paraneoplastic syndromes in lung cancer
TRANSCRIPT
Cancer Therapy Vol 6, page 687
687
Cancer Therapy Vol 6, 687-698, 2008
Paraneoplastic syndromes in lung cancer Review Article
Stefanie Heinemann, Peter Zabel, Hans-Peter Hauber* Medical Clinic, Research Center Borstel, Borstel, Germany
__________________________________________________________________________________
*Correspondence: Hans-Peter Hauber, MD, Medical Clinic, Research Center Borstel, Parkallee 35, 23845 Borstel, Germany; Phone:
+49 (0)4537 188 364; Fax: +49 (0)4537 188 313; E-mail: [email protected]
Key words: Anemia, antidiuretic hormone, autoantibody, cachexia, cancer, chemotherapy, clubbing, Cushing, dermatomyositis,
hypertrophic pulmonary osteoarthropathy, hypercalcaemia, Lambert-Eaton, lung, neurologic, paraneoplastic, syndrome
Abbreviations: Adrenocorticotrophic hormone, (ACTH); antidiuretic hormone, (ADH); atrial natriuretic peptide, (ANP); cancer
procoagulant, (CP); ciliary neutropic factor, (CNTF); cyclic adenosine monophosphate, (cAMP); granulocyte colony stimulating factor,
(G-CSF); Granulocyte macrophage- colony stimulating factor, (GM-CSF); hypertrophic pulmonary osteoarthropathy, (HPO);
hypothalamic-pituitary-adrenal, (HPA); interferon, (IFN); interleukin, (IL); Lambert-Eaton myasthenic syndrome, (LEMS); lipid
mobilizing factor, (LMF); low molecular weight heparin, (LMWH); non-small-cell lung cancer, (NSCLC); Palmo-plantar
hyperkeratosis, (PPH); parathyroid hormone, (PTH); parathyroid hormone-related protein, (PTHrP); polyneuropathy, (PNP); pro-
opiomelanocortin, (POMC); prostaglandins of the E series, (PGE); proteolysis-inducing factor, (PIF); small-cell lung cancer, (SCLC);
syndrome of inappropriate antidiuretic hormone secretion, (SIADH); tissue factor, (TF); transforming growth factor alpha, (TGF)!;
tumor necrosis factor alpha, (TNF)!; unfractionated heparin, (UFH); vascular endothelial growth factor, (VEGF); venous
thromboembolism, (VTE); voltage-gated P/Q calcium channels, (VGCC)
Received: 21 August 2008; Revised: 11 September 2008
Accepted: 12 September 2008; electronically published: October 2008
Summary Paraneoplastic syndromes are frequently found in lung cancer. They can be the first manifestation of disease or
recurrence. Neuromuscular, vascular, haematological and metabolic syndromes, as well as syndromes involving the
connective and skeletal tissues and skin can be distinguished. While some of the paraneoplastic syndromes are
commonly observed (eg. Anemia, cachexia) others are rare disorders (eg. Opsoclonus-myoclonus, tylosis). This
review focuses on the epidemiology, pathogenesis, clinical symptoms and treatement options of frequent and clinical
important paraneoplastic syndromes.
I. Introduction Paraneoplastic syndromes are common in lung
cancer, and may be the first manifestation of the disease or
its recurrence (Bunn and Ridgway, 1993). Paraneoplastic
phenomena are not related to the direct invasion,
obstruction, or metastasis (Patel et al, 1993; Spiro, 1995).
Neuromuscular, vascular, haematological and metabolic
syndromes, as well as syndromes involving the connective
and skeletal tissues and skin can be distinguished. Table 1
gives an overview of the paraneoplastic syndromes that
have been described in lung cancer patients. In the
following epidemiology, pathogenesis, clinical findings,
and treatment options of the most common paraneoplastic
syndromes in lung cancer will be reviewed.
II. Epidemiology Paraneoplastic syndromes are estimated to occur in
7% to 15% of all patients with cancer (Richardson and
Johnson, 1992). If the definition of paraneoplastic
syndromes is broadened to include conditions such as
anemia, cachexia, and hypercalcemia then the incidence
and prevalence of paraneoplastic syndromes is much
higher. Lung cancer and small-cell lung cancer (SCLC) in
particular is the most common cancer to be associated with
paraneoplastic syndromes. However, some paraneoplastic
syndromes are more often found in non-small-cell lung
cancer (NSCLC). For example hypertrophic pulmonary
osteoarthropathy has most often been described in
association NSCLC.
The extent of paraneoplastic syndromes is unrelated
to the size of the primary tumour. In some cases it may
precede diagnosis of malignancy while in other cases it
may occur late in the course of disease or may show up as
the first symptom of recurrence. If lung cancer patients
have paraneoplastic syndromes normally they suffer from
only one syndrome. Literature data on multiple
paraneoplastic syndromes in the same patient are sparse
and are mostly described in case reports (Monsieur et al,
1995).
Heinemann et al: Paraneoplastic syndromes in lung cancer
688
Table 1. Paraneoplastic syndromes in lung cancer.
Endocrine syndromes
SIADH
Nonmetastatic hypercalcemia
Cushing syndrome
Gynecomastia
Hypercalcitonemia
Elevated levels of LSH and FSH
Hypoglycemia
Hyperthyroidism
Carcinoid syndrome
Neurologic syndromes
Subacute sensory neuropathy
Mononeuritis multiplex
Lambert-Eaton myasthenic syndrome
Encephalomyelitis
Necrotizing myelopathy
Cancer associated retinopathy
Opsoclonus-myoclonus
Skeletal syndromes
Hypertrophic osteoarthropathy
Clubbing
Renal syndromes
Glomerulonephritis
Nephrotic syndrome
Metabolic syndromes
Lactic acidosis
Hypouricemia
Systemic syndromes
Cachexia
Fatigue
Fever
Collagen-vascular syndromes
Dermatomyositis and polymyositis
Vasculitis
Systemic lupus erythematosus
Cutaneous syndromes
Acquired hypertrichosis languinosa
Erythema gyratum repens
Erythema multiforme
Tylosis
Erythroderma
Exfoliative dermatitis
Acanthosis nigricans
Sweet syndrome
Pruritus and urticaria
Hematologic syndromes
Anemia
Leucocytosis and eosinophilia
Thrombocytosis and thrombocytopenic purpura
Coagulopathies
Thrombophlebitis
Thromboembolism
Disseminated intravascular coagulation
Reproduced from Scagliotti, 2001 and Carbone et al, 1970 with
kind permission from European Respiratory Monthly and Annals
of Internal Medicine respectively.
.
III. Hypercalcaemia Hypercalcaemia is frequently found in patients with
lung cancer. Its incidence ranges from 2 to 6% at
presentation to 8 to 12% throughout the course of disease
(Spiro et al, 2007). It may arise from bone metastasis but
can also be induced in a paraneoplastic manner by
secretion of parathyroid hormone-related protein (PTHrP),
calcitriol or other cytokines, including osteoclast
activating factors. Hiraki and colleagues examined 1149
patients with lung cancer and found 6% to have
hypercalcemia (Hiraki et al, 2004). Among those with
hypercalcemia 51% had squamous cell carcinoma, 22%
had adenocarcinoma, and 15% had SCLC. Most of those
patients had advanced disease (stage III or IV). Median
survival was only 3.8 months (Hiraki et al, 2004).
Hypercalcaemia in lung cancer patients can be
caused by either bony metastases or less commonly by
paraneoplastic syndromes. Tumours can secrete PTHrP,
calcitriol or other cytokines including osteoclast activating
factors. Moseley and colleagues identified PTHrP
expression in lung cancer cells (Moseley et al, 1987).
PTHrP shares 70% sequence homology with PTH over the
first 13 amino acids at the N-terminus. Both parathyroid
hormone (PTH) and PTHrP bind to a common
PTH/PTHrP receptor (Abou-Samra et al, 1992) and share
similar biological activities (Horiuchi et al, 1987).
However, expression of PTHrP has also been reported in
normal tissue (Danks et al, 1989; Asa et al, 1990). This
implicates that PTHrP has also a physiological effect. It is
now clear that PTHrP has several other functions in
addition to its PTH-like effects (Clines and Guise, 2005).
PTH stimulates osteoclastic bone resorption and
calcium reabsorption and inhibition of phosphate
reabsorption from renal tubules. It also stimulates renal
1!-hydroxylase resulting in production of 1,25-(OH)2D3,
which increases intestinal absorption of calcium and
phosphate. These actions result in increased serum
calcium. PTH actions are mediated through binding of the
amino terminus of the PTH molecule to the PTH receptor,
a member of the family of G protein-coupled receptors that
contain seven transmembrane- spanning domains (Juppner
et al, 1991). The ligand-bound PTH receptor activates
adenylate cyclase, through the activation of G protein
G!s, producing cyclic adenosine monophosphate (cAMP)
while activating protein kinase A. In addition, the
phospholipase C/protein kinase C system also contributes
to PTH signal transduction (Mahon et al, 2002; Swarthout
et al, 2002).
Approximately 80% of cancer patients with
hypercalcemia have detectable or increased plasma
concentrations of PTHrP (Burtis et al, 1990). PTHrP has a
multifunctional role in cancer. It mediates hypercalcaemia
but also aids development and progression of osteolytic
bone metastasis, regulates growth of cancer cells and acts
as a cell survival factor (Luparello et al, 1993; Luparello et
al, 1995; Li et al, 1996; Chen et al, 2002).
Although PTHrP is responsible for he majority of
cases of paraneoplastic hypercalcaemia there have been
rare cases with ectopic PTH production in the tumour.
