Medical Oncology (1999) 16, 129-133 �9 1999 Stockton Press All rights reserved 0736-4)118/99 $12.00

ORIGINAL PAPER

http://www.stockton-press.co.uk/mo

Paraneoplastic syndromes in 68 cases of resectable non-small cell lung carcinoma: can they help in early detection?

N Campanella 1, A Moraca 1, M Pergolini a, W Daher 1, A Fianchini 2, A Sabbatini 2, A Brunelli 2 and M A1-Refai 2

1Medical Pathology Institute, 'Umberto I- Torrette' Regional Hospital; 2Department of Thoracic Surgery, University of Ancona and 'Umberto I-Torrette' Regional Hospital, Ancona, Italy

The aim of this study was to assess the importance of paraneoplastic syndromes as an early sign of non-small cell lung cancer (NSCLC). A procedure for searching paraneoplastic syndromes, based on 40 years of reports in the literature, was established and the prevalence of paraneoplastic syndromes estimated in 68 patients with resectable NSCLC. Stages I and II were considered eligible for surgery straight away. Patients in Stage Ilia underwent surgery if partially or completely responsive to three courses of neo-adjuvant chemotherapy. Paraneo- plastic syndromes were assessed and confirmed in nine patients (13%). Motor-sensory neuropathy, arthritis and arthralgias to the knees, periarthritis to the shoulder, hypertrophic osteopathy, clubbing, pruritus were observed. Only three patients with painful osteoar- thropathies were diagnosed with NSCLC by tracing their paraneoplastic syndrome, whereas most of them (36/68) were diagnosed incidentally through a chest radiograph taken for tumour-unrelated symptoms. A careful research of paraneoplastic syndromes in high risk patients may guide the doctor to a resectable NSCLC diagnosis. Recent onset arthritis and arthralgias, which cannot be explained otherwise, should be considered to be early clues of lung cancer.

Keywords: paraneoplastic syndromes; lung; cancer; bronchogenic; prevalence; non-smaU cell lung carcinoma; early diagnosis

Introduction A paraneoplastic syndrome (PS) is a complex of clinical signs and symptoms brought about by a primary tumour or its metastasis as indirect or 'remote' effects. The following criteria should be fulfilled:

1) it occurs early during the natural process or even precedes the clinical evidence of the malignant disease;

Correspondence: Nando Campanella, via Maratta 37, 60123 Ancona, Italy. Tel: 39 338 3535744; Fax: 39 71 36772 Received 6 October 1998; accepted 11 February 1999

2) it is not caused by the neoplastic mass invasion or compression;

3) it subsides after the removal of the tumour. 1

Non-small cell lung cancer (NSCLC) is detected in a resectable stage only in less than 45% of the cases. As a matter of fact, early diagnosis increases the chances of a curative intent resection and improves the long-term survival. 2 In this respect PSs can be considered to be some of the early markers of lung cancer. Although they are more frequent in small cell lung cancer (SCLC), they do occur in NSCLC as well. Their prevalence in NSCLC is unknown.

Paraneoplastic syndromes and lung cancer N Campanella et al

130

This study was carried out in order to estimate the prevalence of PSs in resectable NSCLC and to assess whether they may be useful as early signs.

Materials and methods Sixty-eight consecutive NSCLC patients, admitted into the Department of Thoracic Surgery of the University of Ancona, were studied.

The pre-operative stage was assessed through fibre optic bronchoscopy, transbronchial or transthoracic biopsy, CT total body scan, and bone radionuclide scan. Mediastinoscopy or anterior mediastinotomy was per- formed in the case of suspected N2 + . The pre-operative stages from I to IIIA, according to the International System for Lung Cancer Staging formulated in 1986, 3 with a performance status of over 70% according to Karnofski's scale, 4 were considered to be eligible for surgery. Stages I and II were proposed for surgery immediately, whereas stage I l iA underwent three courses of neo-adjuvant chemotherapy. Had any sat- isfactory response occurred, the patients were again put forward for surgery. 5'6 Operability was assessed through spirometry, electrocardiography and echocardiography. One patient was not operated on, due to his impaired ventilatory functions, because he could not have with- stood the extent of the proposed lung resection.

