paraneoplastic syndromes in lung cancer

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


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


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


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


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


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


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.

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