Autofluorescence Imaging Bronchovideoscopy and Lung Cancer

Table of contents

Introduction and aim of the work

Review of Literature

1 Epidemiology and Etiology of lung Cancer

2 Pre-invasive Bronchial Lesions & Development of Lung Cancer

3 Screening of Lung Cancer

4 Autoflurescence Bronchoscopy

5 Therapeutic Modalities for Early lung Cancer

Patients and Methods

Results

Case presentations

Discussion

Summary, conclusion and recommendations

References

List of abbreviations

Abbildung in dieser Leseprobe nicht enthalten

Introduction and aim of the work

Lung cancer is the most common cause of cancer-related mortality. Although surgical therapy remains the primary treatment for resectable disease, the composite 5-year survival is only 16%. Moreover, the majority of lung cancer cases are diagnosed in a late stage, when non-specific symptoms such as cough, dyspnea, and hemoptysis are present. Fewer than 15% of patients with invasive lung cancer survive 5 years after treatment. (American Cancer Society, 2007) Significant reduction in lung cancer-related morbidity and mortality will depend not only on aggressive efforts at smoking cessation, but also on earlier detection and treatment.

Centrally arising squamous cell carcinoma of the airway, especially in heavy smokers, is thought to develop through multiple stages from squamous metaplasia to dysplasia, followed by carcinoma in situ (CIS), progressing to invasive cancer (Thiberville et al , 1995 and Niklinski et al, 2001). It would be ideal to be able to detect and treat preinvasive bronchial lesions defined as dysplasia and CIS before progressing to invasive cancer (Lam et al, 1998).

Advances in early diagnostic and treatment options have the potential to manage lung carcinoma while still in an intraepithelial and/or microinvasive stage. White light bronchoscopy (WLB) is one of the most commonly used diagnostic tools for obtaining a definitive diagnosis of lung cancer. However, WLB is limited in its ability to detect small intraepithelial and microinvasive preinvasive lesions, which may be only a few cells thick and might only have a surface diameter of a few millimeters.

Autofluorescence bronchoscopy (AFB) was developed to address this limitation by WLB in detecting intraepithelial and microinvasive lung cancer lesions. AFB is now an established technique that has been shown to be a far more sensitive method of detecting these lesions than WLB. Moreover, AFB increases the diagnostic accuracy for squamous dysplasia, CIS, and early lung carcinoma when used simultaneously with conventional bronchoscopy (Shibuya et al, 2001 and Haussinger et al, 2005). However, the specificity of AFB for diagnosing preinvasive lesions is low (Haussinger et al, 2005). Distiguishing between preinvasive lesions and other benign epithelial changes such as bronchitis is problematic. To increase the specificity, a new autofluorescence imaging (AFI) bronchovideoscope system has been developed recently; where preinvasive lesions and benign changes may be differentiated by color (Chiyo et al, 2005).

Interestingly; the natural history of bronchogenic squamous carcinoma in situ (CIS), the probability of progression, and the time required for progression to invasive cancer are largely not known yet (Melamed, 2006). Previous reports had shown that approximately 46% of severe dysplasia, and 78% of CIS will progress to invasive cancer if left untreated. (Risse et al, 1988 and Venmans et al, 2000). On the contrary, it was reported that dysplasia can be reversed to normal by chemoprevention, or even just on cessation of offending agent as stopping smoking (Band et al, 1986).

Advances in therapeutic bronchology have shown that there are now five techniques available being used to ablate intraepithelial malignant and microinvasive endobronchial malignant lesions without surgical excision. These modalities include Nd-YAG laser therapy, photodynamic therapy (PDT), electrocautery, cryotherapy, and high-dose rate brachytherapy. These modalities may be particularly appropriate treatment options in patients with limited cardiopulmonary reserve. (Kennedy et al , 2007)

The current study was conducted at Chiba University Hospital, Chiba, Japan; from August 2005 to August 2007; according to the Joint Supervision Scheme between The Department of Chest Diseases, Assiut University, Egypt and The Department of Thoracic Surgery, Chiba University, Japan.

The major endpoint (aim of the work):-

is to evaluate the clinical usefulness of AFI bronchovideoscopy as a new modality for detection and localization of both preinvasive bronchial lesions and early hilar lung cancer.

