Endocrine Cancers

Adrenal Cortex Tumors

- Adrenal cortex makes epinephrine with the autonomic nervous system

Epidemiology and Etiology

- M=F
- Tumours more common in in left vs right gland
- Median age of Dx =50 years, general age 1-80 years
- Adrenal adenomas – benign but they can cause hyper secretion of certain hormones
causing other issues

Prognostic Indicators
- Stage at time of Dx  most have advanced disease at presentation
- Ability to complete curative resection  only modality shown to effect survival rate
- Young age at Dx is favorable

Anatomy
- Adrenal glands sit on top of kidneys  have yellow cortex and dark brown medulla
- Blood supply of adrenals from adrenal branches of inferior phrenic artery/ renal artery
- Lymphatic drainage via para-aortic nodes
- Weight of normal adrenal gland = 20 g

Physiology
- Cortex makes steroid hormones  glucocorticoids, mineralocorticoids, and sex
hormones responsible for metabolic regulation which include the following hormones:
cortisol, aldosterone, estrogen, and androgen
 - Normal functioning adrenal cortex can meet metabolic demands and maintain
homeostasis

Clinical Presentation
- Because of location of adrenals in abdo and inaccessibility patients of often present with
pain due to advanced cancer
- Symptoms based on excess hormone productio

- Study on 47 patients with adrenocortical carcinoma shows

a) Non-functional tumor symptoms - abdominal mass in 77% patients, weight loss in
46%, fever in 15%, distant mets in 15%
b) Functional tumors symptoms – Cushing syndrome and virilization in 24%, virilization
in 15%, feminization in 9%

Detection and Dx
- Patients can have functioning or non-functioning tumors
a) Functioning tumors present with clinical syndromes from previous table which leads
to Dx – easily confirmed with lab tests
b) Non-functioning tumor – pain is presenting symptom which is often associated with
advanced disease
- CT or MRI first – allow Dx and shows local/ regional extent of disease
 - Needle Bx with CT guidance – definitive tissue Dx

Pathology
- Adrenocorticoid tumors  usually large single rounded masses of yellow-orange
adrenocortical tissue
- Tumor is large at Dx and shows hemorrhage, necrosis, and calcification
- Grade – based on similarity to healthy adrenal cortical cells
a) Grade I – well differentiated  presence of capsular and vascular invasion and
abnormal mitoses distinguishes them from adenomas
b) Grade II
c) Grade III
NOTE: Grade I/II have better survival rates than grade III

Staging
- No real staging system because rarity of cancer
 - Conventional staging system used which is based on size of tumor / extent

Routes of Spread
- Grow locally into adjacent tissues – right side tumors usually involve kidney, liver, vena
cava and left side often involves kidney, pancreas, diaphragm
- Can spread to regional para-aortic nodes
- Distant spread to lung, liver, brain
NOTE: Local invasion and distant spread usually at time of Dx

Treatment Techniques
- Sx (primary)
Complete resection not always possible because of direct invasion of adjacent tissues, in
this case Sx for debulking reduces pain
- XRT (limited role)
a) Adj XRT  postop XRT for improved local control’
b) XRT alone  palliative metastatic disease
- Cx (little research on use of Cx)  Adriamycin (doxorubicin), cisplatin, etoposide,
cyclophosphamide (Cytoxan) , 5-FU: these agents have some effect but still unclear

Adrenal Medulla Tumors

Epidemiology and Etiology

- Tumors called pheochromocytomas  only 10% have malignant cytologic features
 NOTE: These tumors seen in patients with von Recklinghausen disease (type I
neurofibromatosis)
- Peak incidence at 50’s but can be seen in any age group
- Can be bilateral tumors in many familial syndromes and associated with MEN syndromes

Anatomy
- Refer to adrenal cortex info

Clinical Presentation
- Hypertension
- Severe headache
- Nervousness
- Palpitations
- Excessive perspiration
- Angina
- Blurred vision
- Abdominal and chest pain
NOTE: These symptoms are due to elevated epinephrine production. Symptoms differ
based on benign vs malignant tumors often sporadic

