Lung cancer is today the killer per excellence of smokers in the industrialized countries, in spite of the innumerable attempts over several decades to modify its prognosis. The current epidemiology of pulmonary carcinoma offers dramatically evident data. In Italy, 35,000 new cases in 1999, of which 1/3 were female smokers. The mortality rate due to pulmonary cancer doubled between 1960 and 1980 and had tripled by 1999 from 10% to 30% and has settled at a ratio of 95 cases per 100,000 individuals. More people die from lung cancer than from the three more common neoplasias considered added together: colo-rectal, breast and prostate. Moreover, contrary to these last tumor types, healing is not assured with surgical therapy in the initial, resectable forms. So, it is necessary to first individuate it before individual smokers predisposed to pulmonary cancer get ill (1) The other pulmonary illness of smokers is chronic obstructive pulmonary disease (COPD), very frequent, the first cause of working hours lost and the third cause of death (after cardiovascular diseases and tumors). It strikes 20% of the population over 60 years old and is on the rise, there being an estimated 7,000,000 affected individuals in Italy today. One cannot foresee which smoker will get sick and if it will turn out to be a pulmonary tumor or COPD. But one does know that both diseases have as common denominators genetic predisposition, tabagism, inflammation and chronic respiratory tract infection, plus environmental and professional exposure. The individual shows in any case a clear predisposition to become ill with some form of pneumopathy and in many cases a particularly accentuated reduction of mucociliary clearance may be underlined, or marked damage to pulmonary epithelial permeability with associated signs of lung cell–mediated immunodeficiency or even clear signs of malnutrition. Moreover, in a lot of cases bronchial hyper-reactivity is identifiable in individuals never exposed to the known inhalatory stresses or to other respiratory risk factors. Such aspects suggest a variegated personal situation with numerous pretexts to account for the onset of lung cancer in predisposed subjects, or of COPD in the other cases. Thus the need to better characterize those individuals at risk has spurred the research toward methods that can “sidetrack” the precancerous states or to discover specific biological markers for lung cancer (2). In Italy, cigarette smoke causes 90,000 lung cancer deaths annually (3). Current standing Among the known exogenous factors, cigarette smoke is the cause of tumors or COPD with a frequency 30 times greater in heavy smokers compared to other known causes. In fact, although most smokers will probably not develop a tumor, it is established that over 90% of pulmonary carcinomas are certainly attributable to cigarette smoke. It is also established that in most smokers, within 20 years there is an acceleration of pulmonary function decline that coincides with the functional picture in COPD. Among the thousands of components of the smoke, it emerges that the tar containing polycyclic aromatic hydrocarbons, N-nitrosamine and alkylating agents having certain cancerogenic action, as well as various oxides and superoxides or free radicals of oxygen (O2') OH, H2O2 products of combustion such as carbon monoxide, acrolein, nitrogen oxide and transition metals, are all capable of causing chronic bronchitis through the intrapulmonary recruitment of macrophages and neutrophil granulocytes with the consequent production of free radicals of oxygen such as hydrogen peroxide. Also documented have been anomalies of the mucociliary transport function, susceptibility to infections, increase of bronchial catarrh and loss of equilibrium in the protease-antiprotease system. Workplace exposure and air pollution are also being blamed. Such situations add something to cigarette smoke, e.g. asbestos, nickel, chrome, arsenic, isocyanates and ionizing radiation in some worker categories, while radon, sulphur dioxide and various types of particulate in smoke, vapors, aerosols, gas and dust forms are accused when environmental pollution is considered. Among the endogenous factors for pulmonary cancer and COPD, mucociliary system defects are cited, evident also in monozygote twins. In these subjects the residence time of toxic substances in the respiratory epithelium is prolonged. Nutritional defects too, especially lack of betacarotenes, retinol and vit. C are partly responsible for the beginning of the carcinogenesis process. Vit. A and the retinoids are so involved in cellular differentiation that a deficiency of these leads to squamous keratinizing metaplasia (4). Vit. C is a powerful antioxidant and both these vitamins are also capable of interfering with the bonding between benzopyrene and DNA, avoiding the harm that could then lead to cancer. The various types of cancerogen initially provoke DNA damage (adduction of the DNA and thence the breakup of the helix or else changes to bases such as 5-hydroxymethyltiouracile, glycol thiamin or 8-hydroxideoxyguanidine) and the altered tail thus determines the modification alterations of cellular growth or metabolism. The final way for DNA harm is modification of one or more cellular genes called oncogenes that can have a transforming action (activated genes or proto-oncogenes) or inhibit the neoplastic transformation (oncosuppressors) through the production of a protein located in the cytoplasm or nucleus or a receptor for growth factors. Therefore different molecular events and chromosomal mutations are brought about, with specific