoma
o Neonatal due to Graves
o Secondary – increased TSH from the pituitary
o TSH secreting pit adenoma
!
Clinical manifestations of hyperthyroidism
o Increased basal metabolic rate
o Flushed skin
o Heat intolerance
o Sweating
o Weight loss with increased appetite
o Cardiac manifestations
o Increased cardiac output
o Tachycardia
o Arrhythmias
o Palpitations
o CHF
o Histology – foci of eos and lymphs infiltrating the myocardium, mild interstitial fibrosis and
fatty change
o Left ventricular dysfunction – hyperthyroid cardiomyopathy
o Neuromuscular – overactive symp NS
o Ocular changes
o GI hyperstimulation
o Skeletal – osteoporosis
o Thyroid storm – abrupt onset of severe hyperthyroidism – acute elevation in catecholamines
!
Hypothyroidism
o Primary
o Developmental
o Thyroid hormone resistance syndrome
o Postablative (iatrogenic)
o Hashimotos – most common in iodine-sufficient areas
▪ Variants include subacute lymphocytic and postpartum
▪ CD8+ cytotoxic T cell injury
▪ Anti-thyroglobulin and anti-TPO antibodies
▪ Inflammatory infiltrate with germinal centers, atrophic follicles, hurthle cells
 o Iodine deficiency – most common cause worldwide
o Drugs
o Congenital biosynthetic defect
o Secondary
o Pituitary failure
o Congenital biosynthetic defect
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Clinical manifestations
o Infancy/early childhood
o Cretinism – severe mental retardation, short stature, umbilical hernia, coarse facial features
o Adults
o Myxedema
o Slowing of physical and mental ability
o Listless, cold intolerant, overweight
o Promotion of an atherogenic state – increased cholesterol and LDL
o Histology – accumulation of matrix substances – GAGs, HA in skin, subcutaneous tissue,
visceral sites
!
Differential for granulomatous thyroiditis
o Infectious
o Bacterial (TB), fungal, parasitic
o Subacute/granulomatous/de Quervain – believed to be viral
o Inflammatory
o Subacute/granulomatous/de Quervain
o Sarcoidosis
o Crohn’s
o Iatrogenic
o Foreign body
o Post FNA
o Neoplastic
o PTC
!
Risk factors for thyroid carcinoma
o Exposure to ionizing radiation
o Iodine deficiency
o Familial PTC
o MEN syndromes for medullary ca
!
Classification of thyroid nodules
o Benign – non-neoplastic
o MNG
o Intrathyroidal parathyroid
o Intrathyroidal thymus
o Intrathyroidal lymph node
o Follicular cyst
o Amyloidosis
o Malakoplakia
! o Benign – neoplastic
o Epithelial
▪ Follicular adenoma
▪ Hurthle cell adenoma
▪ Paraganglioma
o Mesenchymal
 ▪ Lipoma
▪ Hemangioma
▪ Lymphangioma
▪ SFT
▪ Leiomyoma
▪ Schwannoma
! o Malignant
o Epithelial
▪ PTC
▪ FC
▪ Hurthle cell ca
▪ SqCC
▪ Insular
▪ Anaplastic
▪ CASTLE
▪ SETTLE
▪ Medullary ca
▪ Mixed medullary PTC
▪ Mixed medullary FC
▪ Small cell ca
o Lymphoma
▪ MALT
▪ DLBCL
o Mesenchymal
▪ Fibrosarc
▪ Liposarc
▪ MPNST
o Secondary
o RCC
o Lung
o Breast
!
Histologic subtypes of PTC
o Better prognosis
o Microcarcinoma (< 1cm)
o Encapsulated
o Same px as PTC NOS
o Cribriform-morular variant
o Diffuse sclerosing variant
o Follicular variant
o Macrofollicular variant
o Oncocytic variant
o Warthin-like variant
o Clear cell variant
o Worse px
o Columnar cell variant
o Tall cell variant
▪ cells are 2x tall as wide, should be composed of at least 50% tall cells overall
▪ freq have Braf mutations (tend to be aggressive)
o Diffuse sclerosis variant:
▪ most often in kids and young adults
▪ almost all are assoc with regional LN mets at tim of dx
o Solid variant:
 ▪ has to be ≥ 50% solid areas of the tumor
▪ higher assoc with post chernobyl PTAs
▪ actually deemed almost as good px as classical variant
o Associated with syndromes
o Cribriform-morular variant – FAP
!
All anaplastic carcinomas are T4 tumors.
All PTC < 45 yo are stage 2 max, positive nodes do not change prognosis for this age group.
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Cytology
o Adequacy criteria – 6 groups of 10 cells on 2 slides
o Bethesda categories:

Bethesda Diagnostic Categories for Thyoid Cytology

Risk of malignancy (%) Management
Non-diagnostic (<10%) 1–4 Repeat FNA
Benign 0–3 Clinical F/U
FLUS 5 – 15 Repeat FNA
Follicular neoplasm 15 – 30 Lobectomy
Suspicious for malignancy 60 – 75 Lobectomy or total
Malignant 97 – 99 Total thyroidectomy

o The DDx of microfollicles on FNA is follicular adenoma, FC, and insular carcinoma!
o The follicular neoplasm category should not have colloid in the microfollicles – see colloid with insular
carcinoma
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Cytomorphology of PTC:
• sheets, papillae, microfollicles
• nuclear changes:
• powdery chromatin
• grooves
• pseudoinclusions
• nucleolus (small or large)
• membrane thickening and irregularity
• nuclear crowding or moulding
• variable cytoplasm (scant, squamoid, Huthle-like or vacuolated)
• psammoma bodies
• histiocytes, incl MNGC
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MEN Syndromes Overview
MEN1 MEN2a MEN2b
Pituitary
Pancreas
Parathyroid Parathyroid
Pheo Pheo
 Medullary thyroid ca Medullary thyroid ca
Mucosal neuroma
Marfanoid

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REPORTING OF THYROID CANCER:
! Procedure
•
• Specimen size and weight
• Tumor focality and laterality
• Tumor size
• Histologic type
• Histologic grade
• NB: some PTC’s are more aggressive: tall cell, columnar cell, diffuse
sclerosing
• technically, grading is not a requirement for thyroid carcinomas
• Margins
• determined by proximity to inked margin
• Tumor capsule
• Tumor capsular invasion
• Criteria: see diagram to right ⟹
• LVI
• vessels should be of venous calibre and located outside of the
tumor
• vessels can include intracapsular and extracapsular
• see diagram on right ⟹
• PNI
• Extrathyroidal extension
• NB: presence of fat associated with thyroid ca should not be
mistaken for ETE
• pTNM staging:
• NB: the stage grouping for PTC and FC (and variants) are stratified
by age, for pts < 45 and those >45
• any T, any N, any M - can not be any higher than Stage II
• Also, with mutifiocal tumors, only the largest is used for classification
!
• pT Stage:
• pT1: tumor ≦ 2cm, limited to thyroid
• pT1a: tumor ≦ 1 cm
• pT1b: tumor 1-2 cm
• pT2: tumor 2-4 cm, limited to thyroid
• pT3: tumor > 4 cm, limited to thyroid OR any size with minimal extrathryoidal extension (to
sternohyoid mm or perithyroidal soft tissue)
• pT4a: mod advanced disease - any size extending beyond thyroid capsule → invade subQ tissue,
larynx, trachea, oesophagus or recurrent laryngeal nerve
• pT4b: very advanced disease → invades pre vertebral fascia or encases carotid or mediastinal
vessels
• NB: for anaplastic ca: pT4a is intrathyroidal, pT4b is gross extra thyroidal extension
• NB: good px for tumors 1 cm or less, worse if >4 cm
 • NB: for follicular ca’s, T >3.5 cm is worse px
• NB: for medullary ca’s, T>1 cm worse px
• NB: PTC, micro-carcinomas are 1 cm or less
! • pN Stage:
• pN1a: mets to level VI nodes
• pN1b: mets to unilateral, bilateral or contralateral cervical levels I-V or level VII nodes
• specify number examined
• ? extranodal extension
!
• pM Stage:
• pM1: distant mets (specify site(s))
• !
• additional pathologic findings (adenomas, hyperplasia, thyroiditis, etc.)
• ancillary studies (type and results)
• clinical hx (rads exp, family hx
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ANCILLARY TESTING IN THYROID CANCER:
!
• IHC: nothing specific, morphology is gold standard
• Molecular:
• RET/PTC translocation (in up to 60% PTC, not in other subtypes)
• BRAF (29-69% PTC, more in classic, tall cell, Warthin-tumor like and oncocytic variants;
• RAS and possibly PAX8/PPARγ in FV-PTC (rarely RET/PTC or BRAF), and in FC
• RET germ-line mutations in MC
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!
More on Molecular Aspects:
• PTC’s: carry point mutations in BRAF, RAS and rearrangements in RET/PTC and TRK → all can activate
the MAPK pathway and all mutations are MUTUALLY EXCLUSIVE
• these are found in >70% PTC’s
• FC’s: have either RAS mutations of PAX8/PPARG𝛾 rearrangements → also mutually exclusive
• found in 70-75& FC’s
• PI3K/AKT signalling pathway can also occur, but tend to be in less differentiated carcinomas and are rare
• MC’s: - familial and sporadic have point mutations in RET
!
• Top 4 genes: BRAF, RAS, RET/PTC, PAX8/PPARG𝛾
• BRAF (the V600E in particular) also found in more poorly differentiated and anaplastic ca’s
• in PTC: may serve as px’s marker → association with more aggressive characteristics (extra-
thyroidal extension), advanced tumor stage at presentations and LN or distant mets
• also an independent predictor of treatment failure and tumor recurrence, even in pts with low