Detection and Dx
- Suspected based on presentation
- CT or MRI – to assess extent of disease
- Lab tests – measures urinary or plasma catecholamines to confirm Dx  measure
epinephrine precursors and vanillylmandelic acid (VMA)
- Needle Bx – tissue Dx but maybe not needed if images and lab tests support Dx

Pathology and Staging

- Well delineated, circumscribed tumors
- Color  dark red to gelatinous pink to gray or brown
- Size 1-30cm with necrotic and hemorrhage areas

Routes of Spread
- Grow locally into adjacent tissues
- Can spread to regional LNs
- Distant spread to lung, liver, brain

Treatment Techniques
- Sx (primary)
a) Malignant tumors - Complete resection not possible if invasion into adjacent tissues
(poorer prognosis with extra-adrenal malignancy)
b) Benign tumors – normal life expectancy after Sx
NOTE: Persistent elevation of blood pressure indicative of residual or metastatic
disease
Results of Tx
- Adrenocortical carcinoma – poor outcome with 5-year survival rates between 25-40% -
stage at Dx and ability to resect really affects prognosis – most patients have advanced
disease (65-75%) with incomplete resection so decreased survival
- Adrenal medulla-pheochromocytoma – most are benign which allows complete
resection  most patients have normal life span

Pituitary
- Tends to be less aggressive than other CNS tumors
- Pituitary has 3 lobes:
a) Anterior
b) Posterior – tumors are rare
c) Intermediate – tumors are rare
- This section will cover adenohypophysis or tumors of anterior lobe of pituitary

Epidemiology and Etiology

- Hormone production serves as a diagnostic and Tx response marker
- Pituitary tumors are benign, pituitary adenomas can be classified as:
a) Functioning – secretes hormones
1) Most common hypersecretory tumor type  prolactinoma: causes amenorrhea
(absence of menstruation) and galactorrhea (discharge of milk when woman is
not pregnant or breastfeeding) in women and impotence/ infertility in men
2) 2nd most common functioning tumor growth hormone (GH) secreting adenoma
 causes acromegaly (enlarged extremities) in adults and gigantism in children
3) 3rd most common functioning tumor) is adrenocorticotrophic hormone (ACTH)
secreting tumor  because of over secretion of cortisol
4) TSH – secreting adenoma (rare

b) Non-functioning – does not secrete hormones  arise from gonadotrophin-

producing cells
- Tumor progression outside Sella turcica can cause pressure or invasion of nearby
structures
 - Headaches, diplopia, or visual impairments if optic chiasm gets compressed

Prognostic Indicators
- Depends on type of adenoma, extent of abnormalities (mass effect or hormonal
alterations), success of Tx to reduce pressure effects or normalize endocrine activity,
morbidity caused by Tx, and effectiveness of Tx in preventing recurrence

Anatomy
- 1.3 cm diameter
- Located in base of brain, sits in sella turcica of sphenoid bone
- Attached to hypothalamus by infundibulum (stalk-like structure)
- Has 3 lobes - Anterior lobe (adenohypophysis)**, posterior lobe (neurohypophysis) and
intermediate lobe
- Pituitary is close to critical CNS structures: optic chiasm (superiorly)

- Pituitary can be found between temporomandibular joint (TMJ) and midplane behind
nasal bone

Physiology
- Anterior lobe is derived from the endoderm and makes the glandular part of pituitary,
glandular cells are acidophils and basophils, which secrete 7 hormones”
1) Growth hormone (GH) – controls body growth  acidophils
2) Prolactin – starts milk production  acidophils
3) TSH – controls thyroid  basophils
4) Follicle-stimulating hormone (FSH) – egg/sperm production  basophils
5) Luteinizing hormone (LH) – other sexual and reproductive activity  basophils
6) Melanocyte-stimulating hormone – skin pigmentation  basophils
7) ACTH – influences adrenal cortex activity  basophils
 - The release/inhibition of these hormones controlled by chemical secretions (regulatory
factors) from hypothalamus
- Posterior lobes releases:
1) Oxytocin – smooth muscle contraction
2) Antidiuretic hormone (ADH) or vasopressin – regulates free water resorption in
kidneys