Other endpoints

1- To try identifying the natural course of preinvasive bronchial lesions, allowing better understanding of the lung carcinogenesis.
2- To evaluate the utility of different endobronchial therapy modalities for management of early lung cancer.

Review of Literature

Chapter 1: Epidemiology and Etiology of lung Cancer

Lung cancer (LC) is the most common cancer in the world. It accounts for 15% and 12.6% of all new cases, and for 29% and 17.8% of cancer deaths, in the United States and world-wide, respectively. Lung cancer is more important in the developed than developing countries as it accounts for 22% versus 14.6% of cancer deaths, respectively. The estimated sex ratio (Male: Female) is 2.7. On the other hand, the 5-year survival rate for all stages combined is only 16%. The survival rate is 49% for cases detected when the disease is still localized. However, only 16% of lung cancers are diagnosed at this early stage (Parkin et al, 2004 and American Cancer Society 2007).

Almost all lung cancers are carcinomas. Small cell carcinomas (SCLC) comprise about 20% of cases and large cell/undifferentiated carcinomas about 9%. For other histological types, the proportions differ by sex; squamous cell carcinomas comprise 44% of lung cancers in men, and 25% in women, while adenocarcinomas comprise 28% cases in men and 42% in women (Parkin et al, 2004).

The situation of lung cancer in Egypt

Lung cancer, beside being a world-wide problem, the situation in Egypt is not better. In Egypt, it was the seventh most common tumor in 1991, representing 2.8% of all cancers presenting to National cancer institute in Cairo (El Bolkiny, 1991). Moreover, there is rapidly increasing rate in recent years and the dimensions of disease are approaching an epidemic proportion as stressed by Gad El Mawla et al, 1986, Madkour, 1991 , Nayel et al, 1995, and Salem et al, 1995 .

The mortality rate from bronchogenic carcinoma in Egypt has been reported to be increasing. There is more than three times increase in the period between 1952 and 1975 from 0.36 to 1.91/100,000 (Madkour, 1980).

In their review for the material available in Egyptian literature in period between 1974 and 1979, Madkour and Nabil, 1985 observed that more than 87% of cases were above the age of 40 years and the maximum age distribution is in the 5th decade. The disease was mainly in males; males to females ration 9:1. The authors added that, the incidence in females is rising recently with the practice of smoking among females.

In Egypt, cigarette smoking seems to be also the predominate risk factor. Interestingely, tobacco consumption was much higher than the national increase of population and the total tobacco consumption become doubled every 7-10 years; predicting a future lung cancer burden. There is also positive correlation between cigarette production and mortality rate from lung cancer (Madkour, 1980). Characteristically, cigarette production has increased very rapidly in the last 3 decades from 22 million cigarettes in 1975 to 33 millions cigarettes in 1981 (Massoud et al, 1982).

Lack of population-based cancer research, epidemiological surveys for evaluation of lung cancer prevalence with its various forms, scare studies on different aspects of disease, as well as delayed diagnosis seem to be adding factors to the gloomy pictures of lung cancer situation in Egypt. (Madkour, 1980, Gad El Mawla et al, 1986, Madkour et al, 1995).

In particular, the problem of delayed diagnosis was evident in the studies conducted by Soliman and Salem, 1972, and Abdalla and Ghoniem, 1978. Also, recently; in Update of Lung Cancer a one Decade (1980-1990), experience of Ain Shams University Hospital, demonstrated that most cases are presented in a late stage when the operation was not possible and that a delay of about one year is the usual for the patients and physicians factors. (Madkour et al, 1995)

