Endocrine manifestations of lung cancer and its management
1. ENDOCRINE MANIFESTATIONS OF
LUNG CANCER AND ITS MANAGEMENT
Dr Sujoy Majumdar
MD,MRCP, FRCP,FTTA- Endo(UK), MACE(USA)
Consultant Endocrinologist , Kolkata, India
sujoypinky@gmail.com
2. TOPICS FOR TODAY’S DISCUSSION
• An Endocrinologist’s idea about lung cancer
• Histological subtypes of lung cancer
• Paraneoplastic syndromes- an overview with special
emphasis on endocrine paraneoplastic features of
different types of lung cancer
• SIADH – pathophysiology and management
• Hypercalcemia –pathophysiology and management
• Cushing’s syndrome
• Rarer endocrine manifestations of lung cancer
• A recent treatment modality
3. An Endocrinologist’s basic knowledge
of Lung Cancer
• Lung cancer is the leading cause of cancer-related
death of men
• Squamous cell carcinoma is thought to be the most
frequent form of the tumor (30-50 percent of all
cases),followed by adenocarcinoma, large cell carcinoma,
and small cell carcinoma.
• Nowadays an increase has occurred in the incidence of
adenocarcinoma, which is the most common histologic
subtype.
5. Newly Diagnosed Cases of
Diagnosed Lung Cancer
Lung Cancer Deaths
2008 Estimates
Total (% of all cancers) 215,020 (15%) 161,840 (29%)
Men 114, 690 90,810
Women 100,330 71,030
2009 Estimates
Total (% of all cancers) 219,440 (15%) 159,390 (28%)
Men 116,090 88,900
Women 103,350 70,490
2010 Estimates
Total (% of all cancers) 222,520 (15%) 157,300 (28%)
Men 116,750 86,220
Women 105,770 71,080
Sources: American Cancer Society. Cancer facts & figures 2008,[15]2009,[19] 2010.[20]
6. WHO Histologic Classification
I. Malignant epithelial tumors
A. Squamous cell carcinoma (epidermoid
carcinoma)
Variant:
· Spindle cell carcinoma
B. Small-cell carcinoma
· Oat cell carcinoma
· Intermediate cell type
· Combined oat cell carcinomas
7. C. Adenocarcinoma
· Acinar adenocarcinoma
· Papillary adenocarcinoma
· Bronchio-alveolar carcinoma
· Solid carcinoma with mucus formation
D. Large-cell carcinoma
Variants:
· Giant cell carcinoma
· Clear cell carcinoma
E. Adenosquamous carcinoma
F. Carcinoid tumor
G. Bronchial gland carcinomas
· Adenoid cystic carcinoma
· Mucoepidermoid carcinoma
H. Others
8. Paraneoplastic syndromes- a brief
history
• More than 100 years ago, it was recognized that
certain cancers cause various symptoms not
attributable to direct tumor invasion or
compression
• Labeled paraneoplastic syndromes in the
1940s, these conditions remained poorly
understood until recently.
• It is estimated that paraneoplastic syndromes affect
up to 8% of patients with cancer
10. Paraneoplastic syndromes – what are these?
• These disorders arise from tumor secretion of hormones,
peptides, or cytokines or from immune cross-reactivity between
malignant and normal tissues
• Paraneoplastic syndromes may affect diverse organ systems,
most notably the endocrine, neurologic, dermatologic,
rheumatologic, and hematologic systems.
• The most commonly associated malignancies include small cell
lung cancer, breast cancer, gynaecologic tumors, and hematologic
malignancies.
• Because paraneoplastic syndromes often cause considerable
morbidity, effective treatment can improve patient quality of life,
enhance the delivery of cancer therapy, and prolong survival.
• Treatments include addressing the underlying malignancy,
immunosuppression (for neurologic, dermatologic, and
rheumatologic paraneoplastic syndromes), and correction of
electrolyte and hormonal derangements (for endocrine
paraneoplastic syndromes)
11. Paraneoplastic endocrine syndromes
• The paraneoplastic endocrine syndromes
generally result from tumor production of
hormones or peptides that lead to metabolic
derangements.
• Successful treatment of the underlying tumor
often improves these conditions.