This has been reported in SCLC as well as in squamous
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689
cell carcinoma of the lung (Yoshimoto et al, 1989; Nielsen
et al, 1996).
While in haematological malignancies extra-renal
production of 1,25-(OH)2D3 appears to be a major
mediator of hypercalcaemia (Seymour et al, 1994) in lung
cancer calcitriol does not seem to be the major mediator of
PTH-like activity even if SCLC cell lines can synthesize
1,25-(OH)2D3 (Mawer et al, 1994).
Other factors that can stimulate osteocalstic bone
resorption and cause hypercalcaemia include interleukin
(IL)-1, IL-6, transforming growth factor alpha (TGF)!,
tumor necrosis factor alpha (TNF)!, and granulocyte
colony stimulating factor (G-CSF) (Clines and Guise,
2005). Human TGF! and TNF! stimulate osteoclastic
bone resorption in vitro and result in hypercalcaemia in
vivo (Bertolini et al, 1986; Yates et al, 1992; Ibbotson et
al, 1995). Factors such as TGF!, IL-1, IL-6 and TNF! can
also enhance the hypercalcaemic effects of PTHrP.
Although prostaglandins of the E series (PGE) are
powerful stimulators of bone resorption (Klein and Raisz,
1970) there role in tumour-associated bone destruction
remains unclear (Mundy, 1995). They may be mediators
of cytokine effects on the bone. Moreover, PGE
expression has been described in the lung cancer tissue of
normocalcaemic patients (Kukrja et al, 1982). This finding
implicates that PGE may not be necessary to induce
hypercalcaemia in cancer patients.
Symptoms of hypercalcaemia include anorexia,
nausea, vomiting, constipation, lethargy, polyuria,
polydipsia, and dehydration. If untreated hypercalcaemia
my lead eventually to confusion and coma. Renal failure
and nephrocalcinosis are late manifestations, too.
Symptomatic patients with a serum calcium of " 3 mmol/L
required treatment that includes hydration and
biphosphonate (Thomas et al, 2004).
IV. Syndrome of inappropriate
antidiuretic hormone secretion Elevated levels of antidiuretic hormone (ADH) and
impaired water handling can be observed in 30 to 70% of
lung cancer patients (Patel et al, 1993). However, excess
production of ADH does not always produce symptoms
(Maurer et al, 1983; Bliss et al, 1990; Moses and
Scheinman, 1991). Only 1 to 5% of all patients with lung
cancer have symptoms attributable to the syndrome of
inappropriate antidiuretic hormone secretion (SIADH).
SIDAH is frequently caused by SCLC. In a study by List
and co-workers approximately 10% of patients with SCLC
had SIADH (List et al, 1986). In that study development
of SIADH did not correlate with clinical stage or
metastatic sites. SIADH occurred most often with initial
presentation and promptly resolved with initiation of
combined chemotherapy in 80% of the patients. Response
to chemotherapy and survival was not influenced by the
presence of SIADH (List et al, 1986). Recurrence of
SIADH was associated with tumour progression.
Biochemically, the SIADH production is defined as
low serum sodium and a dilute plasma osmolality along
with a higher, or "inappropriate," urine osmolality, in the
presence of continued urinary sodium excretion. A variety
of hormones including atrial natriuretic peptide (ANP)
have been implicated as possibly contributing to the
hyponatremia found in lung cancer patients. However,
only elevated plasma ADH levels were consistently found
in patients with lung cancer and may explain the impaired
ability to excrete the water load (Vorherr, 1974).
Physiologically ADH is released from the posterior
pituitary gland whereas in paraneoplastic SIADH cancer
cells secrete ADH (Moses and Scheinman, 1991). Another
possible mechanism is inappropriate peripheral
baroreceptor stimulation of ADH release from the
hypothalamus (Vorherr, 1974). ADH causes hyponatremia
and hypoosmolality that interfere with urinary dilution,
thereby preventing the excretion of ingested water. An
interesting observation in the SIADH is the development
of partial escape from ADH which tends to protect against
progressive water retention (Jaenike and Waterhouse,
1961). Although ADH secretion or effect is
inappropriately increased in the SIADH, up to one-third of
patients have a downward resetting of the osmostat in
which the plasma sodium concentration is normally
regulated (and therefore stable) at a new lower level,
typically between 125 and 135 mmol/L. Establishing the
presence of this condition is clinically important because
correcting the hyponatremia is both unnecessary and likely
to be ineffective, since raising the plasma osmolality will
stimulate both ADH release and thirst.
Hyponatremia, plasma hypoosmolality and urine
hyperosmolality with continuing sodium excretion are
biochemical findings in SIADH. Water retention is
typically only 2 to3 liters and does not lead to edema or
anasarka. The severity of symptoms in SIADH is related
to the degree of hyponatremia and the rapidity of fall in
serum sodium. Anorexia, nausea, and vomiting are
common symptoms. A rapid onset of hyponatremia can
cause cerebral edema. This may lead to irritability,
restlessness, personality changes, confusion, coma,
seizures, and respiratory arrest.
In patients with SCLC, SIADH resolves in up to 80%
after administration of chemotherapy (List et al, 1986).
Adjuvant management of SIADH includes fluid restriction
to 800-1,000 ml/d to increase serum sodium. In patients
with severe symptoms (severe confusion, convulsions, or
coma) intravenous hypertonic saline (5%) solution (eg.
200-300 ml in 3-4 h) should be given.
V. Cushing syndrome Adrenocorticotrophic hormone (ACTH) is the most
commonly produced hormone in lung cancer patients.
Increased levels of ACTH may be detectable in up to 50%
of patients with lung cancer (Mendelsohn and Baylin,
1984). ACTH secretion is almost always associated with
SCLC (Hansen, 1990). About 30% of all cases of SCLC
are associated with hypersecretion of ACTH. However, a
clinical apparent Cushing syndrome is rare (Mennecier et
al, 1999). Cushing syndrome has been described in 1 to
5% of patients with SCLC (Odell et al, 1979; Ilias et al,
2005) but this may overestimate the real rate. In 2005
Hansen and Bork reported only 3 out of 90 cases of
Cushing syndrome to be attributable to SCLC (Hansen and
Bork, 1985). Most commonly, Cushing syndrome
occurred in patients with pulmonary carcinoid (35 of 90
Heinemann et al: Paraneoplastic syndromes in lung cancer
690
patients). While ectopic ACTH syndrome typically
presents as Cushing syndrome in patients with SCLC
bronchial carcinoid tumors are the most common occult
sources of ACTH (Terzolo et al, 2001).
SCLC associated with the ectopic ACTH syndrome
is more resistant to chemotherapy and the severe
hypercortisolism is responsible for a high rate of life-
threatening complications during treatment which worsens
prognosis (Terzolo et al, 2001). Shepherd and collegues
retrospectively analyzed the charts of 545 patients with
SCLC. They identified 23 patiens (4.5%) with Cushing
syndrome and ectopic ACTH production. These patients
had a response rate to chemotherapy of only 46%, and
their median survival was only 3.57 months (Shepherd et
al, 1992).
In pituitary cells ACTH is derived by cleavage from
the precursor, pro-opiomelanocortin (POMC). It is
unlikely that processing of POMC is as efficient in non-
pituitary cells. ACTH precursors and ACTH-related
peptides can be secreted by POMC expressing cells.
ACTH precursors can be detected in the serum of patients
with ectopic ACTH syndrome (Oliver et al, 2003). Stewart
and co-workers reported grossly elevated levels of ACTH
precursors in patients with ectopic ACTH syndrome and
increased concentrations of ACTH precursors in patients
with SCLC without evidence of ectopic ACTH syndrome
(Stewart et al, 1994).
SCLC cells have been shown to express POMC and
secrete ACTH precursors (Stewart et al, 1989; White et al,
1989). POMC expression has also been observed in
bronchial carcinoid tumour cells (Crosby et al, 1990).
NSCLC is rarely associated with ectopic ACTH
syndrome. In a case report of a patient with poorly
differentiated squamous cell lung carcinoma and ectopic
ACTH syndrome ACTH secretion of cancer cells was
confirmed by immunohistochemical staining (Noorlander
et al, 2006). Another case reported described
paraneoplastic Cushing syndrome in a patient with
adenocarinoma of the lung (Yoh et al, 2003).
ACTH and ACTH precursors stimulate the adrenal
glands to secrete glucocorticosteroids. The symptoms and
signs of paraneoplastic Cushing syndrome result directly
from chronic exposure to excess glucocorticoid because of
ectopic ACTH-production. There is a large spectrum of
manifestations from subclinical to overt syndrome.
Diagnosis is often difficult because there is no
pathognomonic symptom. An important clinical hint to the
presence of Cushing syndrome is the simultaneous
development and increasing severity of several of the
following symptoms: Centripetal obesity, facial plethora,
glucose intolerance, weakness, proximal myopathy,
hypertension, psychological changes, easy bruisability,
hirsutism, oligomenorrhea or amenorrhea, impotence,
acne, oily skin, abdominal striae, ankle edema,
osteoporosis, polydipsia, polyuria, hyperpigmentation,
headache, fungal infection specially oral thrush and
hypokalimea.
To treat the paraneoplastic Cushing syndrome,
treatment of the underlying disease is essential. In most
cases treatment of the tumour will also improve the
paraneoplastic syndrom. However, responses to
chemotherapy in patients with SCLC and Cushing
syndrome is only moderate (Shepherd et al, 1992). Severe
symptoms should be treated symptomatically.