Clinical Presentation
- Hormonal effects
a) Functioning pituitary tumors still allow hormone production but do not respond to
regulatory mechanisms and produce hormones regardless of metabolic need
b) PRL secreting tumor – amenorrhea/ galactorrhea
c) GH hypersecretion – weight gain, thickening of bones/ soft tissues of
hands/feet/cheeks, overgrowth of tongue/ jaw – acromegaly if hypersecretion after
puberty and giantism if before puberty
d) Hormones with target organs ( ACTH-adrenals, TSH-thyroid, FSH-ovaries and testes) –
can cause following abnormalities

- Pressure effects
a) Most common presentation of growing pituitary lesion  Headache = local pressure
on sphenoid sinus lining and traction on diaphragm sellae
b) Visual acuity and field defects – most common field defect is bitemporal
hemianopsia (loss of peripheral vision bilaterally)
c) Visual symptomatology – from pressure on inf aspect of optic chiasm
d) Permanent blindness – if prolonged pressure effects on optic chiasm
e) Cranial nerve deficits – tumor grows laterally into cavernous sinuses – rare

Detection and Dx
- Functional tumors
a) Endocrine abnormalities from hypersecretion prompt medical attention
b) Lab tests – directly measures hormone levels confirming pituitary dysfunction
allowing Dx
- Non-functional tumors
a) Pressure effects cause headaches, visual disturbances, and damage of cranial nerves
– these elicit medical attention and strong Dx test
 - CT or MRI

Pathology
- Microadenomas <10cm
- Macroadenomas >10cm
NOTE: Size of tumor can affect prognosis because larger tumors harder to resect and
recurrences occur
- Can be classified via growth pattern (expansion or invasion) and then separated into:
a) Intrahypophyseal – tumor stays in pituitary
b) Intrasellar – tumors grow within confines of Sella turcica
c) Diffuse – fill entire Sella turcica and can erode wall
d) Invasive adenoma - rapid growth rate and grow out of Sella turcica into nearby
tissues – malignant adenomas when mets are present which occurs via CSF OR
vasculature but this is rare
Staging
- Most tumors benign no true staging system
- 4 grades – depends on extent of expansion or erosion of the sella and suprasellar
extension

Treatment Techniques
- Primary goal to normalize pituitary hormone function or relieve pressure effects
- Sx - Sx typically only Tx
a) Trans frontal Craniotomies – before 1970s – invasive
b) Transsphenoidal approach - current std – less invasive with direct access of pituitary
without disturbance to CNS structures = decreased mortality rate – complications of
 procedure: CSF leakage, infection, visual defects

NOTE: If Sx of functioning adenoma is successful then hormone normalization

immediate
- XRT
a) Adj XRT – reduce recurrence rates as compared to Sx alone – incomplete resection or
tumors with suprasellar extension associated with visual field defect or large tumors
where Sx is risky or elevated hormone levels even after Sx
b) XRT alone – patients who refuse Sx/ or those unfit for Sx
- XRT Techniques
a) For initial CT sim – chin is flexed toward chest to reduce XRT dose to eyes
b) Bite blocks or intraoral stents to fixate position of chin, mouth, and H&N
c) Improvements in immobilization with precise thermoplastic masks and fixed or
relocatable framed can reduce PTV from 1.5-2ccm to 0.5-1cm
d) IMRT or SRS used
 e) Proton beam therapy – Braggs’ peak and rapid dose fall off at depth – dose can
accurately deliver within a mm of defined target – good because of OARs
f) SRS – high energy photon beam with multiple ports of entry convergent on target
tissue – single large fraction with patient immobilized using a frame – not optimal for
pituitary adenomas which are benign and high single fraction doses can cause a lot
of NT morbidity if an uncertainty exist with target volume definition – can use
fractionated SRS to mitigate this but lower dose per fraction