12. Some facts regarding paraneoplastic
hormonal secretions in lung cancer
• Tumors like small cell carcinoma that secrete corticotropin
(ACTH),vasopressin(ADH), calcitonin, gut peptides (GRP,
somatostatin, vasoactive intestinal peptide [VIP]), and
biogenic amines such as 5-hydroxytryptamine (5-HT) are
characteristically of neuroendocrine cell origin.
• Many of the hormones typically secreted by small cell lung
carcinoma—vasopressin, calcitonin, and gastrin-releasing
peptide (GRP)—are thought to be present in the
neuroendocrine cells in the normal bronchial mucosa that are
the probable precursors of the tumor.
• PTHrP is a normal product of the keratinocyte, the cell of
origin of squamous carcinomas that causes humoral
hypercalcemia
13. CRITERIA FOR DIAGNOSIS OF ECTOPIC
HORMONE SECRETION
CLINICAL CRITERIA
• A clinical syndrome of hormone excess is associated with a neoplasm.
• Serum or urine levels of the hormone are inappropriately elevated.
• The hormone level is not suppressible.
• Other possible causal mechanisms are excluded.
• The syndrome is reversed by resection of the tumor (rare).
RESEARCH CRITERIA
• The hormone can be detected in tumor tissue.
• Messenger RNA for the hormone is present in tumor tissue.
• The hormone is secreted from tumor cells in culture.
• There is an arteriovenous gradient for the hormone across the tumor.
Williams Textbook of Endocrinolgy 11th Edition
14.
15. PARANEOPLASTIC PRESENTATIONS OF
SMALL CELLCARCINOMA
Organ System Syndrome Mechanism Frequency
Endocrine SIADH Antidiuretic
hormone
10-45%
Ectopic secretion of ACTH Adrenocorticotropic
hormone
5%
Atrial natriuretic factor
Neurologic Eaton-Lambert reverse myasthenic
syndrome
5-6%
Subacute cerebellar degeneration
Subacute sensory neuropathy
Limbic encephalopathy Anti-Hu, Anti-Yo
antibodies
ACTH = adrenocorticotropic hormone; SIADH = syndrome of inappropriate antidiuretic
hormone.
16. Function of ADH
Antidiuretic hormone = vasopressin
• ADH is made in the supra-optic
nuclei in the hypothalamus, stored
in the posterior pituitary
• Normally released into the
bloodstream when osmo-receptors
detect high plasma osmolality
• At the kidney, attaches to
receptors in the collecting ducts,
opens up water channels
• Water is passively reabsorbed
along the kidney’s medullary
concentration gradient
17. Syndrome of Inappropriate Antidiuretic
Hormone Secretion(SIADH)
• Characterized by hypo-osmotic, euvolemic hyponatremia,
affects 1% to 2% of all patients with cancer
• Levels of ADH are inappropriately elevated compared to
body’s low osmolality, and ADH levels are not suppressed by
further decreases in plasma osmolality
• Small cell lung cancer accounts for most of these cases, with
approximately 10% to 45% of all patients with small cell lung
cancer developing SIADH.
• Paraneoplastic SIADH arises from tumor cell production of
antidiuretic hormone (ADH, also known as arginine
vasopressin or vasopressin) and atrial natriuretic peptide.
• Antidiuretic hormone leads to increased free-water
reabsorption; atrial natriuretic peptide has natriuretic and
antidiuretic properties.
18. SIADH- basic pathophysiology
• In contrast to the hypovolemic hyponatremia caused by
gastrointestinal losses, excessive diuresis, adrenal
insufficiency, salt-wasting nephropathy, and cerebral salt
wasting—all of which may be encountered in cancer
patients—SIADH causes euvolemic hyponatremia
• A euvolemic state is supported by
-Absence of orthostatic vital sign changes or edema
-Normal central venous pressure
-Serum uric acid concentration less than 4 mg/dL and
-Blood urea nitrogen level less than 10 mg/dL
-Urinary sodium level greater than 40 mmol/L or
- Urine osmolality greater than 100 mOsm/kg of water
19. SIADH in small cell lung cancer ; List A F et
al J Clin Onc o; August 4(8) 1986
p1101-98
20. SIADH: signs
• Decreased/low urine output
• Signs of hyponatremia: lethargy, apathy, disorientation,
muscle cramps, anorexia, agitation
• Signs of water toxicity: nausea, vomiting, personality
changes, confused, combative
• Serum sodium levels less than 125 mEq/L particularly if
developing within 48 hours, can be marked by altered
mental status, seizures, coma, respiratory collapse, and
death.