Early detection of cancer offers greater hope for earlier intervention and possible cure. To study the prevalence rate of lung cancer in the Suez Canal region, a study was conducted by, Khaled, 1989 . A screening program for 11692 subjects 40 years old and above, was applied. These subjects were randomly selected from Suez, lsmailia and Port Said. All subjects were interviewed and completed questionnaires. Mass Miniature Radiography (MMR) was done and chest x-ray films were done when MMR abnormalities were detected. Those subjects showed x-ray findings consistent with lung cancer were investigated by sputum cytology and bronchoscopy. Twenty one patients with lung cancer were detected in this screening program, 15 (71.4%) were squamous cell carcinoma, 3 (14.3%) adenocarcinoma, (9.5%) large cell and one small cell carcinoma, 66.7% of cancer patients were smoker while 19% were ex-smoker. Sputum cytology was positive in 7 patients, and 19 patients showed positive bronchoscopic examination. The author reported that the prevalence rate of lung cancer among the residents of Suez Canal area who 40 years old and above ranged between 2.6-3.0 per 1000 people. He concluded from this study the following: (1) Smoking has a definite relationship with lung cancer. (2) For early detection of lung cancer, periodic screening of high risk population is mandatory. (3) Sputum cytology is a highly specific test for lung cancer but of limited sensitivity, and (4) Radiological examination is invaluable in early detection of lung cancer

On the other hand, recently, new technologies for screening of early lung cancer have been developed and seem to be promising tools for better detection, hence treatment for patients with lung cancer. (Farouk et al, 2002)

In the study conducted by Salama, 1987, the prevalence of bronchial carcinoma in Upper Egypt was investigated. The study pointed out the exponential increase in bronchial cancer in this area during the 1976-1980 period compared with 1981-1986 period. The author stressed upon the catastrophic problem of late presentation of patients with bronchial cancer in this locality and reported several factors responsible for delay in diagnosis of bronchial cancer in Upper Egypt. (Salama, 1987)

Even earlier studies showed that the incidence of bronchogenic carcinoma had increased in the last 3 decades. Analysis of the discharged patients from chest department of Cairo University Hospital (1966-1970) showed that most of patients were males of 50 years old and above. Sputum cytology was the only diagnostic tool in 16% and bronchoscopic examination in 28% of patients. It was also shown that the delay in diagnosis is responsible for the delay in the radical management of the disease in about two third of patients (Soliman, 1972).

Also Philip, 1984 conducted his study on lung cancer patients admitted from 1972-1982 at El-Abbassia Chest Hospital. The results revealed a highly significant rise in lung cancers incidence compared to the total admitted patients (0.2% in 1978 compared to 2.2% in 1982). The highest incidence was between 51-59 years old and 76% of patients were smokers (Philip, 1984).

On the other hand, based upon official statistics from both mortality and morbidity statistics and reasonable assumptions; Sherif et al, 1987 concluded that a figure between 50 and 60 thousands may be considered as amidst national estimate for the number of new cases occurring every year in Egypt, referring to a total population of 40 millions at that time. The incidence rate ranges between 235 and 270/100,000.

In a report to the First International Congress for Recent Advances in cancer chemotherapy for bronchogenic carcinoma in Egypt, Madkour, 1980 stressed the lack of epidemiological surveys for evaluation of the prevalence of lung cancer with its various forms and it has been shown that more cases of bronchogenic carcinoma are now seen. This increase of lung cancer in Egypt was attributed to the increase in tobacco consumption much higher than the national increase of population and total tobacco consumption become doubled every 7-10 years (Madkour, 1980).

Also, a prospective study on lung cancer patients presenting to the national cancer institute in Cairo in the year 1981 showed 114 patients. Males were predominating with ratio 12:1, most of the patients were heavy smokers (Gad El Mawla et al, 1986). A review of 120 cases with bronchogenic carcinoma admitted to the cardiothoracic surgery department in Cairo University Hospitals and EI-Mabara Hospital in Tanta was carried out at 1991. Out of this group, 75 patients were heavy cigarette smokers, more than 20 cigarettes/day for more than 10 years (62.5%) and 26 patients were Goza smokers (21.6%). Non smokers were only 19 cases (15.8%). The male to female ratio was 7.6: 1. (Gomaa et al, 1991 )

On evaluating bronchogenic carcinoma, Madkour et al, 1985, reviewed the available material in the Egyptian literature and analyzed their cases, the biggest in the Egyptian series in the period 1974-1979, they analyzed 390 cases of chest malignancy, 109 were pleural and 281 in the lung. In all the reviewed cases, more than 87% of cases were above the age of 40 years and maximum age distribution is in the 5th decade. The disease was mainly in males, the males/females ratio was 9:1. However, the incidence in females is rising recently with the practice of smoking among females.