The operations on the patients may range from explorative thoracotomy to pneumonectomy surgery, which may include extended resections (extrapleural pneumonectomy, chest wall resections).

WHO histologic typing was followed in principle, but bronchioloalveolar variant was distinguished from adenocarcinoma. 7

In all the patients clinical history focused on the circumstances leading to the diagnosis of lung cancer. Three main groups were established:

1) mass-related symptoms and signs (cough, hemoptysis, pneumonitis, wheeze, dyspnea, chest pain);

2) PSs;

3) accidental detection through a routine chest radiograph.

All patients, before being operated, were checked for the existence of PSs, reports of which were retrieved through an extensive search of the cumulative English literature in the Medline database. The PSs groups and the proper tests for excluding or confirming them are displayed in Table 1. s'9"t~

As a first step exclusion criteria were checked for any PS. All the tests, shown in Table 1, column 2, were routinely performed. If a PS could not be excluded,

Table 1 Paraneoplastic syndromes and criteria to assess/exclude

Syndromes Exclusion Confirmation

Neuromuscolar and ocular A, PE, FOO, CPK

Cutaneous

Endocrine-metabolic

Vascular

Osteo-articular

Haematologic

Miscellanea

A, PE

A, PE, P-potassium, P-glucose, Glycosuria, P-sodium, P-calcium, P-inorganic phosphorus, PTH, P-calcitonin

A, PE, FSP, PT, PTF, platelets-C, ECG, P-potassium, cardiac ultrasound scan

A, PE

P-haemoglobin, white blood cell-C, blood smear examination

A, PE, serum creatinine, proteinuria, P-IgA, eosinophils-C

EEG, RM, VF, EMG, CPK, MB, Anticholinesterase test

CB, MB

Refs 8, 9, 10, FSH and LH, Beta-HCG, pelvis ultrasound scan, T3, T4

Doppler ultrasound scan, venography, Doppler scan and cold test, biopsy, P-renin activity, urinary-potassium Aldosterone excretion, bicycle ergometer test, cardiac thallium 201 scintigraphy

X-ray scan, erythrocite sedimentation rate, ARA criteria

Reticolocytes-C, erithropoietin, BMB

RB, xylose absorption, stool fat and muscle fibre test, small intestine X-ray, SIB, Jejunal biopsy

Abbreviations: A=anamnesis; ARA=American Rhematism Association; BMB=bone marrow biopsy; C=count; CPK=creatine phosphokinase; CB=cutaneous biopsy; EEG=electroencephalography; EMG=electromyography; FOO=fundus oculi examination; FSP=fibrin split products; MB=muscular biopsy; P=plasma; PE=physical examination; PT=prothrombin time; PTH=parathormon; PTT=partial thromboplastin time; RB=renal biopsy; RM=magnetic resonance; SIB=small intestine biopsy; VF=visual field.

Paraneoplastic syndromes and lung cancer N Campanella et al

131

specific confirmation procedures were carried out. Whenever symptoms or clinical signs consistent with a paraneoplastic syndrome were assessed, a further confirmation was requested according to the following criteria:

a) within two years of the onset;

b) no relationship with chemotherapy or underlying chronic diseases;

c) no presumed family origin.

Confirmed PSs were followed up for at least three months from the resection.

Results Sixty-eight NSCLC patients (63 males and 5 females, mean age +/-SD: 66 +/-8, extremes 37-79) were stud- ied in a period of 18 months. The circumstances leading to the diagnosis of lung cancer were: 29 mass related symptoms and clinical signs, 3 PSs, 36 accidental detec- tion through routine chest radiographs.

One patient with squamous carcinoma could not undergo surgery due to his poor respiratory condition. In the 67 patients operated on the hystotype was: 27 squamous, 33 adeno, two adenosquamous, two bron- chioloalveolar, three large cell anaplastic carcinoma. 9/68 (13%) were highly probable PS bearing patients. Seven more suspected cases could not be confirmed by more accurate investigation: three inferior limb hypos-

tenia (consequences of polimyelitis, spondylosis, dia- betic neuropathy), three clubbings (chronic respiratory failure under obstructive pulmonary disease), one Raynaud phenomenon.