stage disease (ie. pT1, which encompasses micro carcinomas)
• RET/PTC: numerous rearrangements identified
• occur with higher incidence in pts with rads exposure and in tumors from kids and young
adults
• typ present at younger age, have classical PTC histology and a high rate for LN mets
• RAS mutations found with variable freq in all types of thyroid carcinomas
• almost all PTCS with RAS mutation have the follicular variant
• also found in benign adenomas and FC’s
• PAX8/PPAR𝛾: tend to present at younger age, be smaller in size and more often have vascular invasion
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When to use molecular testing:
• for risk stratification of indeterminate FNA results
• when FNA results show FLUS or follicular neoplasm - risk of malignancy with these cyto lesions ranges
from 5-32% and most undergo surgery (which often ends up being benign)
• can test in two ways:
1. using specific molecular markers (BRAF, RAS, etc)
2. using high density genomic data (mRNA classifier which measure activity level of 167 genes
within nodule) for molecular classification (this method has had better diagnostic
correlation outcomes)
• can potentially save numerous surgeries for benign lesions and just watch (though neither method
completely accurately predicts, which lesions are malignant
• ???What do we do in Calgary
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Revised Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer:
• recommends use of molecular markers, such as BRAF, RAS, RET/PTC and PAX8/PPAR𝛾, may be
considered for pts with indeterminate FNA cytology to help guide mgmt
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PARATHYROID GLANDS
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Anatomy
o Develop from 3rd and 4th pharyngeal pouches
o Produce PTH – increases serum calcium levels
o Normal overall weight is 120 – 140 mg
o Negative for TTF-1 and tend not to have calcium oxalate crystals
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Classification of parathyroid hyperplasia
• Primary – normally an adenoma (85%), hyperplasia (15%), no known stimulus
• Secondary – known stimulus such as CRF, malabsorption, Vit D deficiency
• Tertiary – long standing renal failure with autonomous PTH hyperfunction
! Up to 20% of patients presenting with primary hyperplasia have a MEN syndrome (1 or 2a).
•
• Water clear cell hyperplasia must be distinguished from metastatic RCC.
• Autotransplantation – the cells can be mitotically active and infiltrative; do not call carcinoma!
• Parathyromatosis – numerous nests of hyperplastic parathyroid found throughout the neck –
associated with MEN or previous surgery.
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Causes of hypercalcemia
o Raised PTH
o Hyperparathyroidism (primary, secondary, tertiary)
o Familial hypocalciuric hypercalcemia
o Parathyroid ca
o Decreased PTH
o Hypercalcemia of malignancy
o Vit D toxicity
o Immobilization
o Drugs
o Granulomatous disease – sarcoid
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Parathyroid Carcinoma
o Clinical presentation
o Profound hypercalcemia
o Renal calculi and insufficiency
o Osteopenia and brown tumors
o Gross
o Large and adherent to other structures
o Micro
o Thick capsule with thick fibrous bands
o Capsular invasion and invasion of soft tissues
o No single diagnostic feature other than mets
!
Major causes of hypoparathyroidism
o Iatrogenic
o Autoimmune hypoparathyroidism
o May be part of autoimmune polyendocrinopathy syndrome
o AD hypoparathyroidism
o Familial isolated hypoparathyroidism
o Congenital absence
o DiGeorge syndrome
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MOST COMMON DX FOR PARATHYROID GLANDS:
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Normal Parathyroid Glands
• Normal size
◦ 4-6 mm x 2-4 mm x 0.5-2 mm
• Normal weight
◦ Men: 30 ± 3.5 mg
◦ Women: 35 ± 5.2 mg
◦ Any gland > 60 mg is enlarged
• Normal parathyroid glands can show significant variation in cellularity, even in a single individual
◦ Age, gender, constitutional factors (body fat, etc.) affect cellularity of normal parathyroid
◦ Normal parathyroid cellularity distributed unevenly, high in infants and children, decreases
with age
◦ Adipose tissue
▪ Stromal fat constitutes 10-30% of parathyroid
▪ Increases with age
▪ Not a reliable feature to distinguish normal glands from adenomas or hyperplasia
▪ More stromal fat in polar regions of parathyroid than central
!
Comparison of Normal Parathyroid and Diseased Parathyroid
Feature Normal Glands Abnormal Glands
Number Usually 4 glands Up to 12 glands, ectopic location, intrathyroidal or intrathymic
Weight ~ 30 mg each Any gland > 60 mg
Size Up to 6 mm > 6 mm
% adipose tissue Usually > 25%, increases with age < 5%