VI. Hematological abnormalities Hematologic abnormalities including anemia,
leukocytosis, thrombocytosis, and eosinophilia are
frequently observed in lung cancer patients. Anemia is
common in lung cancer patients. In one series 38% of
untreated patients had a haemoglobin # 12 g/dL. In
contrast 80% of patients that were treated with
chemotherapy were anaemic at one time (Kosmidis and
Krzakowski, 2005). Leukocytosis is often found in
patients with lung cancer either at time of diagnosis or
during the course of the disease (Thomson et al, 1986). In
one study leukocytosis had been described in 15% of all
patients with lung cancer (n = 227). Nearly all patients had
NSCLC. Leukocytosis was thought to be due to
overproduction of granulocyte-colony stimulating factor
(Kasuga et al, 2001). Tumor-related leukocytosis was
associated with a poorer prognosis compared to patients
without leukocytosis (median survival: 4.6 months vs 20.8
months) (Kasuga et al, 2001). Leukocytosis has also been
associated with hypercalcaemia (Kasuga et al, 2001;
Hiraki et al, 2004). Thrombocytosis is observed in 16% to
32% of all lung cancer patients (Moller Pedersen and
Milman, 1996; Aoe et al, 2004). It has been identified as
an independent predictor of shorten survival (Moller
Pedersen and Milman, 1996; Aoe et al, 2004).
Eosinophilia in tissue or blood is rare. While tumour-
associated tissue eosinophilia appear to have a better
prognosis tumour-associated blood eosinophilia seem to
be associated with a worse prognosis (Lowe, et al 1981).
The cause of anemia associated with cancer is
multifactorial. Bleeding, hemolysis, bone marrow
infiltration, and nutritional deficiencies may all contribute
to the development of anemia in patients with cancer. In
addition, inflammatory cytokines, such as TNF-!, IL-1,
IL-6, and IFN-$, inhibit erythropoiesis, which leads to
decreased production of erythrocytes, resulting in anemia.
It has to be taken into account that anemia is a common
complication of myelosuppressive chemotherapy
(Groopman and Itri, 1999). On average, over one third of
patients become anemic after three cycles of chemo-
therapy (Glaspy et al, 2002).
Lung cancer has been shown to produce G-CSF
which leads to leukocytosis (Asano et al, 1977).
Granulocyte macrophage- colony stimulating factor (GM-
CSF) and interleukin-6 production of lung carcinomas has
also been reported to be associated with leukocytosis
(Sawyers et al, 1992; Matsuguchi et al, 1991).
Anemia should be treated to improve quality of life.
Erythropoiesis-stimulating agents such as epoetin and
darbepoetin should be used with caution in cancer patients
with anemia who are not receiving chemotherapy (Rizzo
et al, 2008).
VII. Hypercoagulable disorders A variety of hypercoagulable disorders including
Trousseau´s syndrome (migratory superficial
thrombophlebitis), deep venous thrombosis and
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691
thromboembolism, dissiminated intravascular
coagulopathy, thrombotic microangiopathy, and
nonthrombotic microangiopathy can be found in lung
cancer. The incidence of venous thromboembolism (VTE)
in lung cancer patients is around 40-100 cases per 1000
person-years compared to an estimated 1-2 cases per 1000
person-years in the general population (Tesselaar and
Osanto, 2007). Chew and collegues analyzed the data from
91.933 patients with newly diagnosed lung cancer and
found that approximately 3% developed VTE within two
years (Chew et al, 2008). Venous thromboembolism was
associated with a higher risk of death within two years for
NSCLC and SCLC. Lung cancer is one of the greatest
purveyors of VTE (Girard et al, 2008).
Tumour cells can directly activate the clotting
through two procoagulants: tissue factor (TF) and cancer
procoagulant (CP) (Molnar et al, 2007). Human TF is the
physiological initiator of blood coagulation. Goldin-Lang
and co-workers found increased expression of full length
human TF and alternatively spliced human tissue factor in
NSCLC tissue compared to healthy controls (Goldin-Lang
et al, 2008). Moreover, in that study expression of tissue
factor was correlated with tumour stage and prognosis.
Active TF-bearing microparticles, which may originate
from the tumour cells themselves, have been found in the
circulation of cancer patients. Microparticle-associated TF
activity may provide a link between cancer and thrombosis
and play a decisive role in the pathogenesis of the
prothrombotic state in cancer patients (Tesselaar et al,
2007).
VTE in lung cancer should be treated the same was
as in non-cancer patients. Data from the literature suggest
that low molecular weight heparin (LMWH) is likely to be
superior to unfractionated heparin (UFH) in the initial
treatment of VTE (Akl et al, 2008). For the long term
treatment of VTE in cancer patients LMWH reduce VTE
but not dead compared to oral anticoagulant therapy (Akl
et al, 2008). In cancer patients without previous
thrombotic incidents heparin has been shown to have a
survival benefit especially in patients with limited SCLC
(Akl et al, 2007). In contrast oral anticoagulation may not
prolong survival. Only in patients with extensive SCLC a
survival benefit of six months from warfarin is suggested
according to the data from the literature (Akl et al, 2007).
VIII. Skeletal and collagen-vascular
syndromes Digital clubbing and hypertrophic pulmonary
osteoarthropathy (HPO) is observed in approximately 12%
of patients with adenocarcinoma of the lung and less
frequently in other cell types (Stenseth et al, 1967).
Inflammatory symptoms and pain may disappear with
successful treatment of the tumour.
Dermatomyositis and polymyositis are associated
with neoplasms in 40% of all cases. Besides ovarian
cancer SCLC is the most frequent type of cancer (Hill et
al, 2001). Gomm and colleagues studied 100 patients with
lung cancer (35% had SCLC, 65% had NSCLC). In that
study one patient presented with dermatomysositis and 33
patients had polymyopathie (Gomm et al, 1990).
The exact pathogenesis of digital clubbing and HPO
is not known. In digital clubbing proliferation of
connective tissue beneath the nail matrix is observed.
Histochemical features of HPO include vascular
hyperplasia, edema, and excessive fibroblast and
osteoblast proliferation (Myers and Farquhar, 2001). In the
past, neurogenic, hormonal, and vascular mechanisms
have been discussed (Shneerson, 1981). More recently, the
overexpression of vascular endothelial growth factor
(VEGF) has been implicated as contributing to the
pathogenesis of clubbing and HPO. Olan and collegues
reported the case of a young woman with lung cancer and
HPO. Serum levels of VEGF were elevated. After
resection of the cancer VEGF levels fell and HPO
remitted. Histochemical studies of the resected tumor
showed increased VEGF messenger RNA expression,
suggesting ectopic production by the lung cancer cells
(Olan et al, 2004).
Dermatomyositis is characterized by infarcts,
perifascicular atrophy, endothelial cell swelling and
necrosis, vessel wall membrane attack complex
deposition, and myocyte-specific MHC I upregulation in
the muscle. Histopathological findings in the skin include
hyperkeratosis, epidermal basal cell vacuolar degeneration
and apoptosis, increased dermal mucin deposition, and a
cell-poor interface dermatitis. The precise link between
malignancy and inflammatory myopathy remains
incompletely understood (Casciola-Rosen et al, 2005).
Although dermatomyositis has been classically considered
as humorally mediated disease newer evidence suggest
that cell-mediated mechanisms and innate immune system
dysfunction play a more important role in the pathogenesis
(Krathen et al, 2008). Myositis-specific autoantigens are
expressed at high levels in regenerating cell in myositic
muscles and in several cancer cells (Levine, 2006). This
may provide a link between cancer and paraneoplastic
myositis syndromes.
Digital clubbing is an enlargement of the terminal
segments of the fingers and/or toes due to proliferation of
connective tissue beneath the nail matrix. HPO is a
systemic disorder, which involves both a painful
symmetrical arthropathy, usually of the ankles, wrists, and
knees, and periosteal new bone formation in the distal long
bones of the limbs.
Myositis is characterized by muscle weakness and
muscle pain. Typically proximal muscles are involved.
Dermatomyositis also shows characteristic cutaneous
findings of heliotrope eruption, Gottron's papules and a
photodistributed eruption with poikiloderma. Raynaud
phenomenon, interstitial lung disease and inflammatory
arthritis can also be found.
Symptoms of HPO may resolve after tumour
resection. If a patient is not operable the usual treatment
includes nonsteroidal anti-inflammatory agents or a
bisphophonate (Amital et al, 2004). The mainstay of
therapy for dermatomyositis is corticosteroids (Iorizzo and
Jorizzo, 2008).
IX. Neurologic syndromes Paraneoplastic neurological syndromes are observed
in only 0.01% of cancer patients chiefly those affected by
Heinemann et al: Paraneoplastic syndromes in lung cancer
692
lung, breast, ovarian or stomach cancer. However, these
syndromes frequently cause major disability and limitation
in patients´ daily activities (Mollina-Garrido et al, 2006).
Neurologic syndromes in lung cancer include the Lambert-
Eaton myasthenic syndrome (LEMS), limbic
encephalopathy, polyneuropathy (PNP), cerebellar
degeneration, retinopathy, opsoclonus-myoclonus, and
autonomic neuropathy (Swash and Schwartz, 1990;
Martina and Clay, 2005). Paraneoplastic neurologic
syndromes may occur almost exclusively with SCLC.
Incidence in lung cancer patients has been reported to
range between 4 and 5% but may probably be lower
(Swash and Schwartz, 1990). In a 1991 survey of 150
consecutive SCLC patients only two patients had LEMS
(1%) and one patient suffered from PNP (< 1%) (Elrington
et al, 1991). In 2005 similar results were obtained in a
study of 432 consecutive patients with SCLC (LEMS:
1.6%, PNP: < 1%, subacute cerebellar degeneration: < 1%,
limbic encephalitis: < 1%) (Seute et al, 2004).