Table 2 gives the main features of the ascertained PSs. Although in the entire series the squamous/ adenocarcinomas ratio was 0.8, in the PSs the ratio was 2. No difference was noted in terms of stage distribution.

Lung cancer was diagnosed in three patients (nos 2, 3 and 5) by tracing a paraneoplastic syndrome. In patients 1, 2 and 3, symptoms and clinical signs disappeared within three months of surgery. In patient 1 remission was confirmed by electromiography. Patients 4, 5 and 9 also became asymptomatic. How- ever, X-rays showed signs that scapulomeral periar- thritis and hypertrophic osteopathy were still evident.

Discussion The early diagnosis of lung cancer is still a major problem. In high risk patients sputum cytology can help but unfortunately this test requires the patient's total collaboration and availability. It does not detect periph- eral cancers and has low sensitivity) 1 Thus, it is no longer extensively performed but only in high risk workers.

Biochemical markers have also been disappointing. Although specificity rate may be as high as 95%, the sensitivity rate is usually below 40%. 12 In recent

Table 2 Paraneoplastic syndromes

Sex and Age

Histotype Stage Surgery Paraneoplastic syndromes (PS)

lnitial symptoms or clinical signs leading to the diagnosis of cancer

Follow-up within three months

1. m/70 squamous I

2. f /48 adeno I

3. m/67 squamous IliA

4. m/68 adeno II

5. m/61 adeno I

6. m/65 squamous IIIA

7. rn/78 squamous I

8. m/69 squamous I

9. m/75 squamous IliA

lobectomy

lobectomy

pneumonectomy

lobectomy

Iobectomy+ wedge resection

not operated (poor respiratory volumes)

lobectomy

lobectomy

right bilobectomy

motor-sensory neuropathy

bilateral arthritis to the knees

arthralgias to the knees

periathritis to the shoulder controlateral to the cancer

hypertrophic osteopathy

cutaneous vasculitis

clubbing

clubbing

pruritus sine materia, clubbing

tumour-related pneumonitis

PS

PS

accidental diagnosis

PS

cough, dyspnea

subscapular pain

accidental diagnosis

accidental diagnosis

healthy, complete remission of PS

healthy, complete remission of PS

healthy, complete remission of PS

healthy, remission of symptoms of PS

healthy, remission of symptoms of PS

death from pneumonitis

healthy

healthy

healthy, remission of symptoms of PS

Paraneoplasfic syndromes and lung cancer N Campanella et al

132

decades in developed countries, the vast and affordable radiology facilities have meant that more chest radio- graphs are prescribed. Thus, the accidental diagnosis of lung cancer in Karnofski's scale 100 is frequent and resection with curative intent is successful.

In this study PS led to the diagnosis of lung cancer in three patients (4.4%). Even though it is merely speculative, we assume that the remaining six patients might have been diagnosed earlier by tracing their PSs. In spite of that assumption, the above mentioned procedure cannot be extensively carried out to screen for lung cancer in the population because of low sensitivity and high cost (the estimated cost of the exclusion test is approximately 350 US$ per patient).

Nevertheless, it must be said that all the PSs in our series, which prompted a diagnosis of lung cancer, were painful osteoarticular syndromes. According to Morgan and co-workers, 17% of patients with lung cancer had hypertrophic osteoarthropathyJ 3 Since the latter is a syndrome easy to detect by X-ray and often causes arthralgia and arthritis, recent onset arthralgia in high risk patients should be taken as a likely sign leading to the diagnosis of resectable lung cancer. Unfortunately hypertrophic osteoarthropathy is not specific for lung cancer.

Clubbing without painful arthritis is a clinical sign usually overlooked by both the patient and the physi- cian and it is even less significant than hypertrophic osteoarthropathy. Isolated clubbing was detected in six of our patients, but confirmed as paraneoplastic only in three (patients 7, 8 and 9). In the remaining three patients, lung cancer was superimposed on severe obstructive pulmonary disease of long duration, and the clinical criteria to include them as paraneoplastic cases was not fulfilled. Therefore clubbing was presumably caused by the severe obstructive pulmonary disease rather than by lung cancer.