Intracytoplasmic lipid Abundant Lack of intracellular and intercellular lipid deposition (negative oil red O
stain)
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Parathyroid Adenoma
• ~ 85% of surgical cases are to resect an adenoma
◦ Excision of adenoma is curative and should result in immediate decrease in circulating PTH
◦ If PTH is not decreased, 2nd adenoma may be present
• Majority (~ 96%) of adenomas are solitary
◦ Rare cases of ≥ 2 adenomas can occur
• Size: 1-3 cm
• Weight: 300 mg to several grams
• Light tan color
◦ Thyroid tissue is dark red
• Usually < 5% adipose tissue
◦ However, some adenomas do have intracellular fat and adipose tissue
• Cystic change can occur in large adenomas
• Spontaneous infarction may result in adjacent inflammatory changes and adherence to surrounding
tissue
• Scattered cells with marked nuclear atypia may be present
◦ Not a diagnostic feature of malignancy
• Normal-appearing parenchyma may be seen compressed to 1 side in ~ 50%
• Rarely located completely within thyroid gland
• Rarely associated with genetic syndromes such as hyperparathyroidism-jaw tumor syndrome (HPT-
JT) and familial hypercalcemic hypercalciuria
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Parathyroid Adenoma Variants
• Parathyroid microadenoma: Weight < 0.1 g
• Oxyphil parathyroid adenoma: Composed of > 90% mitochondria-rich oncocytes
• Water clear cell parathyroid adenoma: Composed of cells with extensively vacuolated clear
cytoplasm
• Parathyroid lipoadenoma: Composed of abundant adipose tissue with scattered nests of
parenchymal chief cells
• Ectopic parathyroid adenoma: Located at abnormal sites
◦ Intrathyroidal, mediastinum, thymus, soft tissue behind esophagus and pharynx
• Predominantly macropseudofollicular growth pattern with colloid-like material are relatively
common in parathyroid adenomas
◦ This pattern may mimic thyroid follicles
• Cystic parathyroid adenoma
◦ Varying degrees of cystic change can be seen in parathyroid adenomas
◦ Particularly common in larger parathyroid adenomas
◦ Associated with hyperparathyroidism-jaw tumor syndrome
▪ HPT-JT is an autosomal dominant disorder caused by inactivating mutations in
HRPT2 tumor suppressor gene that encodes parafibromin
!
Secondary Hyperplasia
• All 4 glands are usually enlarged, but enlargement may not connote level of involvement
◦ Each, some, or all 4 glands may be multinodular
◦ Asymmetric enlargement can resemble an adenoma or adenomas (pseudoadenomatous
variant)
◦ Nodular growth pattern is usually seen in parathyroid hyperplasia
◦ Cell populations can consist of multiple types with nodules of chief cells, oxyphil cells, and
clear cells
◦ Scattered fat cells are usually present
◦ Adipose tissue may be decreased and rarely absent
▪ Oil red O or other stains for fat show diminished staining in most cases
• It may not be possible to distinguish an adenoma from hyperplasia if only 1 gland is examined and
clinical history is not provided
• 3 glands are removed
◦ 4th gland is biopsied to ensure parathyroid tissue has been identified and left in situ
!
Primary Hyperplasia
• Very rare
• 1-4 glands may be enlarged
• 20% of patients will have a multiple endocrine neoplasia (MEN) syndrome
◦ Generally MEN1 or MEN2A
!
Hyperparathyroidism (Increased Serum PTH)
Type Usual Cause Number of Glands Involved Serum Calcium
Primary Solitary adenoma (common) Usually 1, rarely ≥ 2 Elevated
Primary Primary hyperplasia (rare) 2-4 Elevated
Secondary Chronic renal failure 4: All glands involved Decreased
Tertiary Chronic renal failure 4: All glands involved Elevated
Tertiary hyperplasia occurs after a long period of secondary hyperplasia. The glands become autonomously functioning and the calcium level is elevated.