• If Na < 110 mEq/L, seizures, bulbar palsies,
hypothermia, stupor, coma & ultimately death
• When hyponatremia develops during a longer time
frame, neurologic complications may not occur
21. Correlation between SIADH and extent
of primary tumour
• Amongst 350 patients noted in 40 (11%)
• Median Na 117mEq/l (Water intoxication noted in only 27%)
• Development of SIADH showed no correlation with clinical stage,
distribution of metastatic sites, sex, or histologic subtype of small-cell
carcinoma
• SIADH occurred most often with initial presentation (33 of 40), and
resolved promptly (less than 3 weeks) with initiation of combination
chemotherapy in 80% of evaluable patients
• The presence of SIADH did not influence response to chemotherapy or
overall survival as an independent variable.
• Despite initial control of SIADH, dilutional hyponatremia recurred in 70% of
patients with tumor progression.
• The development of clinically demonstrable SIADH in patients with SCLC is
dependent on functional properties of the neoplastic cells, rather than
tumor burden or metastatic site.
SIADH in small cell lung cancer ; List A F et al J Clin Onco; August 4(8) 1986 p1191-98
22. SIADH: lab values
• Serum Na < 130 (Na is diluted by excessive free water re-
absorption)
• Serum osmolality low, normal is ~ 270-310mosm/kg
• Urine Na is inappropriately high, >20 mmol/L, actually
losing Na in urine instead of retaining it
• Urine osmolality is inappropriately high, can range between
300-1400 mosm/L
• CVP is high from free water retention
23. SIADH: treatment
• In the setting of symptomatic hyponatremia developing within 48 hours,
the serum sodium level may be raised 1 to 2 mmol/L per hour and usually
no more than 8 to 10 mmol/L during the first 24 hours of treatment.
• With chronic hyponatremia, the brain generates endogenous osmoles to
minimize intracellular swelling.
• Rapid correction leads to brain dehydration, and central pontine and
extrapontine myelinolysis, a condition characterized by lethargy, dysarthria,
spastic quadriparesis, and pseudobulbar palsy—all of which can be
permanent
• Thus, a correction goal of 0.5 to 1.0 mmol/L per hour is generally
recommended for these patients
• In the short term, fluid restriction (usually <1000 mL/d, depending on the
degree of hyponatremia and the extent of urinary excretion) may be
implemented
• When possible, offending medications (eg, opiates, certain antidepressants,
vinca alkaloids, and cisplatin) should be discontinued
• The optimal therapy for paraneoplastic SIADH is treatment of the
underlying tumor, which, if successful, can normalize the sodium level in a
matter of weeks.
24. SIADH : Fluids & Salts
• Normal (0.9%) saline has an osmolality of 308 mOsm/kg. If
the urine osmolality is higher than 308 mOsm/kg, as is often
the case in SIADH, normal saline infusion will result in
retention of free water and further decline in the serum
sodium level.
• Hypertonic (3%) saline has an osmolality of 1026 mOsm/kg,
which often exceeds that of the urine. Its administration
requires central venous access and carries a risk of overly
rapid correction
• With frequent assessment of the serum sodium level,
hypertonic saline offers a means of correcting severe,
symptomatic hyponatremia within days
• Adequate intake of dietary protein and sodium (with the use
of salt tablets if necessary) is also a contributing factor in
correcting hyponatremia and affects the degree of free water
restriction that can be used.
25. SIADH:pharmacotherapy
• Primary agents are demeclocycline (Demeclochlorotetracycline ) and
vasopressin receptor antagonists.
• Demeclocycline blocks ADH receptors in the renal collecting ducts &
does not require simultaneous fluid restriction to achieve its effect
• Adverse effects of demeclocycline include nausea, anorexia, diarrhea,
and renal toxicity (especially in the presence of baseline renal
impairment). Long-term use can lead to diabetes insipidus
• Vasopressin receptor antagonists conivaptan (administered
intravenously,approved 2005) & tolvaptan (oral agent approved
2009), have become available for the treatment of hyponatremia.