In a study of 200 patients with paraneoplastic
encephalomyelitis and anti-Hu antibodies pathological or
X-ray evidence of a tumour was obtained in 83%.
Diagnosis of SCLC was made in 74% of those with
histological diagnosis (Graus et al, 2001). The prognosis
of patients with SCLC and paraneoplastic
encephalomyelitis is poor (Spiegelman et al, 1989; Graus
et al, 2001).
Opsoclonus-myoclonus is a rare paraneoplastic
neurologic disorder that is most often associated with
SCLC (Anderson et al, 1988; Bataller et al, 2001). The
presence of the anti-neuronal antibodies in the serum
indicate a poor prognosis (Margery et al, 2003). In a study
by Hassan and co-workes SCLC patients with opsoclonus-
myoclonus died within 3 months without treatment. In
contrast, in that same study with appropriate
chemotherapy about half of the patients reported
improvement of neurologic symptoms and several became
long-term survivors (6 to 84 months) (Hassan et al, 2008).
Autoimmune mechanisms seem to be responsible for
the development of neurologic syndromes in cancer.
Autoantibodies are commonly found in neurologic
syndromes associated with cancer. Autoantibodies that are
directed against ligand- or voltage-gated channels have
been identified in several neuromuscular syndromes.
These include antibodies against voltage-gated calcium
channels (Lambert-Eaton syndrome), antibodies against
voltage-gated potassium channel (acquired
neuromyotonia), and antibodies against the neuronal
AChR in autonomic ganglia (autoimmune autonomic
ganglionopathy). There is good evidence that antibodies in
these disorders cause changes in synaptic function or
neuronal excitability by directly inhibiting ion channel
function (Vernino, 2007).
In Lambert-Eaton syndrome antibodies against the
presynaptic voltage-gated calcium channels can be found.
This decreases calcium entry into the presynaptic terminal
which prevents binding of vesicles to the presynaptic
membrane and acetylcholine release (Mareska and
Gutmann, 2004). Antibodies are most often directed
against voltage-gated P/Q calcium channels (VGCC) but
also antibodies against voltage-gated N calcium channels
can be found (Lennon et al, 1995). Low titers of antibodies
against the P/Q and the N type calcium channel were also
found in approximately 50% of patients with
paraneoplastic encephalomyeloneuropathic complications
(Lennon et al, 1995).
Paraneoplastic encephalomyelitis is characterized by
neuronal loss and inflammatory infiltrates in particular
areas of the nervous system (Henson and Urich, 1982). It
usually causes a severe neurological dysfuction, and
antedates the diagnosis of SCLC in >70% of cases. In the
majority of patients with paraneoplastic encephalomyelitis
an antineuronal antibody, anti-Hu, can be found (Graus et
al, 1985, 1986). This antibody recognizes a family of
RNA-binding proteins (HuD, HuC, Hel-N1 and Hel-N2)
expressed in the nuclei of neurones and SCLC cells (Szabo
et al, 1991; King and Dropcho, 1996). Despite their crucial
role in the development and maintenance of the neuronal
phenotype the function of Hu antigens in the tumour cells
is unknown. There is even no evidence that the anti-Hu
antibodies are the cause of the neuronal damage (Sillevis
Smitt et al, 1995; Carpentier et al, 1998). Nevertheless
anti-Hu antibodies represent a useful diagnostic marker
(Molinuevo et al, 1998). The antibodies probably are part
of a more complex immune response against Hu antigens
that is initially driven to control tumour growth but
misdirected to cause neurological dysfunction (Posner and
Dalmau, 1997).
At autopsy of patients with paraneoplastic neurologic
syndromes lymphocytic infiltration is found in the areas of
the central nervous system that correspond to neurologic
deficits. This finding supports the hypothesis that
autoantibodies play a key role in the pathogenesis of the
neurologic syndromes.
Clinical features of paraneoplastic syndromes
correspond to the underlying neurologic deficits. LEMS is
characterized by muscle weakness with a predominance of
the hip girdle. The motor weakness progresses in a
craniocaudal direction. Patients with limbic
encephalopathy usually present with rapidly progressive
short-term memory deficits, psychiatric symptoms, and
seizures. Paraneoplastic PNP leads to distal symmetric
sensorimotor deficits. Cerebellar degeneration is
characterized by ataxia. Retinopathy leads to visus loss.
Opsoclonus is characterized by irregular, continual and
conjugated chaotic saccades of the eyes. Opsoclonus when
accompanied by other symptoms of central nervous
system involvement (head, appendicular myoclonus and
truncal ataxia) constitutes the opsoclonus-myoclonus
syndrome. Paraneoplastic autonomic neuropathy is
associated with a variety of symptoms including
hypothermia, hypoventilation, sleep apnea, intestinal
pseudo-obstruction, and cardiac arrhythmias.
Two general approaches have been tried to treat
paraneoplastic neurologic syndromes based on the
assumption that these syndromes are immune-mediated:
removal of the antigen source by treatment of the tumour
and suppression of the immune response. LEMS can be
treated 3,4-diaminopyridine or intravenous
immunoglobulin that have been shown to improve muscle
strength. However, evidence from studies is limited
(Maddison and Newsom-Davis, 2005). In patients with
Cancer Therapy Vol 6, page 693
693
underlying cancer chemotherapy has been successful
(Verschuuren et al, 2006). For other paraneoplastic
neurologic syndromes there is evidence that prompt
oncologic treatment and immunotherapy (eg.
Immunosuppression) can be beneficial (Keime-Guibert et
al, 2000; Rosenfeld and Dalmau, 2003; Vernino et al,
2004).
X. Cutaneous syndromes A variety of paraneoplastic cutaneous syndromes has
been described in lung cancer patients (refer to Table 1).
However, these syndromes are mostly non-specific and
can be observed in both malignant and benign disease.
Palmo-plantar hyperkeratosis (PPH) also called
tylosis is a rare paraneoplastic syndrome in lung cancer. In
the literature it is mostly described in case reports
(Schwindt et al, 1970; Nomori et al, 1996; Engin et al,
2002). It may typically precede the diagnosis of lung
cancer for months or years (Burgdorf and Goltz, 1987).
Prognosis of patients with lung cancer and PPH is poor
(Nomori et al, 1996). Akanthosis nigricans has also been
described in several case reports to be associated with
adenocarcinoma, with squamous cell lung carcinoma or
also with alveolar cell carcinoma (Horiuchi et al, 1986;
Menzies et al, 1988; Onai et al, 1989).
XI. Cachexia and fatigue Cancer cachexia is perhaps the most common
manifestation of advanced malignant disease (50%) and is
responsible for approximately 25% of deaths from cancer
(Lelbach et al, 2007). The degree of cachexia is inversely
correlated with survival time and always implies a poor
prognosis.
Symptoms of cachexia include anorexia, weight loss,
muscle loss, anemia, and alterations in carbohydrate, lipid
and protein metabolism.
Cachexia is mainly driven by anorexia and metabolic
alterations. Cancer patients frequently exhibit a relative
glucose intolerance and insulin resistance. While
significant loss of adipose tissue is observed in cancer
cachexia lipolytic rates are not significantly increased.
Lipogenesis seem to be reduced. Loss of skeletal muscle
protein and decreased muscle protein synthesis is
commonly observed in cachexia (Dworzak et al, 1998;
Giordano et al, 2003). Changes in liver protein synthesis
refect aspects of the so-called acute-phase protein
response. This is part of the general adaptation of the body
often seen in trauma, inflammation, infection, and cancer.
An acute-phase protein response can be observed in a
significant proportion of patients with lung cancer. The
presence of an acute-phase protein response has been
related to accelerated weight loss in patients with lung
cancer (Harvie et al, 2003).
A variety of mediators has been described to be
involved in development of cachexia (Lelbach et al, 2007).
The tumour behaves like a new metabolically active organ.
However, it is not clear whether the metabolic changes
result from mediators released by the cancer or the host
response (Argiles et al, 2003, 2008; Lelbach et al, 2004).
In general, serotinergic activity in the hypothalamus
decreases appetite. In cancer patients increased levels of
free tryptophan, a precursor of serotonin, are found (Brink
et al, 2002). Amounts of tryptophan are closely related
with reduced food intake. Changes in hormone levels and
target-organ sensitivity have also been described in tumour
patients. Elevated levels of cortisol and glucagons may
amplify the acute-phase protein response in cancer patients
(Schaur et al, 1979; Knapp et al, 1991). In addition,
several proinflammatory cytokines including (TNF)-!,
(IL)-1, IL-6, interferon (IFN)-$, and ciliary neutropic
factor (CNTF) have been implicated in cachexia (Lelbach
et al, 2007). Apart from factors produced by the host
tumour derived mediators have been described that may
play an important role in the pathogenesis of cachexia.
These mediators include proteolysis-inducing factor (PIF)
and lipid mobilizing factor (LMF) (Cariuk et al, 1997;
Hiraki et al, 1997).
At present therapy for cancer cachexia is difficult.
Reversing malnutrition by traditional food intake is
hampered by the protein-energy deficit and the associated
wasting as well as the anorexia and the early satiety.
Several drugs have been used to “repair” the altered
metabolism. Corticosteroids are most widely used with a
short benefit. Ibuprofen has been used with some effect
due to its anti-inflammatory properties.
Medroxyprogesteron acetate may improve appetite and
stabilize weight. Eicosapentaenoic acid can lower the
production of proinflammatory cytokines.