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Thyroid Lesion
• Often show follicular growth, which can be seen in some parathyroid adenomas
• Sometimes ectopic nodule of multinodular hyperplasia may grossly mimic a parathyroid gland
• Thyroid tissues and neoplasms often
◦ Have colloid and calcium oxylate crystals (highlighted by polarization)
◦ Lack intracytoplasmic lipid and well-defined cytoplasmic membranes of parathyroid tissue
!
Atypical Parathyroid Adenoma
• Noninvasive parathyroid neoplasm composed of chief cells with variable oncocytes, transitional
cells, and water-clear cells with some features of parathyroid carcinoma
◦ Adherence to adjacent structures
◦ Mitotic activity
◦ Fibrosis
◦ Trabecular growth
◦ Tumor cells in capsule
• No definitive invasion
◦ No invasion into adjacent structures
◦ No capsular invasion
◦ No vascular invasion
◦ No perineural invasion
!
Parathyroid Carcinoma
• Majority are functional and cause hyperparathyroidism
• Parathyroid carcinoma usually necessitates en bloc resection
◦ En bloc resection is necessary because carcinomas adhere to/infiltrate adjacent tissues
◦ Removed with attached skeletal muscle and adjacent thyroid
◦ Specimen should be inked and margins evaluated
• Invasion into adjacent structures, vessels, perineural space
• Very rare (~ 2% of cases)
• Usually in older adults (4th-6th decades)
• Generally large: 2-6 cm, over 40 grams
• Histologic features
◦ Monotonous or trabecular growth, prominent nucleoli, high nuclear to cytoplasmic ratios
are frequently identified
◦ ~ 2/3 have marked nuclear pleomorphism present throughout carcinoma
◦ Thick capsule that may be invaded
◦ Numerous mitoses
◦ Necrosis
◦ Lymphovascular or perineural invasion
◦ Dense fibrous bands
▪ Fibrosis and fibrous bands but can be seen in both parathyroid adenoma and
carcinoma
!
Metastatic Carcinoma
• Rarely identified during life
• Autopsy studies show up to 12% of patients with known cancer have parathyroid involvement
• Metastases are usually from breast, prostate, liver, lung, and hematolymphoid malignancies
• Also may be involved from direct extension from a thyroid tumor or head and neck neoplasm
• Immunohistochemistry studies are very helpful to confirm primary site
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SURGICAL/CLINICAL CONSIDERATIONS:
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Goal of Consultation
• Confirm a parathyroid gland has been biopsied or resected
• Confirm parathyroid disease
!
Change in Patient Management
• After removal of parathyroid gland(s) or biopsy confirmed, additional surgery is not necessary
◦ Differentiation of adenoma, primary hyperplasia, and normal parathyroid may be used to
guide surgery
• In rare cases, confirmation of parathyroid carcinoma can guide completion of surgery
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Clinical Setting
• Primary hyperparathyroidism
◦ Patients usually present with elevated parathyroid hormone (PTH) and hypercalcemia as
detected by serum levels
▪ Less commonly, patients present with symptoms of osteoporosis or renal calculi
◦ 85% have solitary adenoma
▪ Primary hyperplasia involving multiple glands is less common
◦ Surgery continues until adenoma has been removed
▪ In cases of primary hyperplasia, multiple glands are removed
◦ Imaging techniques with sestamibi can identify > 90% of adenomas
▪ Useful to identify adenomas in unusual locations
▪ Less useful to detect multiple hyperplastic glands
▪ Single enlarged gland is removed
▪ Remaining glands are inspected to ensure they are normal in size
◦ Frozen section has been replaced by intraoperative PTH assays in some places
▪ If serum level of PTH decreases by > 50% after removal of adenoma, further
surgery is not necessary
! • Secondary hyperparathyroidism
◦ Parathyroid glands become enlarged and hyperplastic in response to low calcium levels
▪ Most commonly due to renal failure
▪ Causes debilitating loss of calcium from bones