In Update of Lung Cancer a one Decade (1980-1990), experience of Ain Shams University Hospital, reviewing of 1134 cases analyzing the cases, the operative procedures and adjuvant therapy, found that most of the cases are presented in a late stage when operation was not possible and that a delay of about one year is the usual for patients and physicians factors. (Madkour et al, 1995)

In a study to evaluate the different diagnostic procedures for bronchogenic carcinoma, Zeerban, 1983 investigated 30 patients with lung cancer diagnosed on radiological findings. He found that sputum cytology yielded a positive results in 57% after repetition for 3 times, bronchial biopsy yielded positive results in 52% while mediastinoscopy yielded 65%. He recommended that good percentage of sputum cytology could be obtained by examining at least 3 sputum samples, also he recommended to use all the possible utilities during bronchoscopy to obtain tissue diagnosis as forceps, brush, lavage and post-bronchoscopic sputum.

Recently (2006), a new bronchovideoscopic system (SAFE-3000, Pentax, Japan) has been introduced into the Bronchoscopy Division of The Chest Department, Assiut University Hospital. It is hoped that bronchoscopic evaluation of high-risk populations for lung cancer, using this system groups will contribute to earlier detection, hence better management outcomes of lung cancer cases at that locality of Upper Egypt.

Also recently; an interesting study (Gad, 2007) was conducted at the Chest Department, Assiut University Hospital; to evaluate the role of Argon Plasma Coagulation (APC) and cryotherapy as two promising interventional bronchoscopic modalities.

Thirty-two patients with symptoms related to airway obstruction (dyspnea, cough, haemoptysis and chest pain) received either APC (20 patients) or cryotherapy (12 patients). Results of this study proved that APC and cryotherapy are useful as palliative tools during the course of advanced lung cancer management and should be considered when respiratory physicians are facing life-threatening problems related to the endobronchial obstruction. (Gad, 2007)

Cigarette smoking and other risk factors for lung cancer

Not all LC is smoking related, however. Two to ten percent of lung cancer cases occur in never smokers, with women more commonly inflicted than men (Subramanian and Govindan, 2007). Additional risk factors for lung cancer include exposure to asbestos, haloethers, polycyclic aromatic hydrocarbons, nickel, and arsenic. Interest has also focused on the potential roles of exposure to environmental tobacco smoke (ie, passive exposure to "second-hand" smoke) and to radon. Other potential risk factors include dietary factors, genetic factors, and the presence of underlying benign forms of parenchymal lung disease, especially pulmonary fibrosis.

I- Smoking

Global cigarette consumption continues to rise, and smoking is estimated to be responsible for approximately 87% of cases of LC, including 90% of cases in men and 79% of cases in women. Bronchogenic carcinoma is undoubtedly the most preventable of the common forms of cancer because of the indisputable link between cigarette smoking and risk of LC. (Wingo et al, 1999).

* Cigarettes

The earliest epidemiologic association between cigarette smoking and LC mortality was reported by Doll and Hill, in 1950 (Doll and Hill, 1950). Until recently, the evidence linking cigarette smoking to LC has been primarily indirect. However, a direct link between tobacco and LC was established, based upon the finding that a specific metabolite of benzo(a)pyrene, a chemical constituent of tobacco smoke, damages three specific loci on the p53 tumor-suppressor gene that are known to be abnormal in approximately 60 percent of cases of primary LC. Related polycyclic aromatic hydrocarbons found in smoke appear capable of targeting other LC mutational hotspots (Smith et al, 2000).

Relative risk (RR) :-

The risk among smokers relative to the risk among never-smokers is in the order of 8-15 in men and 3-10 in women. For those who smoke without quitting, relative risk estimates are as high as 20 to 30. The overall RR reflects the contribution of the different aspects of tobacco smoking: average consumption, duration of smoking, time since quitting, age at start, type of tobacco product and inhalation pattern (Samet, 1991 and Harris et al, 2004).

Impact of sex and ethnicity

Whilst earlier studies have suggested a difference in risk of LC between men and women who have smoked a comparable amount of tobacco, more recent evidence does not support this notion: the carcinogenic effect of smoking on the lung appears to be similar in men and women. The higher rate of LC among Blacks in the USA as compared to other ethnic groups is likely explained by higher tobacco consumption. Indeed, there is no clear evidence of ethnic differences in susceptibility to lung carcinogenesis from tobacco (Parkin et al, 2004).