Cancer-related fatigue is also extremely common. Up
to 90% of cancer patients report fatigue symptoms while
in most studies prevalence rates are 60% (Cella et al,
2001). Fatigue is a highly subjective multidimensional
experience. Individuals may perceive fatigue as physical
tiredness or exhaustion, a need for reduced activity,
reduced motivation, and/or mental fatigue (Ahlberg et al,
2003). Fatigue is experienced due to cancer and to
treatment. The basic mechanisms of fatigue are broadly
characterized into two main components: peripheral and
central. Peripheral fatigue occurs in the neuromuscular
junctions and muscle tissues. This results in the inability of
the peripheral neuromuscular apparatus to perform a task
in response to central stimulation. Central fatigue arises
from the progressive failure to transmit motor neuron
impulses. This leads to difficulties in the initiation or
maintenance of voluntary activities (Chaudhuri and Behan,
2004; Ronnback and Hansson, 2004).
The etiology of fatigue is poorly understood. Several
underlying mechanisms have been proposed based on
studies in normal (exercise) conditions and in the context
of chronic diseases, including chronic fatigue syndrome
and rheumatoid arthritis (Ryan et al, 2007).
Several mechanisms have been shown to be involved
in cancer-related fatigue. Studies in patients with chronic
fatigue syndrome have demonstrated raised plasma levels
of free tryptophan, which could potentially lead to high
central serotonin levels (Castell et al, 1999; Badawy et al,
2005). An increase in brain serotonin (5-HT) levels and/or
upregulation of a population of 5-HT receptors, may lead
to reduced somatomotor drive, modified hypothalamic-
pituitary-adrenal (HPA) axis function, and a sensation of
reduced capacity to perform physical work (Andrews et al,
2004). Low levels of circulating cortisol have been
Heinemann et al: Paraneoplastic syndromes in lung cancer
694
observed in patients with chronic fatigue syndrome
(Cleare, 2003). Cancer, and/or cancer treatment may also
alter the function of the HPA axis, resulting in endocrine
changes that cause or contribute to fatigue. Cancer may
cause fatigue by circadian rhythm disruption. Several
alterations in circadian function have been demonstrated in
patients with cancer. These include changes in endocrine
rhythms (e.g., cortisol, melatonin, and prolactin secretion),
metabolic processes (e.g., temperature and circulating
protein levels), the immune system (e.g., levels of
circulating leukocytes and neutrophils), and rest-activity
patterns (Focan et al, 1986; Mormont and Levi, 1997;
Vgontzas and Chrousos, 2002; Sephton and Spiegel, 2003;
Levin et al, 2005). Cancer can lead to a defect in the
mechanism for regenerating ATP in skeletal muscle can
compromise the ability to perform mechanical tasks
(Andrews et al, 2004). Reduced oxidative muscle
metabolism, epleted cellular ATP associated with a
dysregulated 2',5'-oligoadenylate synthetase/RNase L
pathway, and impaired synthesis of ATP have been
reported (McCully et al., 1996; Lane et al, 1998; Forsyth
et al, 1999). Proinflammatory cytokines, such as TNF-!
and IL-1%, are implicated in many of the mechanisms
proposed for the etiology of fatigue associated with cancer
and various illnesses (Konsman et al, 2002).
Treatment of cancer-related fatigue should be
individualized according to the underlying pathology
when a specific cause has been identified. In addition to
older therapies, such as hematopoietics, antidepressants,
corticosteroids, and psychostimulants, the new wake-
promoting agent modafinil may offer an alternative
therapeutic approach.
XII. Conclusions Paraneoplastic syndromes are common in lung
cancer patients. Some paraneoplastic syndromes can
severely affect organ function and quality of life. Treating
the underlying cancer is the first step. However, specific
therapy may also be necessary.
References Abou-Samra AB, Juppner H, Force T, Freeman MW, Kong XF,
Schipani E, Urena P, Richards J, Bonventre JV, Potts JT Jr
(1992) Expression cloning of a common receptor for
parathyroid hormone and parathyroid hormone-related
peptide from rat osteoblast-like cells: a single receptor
stimulates intracellular accumulation of both cAMP and
inositol trisphosphates and increases intracellular free
calcium. Proc Natl Acad Sci USA 89, 2732-2736.
Ahlberg K, Ekman T, Gaston-Johansson F, Mock V (2003)
Assessment and management of cancer-related fatigue in
adults. Lancet 362, 640-650.
Akl EA, Kamath G, Kim SY, Yosuico V, Barba M, Terrenato I,
Sperati F, Schünemann HJ (2007) Oral anticoagulation for
prolonging survival in patients with cancer. Cochrane
Database Syst Rev 18, CD006466.
Akl EA, Rohilla S, Barba M, Sperati F, Terrenato I, Muti P,
Schünemann HJ (2008) Anticoagulation for the initial
treatment of venous thromboembolism in patients with
cancer. Cochrane Database Syst Rev 23, CD006649.
Akl EA, Rohilla S, Barba M, Sperati F, Terrenato I, Muti P,
Schünemann HJ (2008) Anticoagulation fro the long term
treatment of venous thromboembolism in patients with
cancer. Cochrane Database Syst Rev 16, CD006650.
Akl EA, van Doormaal FF, Barba M, Kamath G, Kim SY,
Kuipers S, Middeldorp S, Yosuico V, Dickinson HO,
Schünemann HJ (2007) Parenteral anticoagulation for
prolonging survival in patients with cancer who have no
other indication for anticoagulation. Cochrane Database
Syst Rev 18, CD006652.
Amital H, Applbaum YH, Vasiliev L, Rubinow A (2004)
Hypertrophic pulmonary osteoarthropathy: control of pain
and symptoms with pamidronate. Clin Rheumatol 23, 330-
332.
Anderson NE, Budde-Steffen C, Rosenblum MK, Graus F, Ford
D, Synek BJ, Posner JB (1988) Opsoclonus, myoclonus,
ataxia, and encephalopathy in adults with cancer: a distinct
paraneoplastic syndrome. Medicine (Baltimore) 67, 100-
109.
Andrews PLR, Morrow GR, Hickok JT (2004) In: Armes J,
Krishnasamy M, Higginson I, eds. Fatigue in Cancer.
Mechanisms and models of fatigue associated with cancer
and its treatment: Evidence of pre-clinical and clinical
studies. Oxford, Oxford University Press, pp 51-87.
Aoe K, Hiraki A, Ueka H, Kiura K, Tabata M, Tanaka M,
Tanimoto M (2004) Thrombocytosis is a useful prognostic
indicator in patients with lung cancer. Respiration 71, 170-
173.
Argiles JM, Moore-Carrasco R, Busquets S, Lopez-Soriano FJ
(2008) Catabolic mediators as targets for cancer cachexia.
Drug Discov Today 8, 838-844.
Argiles JM, Moore-Carrasco R, Fuster G, Busquets S, Lopez-
Soriano FJ (2003) Cancer cachexia: the molecular
mechanism. Int J Biochem Cell Biol 35, 405-409.
Asa SL, Henderson J, Goltzman D, Drucker DJ (1990)
Parathyroid hormone-like peptide in normal and neoplastic
human endocrine tissues. J Clin Endocrinol Metab 71,
1112-1118.
Asano S, Urabe A, Okabe T, Sato N, Kondo Y (1977)
Demonstration of granulopoietic factors in the plasma of
nude mice transplanted with a human lung cancer and in the
tumor tissue. Blood 49, 845-52.
Badawy AA, Morgan CJ, Llewelyn MB, Albuquerque SR,
Farmer A (2005) Heterogeneity of serum tryptophan
concentration and availability to the brain in patients with the
chronic fatigue syndrome. J Psychopharmacol 19, 385-391.
Bataller L, Graus F, Saiz A, Vilchez JJ and for the Spanish
Opsolconus-Myoclonus Study Group (2001) Clinical
outcome in adult onset idiopathic or paraneoplastic
opsoclonus-myoclonus. Brain 124, 437-443.
Bertolini DR, Nedwin GE, Bringman TS, Smith DD, Mundy GR
(1986) Stimulation of bone resorption and inhibition of bone
formation in vitro by human tumour necrosis factors. Nature
319, 516-518.
Bliss DP Jr, Battey JF, Linnoila RI, Birrer, MJ, Gazdar AF,
Johnson BE (1990) Expression of the atrial natriuretic factor
gene in small cell lung cancer tumors and tumor cell lines. J
Natl Cancer Inst 82:, 305-310.
Brink M, Anwar D, Delafontaine P (2002) Neurohormonal
factors in the development of catabolic/anabolic imbalance
and cachexia. Int J Cardiol 85, 111-121.
Bunn PA, Ridgway EC (1993) Paraneoplastic syndromes. In:
DeVita VT, et al, eds. Cancer: Principles and Practice of
Oncology. 4th Edn. JB Lippincott Co, pp 2026-2071.
Burgdorf WHC, Goltz RW (1987) Figurate erythemas. In:
Fitzpatrick TB, Eisen AZ. Wolff K, et al. eds. Dermatology
in General Medicine. New York, McGraw-Hill, pp 1010-
1018.
Burtis WJ, Brady TG, Orloff JJ, Ersbak JB, Warrell RP Jr, Olson
BR, Wu TL, Mitnick ME, Broadus AE, Stewart AF (1990)
Cancer Therapy Vol 6, page 695
695
Immunochemical characterization of circulating parathyroid
hormone-related protein in patients with humoral
hypercalcemia of cancer. New Engl J Med 322, 1106-1112.