◦ Usually 3 parathyroid glands will be removed while 1 gland is partially resected
▪ Frozen section confirms identification of all 4 removed glands
! • Surgery for thyroid resection or neck exploration
◦ Parathyroid glands may be resected inadvertently
!
Practical Considerations in Parathyroid Intraoperative Consultation
• Parathyroid glands can be difficult for surgeon to identify
◦ Normal glands are very small
◦ Location and number of glands can vary
▪ 15% are found in unusual locations
◦ Lymph nodes, thymic tissue, thyroid nodules, and other areas of nodular tissue may
resemble glands grossly
• Frozen section is necessary to definitively identify tissue as parathyroid
◦ Tissue is assessed as normal or abnormal
◦ Disease involving gland should be diagnosed when possible
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Frozen Section
• Document that parathyroid tissue is present
◦ If entire gland has been removed, size and weight are reported
• Report if ≥ 1 gland(s) are hypercellular
◦ % of adipose tissue should be reported
▪ Specific diagnosis of adenoma or hyperplasia is not necessary and is often not
possible
◦ If single gland is enlarged and if rim of normocellular parathyroid, diagnosis of adenoma
may be rendered
• Presence or absence of intracellular and extracellular lipid on oil red O stain (when used)
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Cytology
• Reported in conjunction with gross and frozen section findings
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THE ADRENAL GLAND
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Anatomy
o Normal combined adult weight should not exceed 6 grams
o GFR (aldosterone, cortisol, sex steroids)
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Heterotopias
o Most commonly found along the inguinal scrotal path
o Spermatic cord
o Inguinal hernia sac
o Epididymis
o May contain heterotopic liver, thyroid, ovarian stroma
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Classification of adrenal cortical insufficiency
o Primary – issue with the gland itself
o Autoimmune adrenalitis (Addison disease)
o Autoimmune polyendocrinopathy
o Inborn errors of metabolism
o Infections – TB, fungal, viral
o Hemorrhage
o Infiltrative causes
▪ Neoplasms
▪ Amyloidosis
o Drugs
o Secondary – failure of the pit to secrete ACTH
o Tertiary – failure of the hypothalamus to secrete CRH
o Zona glomerulosa and medulla are spared
!
Classification of adrenal cortical hyperplasia
o Congenital
o CAH – AR disorder, 21-hydroxylase most common
o Cortical neoplasms can develop
o Acquired
o Diffuse
▪ Hyperfunctioning pit tumor
▪ Ectopic ACTH from a tumor
o Nodular – generally ACTH independent
o Pigmented – associated with Carney complex
o Conn syndrome – most cases due to an adenoma, 30% of cases due to diffuse hyperplasia
!
Classification of hypercortisolism
o Exogenous – steroids
o Endogenous
o ACTH dependent
▪ Pituitary adenoma
▪ Ectopic – part of paraneoplastic syndrome
o ACTH independent
▪ Adrenal adenoma
▪ Adrenal carcinoma
▪ Macronodular hyperplasia
▪ Primary pigmented adrenal nodular disease
▪ McCune Albright syndrome
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Classification of adrenal nodules
o Cysts
o Pseudocysts
o Endothelial cysts
o Epithelial cysts
o Parasitic cysts
o Benign tumors
o Cortical
▪ Cortical adenoma
o Mesenchymal
▪ Myelolipoma
▪ Adenomatoid tumor
▪ Schwannoma, lipoma, hemangioma, SFT, hemangioblastoma
o Medullary
▪ Pheochromocytoma
▪ Ganglioneuroma
▪ Composite tumors – may be associated with syndromes
o Malignant tumors
o Cortical
▪ ACC
o Medullary
▪ Pheochromocytoma
▪ Neuroblastoma
▪ GNB
o Mesenchymal
▪ MPNST
▪ Wilms
▪ Sarcomas
o Secondary
o Breast, lung, kidney, stomach, colon
o Cause adrenal insufficiency in 20 - 30%
!
Types of functioning adenomas
o Conn syndrome (aldosterone secreting)
o May have spironolactone bodies (if treated with spironolactone) – look like psammoma
bodies
o Cushing syndrome
o Adrenogenital syndrome/CAH – cause virilization
!
Ddx for Adrenocortical Adenoma