• They block arginine vasopressin(AVP) binding to receptors in the
renal collecting ducts, result in the excretion of free water
• Adverse effects of conivaptan include infusion site reactions, nausea
and vomiting, and diarrhea. Adverse effects of tolvaptan include dry
mouth, thirst, and constipation
• Vasopressin receptor antagonists are generally considered only after
failure of fluid restriction. They should be initiated in a hospital
setting, where rapid and repeated assessment of the serum sodium
level is feasible.
26. Hypercalcemia of malignancy
Primary Site No. (%) of Cases Known Metastatic Disease (%)
Lung 111 (25.0) 62
Breast 87 (19.6) 92
Multiple myeloma 43 (9.7) 100
Head and neck 36 (8.1) 73
Renal and urinary tract 35 (7.9) 36
Esophagus 25 (5.6) 53
Female genitalia 24 (5.2) 81
Unknown primary 23 (5.2) —
Lymphoma 14 (3.2) 91
Colon 8 (1.8) —
Liver, biliary 7 (1.6) —
Skin 6 (1.4) —
Other 25 (5.6) —
Total 444 (100)
27. Hypercalcemia- pathophysiology
• Malignancy-associated hypercalcemia occurs in up to 10%
of all patients with advanced lung cancer and generally
conveys a poor prognosis .
• 30-day mortality rate for cancer patients with
hypercalcemia approximately 50%.
• 4 principal mechanisms of hypercalcemia in cancer patients
a)Secretion of parathyroid hormone (PTH)-related protein
(PTHrP) by tumor cells—known as humoral hypercalcemia
of malignancy—accounts for 80% of cases and occurs most
commonly with squamous cell carcinoma. It is a larger
molecule than parathyroid hormone and has a lower
capacity to stimulate 1-alpha-hydroxylase activity in the
proximal tubule and calcium reabsorption in the distal
tubule On binding to PTH receptors in bone and kidney,
PTHrP regulates bone resorption and renal handling of
calcium and phosphate.
28. Hypercalcemia- pathophysilogy
b) Another 20% of cases arise directly from
osteolytic activity at sites of skeletal
metastases.(Commonly seen with breast cancer,
multiple myeloma, and lymphomas, sometimes
squamous cell carcinoma & RARELY with small
cell carcinoma)
c) Rarely, may result from tumor secretion of
vitamin D, which has been described in
association with certain lymphomas
d)From ectopic secretion of PTH (small cell
carcinomas)
29. Hypercalcemia : Clinical features
• Symptoms & signs :Nausea, vomiting, lethargy, renal
failure, and coma.
• Physical examination and a chest radiograph disclose
the underlying tumor in about 98% of patients.
• Symptom severity depends not only on the degree of
hypercalcemia (calcium levels >14 mg/dL) but also on
the rapidity of onset and the patient's baseline
neurologic and renal function.
• The need for and nature of treatment should take all of
these factors into account, as not all patients with
hypercalcemia require aggressive therapy.
30. Laboratory evaluation of hypercalcemia
• Serum levels of ionized calcium (4.5-5.6 mg/dL)
• PTH (10-55 pg/mL )
• PTHrP (<2.0 pmol/L)
• In the absence of an ionized calcium level, total
calcium, which represents both bound and unbound
calcium, should be corrected for the albumin
concentration using the following formula:
Corrected Ca (mg/dL) =
Measured Ca (mg/dL) + [0.8 × (4.0 -Albumin(mg/dL)].
• Typical laboratory findings include an elevated calcium
level, a low-to-normal PTH level, and often a high
PTHrP level.
31. Management of hypercalcemia
• The first-line approach to persistent hypercalcemia is fluid repletion
with normal saline, which increases the glomerular filtration rate and
inhibits renal calcium reabsorption.
• Loop diuretics, which further inhibit renal calcium reabsorption, may
be added after adequate volume resuscitation.
• These agents may exacerbate dehydration and worsen hypercalcemia
and renal function if used prematurely,
• Intravenous bisphosphonates, such as pamidronate and zoledronate,
inhibit osteoclast bone resorption and are widely used
• Generally, serum calcium levels will decline within 2 to 4 days, reach a
nadir between 4 and 7 days after infusion, and remain suppressed for
up to 3 weeks
• Mild, asymptomatic hypocalcemia may follow
bisphosphonate administration, and repletion is not
recommended.