Carbone PP, Frost JK, Feinstein AR (1970) Lung cancer:
perspectives and prospects. Ann Intern Med 73, 1003-1024.
Cariuk P, Lorite MJ, Todorov PT, Field WN, Wigmore SJ,
Tisdale MJ (1997) Induction of cachexia in mice by a
product isolated from the urine of cachectic cancer patients.
Br J Cancer 76, 606-613.
Carpentier AF, Rosenfeld MR, Delattre JY, Whalen RG, Posner
JB, Dalmau J (1998) DNA vaccination with HuD inhibits
growth of a neuroblastoma in mice. Clin Cancer Res 4,
2819-2824.
Casciola-Rosen L, Nagaraju K, Plotz P, Wang K, Levine S,
Gabrielson E, Corse A, Rosen A (2005) Enhanced
autoantigen expression in regenerating muscle cells in
idiopathic inflammatory myopathy. J Exp Med 201, 591-
601.
Castell LM, Yamamoto T, Phoenix J, Newsholme EA (1999)
The role of tryptophan in fatigue in different conditions of
stress. Adv Exp Med Biol 467, 697-704.
Cella D, Davis K, Breitbart W, Curt G, Fatigue Coalition (2001)
Cancer-related fatigue: Prevalence of proposed diagnostic
criteria in a United States sample of cancer survivors. J Clin
Oncol 19, 3385-3391.
Chaudhuri A, Behan PO (2004) Fatigue in neurological
disorders. Lancet 363, 978-988.
Chen HL, Demiralp B, Schneider A, Koh AJ, Silve C, Wang CY,
McCauley LK (2002) Parathyroid hormone and parathyroid
hormone-related protein exert both pro- and anti-apoptotic
effects in mesenchymal cells. J Biol Chem 277, 19374-
19381.
Chew HK, Davies AM, Wun T, Harvey D, Zhou H, White RH
(2008) The incidence of venous thromboembolism among
patients with primary lung cancer. J Thromb Haemost 6,
601-608.
Cleare AJ (2003) The neuroendocrinology of chronic fatigue
syndrome. Endocr Rev 24, 236-252.
Clines GA, Guise TA (2005) Hypercalcaemia of malignancy and
basic research on mechanisms responsible for osteolytic and
osteoblastic metastasis in bone. Endocr Rel Cancer 12, 549-
583.
Crosby SR, Stewart MF, Farrell WE, Gibson S, White A (1990)
Comparison of ACTH and ACTH precursor peptides
secreted by human pituitary and lung tumour cells in vitro. J
Endocrinol 125, 147-152.
Danks JA, Ebeling PR, Hayman J, Chou ST, Moseley JM,
Dunlop J, Kemp BE, Martin TJ (1989) Parathyroid hormone-
related protein: immunohistochemical localization in cancers
and in normal skin. J Bone Min Res 4, 273-278.
Dworzak F, Ferrari P, Gavazzi C, Maiorana C, Bozzetti F (1998)
Effects of cachexia due to cancer on whole body and skeletal
muscle protein turnover. Cancer 82, 42-48.
Elrington GM, Murray NMF, Spiro SG, Newsom-Davis J (1991)
Neurological paraneoplastic syndromes in patients with small
cell lung cancer: a prospective survey of 150 patients. J
Neurol Neurosurg Psychiatry 54, 764-767.
Engin H, Akdogan A, Altundaq O, Kars A, Güler N (2002) Non-
small-cell lung cancer with nonfamilial diffuse palmoplantar
keratoderma. J Exp Clin Cancer Res 21, 45-47.
Focan C, Focan-Henrard D, Collette J, Mechkouri M, Levi F,
Hrushesky W, TouitouY, Franchimont P (1986) Cancer-
associated alteration of circadian rhythms in
carcinoembryonic antigen (CEA) and alpha-feto-protein
(AFP) in humans. Anticancer Res 6, 1137-1144.
Forsyth LM, Preuss HG, MacDowell AL, Chiazze L Jr,
Birkmayer GD, Bellanti JA (1999) Therapeutic effects of
oral NADH on the symptoms of patients with chronic fatigue
syndrome. Ann Allergy Asthma Immunol 82, 185-191.
Giordano A, Calvani M, Petillo O, Carteni M, Melone MR,
Peluso G (2003) Skeletal muscle metabolism in physiology
and in cancer disease. J Cell Biochem 90, 170-186.
Girard P, Raynaud C, Meyer G, Parent F, Besse B (2008)
Thrombosis and lung cancer. Rev Pneumol Clin 64, 85-91.
Glaspy J, Degos L, Dicato M, Demetri GD (2002) Comparable
efficacy of epoetin alfa for anemic cancer patients receiving
platinum-and nonplatinum-based chemotherapy: A
retrospective subanalysis of two large, community-based
trials. The Oncologist 7, 126-135.
Goldin-Lang P, Tran QV, Fichtner I, Eisenreich A, Antoniak S,
Schulze K, Coupland SE, Poller W, Schultheiss HP, Rauch U
(2008) Tissue factor expression pattern in human non-small
cell lung cancer tissues indicate increased blood
thrombogenicity and tumour metastasis. Oncol Rep 20, 123-
128.
Gomm SA, Thatcher N, Barber PV, Cumming WJ (1990) A
clinicopathological study of the paraneoplastic
neuromuscular syndromes associated with lung cancer. Q J
Med 75, 577-595.
Graus F, Cordon-Cardo C, Posner JB (1985) Neuronal
antinuclear antibody in sensory neuronopathy from lung
cancer. Neurology 35, 538-543.
Graus F, Elkon KB, Cordon-Cardo C, Posner JB (1986) Sensory
neuronopathy and small cell lung cancer. Antineuronal
antibody that also reacts with the tumor. Am J Med 80, 45-
52.
Graus F, Keime-Guibert F, Reñe R, Benyahia B, Ribalta T,
Ascaso C, Escaramis G, Delattre JY (2001) Anti-Hu-
associated paraneoplastic encephalomyelitis: analysis of 200
patients. Brain 124, 1138-1148.
Groopman JE, Itri LM (1999) Chemotherapy-induced anemia in
adults: Incidence and treatment. J Natl Cancer Inst 91,
1616-1634.
Hansen M (1990) Paraneoplastic syndromes and tumor markers
for small-cell and non-small-cell lung cancer. Curr Opin
Oncol 2, 345-351.
Hansen M, Bork E (1985) Peptide hormones in patients with
lung cancer. Recent Results Cancer Res 99, 180-186.
Harvie MN, Campbell IT, Thatcher N, Baildam A (2003)
Changes in body composition in men and women with
advanced nonsmall cell lung cancer (NSCLC) undergoing
chemotherapy. J Hum Nutr Diet 16, 323-326.
Hassan KA, Kalemkerian GP, Trobe JD (2008) Long-term
survival in paraneoplastic opsoclonus-myoclonus syndrome
associated with small cell lung cancer. J Neuroophthalmol
28, 27-30.
Henson RA, Urich H (1982) Encephalomyelitis with carcinoma.
In: Henson RA, Urich H, editors. Cancer and the nervous
system. Oxford. Blackwell Scientific, pp 314-345.
Hill CL, Zhang Y, Sigugeirsson B, Pukkula E, Mellemkjaer L,
Airiro A, Evans SR, Felson DT (2001) Frequency of specific
cancer types in dermatomyositis and polymyositis: a
population-based study. Lancet 357, 96-100.
Hiraki A, Ueoka H, Takata I, Gemba K, Bessho A, Segawa Y,
Kiura K, Eguchi K, Yoneda T, Tanimoto M, Harada M
(2004) Hypercalcemia-leukocytosis syndrome associated
with lung cancer. Lung Cancer 43, 301-307.
Hiraki K, Ishiko O, Tisdale M (1997) Mechanisms of depletion
of liver glycogen in cancer cachexia. Biochem Biophys Res
Commun 241, 49-52.
Horiuchi N, Caulfield MP, Fisher JE, Goldman ME, McKee RL,
Reagan JE, Levy JJ, Nutt RF, Rodan SB, Schofield TL
(1987) Similarity of synthetic peptide from human tumor to
parathyroid hormone in vivo and in vitro. Science 238, 1566-
1568.
Heinemann et al: Paraneoplastic syndromes in lung cancer
696
Horiuchi Y, Katsuoka K, Yoshimura H, Kanzaki T, Nishiyama S
(1986) Acanthosis nigricans and Leser-Trelat sign associated
with squamous cell carcinoma and adenocarcinoma of the
lung. Int J Dermatol 25, 459-460.
Ibbotson KJ, Twardzik DR, D’Souza SM, Hargreaves WR,
Todaro GJ, Mundy GR (1995) Stimulation of bone
resorption in vitro by synthetic transforming growth factor-
alpha. Science 228, 1007-1009.
Ilias K, Torpy D, Pacak K, Mullen N, Wesley RA, Nieman LK
(2005) Cushing’s syndrome due to ectopic corticotropin
secretion. J Clin Endocrinol Metab 90, 4955-4962.
Iorizzo LJ 3rd, Jorizzo JL (2008) The treatment and prognosis of
dermatomyositis: an uodated review. J Am Acad Dermatol
59, 99-112.
Jaenike JR, Waterhouse C (1961) The renal response to sustained
administration of vasopressin and water in man. J
Clin.Endocrinol.Metab 21, 231-242.
Juppner H, Abou-Samra AB, Freeman M, Kong XF, Schipani E,
Richards J, Kolakowski LF Jr, Hock J, Potts JT Jr,
Kronenberg HM (1991) A G protein-linked receptor for
parathyroid hormone and parathyroid hormone-related
peptide. Science 254, 1024-1026.