In a series of 222 vasculitis, Sanchez Guerrero and co-workers considered 11 to be paraneoplastic. In seven cases they were associated with haematological malignancies and in four cases with solid tumours. None of them had lung cancer. 14 In the literature the majority of the reports of vasculitis combined with lung cancer (oat and squamous cell) deal with Schonlein- Henoch purpura, affecting both the skin and the visceral vessels. 15 Mitchell assumed that the neoplasia was only indirectly responsible for the vasculitis recur- rences by interfering with the immunological system) 6

To our knowledge this is the first comprehensive report about PS in a homogeneous series of resectable

lung NSCLC. Although our series of patients was small and highly selected, it is concluded that:

1) the prevalence of paraneoplastic syndromes in NSCLC, eligible for curative intent surgery, is 13%;

2) paraneoplastic syndromes led to lung cancer diagnosis in three patients (4.4%);

3) keen awareness of osteoarticular PSs is recom- mended to family doctors dealing with high risk lung cancer patients.

References 1 Shneider BS, Manalo A. Paraneoplastic syndromes. Unu-

sual manifestations of malignant disease. DM 1979; 2: 1-60.

2 Figlin RA, Holmes EC, Turrisi AT. Non small cell lung cancer. In: Haskell CM (ed). Cancer Treatment. Saunders: Philadelphia, 1995, pp385-413.

3 Mountain CE A new international staging system for lung cancer. Chest 1986; 89 (suppl): 225-233.

4 Karnofski DA. In evaluation of chemiotherapeutic agents. In: MacLeod CT (ed). Columbia University Press: New York, 1949, p 161.

5 Rusch VW et al. Surgical resection of stage IIIA and stage IIIB non-small-cell-lung cancer after concurrent induction chemoradiotherapy. J Thor Cardiovasc Surg 1993; 105(1): 97-104.

6 Martini N, Ginsberg RJ. Lung Cancer. Surgical Manage- ment. In: Pearson FG, Deslauriers J, Hiebert CA (eds). Thoracic Surgery. Churchill Livingstone: New York, Edin- burgh, London, Melbourne, Tokyo, 1995, pp. 690-705.

7 World Health Organization. Histologic typing of lung tumors. Neoplasma 1982; 29(1): 111-123.

80 r th ND, Kovacs WJ, DeBold CR. The adrenal cortex. In: Wilson JD, Foster DW (eds). Williams' Textbook of Endocrinology. Saunders: Philadelphia, London, Toronto, Montreal, Sydney, Tokyo, 1992, pp 489-619.

9 Reeves WB, Andreoli TE. The posterior pituitary and water metabolism. In: Wilson JD, Foster DW (eds). Williams' Textbook of Endocrinology. Saunders: Phil- adelphia, London, Toronto, Montreal, Sydney, Tokyo, 1992, pp 346-348.

10 Aurbach GD, Marx S J, Spiegel AM. Parathyroid hormone, calcitonin and the calciferols. In: Wilson JD, Foster DW (eds). Williams' Textbook of Endocrinology. Saunders: Philadelphia, London, Toronto, Montreal, Sydney, Tokyo, 1992, pp 1437-1440.

11 Johnston WW, Elson CE. Respiratory tract. In: Bibbo M (ed). Comprehensive Cytopathology. Saunders: Philadel- phia, 1997, pp 315--401.

12 Gail MH et al. Multiple markers for lung cancer diagnosis. Validation of models for localized lung cancer. J Natl Cancer Inst 1988; 80(2): 97-101.

13 Morgan B, Coaldey F, Finlay DB, Belton I. Hypertrophic osteoarthropathy in staging skeletal scintigraphy for lung cancer. Clin Radiol 1996; 51(10): 494-497.

Paraneoplastic syndromes and lung cancer N Campanella et al

14 Sanchez Guerrero J e t al. Vasculitis as a paraneoplastic syndrome. Report of eleven cases and review of the literature. J Rheumatol 1990; 17(11): 1458-1462.

15 Maurice TR. Carcinoma of the bronchus presenting with Henoch-Schonlein purpura. Br Med J 1978; 2: 831.

16 Mitchell DM, Hoffbrand BI. Relapse of Henoch-Schon- lein disease associated with lung carcinoma. J Roy Soc Med 1979; 72: 614-615.

133