32. Management of hypercalcemia
• Calcitonin, which inhibits bone resorption and increases renal calcium
excretion, may be considered in patients with baseline renal disease for
whom bisphosphonates may not be safe.
• Mithramycin blocks bone resorption by inhibiting osteoclast RNA synthesis.
However, it requires frequent dosing, is less effective than bisphosphonates,
and has associated hepatic, renal, and hematologic toxicities
• Gallium nitrate, which requires a continuous 5-day infusion, is usually
reserved for cases refractory to bisphosphonate therapy.
• Hemodialysis provides an effective strategy for patients with substantial
renal or cardiac disease who cannot tolerate large fluid infusions or
bisphosphonates.
• Optimal approach to paraneoplastic hypercalcemia is treatment of the
underlying tumor.
• Discontinue medications that contribute to hypercalcemia (eg, calcium
supplements, vitamin D, thiazide diuretics, calcium-containing antacids,
and lithium) or that aggravate mental status changes.
33. Cushing’s syndrome
• Approximately 5% to 10% of cases of Cushing’s
syndrome (hypercortisolism) are paraneoplastic.
• Approximately 50% to 60% of these paraneoplastic
cases are neuroendocrine lung tumors (small cell
lung cancer and bronchial carcinoids)
• In contrast to SIADH and hypercalcemia, patients
often present with symptoms of paraneoplastic
Cushing syndrome before a cancer diagnosis is
made
• Similarly, relapse of paraneoplastic Cushing’s
syndrome may herald tumor recurrence
34. Paraneoplastic Cushing’s syndrome-
pathophysiology
• Paraneoplastic Cushing syndrome arises from
tumor secretion of adrenocorticotropic
hormone (ACTH)or corticotropin-releasing
hormone (CRH)
• These factors result in production and release
of cortisol from the adrenal glands
• The diagnosis of CRH producing small cell
cancer is usually made retrospectively
35. Paraneoplastic Cushing’s syndrome-
clinical features
• Hypertension
• Hypokalemia
• Muscle weakness
• Generalized edema
• Weight gain with centripetal fat distribution is
more common in nonparaneoplastic than in
paraneoplastic Cushing syndrome
36. Cushing’s syndrome – Lab findings
• Baseline serum cortisol level greater than 29
μg/dL
• Urinary free cortisol level greater than 47
μg/24 h
• Midnight adrenocorticotropic hormone
(ACTH)level greater than 100 ng/ml
37. High dose Dexamethasone
suppression test- the gold standard
• Failure to respond to high-dose dexamethasone
suppression distinguishes ectopic (ie, paraneoplastic)
Cushing’s syndrome from a pituitary / adrenal source
• 2 mg of dexamethasone is given orally every 6 hours for
72 hours, and levels of serum cortisol & urine 17-
hydroxycorticosteroid (an inactive product resulting
from cortisol breakdown) are measured at 9 AM and
midnight of days 2 and 3 of the test.
• The suppression test is considered positive if serum
cortisol & 17-hydroxycorticosteroid levels are reduced
by 50% or more
38. Other diagnostic tests
TO LOCALISE PRIMARY TUMOR
• Computed tomography (CT),
• Magnetic resonance imaging, and
• Somatostatin receptor scintigraphy (ie, octreotide
scan)
• Inferior petrosal sinus sampling of no benefit
SI
39. Paraneoplastic Cushing’s syndrome-
management
• First-line pharmacologic options are directed toward inhibition of
steroid production.
• Drugs- ketoconazole, mitotane, metyrapone, and
aminoglutethimide
• Despite associated nausea and hepatotoxicity, ketoconazole is
usually the best tolerated of these agents.
• Less commonly used options include octreotide, which blocks the
release of adrenocorticotropic hormone
• Etomidate, which inhibits aspects of steroid synthesis has been
used to decrease serum cortisol levels in patients who are unable
to take oral medications
• Mifepristone, which binds competitively to the glucocorticoid
receptor, has recently been shown to improve clinical and
biochemical parameters of Cushing syndrome
• When medical therapy is not successful, adrenalectomy may be
considered.