Kasuga I, Makino S, Kiyokawa H, Katoh H, Ebihara Y,
Ohyashiki K (2001) Tumor-related leukocytosis is linked
with poor prognosis in patients with lung carcinoma. Cancer
92, 2399-2405.
Keime-Guibert F, Graus F, Fleury A, Rene R, Honnorat J, Broet
P, Delattre JY (2000) Treatment of paraneoplastic
neurological syndromes with antineuronal antibodies (Anti-
Hu, anti-Yo) with a combination of immunoglobulins,
cyclophosphamide, and methylprednisolone. J Neurol
Neurosurg Psychiatry 68, 479-482.
King PH, Dropcho EJ (1996) Expression of Hel-N1 and Hel-N2
in small-cell lung carcinoma. Ann Neurol 39, 679-681.
Klein DC, Raisz LG (1970) Prostaglandins: stimulation of bone
resorption in tissue culture. Endocrinology 86, 1436-1440.
Knapp ML, al-Sheibani S, Riches PG, Hanham IW, Phillips RH
(1991) Hormonal factors associated with weight loss in
patients with advanced breast cancer. Ann Clin Biochem 28,
480-486.
Konsman JP, Parnet P, Dantzer R (2002) Cytokine-induced
sickness behaviour: Mechanisms and implications. Trends
Neurosci 25, 154-159.
Kosmidis P, Krzakowski M (2005) Anemia profiles in patients
with lung cancer: what have we learned from the European
Cancer Anaemia Survey (ECAS)? Lung Cancer 50, 401-
412.
Krathen MS, Fiorentino D, Werth VP (2008) Dermatomyositis.
Curr Dir Autoimmun 10, 313-323.
Kukrja SC, Shemerdiak WP, York PA, Lad TE, Abramson EC,
Thomas PA, Mir J (1982) Presence of prostaglandin E in
lung tumors from normocalcemic patients. Am J Med 72,
737-742.
Lane RJ, Barrett MC, Taylor DJ, Kemp GJ, Lodi R (1998)
Heterogeneity in chronic fatigue syndrome: Evidence from
magnetic resonance spectroscopy of muscle. Neuromuscul
Disord 8, 204-209.
Lelbach A, Munez G, Feher J (2004) Molecular mechanisms of
cancer cachexia. Orv Hetil 46, 2329-2334.
Lelbach A, Muzes G, Feher J (2007) Current perspectives of
catabolic mediators of cancer cachexia. Med Sci Monit 13,
RA168-173.
Lennon VA, Kryzer TJ, Griesmann GE, O’Suilleabhain BE,
Windebank AJ, Woppmann A, Miljanich GP, Lambert EH
(1995) Calcium-channel antibodies in the Lambert-Eaton
syndrome and other paraneoplastic syndromes. New Engl J
Med 332, 1467-1474.
Levin RD, Daehler MA, Grutsch JF, Quiton J, Lis CG, Peterson
C, Gupta D, Watson K, Layer D, Huff-Adams S, Desai B,
Sharma P, Wallam M, Delioukina M, Ball P, Bryant M,
Ashford M, Copeland D, Ohmori M, Wood PA, Hrushesky
WJ (2005) Circadian function in patients with advanced non-
small-cell lung cancer. Br J Cancer 93, 1202-1208.
Levine SM (2006) Cancer and myositis: new insights into an old
association. Curr Opin Rheumatol 18, 620-624.
Li H, Seitz PK, Selvanayagam P, Rajaraman S, Cooper CW
(1996) Effect of endogenously produced parathyroid
hormone-related peptide on growth of a human hepatoma
cell line (Hep G2). Endocrinol 137, 2367-2374.
List AF, Hainsworth JD, Davis BW, Hande KR, Greco FA,
Johnson DH (1986) The syndrome of inappropriate secretion
of antidiuretic hormone (SIADH) in small-cell lung cancer. J
Clin Oncol 4, 1191-1198.
Lowe D, Jorizzo J, Hutt MRS (1981) Tumour-associated
eosinophilia: a review. J Clin Pathol 34, 1343-1348.
Luparello C, Burtis WJ, Raue F, Birch MA, Gallagher JA (1995)
Parathyroid hormone-related peptide and 8701-BC breast
cancer cell growth and invasion in vitro: evidence for
growth-inhibiting and invasion-promoting effects. Mol Cell
Endocrinol 111, 225-232.
Luparello C, Ginty AF, Gallagher JA, Pucci-Minafra I, Minafra
S (1993) Transforming growth factor-beta 1, beta 2, and beta
3, urokinase and parathyroid hormone-related peptide
expression in 8701-BC breast cancer cells and clones.
Differentiation 55, 73-80.
Maddison P, Newsom-Davis J (2005) Treatment for Lambert-
Eaton myasthenic syndrome. Cochrane Database Syst Rev
18, CD 003279.
Mahon MJ, Donowitz M, Yun CC, Segre GV (2002) Na(+)/H(+)
exchanger regulatory factor 2 directs parathyroid hormone 1
receptor signalling. Nature 417, 858-861.
Mareska M, Gutmann L (2004) Lambert-Eaton myasthenic
syndrome. Semin Neurol 24, 149-153.
Margery J, Ferroir JP, Epaud C, Martin C, Milleron B (2003)
Paraneoplastic opsoclonus-myoclonus syndrome associated
with small-cell lung cancer. Rev Pneumol Clin 59, 321-324.
Martina T, Clay AS (2005) A 50-year-old woman with bilateral
vocal cord paralysis and hilar mass. Chest 128, 1028-1031.
Matsuguchi T, Okamura S, Kawasaki C, Shimoda K, Omori F,
Hayashi S, Kimura N, Niho Y (1991) Constitutive
production of granulocyte colony-stimulating factor and
interleukin-6 by a human lung cancer cell line, KSNY: gene
amplification and increased mRNA stability. Eur J
Haematol 47, 128-133.
Maurer LH, O’Donnell JF, Kennedy S, Faulkner CS, Rist K,
North WG (1983) Human neurophysins in carcinoma of the
lung. Cancer Treat Rep 67, 971-976.
Mawer EB, Hayes ME, Heys SE, Davies M, White A, Stewart
MF, Smith GN (1994) Constitutive synthesis of 1,25-
dihydroxyvitamin D3 by a human small cell lung cancer cell
line. J Clin Endorcinol Meatbol 79, 554-560.
McCully KK, Natelson BH, Iotti S, Sisto S, Leigh JS Jr (1996)
Reduced oxidative muscle metabolism in chronic fatigue
syndrome. Muscle Nerve 19, 621-625.
Mendelsohn G, Baylin SB (1984) Ectopic hormone production:
biological and clinical implications. Prog Clin Biol Res 142,
291-316.
Mennecier B, Moreau L, Goichot B, Quoix E (1999)
Paraneoplastic Cushing´s syndrome and small cell bronchial
carcinoma. Rev Pneumol Clin 55, 77-80.
Menzies DG, Choo-Kang J, Buxton PK, Campbell IW (1988)
Acanthosis nigricans associated with alveolar cell carcinoma.
Thorax 43, 414-415.
Molinuevo JL, Graus F, Serrano C, Reñé R, Guerrero A, Illa I
(1998) Utility of anti-Hu antibodies in the diagnosis of
Cancer Therapy Vol 6, page 697
697
paraneoplastic sensory neuropathy. Ann Neurol 44, 976-
980.
Moller Pedersen L, Milman N (1996) Prognostic significance of
thrombocytosis in patients with primary lung cancer. Eur
Respir J 9, 1826-1830.
Mollina-Garrido MJ, Guillen-Ponce C, Martinez S, Guirado-
Risueno M (2006) Diagnosis and current treatment of
neurological paraneoplastic syndromes. Clin Transl Oncol
8, 796-801.
Molnar S, Guglielmone H, Lavarda M, Rizzi ML, Jarchum G
(2007) Procoagulant factors in patients with cancer.
Hematology 12, 555-559.
Monsieur I, Meysman M, Noppen N, de Greve J, Delhove O,
Velckeniers B, Jacobvitz D, Vincken W (1995) Non-small-
cell lung cancer with multiple paraneoplastic syndromes.
Eur Respir J 8, 1231-1234.
Mormont MC, Levi F (1997) Circadian-system alterations during
cancer processes: A review. Int J Cancer 70, 241-247.
Moseley JM, Kubota M, Diefenbach-Jagger H, Wettenhall REH,
Kemp BE, Suva LJ, Rodda CP, Ebeling PR, Hudson PJ,
Zajac JD, Martin TJ (1987) Parathyroid hormone-related
protein purified from a human lung cancer cell line. Proc
Natl Acad Sci USA 84, 5048-5052.
Moses AM, Scheinman SJ (1991) Ectopic secretion of
neurohypophyseal peptides in patients with malignancy.
Endocrinol Metab Clin North Am 20, 489-506..
Mundy GR (1995) Hypercalcemia. In: Bone Remodeling and its
Disorders. Ed. GR Mundy. London, Martin Dunitz, pp 88-
103.
Myers KA, Farquhar DRE (2001) Does this patient have
clubbing? JAMA 286, 341-347.
Nielsen PK, Rasmussen AK, Feldt-Rasmussen U, Brandt M,
Christensen L, Olgaard K (1996) Ectopic production of intact
parathyroid hormone by a squamous cell lung carcinoma in
vivo and in vitro. J Clin Endocrinol Metabol 81, 3793-
3796.