Neoplasm Inhibin Melan-A Chrg Syn Hep-Par1 CD10

Adrenocortical adenoma Positive Positive Negative Positive (57%) Negative Negative

Pheochromocytoma Negative Negative Positive Positive Negative Negative

Hepatocellular carcinoma Negative Negative Negative Negative Positive Positive (61%)

Renal cell carcinoma Negative Negative Negative Negative Negative Positive

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Morphologic variants
o Black adenoma – mostly Cushings, pigment is lipofuscin
o Oncocytic – most are non-functioning
o Myxoid
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Features of adrenocortical carcinoma
o Associated with Li Fraumeni and Beckwith-Weidemann syndrome
o Most are non-functional
o Gross features
o Large - > 10 cm, > 100 g
o Hemorrhage and necrosis
o Direct extension to other organs
o Vessel invasion
o Microscopic features
o Weiss criteria
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Medullary lesions
o Hyperplasia
o Seen in MEN, Beckwith-Weidemann syndrome, NF, duodenal carcinoid, CF
o Nodules should be less than 1 cm, if larger call it a pheo
o Pheochromocytoma
o Associated syndromes
▪ MEN2a and b
▪ NF1
▪ VHL
▪ TS
▪ Sturge Weber
▪ Familial – mutations in SDH
o Malignant if mets present, PASS criteria
o Composite Pheo – ganglioneuromatous, ganglioneuroblastomatous, neuroblastomatous,
MPNST, NE carcinoma component
▪ Reported in NF1 and MEN2a
o Neuroblastoma
o Associated with Beckwith Weidemann syndrome, NF1, Hirschsprung’s disease
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Neuroblastoma Shimada Classification:
o Schwannian stroma poor (<50%)
o Undifferentiated – no neuropil, no ganglion cells
o Poorly differentiated – neuropil, <5% ganglion cells
o Differentiating – neuropil, at least 5% ganglion cells
o Schwannian stroma rich (>50%)
o Ganglioneuroblastoma
▪ Nodular
▪ Intermixed
o Ganglioneuroma
• Many prognostic factors but age <1 and stage are the most important.
• MKI is per 5000 cells.
!
• Favorable histology group:
o Patients of any age with stroma-rich tumors without a nodular pattern
o Patients younger than 18 months, with stroma-poor tumors, an MKI less than 200/5000 (200
karyorrhectic cells per 5000 cells scanned)
o Patients 18-60 months with stroma-poor tumors, an MKI less than 100/5000, and well-
differentiated tumor cells
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• Unfavorable histology group:
o Patients of any age with stroma-rich tumors and a nodular pattern
o Patients of any age with stroma-poor tumors and an MKI more than 200/5000
o Patients 18-60 months with stroma-poor tumors, differentiated neuroblasts, and an MKI of
100-200/5000
o Patients 18-60 months with stroma-poor tumors, undifferentiated neuroblasts
o Patients older than 60 months with stroma-poor tumors
!
• Staging: 4S - localized primary tumor (stage 1, 2A or 2B) with dissemination limited to skin, liver or
bone marrow (limited to infants < 1 year of age); note: marrow involvement should be minimal (<10%
of total nucleated cell identified as malignant); more extensive involvement should be classified as
stage 4
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Favorable vs. Unfavorable Histology in Neuroblastic Tumors
Classification Subclass MKI Age at Diagnosis Histologic Category
Neuroblastoma (NB) Undifferentiated Any MKI Any age Unfavorable histology
Poorly differentiated High MKI Any age Unfavorable histology
Low or intermediate MKI > 1.5 years Unfavorable histology
< 1.5 years Favorable histology
Differentiating High MKI Any age Unfavorable histology
Intermediate MKI > 1.5 years Unfavorable histology
< 1.5 years Favorable histology
Low MKI > 5 years Unfavorable histology
< 5 years Favorable histology
Ganglioneuroblastoma (GNB) Nodular ** ** Unfavorable or favorable
**The determination of favorable vs. unfavorable histology in nodular GNB is based on the NB component. MKI = mitosis-karyorrhexis index.

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Neuroblastoma Staging System
Stage Definition
I Localized confined tumor; complete gross excision; ipsilateral and contralateral nodes negative
IIA Unilateral tumor; incomplete gross excision; identifiable ipsilateral and contralateral nodes negative
IIB Unilateral tumor ± complete gross excision; identifiable ipsilateral nodes positive, identifiable ipsilateral and contralateral
nodes negative
III Tumor infiltrating across midline without positive nodes; or unilateral tumor with positive contralateral nodes
IV Distant metastases to nodes, bone, bone marrow, liver, skin, &/or other organs not stage 4S
IV-S Localized primary tumor (stage 1 or 2) with metastases limited to liver, skin, &/or bone marrow