Results of Tx
- Sx for microadenomas are typically curative
- XRT alone shown excellent disease free survival

Thyroid
Epidemiology
 - Most common endocrine cancer (94%) but make up only 2% of all cancers

Etiology
- External XRT to thyroid (radiation event or therapeutic)– specifically before puberty –
mainly develop low-grade papillary subtype – latent period between exposure to XRT
and incidence of cancer varies with age: for infants =11yrs, for teens 15-30yrs
- Exact mechanism of thyroid cancer development is unknown

Prognostic Indicators
- Age
- Gender
- Histologic subtype – well differentiated thyroid carcinoma (papillary or follicular) better
outcomes than undifferentiated subtypes (anaplastic)
- Capsular invasion – lesion confined to gland has better outcomes than with capsular
invasion

Anatomy
- Right and left lobes about 5 cm in length and extend to level of midthyroid cartilage
superiorly and 6th tracheal ring inferiorly, lobes connected with isthmus which lies at 2nd-
4th tracheal ring
- Lymphatic capillaries are all throughout gland and drains to many nodal sites: internal
jugular chain, Delphian node (anterior cervical node), pretracheal nodes, paratracheal
nodes in lower neck
- If superior mediastinal nodes which is the lowest part of cervical lymphatic chain, then
there is significant regional spread of disease
Physiology
- Thyroid makes many hormones such as:
a) Tri-iodothyronine (T3)
b) Thyroxine (T4)
NOTE: These are responsible for metabolic regulation
c) Calcitonin – made by C-cells in thyroid which is responsible for calcium metabolism
- Thyroid function is regulated by pituitary and hypothalamic hormones which respond to
systemic negative feedback mechanisms based on metabolic needs
- TSH made by pituitary stimulate thyroid cells to release hormones that are needed for
carbohydrate and protein metabolism
NOTE: to make these hormones the thyroid has to be able to remove iodine from the
blood – insufficient iodine levels  deficiency in thyroid hormone production which
cause other disorders
- Functional thyroid disorders
a) Hyperactivity = hyperthyroidism
1) Graves’ disease – inherited autoimmune disease characterized by elevated
metabolic rate, abnormal weight loss, excessive sweating, muscle weakness,
emotional instability, exophthalmos (eyeballs sticking out) – no significant health
consequences if prompt medical attention received
2) Goiter – physical sign of enlarged thyroid gland because of overstimulation by
TSH on thyroid cells. Toxic goiter if associated with more hormone production
b) Underactivity = hypothyroidism, this causes;
1) cretinism - infants right after birth, congenital condition characterized by
dwarfism, stunted growth, abnormal bone formation, slow mental development,
lack of muscle coordination, low body temp and sluggishness
2) myxedema – occurs when hypothyroidism happens after growth – leads to low
metabolic rate, mental slowness, weight gain, edema of face and extremities can
progress to coma and death