qualitative and quantitative anomalies (deletions, amplifications, translocations - very rare - punctiform mutations and rearrangement). The proto-oncogenes and oncosuppressor genes implicated in pulmonary cancerogenesis are numerous. Punctiform mutation of chromosomes 11, 12 and 1 produces oncogenes of the ras family (Ha, Ki, N) that have GTP binding proteins as a product in the cytoplasm inducing alterations in cellular growth and, particularly correlated with cigarette smoke, is found in about a quarter of pulmonary adenocarcinomas and generally in NSCLC. While heterogeneous deletion (loss of a segment of chromosome or gene) and rearrangement of chromosomes 3p 14 and 23 in correspondence with its 3p (short arm) gene produces an Erb AB receptor, a rethinoic acid receptor and PTP. Chromosome 13q (long arm) in its Rb gene whose function is still not known has the nucleus as the site of action. It has a phosphoprotein with nuclear action as a product and regulates cellular cycle and protection. Chromosome 17p (short arm) in its p53 gene produces a phosphoprotein having nuclear action and controls the cellular cycle, is frequently found in small cell pulmonary carcinoma. Deletion of the short arm of chromosome 3 represents a recessive mutation and cigarette smoke induces its expression. It has also been discovered that the gene responsible for Rb retinoblastoma situated on the q14 band of chromosome 13 also presents with homozygous deletions in small-cell carcinoma. The p53 gene located on chromosome 17p acts instead as an anti-oncogenic regulator of the cellular cycle and repressor of pulmonary carcinoma. When its antibody inactivation is brought about, the lung cancer is able to develop. The genetic alterations also involve some enzymes. It is seen that the DNA alterations caused by cigarette smoke and generally by polycyclic aromatic hydrocarbons are due to the enhanced action of the genetically inducible membrane enzymes aril-hydrocarbon-hydroxylase, 4-debridokine-hydroxylase and to the mono-oxygenases dependent upon alterations on the polymorphic sites of the P450c gene sequence that transforms them into mutagenic (cancerogenic) substances such as benzo(a)pyrene. In the healthy lungs of smokers there are elevated levels of produced DNA-carcinogens, these levels being higher in female smokers and in subjects having a deficiency of isoform 1 of the enzyme glutathione S-transferase. c-erbB-2 is a proto-oncogene responsible for the production of a protein similar to Epidermal Growth factor. It has tyrosine-kinase activity and presents with an elevated expression in pulmonary adenocarcinoma in women, and is activated by estradiol. Anomalies in the number of chromosomes as contained by DNA (ploidy) is present in 85% of highly malign pulmonary carcinomas. Aneuploidy on the other hand characterizes patients with pulmonary carcinoma that have lower survival time than those with euploidy. Genic amplification consists in the production of additional copies of a gene sequence and concerns the myc family of proto-oncogenes (c-N-L) belonging to the chromosomes 8q-24, 2p-23-24 and Ip32 present in 20% of the SCLC pulmonary carcinomas, and seems to be associated with the ability to metastasize, producing a phosphoprotein with nuclear action that regulates the cellular cycle. Other endogenous factors include greater frequency in males in the age band 45 to 65 years. This is a characteristic that is losing importance since the statistical distance from the opposite sex is closing in because of known socio-environmental considerations. On the contrary, the role of the immune system, the cell-mediated kind entrusted to lymphocytes and macrophages, is taking on ever greater significance, especially in the onset phase of lung cancer, while in the advanced phases it is the humoral immune system that intervenes with the formation of immune complexes having a blocking action on the phagocytosis with a different enhancement effect for the various histological types. Epidermoidal carcinoma is able to provoke a greater immune response to neoplastic antigens than other tumor types especially in comparison with adenocarcinoma. Research aims But then, what difference is there (if one exists) between the smokers that are destined for cancer and those that will instead be affected by COPD? Here is what the current research emphasis is, and which offers very interesting results. We ask ourselves: how come a strong healthy smoker can be allowed an apparently normal life? Carrying on an active life both intellectually and physically almost regardless of the known damage from smoke? The answer is simple: their respiratory system reveals the pulmonary damage of the smoke only late on, and so their respiratory function stays normal for many years. In such conditions this type of smoker feels well and finds no reason to stop smoking and does not present with the symptoms of COPD, such as cough, bronchial catarrh and recurring respiratory infections. They tend to expose themselves to smoke without any control, thereby receiving all the possible damage, due also to the excellent bronchial permeability. We now ask if it is precisely this kind of smoker that is predisposed to lung cancer. Indeed, should this be so, it would be possible to make an early diagnosis of lung cancer by having such smokers undergo focused periodic clinical check-ups. Survey and results To verify the clinical and epidemiological usefulness of this hypothesis, we checked 552 consecutive patients hospitalized in the last 5 years at the Divisione di Pneumologia e Terapia Intensiva Respiratoria in Perugia for both COPD