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Extra-adrenal paraganglioma
o Associated syndromes:
o Carneys triad
o Carney-Stratakis dyad
 o Familial – SHD mutations
o Sympathetic
o Along the sympathetic chain
o Organ of Zuckerkandl
o Parasympathetic
o Jugulotympanic
o Carotid body
o Vagal
o Laryngeal
o Aorticopulmonary

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REPORTING ON ADRENAL GLAND CANCERS
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• Specimen, Procedure, Laterality
• Tumor size and gland weight
• Histologic type
• NB: no histologic grading, however may comment on features tat may suggest malignancy in
cortical tumors only (modified Weiss criteria)
• also, features of malignancy differ between adult and paediatric groups
• Tumor description (hem’g, necrosis, invasion of capsule, vessels or extra-adrenal tissue)
• ?microscopic tumor extension
• Margins
• LVI (small versus large vessel invasion), PNI
• LN status, ENE?
• Relevant clinical hx (known syndrome, hormonal alterations, etc)
• TNM staging:
• pT1: ≤5 cm
• pT2: >5 cm, no extra-adrenal extension
• pT3: any T with local inv, but not adjacent organs
• pT4: any size, with inv of adjacent organs
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Tumor Syndromes:
• MEN, types 1, 2a, 2b
• Carney Complex (NAME, LAMB)
• Neurofibromatosis
• Polyglandular Autoimmune Syndomre, type 1
• McCune-Albirght
• VHL
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Differential Diagnosis of Adrenal Cortical Adenoma

Neoplasm Inhibin Melan-A Chrg Syn Hep-Par1 CD10

Adrenocortical adenoma Positive Positive Negative Positive (57%) Negative Negative

Pheochromocytoma Negative Negative Positive Positive Negative Negative

Hepatocellular carcinoma Negative Negative Negative Negative Positive Positive (61%)

Renal cell carcinoma Negative Negative Negative Negative Negative Positive

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 Tumor Distributions in Major Familial Paraganglioma Syndromes
Gene Other
Syndrome (Chromosome Adrenal Sympatheti Head & Other Tumors
Neck
) c
MEN2A RET (10q11) +++ +/- +/- Medullary thyroid carcinoma, parathyroid adenoma (MEN2A only)
and MEN2B
VHL VHL +++ ++ +/- Renal cell carcinoma (RCC); hemangioblastoma; endolymphatic sac
(3p25-26) tumor; carcinoid, pancreatic endocrine tumor
NF1 NF1 +++ +/- +/- Neurofibroma, GIST, carcinoid
(17q11.2)
PGL1 SDHD ++ ++ ++
(11q23)
PGL3 SDHC +/- +/- +++ GIST
(1q21-23)
PGL4 SDHB (1p36) ++ +++ + RCC, GIST

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Histologic Criteria for Distinguishing Benign from Malignant Adrenal Cortical Neoplasms
Weiss Criteria* Van Slooten System**
High nuclear grade; Fuhrman criteria used Histologic criteria/weight
> 5 mitoses/50 HPF Extensive regressive changes (necrosis, hemorrhage, fibrosis, calcification)/5.7
Atypical mitotic figures Loss of normal structure/1.6
< 25% of tumor cells are clear cells Nuclear atypia (moderate/marked)/2.1
Diffuse architecture (> 33% of tumor) Nuclear hyperchromasia (moderate/marked)/2.6
Necrosis Abnormal nucleoli/4.1
Venous invasion (smooth muscle in wall) Mitotic activity (≥ 2/10 HPF)/9.0
Sinusoidal invasion (no smooth muscle in wall) Vascular or capsular invasion/3.3
Capsular invasion
*Presence of 3 or more criteria highly correlates with malignant behavior. **Histologic index > 8 correlates with malignant behavior.

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System of Hough for Distinguishing Benign from Malignant Adrenal Cortical Neoplasms
Histologic Criteria/Value Nonhistologic Criteria/Value*
Diffuse growth pattern/0.92 Tumor mass > 100 g/0.60
Vascular invasion/0.92 Urinary 17-ketosteroids (10 mg/g creatinine/24 h)/0.50
Tumor cell necrosis/0.69 Response to ACTH (17-hydroxysteroids increased 2 x after 50 mg ACTH IV)/0.42
Broad fibrous bands/1.00 Cushing syndrome with virilism, virilism alone, or no clinical manifestations/0.42
Capsular invasion/0.37 Weight loss (10 lb/3 months)/2.00
Mitotic index (1/10 HPF)/0.60
Pleomorphism (moderate/marked)/0.39
*Mean histologic index of malignant tumors is 2.91, indeterminate tumors 1.00, and benign tumors 0.17.