Clinical Presentation
- palpable neck mass* (most patients have this)
- palpable cervical LNs – 25% of young people with differentiated thyroid cancer
Bx on persistent enlarged LNs found in children, teens, and young adults to see if they
have Hodgkin’s, benign inflammatory disease or papillary carcinoma of thyroid
- anaplastic carcinoma is usually large, fixed , and grows rapidly and found in older
patients – symptoms from compression or invasion of esophagus, airway, recurrent
laryngeal nerves – pain, dysphagia, dyspnea, stridor, hoarseness
- medullary carcinoma – start with asymptomatic painless mass, systemic symptoms of
diarrhea bc of vasoactive substances (calcitonin) made by tumor= sign of advanced
disease
Detection and Dx
- Bx to confirm Dx – most important – needle Bx can tell if Sx is possible by identifying
malignant from non-malignant lesions
a) Needle aspiration Bx – small gauge needle
b) Core needle Bx – large cutting Bx needle
NOTE: Not useful for telling if it is a follicular carcinoma because Dx made based on
capsular or vascular invasion which can only be determined via surgical specimen
( larger piece of tissue needed) but can be used for anaplastic and lymphomas
- Lab tests
a) Thyroglobulin levels - Post-op elevated levels indicate residual, recurrent, or
metastatic differentiated thyroid cancer
b) Calcitonin levels – preop elevated levels indicate C-cell hyperplasia or MTC. Post-op
elevated levels indicate residual, recurrent, or metastatic MTC
- Imaging studies:
a) Radionuclide imaging – to assess function and anatomic location of palpable thyroid
nodule from hot or cold spots in gland – improved detection of occult cancers in high
risk patients – also allows to see locoregional and metastatic disease at Dx and post
Tx surveillance
4 most commonly radiopharmaceuticals: I-131, I-125, I-123, Tc-99m
Thyroid nodules can be imaged in 3 ways:
1) Cold thyroid nodule – no radionuclide uptake – most are thyrpid adenomas or
colloid cysts with only 5-20% thyroid cancers
2) Warm thyroid nodule – slightly higher concentration than rest of thyroid gland
3) Hot thyroid nodule - radionuclide uptake higher than rest of thyroid gland
NOTE: Incidence of cancer is warm/hot nodules is low and represents a
functioning adenoma or areas of NT in otherwise diseased gland. Most
differentiated thyroid tumors don’t accumulate radioiodine until all healthy
tissue ablated which preferentially accumulates iodinated radiopharmaceuticals
relative to tumor
b) U/S – determines if nodule is solid or cystic – complimentary test to radionuclide
imaging – solid nodules more likely to being cancer
c) CT – local and regional extent of advanced or recurrent disease and for Tx planning
 d) MRI – depicting lesion margins, extent, tissue heterogeneity, cystic or hemorrhage
regions etc – not routinely used to asses thyroid
Pathology
- Four main categories
1) Papillary – most common thyroid cancer – most common type seen in people with
previous irradiation - slow growing, non-aggressive with good prognosis, 2-4x more
common in women than men, peak incidence 30-50s- also in most common in
children less than 15 yrs
2) Follicular – greatest propensity to concentrate I-131, 3-4x more common in women,
average age 50-58yrs, rare in children, worse prognosis than papillary
3) Medullary – 80% of MTC appear spontaneously and 20% because of familial
endocrine neoplasia (MEN) syndromes, M=F, spontaneous MTC in 50s and familial
MTC 10-80s, worse prognosis than papillary, mixed type and follicular
4) Anaplastic – worst overall prognosis, life expectancy is 1yr or less
5) Other rare thyroid malignancies (accounts for <5% of cases)
- Differentiated thyroid cancers  papillary, mixed papillary-follicular carcinomas  arise
in thyroid follicle cell and Tx’ed with Sx , RAI (I-131) or other hormone suppressive
therapies
Staging
- AJCC stages based on histology and age of patient
Routes of Spread
- Papillary and mixed papillary-follicular carcinomas – mets to regional LNs lymphatically –
at time of Sx 50-70% have cervical LNs mets – hematogenous spread can occur also
- Follicular cancers – tend to invade vasculature and mets to bone, lung, liver and brain via
blood – lymphatic spread uncommon
- Medullary thyroid cancer – varies from indolent to rapidly fatal growth patterns –
spreads regionally before distant mets via lymph or blood to cervical nodes, lung, liver
and bone
- Anaplastic – local invasion of structures like trachea – can also invade skin and result in
dermal mets to chest/ abdominal wall – regional neck nodes typically affected