and lung cancer, the two diseases primarily caused by cigarette smoke. The patients were comparable as regards the amount smoked (packets/year), age and sex; of these, 311 were affected by lung cancer but turned out to be very different regarding respiratory function in comparison with the smokers having COPD. In fact, the patients with bronchogenic carcinoma did not present with perceptible air flow obstruction. The spirometric data for the lung cancer smoker patients was compared with that of a group of smoker patients with COPD in a stability phase of the disorder, yet perfectly balanced concerning all the demographic data. The differences were analyzed for statistical significance by the Student t test for non-coupled data (see Tab. 1). The analysis of the data reported in Table 1 confirms without a shadow of doubt the hypothesis that cigarette smokers, on the same terms for packets/year smoked and every other clinical characteristic, can become ill with lung cancer when there are still no signs of the COPD that is instead the more common illness for smokers. Discussion 4% of the hospital admissions in pneumology were identified with the DRGs: 162.9, 162.3, 162.0, 197.0, 197.3, V.58.1 (lung cancer). The case history and picture of this type of disorder is always the same: man or woman, of middle age, heavy smokers (20-60 cigarettes a day for at least 20 years), born into smoker families with a certain acquaintance with lung cancer. These smokers are devoid of any major respiratory problem until the day when a sudden telling symptom leads them to the physician. But in most cases it is already too late: the tumor has silently superceded the danger level, is already inoperable and any other therapy would do no other than prolong life expectancy by a few weeks. The disclosing symptom could be hemoptysis or a pneumonia that is slow to heal. Sometimes the smoker goes to the doctor on account of dyspnea accompanied by chest pain or long-standing persistent cough that had been assumed to be a “normal” smokers’ cough. Moreover, in cases where this type of smoker undergoes spirometric examination this would turn out to be normal or only suggestive of a disorder of the small respiratory airways, considered typical in smokers but without important air flow limitations in the major bronchial tracts. In all cases the anamnesis will reveal that the patient never underwent a check-up (essential in anyone smoking for years), precisely because he/she had felt no reason to go to the doctor since there was no respiratory upset. In such apparently normal subjects there is no flow obstruction and the lack of coughing or other respiratory symptoms induces the subject to inhale the smoke deeply and consume the cigarette. This brings about a prolongation of the respiratory tree’s exposure time to the inhaled cancerogens especially if there coexists a diminished mucociliary clearance (often associated with the simple chronic bronchitis picture). This is a particular form of chronic bronchitis that is not associated with broncho-obstruction documentable with spirometry and flow volume curves (6). In cases where there were symptoms, these were considered “normal” in a smoker. Moreover, no-one would have suggested to the smoker the importance of early diagnosis in lung cancer as the only possibility for being able to hope in a complete recovery through the surgical removal of the tumor caught at an initial stage. In fact, carrying out a pneumological control consisting in a pneumology consultation, spirometry and chest X-ray would have been sufficient to discover the tumor in the initial phase and thus still curable. On the other hand, the smokers who become affected by COPD present with a great abundance of symptoms, starting with a cough with abundant sputum and recurrent respiratory infections in such quantity that they turn up at their physicians’ consulting rooms at least three times a year for years. Paradoxically, this protects them from lung cancer in that an early diagnosis is likely in the non-frequent cases where the two disorders coexist. An important new aspect emerges from these observations: it is possible to portray the type of smoker predisposed to lung cancer, useful for proceeding to the necessary early diagnosis measures. Indeed, dealing with a heavy smoker with no significant respiratory symptoms and preserving excellent respiratory function (normal or nearly normal spirometry): such a person should undergo periodic pneumological examination, being at risk for lung cancer (in our view). Early diagnosis of metaplasia or bronchial cancer may be obtained by performing a careful pneumological consultation periodically (at least every 6 months) at an accredited pneumology center: spirometry, bronchoscopy complete with cytohistological and autofluorescence tests, and chest X-rays. Early-phase lung cancer may be diagnosed by traditional fibrobronchoscopy in 30% of cases only, since it is often invisible to white light. The bronchoscopy technique with the Pentax SAFE-1000 system increases the sensitivity of lung cancer research by a factor of at least 4. This clearly improves the chances that the patient would receive an appropriate therapy in an early stage. Such behavior will also be useful for convincing the inveterate smoker to stop smoking, in time, or in the case of the cancer’s early individuation, to be able to accede to radical therapy with excellent chances for a complete recovery.

(traduzione Dr. Aldo Magliocco- Milano)

Tommaso Todisco

Primario UOA di Pneumologia e Terapia Intensiva Respiratoria Azienda Ospedaliera di Perugia Ospedale Silvestrini