Nomori H, Horio H, Iga R, Fuyuno G, Kobayashi R, Morinaga S
(1996) Squamous cell carcinoma of the lung associated with
palmo-plantar hyperkeratosis. Nihon Kyobu Shikkan
Gakkai Zasshi 34, 76-79.
Noorlander I, Elte JW, Manintveld OC, Tournoy KG, Praet MM,
van Meerbeeck JP, Aerts JG (2006) A case of recurrent non-
small-cell lung carcinoma and paraneoplastic Cushing´s
syndrome. Lung Cancer 51, 251-255.
Odell WD, Wolfsen AR, Bachelot I, Hirose FM (1979) Ectopic
production of lipotropin by cancer. Am J Med 66, 631-638.
Olan F, Portela M, Navarro C, Gaxiola M, Silveira LH, Ruiz V,
Martinez-Lavin M (2004) Circulating vascular endothelial
growth factor concentrations in a case of pulmonary
hypertrophic osteoarthropathy. J Rheumatol 31, 614-616.
Oliver RL, Davis JR, White A (2003) Characterization of ACTH
related peptides in ectopic Cushing´s syndrome. Pituitary 6,
119-126.
Onai T, Mori M, Akuzawa M, Kuribara M, Kobayashi S (1989)
A case of lung carcinoma associated with acanthosis
nigricans and increased titer of anti-nuclear antibody.
Nippon Naika Gakkai Zhasshi 78, 1607-1608.
Patel AM, Davila DG, Peters SG (1993) Paraneoplastic
syndromes associated with lung cancer. Mayo Clin Proc 68,
278-287.
Posner JB, Dalmau J (1997) Paraneoplastic syndromes. Curr
Opin Immunol 9, 723-729.
Richardson GE, Johnson BE (1992) Paraneoplastic syndromes in
lung cancer. Curr Opin Oncol 4, 323-333.
Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J,
Bennett CL, Cella DF, Djulbegovic B, Goode MJ,
Jakubowski AA, Rarick MU, Regan DH, Lichtin AE (2008)
Use of epoetin and darbepoetin in patients with cancer: 2007
American Society of Hematology/American Society of
Clinical Oncology clinical practice guideline update. Blood
111, 25-41.
Ronnback L, Hansson E (2004) On the potential of glutamate
transport in mental fatigue. J Neuroinflammation 1, 22.
Rosenfeld MR, Dalmau J (2003) Current therapies for
paraneoplastic neurologic syndromes. Curr Treat Options
Neurol 5, 69-77.
Ryan JL, Carroll JK, Ryan EP, Mustian KM, Fiscella K, Morrow
GR (2007) Mechanisms of cancer-related fatigue.
Oncologist 12 Suppl 1, 22-34.
Sawyers CL, Golde DW, Quan S, Nimer SD (1992) Production
of granulocyte-macrophage colony stimulating factor in two
patients with lung cancer, leukocytosis and eosinophilia.
Cancer 69, 1342-1346.
Scagliotti G (2001) Symptoms, signs and staging of lung cancer.
Eur Respir Mon 17, 86-119.
Schaur RJ, Fellier H, Gleispach H, Fink E, Kronberger L (1979)
Tumor host relations I. Increased plasma cortisol in tumor-
bearing humans compared with patients with benign surgical
diseases. J Cancer Res Clin Oncol 93, 281-285.
Schwindt WD, Bernhardt LC, Johnson SAM (1970) Tylosis and
intrathoracic neoplasms. Chest 57, 590-591.
Sephton S, Spiegel D (2003) Circadian disruption in cancer: A
neuroendocrine-immune pathway from stress to disease?
Brain Behav Immun 17, 321-328.
Seute T, Leffers P, ten Velde GPM, Twijnstra A (2004)
Neurologic disorders in 432 consecutive patients with small
cell lung carcinoma. Cancer 100, 801-806.
Seymour JF, Gagel RF, Hagemeister FB, Dimopoulos MA,
Cabanillas F (1994) Calcitriol production in hypercalcemic
and normocalcemic patients with non-Hodgkin lymphoma.
Ann Intern Med 121, 633-640.
Shepherd FA, Laskey J, Evans WK, Gross PE, Johansen E,
Khamsi F (1992) Cushing´s syndrome associated with
ectopic corticotropin production and small-cell lung cancer. J
Clin Oncol 10, 21-27.
Shneerson JM (1981) Digital clubbing and hypertrophic
osteoarthropathy. Br J Dis Chest 75, 113-131.
Sillevis Smitt PA, Manley GT, Posner JB (1995) Immunization
with the paraneoplastic encephalomyelitis antigen HuD does
not cause neurologic disease in mice. Neurology 45, 1873-
1878.
Spiegelman D, Maurer LH, Ware JH, Perry MC, Chahinian AP,
Comis R, Eaton W, Zimmer B, Green M (1989) Prognostic
factors in small-cell carcinoma of the lung: an analysis of
1,521 patients. J Clin Oncol 7, 344-354.
Spiro SG (1995) Bronchial tumours. In: Brewis RAL, Corrin B,
Geddes DM eds. Respiratory medicine WB Saunders,
London, UK.
Spiro SG, Gould MK, Colice GL (2007) Initial evaluation of the
patient with lung cancer: symptoms, signs, laboratory tests,
and paraneoplastic syndromes. ACCP evidence-based
clinical practice guidelines (2nd edition). Chest 132, 149S-
160S.
Stenseth JH, Clagett OT, Woolner LB (1967) Hypertrophic
pulmonary osteoarthropathy. Dis Chest 52, 62-68.
Stewart MF, Crosby SR, Gibson S, Twentyman PR, White A
(1989) Small cell lung cancer cell lines secrete
predominantly ACTH precursor peptides not ACTH. Br J
Cancer 60, 20-24.
Stewart PM, Gibson S, Crosby SR, Penn R, Holder R, Ferry D,
Thatcher N, Phillips P, London DR, White A (1994) ACTH
precursors characterize the ectopic ACTH syndrome. Clin
Endocrinol (Oxf) 40, 199-204.
Swarthout JT, D’Alonzo RC, Selvamurugan N, Partridge NC
(2002) Parathyroid hormone-dependent signaling pathways
regulating genes in bone cells. Gene 282, 1-17.
Heinemann et al: Paraneoplastic syndromes in lung cancer
698
Swash M, Schwartz MS (1990) Paraneoplastic syndromes.
Johnson, RT eds. Current therapy in neurologic disease. BC
Decker. Philadelphia, PA, pp 236-243.
Szabo A, Dalmau J, Manley G, Rosenfeld M, Wong E, Henson J,
Posner JB, Furneaux HM (1991) HuD, a paraneoplastic
encephalomyelitis antigen, contains RNA-binding domains
and is homologous to Elav and sex-lethal. Cell 67, 325-333.
Terzolo M, Reimondo G, Ali A, Bovio S, Daffara F, Paccotti P,
Angeli A (2001) Ectopic ACTH syndrome: molecular basis
and clinical heterogeneity. Ann Oncol 12, S83-S87.
Tesselaar ME, Osanto S (2007) Risk of venous
thromboembolism in lung cancer. Curr Opin Pulm Med 13,
362-367.
Thomas L, Kwok Y, Edelman MJ (2004) Management of
paraneoplastic syndromes in lung cancer. Curr Treat
Options Oncol 5, 51-62.
Thomson SP, Kessler JF, Miller TP (1986) Leukocyte
concentrations in discrimination of benign from malignant
lung lesions. Am J Med 80, 1035-1040.
Vernino S (2007) Autoimmune and paraneoplastic
channelopathies. Neurotherapautics 4, 305-314.
Vernino S, O`Neill BP, Marks RS, O`Fallon JR, Kimmel DW
(2004) Immunomodulatroy treatment trial for paraneoplastic
neurological disorders. Neuro Oncol 5, 55-62.
Verschuuren JJ, Wirtz PW, Titulaer MJ, Willems LN, van
Gerven J (2006) Available treatment for the management of
Lambert-Eaton myasthenic syndrome. Expert Opin
Pharmacother 7, 1323-1336.
Vgontzas AN, Chrousos GP (2002) Sleep, the hypothalamic-
pituitary-adrenal axis, and cytokines: Multiple interactions
and disturbances in sleep disorders. Endocrinol Metab Clin
North Am 31, 15-36.
Vorherr H. Para-endocrine tumor activity with emphasis on
ectopic ADH secretion (1974) Oncology 29, 382-416.
White A, Stewart MF, Farrell WE, Crosby SR, Lavender PM,
Twentyman PR, Rees LH, Clark AJ (1989) Pro-
opiomelanocortin gene expression and peptide secretion in
human small-cell lung cancer cell lines. J Mol Endocrinol 3,
65-70.
Yates AJ, Boyce BF, Favarato G, Aufdemorte TB, Marcelli C,
Kester MB, Walker R, Langton BC, Bonewald LF, Mundy
GR (1992) Expression of human transforming growth factor
alpha by Chinese hamster ovarian tumors in nude mice
causes hypercalcemia and increased osteoclastic bone
resorption. J Bone Min Res 7, 847-853.
Yoh K, Kubota K, Nomura M, Niho S, Goto K, Ohmatsu H,
Kakinuma R, Nishiwaki Y (2003) Cushing´s syndrome
associated with adenocarcinoma of the lung. Intern Med 42,
831-833.
Yoshimoto K, Yamasaki R, Sakai H, Tezuka U, Takahashi M,
Iizuka M, Sekiya T, Saito S (1989) Ectopic production of
parathyroid hormone by small cell lung cancer in a patient
with hypercalcemia. J Clin Endocrinol Metabol 68, 976-
981.