Treatment Techniques
- Sx:
a) Papillary and mixed papillary-follicular carcinomas rarely invasive (mainly indolent)
so Sx focused on thyroid gland – radical neck dissections (care taken to spare
recurrent laryngeal, vagus, spinal accessory, phrenic nerves, and parathyroid glands))
only if nodes involved with metastatic disease
b) Lobectomy (partial thyroidectomy with removal of isthmus) – for small, lateralized
lesions with no extrathyroidal involvement or LN mets,
 c) organ confined follicular carcinoma – early stage has low risk of LNI so prophylactic
neck dissection not needed
NOTE: if a second lesion is present from follicular carcinoma in contralateral node
then total or near total thyroidectomy preformed, if disease is extrathyroidal or mets
present then bilateral total thyroidectomy needed
d) medullary carcinoma (MTC) – usually have bilateral or multifocal disease = total
thyroidectomy and central compartment LN removal with modified radical neck
dissection if LNI – elective neck dissection usually because 50% have regional LNI
e) anaplastic carcinoma – Sx is specific situations – typically to alleviate airway
obstruction, tracheotomy typically needed to preserve airway. Radical Sx not
advisable or possible because of invasion of nearby and deeper structures
f) cancers that metastasize to thyroid – Tx is variable based on primary site so Bx to
determine whether disease is thyroid primary or mets
Sx S/E’s
Tumor hemorrhage
Parathyroid gland damage  temporary or permanent hypoparathyroidism
Vocal cord paralysis – permanent or temporary
- Radioactive Iodine (I-131)
a) To Tx papillary and follicular cancers with following indications
Inoperable primary tumor
Thyroid capsular invasion
Thyroid ablation after partial or subtotal thyroidectomy
Post-op residual disease in neck or recurrent disease
Cervical or mediastinal LNI
Distant mets
b) Healthy thyroid tissue has greater propensity to absorb Iodine than differentiated
thyroid cancer so healthy tissue is ablated to allow residual or metastatic disease to
absorb I-131
NOTE: ablation dose after Sx of 50-100mCi given if persistent thyroid activity a
second ablation dose given and after all healthy thyroid tissue ablated I-131 given to
Tx local/ regional disease and distant mets to Tx differentiated disease
Sx RAI
Inflammation of salivary glands
N/V
Fatigue
Bone marrow suppression after repeated administration)
- Thyroid hormonal therapy
a) Thyroid hormone suppression therapy given differentiated cancers which grows
under TSH stimulation, so we lower TSH levels to decrease tumor activity
- EBRT
a) Effectiveness depends on histology  Papillary and mixed papillary-follicular
carcinomas more radiosensitive than follicular, medullary is less radiosensitive than
papillary – anaplastic not responsive to any Tx
b) Can be used alone or in conjunction with I-131, Sx
 c) Indications for EBRT use:
Inoperable
Unfit for Sx
Incomplete resection
SVC syndrome
Skeletal mets with minimal I-131 accumulation
Residual disease in trachea, larynx, or esophagus
- 60-70Gy (180-200cGy per fraction) for curative Tx of differentiated thyroid cancer  for
inoperable localized disease or gross residual disease
NOTE: XRT field includes entire thyroid, neck, superior mediastinum. 3D planning
techniques including IMRT. CT sim and any additional info from PET/CT or MRI to assess
anatomy, disease extent, and treatment plan
- CT sim = extended neck to avoid oral cavity and immobilization for daily reproducibility,
scan limits for sim is from apex of head to carina or entire lungs to assess dose to healthy
lungs if mediastinal nodes are being treated
- Medullary carcinoma which hasn’t extended past clavicles, XRT can be considered, dose
50-70Gy depending on fts of case – XRT field covers primary lesion, bilateral cervical
node chains and superior mediastinum
- Anaplastic carcinoma – least radiosensitive of all thyroid cancers – control is disease not
really accomplished even after 60Gy to primary lesion, neck and superior mediastinum