40. SOME INTERESTING CASES AND
CONCEPTS
SIADH in small cell lung cancer ; List A F et
al J Clin Onc o; August 4(8) 1986
p1101-98
41. Unusual Presentation of bronchogenic
Carcinoma(1)
Pituitary FDG uptake in a patient of lung cancer with bilateral adrenal
metastases causing adrenal cortical insufficiency.
Weng JH, Lee JK, Wu MF, Shen CY, Kao PF.
Department of Nuclear Medicine, Chung Shan Medical University Hospital,
Taichung, Taiwan.
A 64-year-old woman with history of lung cancer and left adrenal gland
metastasis was referred for FDG PET/CT to assess the response to
target therapy and local radiotherapy treatment. In addition to bilateral
adrenal gland FDG uptake lesions, the PET/CT also showed focal FDG uptake
in pituitary gland with standardized uptake value of 3.9.
Adrenocorticotropic hormone serum level was 439 pg/mL (normal <46 pg/mL),
and serum cortisol level was 6 μg/dL (normal range, 5-25 μg/dL). The image
and serum test results suggested the diagnosis of lung cancer, with bilateral
adrenal metastases causing adrenal cortical insufficiency with secondary
pituitary gland hyperplasia
Clin Nucl Med 2011Aug 36(8) : 731-32
42. Unusual presentation of Bronchogenic
carcinoma (2)
Ectopic corticotropin-releasing hormone (CRH) syndrome from metastatic small cell carcinoma: a case
report and review of the literature.Shahani S, Nudelman RJ, Nalini R, Kim HS, Samson SL.
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, One
Baylor Plaza, Houston, Texas 77030, USA.
BACKGROUND:
Cushing's Syndrome (CS) which is caused by isolated corticotropin-releasing hormone (CRH)
production, rather than adrenocorticotropin (ACTH) production, is extremely rare.
RESULTS:
• A 56 year old woman presented with clinical and laboratory features consistent with ACTH-
dependent CS. Pituitary imaging was normal and cortisol did not suppress with a high dose
dexamethasone test, consistent with a diagnosis of ectopic ACTH. CT imaging did not reveal
any discrete lung lesions but there were mediastinal and abdominal lymphadenopathy and
multiple liver lesions suspicious for metastatic disease. Laboratory testing was positive for
elevated serum carcinoembryonic antigen and the neuroendocrine marker chromogranin A.
Serum markers of carcinoid, medullary thyroid carcinoma, and pheochromocytoma were in
the normal range. Because the primary tumor could not be identified by imaging, biopsy of
the presumed metastatic liver lesions was performed. Immunohistochemistry was consistent
with a neuroendocrine tumor, specifically small cell carcinoma. Immunostaining for ACTH
was negative but was strongly positive for CRH and laboratory testing revealed a plasma CRH
of 10 pg/ml (normal 0 to 10 pg/ml) which should have been suppressed in the presence of
high cortisol.
CONCLUSIONS:
• This case illustrates the importance of considering the ectopic production of CRH in the differential
diagnosis for presentations of ACTH-dependent Cushing's Syndrome.
Diagn Pathology 2010; Aug 31; 5 :56
43. Lanreotide- a new molecule for small
cell carcinoma
• As a neuroendocrine cancer, small cell lung tumors often posses high densities of
somatostatin receptors.
• Long-acting somatostatin analogues combined with platinum analogues have demonstrated
an anti-proliferative effect on growth of human SCLC xenographs.
• 130 previously untreated patients with SCLC in a phase 2/3 randomized clinical study. All of
the patients were treated with paclitaxel plus carboplatin for up to six cycles.
• By random allocation, 47 patients received no other therapy (Group A; control group); 43
patients received 30 mg lanreotide (Somatulin) by subcutaneous injection 48 hours after
each chemotherapy cycle to stimulate somatostatin receptors for two weeks (Group B); and
the remaining 40 patients received 60 mg sustained release lanreotide for four weeks
(Group C).
• Patients on subcutaneous lanreotide fared best. They had median survival of 476 days,
which was significantly longer than that of Group A and Group C (300 and 347 days,
respectively; p=0.029).
• The median time to progression was also significantly longer in Group B relative to Group A
and C (350 days vs. 224 days and 294 days; p=0.034). Patients with limited disease in Group
B had a median time to progression of 371 days compared with 231 and 217 days for limited
disease patients in groups A and C, respectively. Zaroguilidis K et al Lung Cancer
October ,2011