Dose and duration

Several studies have provided information on the relative contribution of duration and amount of cigarette smoking in excess LC risk. Duration of smoking is the strongest determinant of risk, but this also increases in proportion to the number of cigarettes smoked. The strong role of duration of smoking explains the observation that early age of starting is associated with a morbid LC risk later in life (Parkin et al, 2004).

Type of cigarettes and inhalation

Some reports show a lower LC risk among smokers of low-tar and low-nicotine cigarettes than among other smokers, but recent evidence suggests that low-tar cigarettes are not less harmful, and may be worse. A similar effect has been observed among long-term smokers of filtered cigarettes, compared to smokers of unfiltered cigarettes. A 1.5- to 3-fold difference in relative risk of LC has been observed in several studies between smokers who deeply inhale cigarette smoke and smokers of comparable amounts who do not inhale or inhale slightly ( Harris et al, 2004).

Type of tobacco products

Although cigarettes are the main tobacco product smoked in western countries, a dose-response relationship with LC risk has been shown also for cigars, cigarillos and pipe, with a similar carcinogenic effect of these products. A stronger carcinogenic effect of cigarettes than of cigars and pipe might arise due to different inhalation patterns or composition of cigars.

Lung cancer type

Tobacco smoking increases the risk of all major histological types of LC, but appears to be strongest for squamous cell carcinoma, followed by small cell carcinoma and adenocarcinoma. The association between adenocarcinoma and smoking has become stronger over time, and adenocarcinoma has become the most common type in many Western countries (Parkin et al, 2004).

Involuntary smoking

The magnitude of exposure to environmental tobacco smoke (ie, passive or "second-hand" exposure) is far less than the exposure that occurs with active smoking. On the other hand, exposure to environmental tobacco smoke usually begins much earlier in life than it does with active smoking, and the duration of exposure to carcinogens occurs over a longer period of time. Epidemiologic studies have shown that non-smokers exposed to high levels of environmental tobacco smoke demonstrate an increased risk of LC compared to individuals with lower cumulative exposures. There is also a dose-response relationship between intensity of exposure and relative risk (Fontham et al, 1994).

Smoking cessation

An important aspect of tobacco-related lung carcinogenesis is the effect of cessation of smoking. Smoking cessation clearly decreases the risk of lung cancer among former smokers compared with current smokers (Samet, 1991). The excess risk sharply decreases in ex-smokers after approximately 5 years since quitting, and the risk after 20 or more years since cessation approaches that of never-smokers. However, and excess risk throughout life likely persists even in long-term quitters (Peto et al, 2000). Thus, smoking cessation is beneficial at all ages.

II Occupational and Environmental Carcinogens

Numerous occupational and environmental carcinogens increase the risk of LC. The best known factors are asbestos and radon; other exposures include arsenic, bis-chloromethyl ether, chromium, formaldehyde, ionizing radiation, nickel, polycyclic aromatic hydrocarbons, hard metal dust, and vinyl chloride. Many of these factors act synergistically with tobacco smoke to produce LC, are also independent risk factors in non-smokers.

* Asbestos

Asbestos exposure is a risk factor for LC to which there can be occupational or non-occupational exposure.

Occupational; Many studies have demonstrated a causal relationship between occupational asbestos exposure and bronchogenic carcinoma. The risk of LC associated with asbestos exposure is dose-dependent but varies according to the type of asbestos fiber. In particular, for a given level of exposure, the risk appears to be considerably higher for workers exposed to amphibole fibers than for those exposed to chrysotile fibers. Also, the increased risk of LC associated with asbestos is greatly magnified by coexisting exposure to tobacco smoke. (van Loon et al, 1997)

Non-occupational;

The degree to which low level, non-occupational asbestos exposure increases the risk of lung cancer is less well defined. However, the potential risk is of great public health concern because of the large number of individuals who work or attend school in buildings that contain asbestos, and the cost and potential hazards of asbestos removal.

* Radon

Radon is a gaseous decay product of uranium-238 and radium-226, which is capable of damaging respiratory epithelium via the emission of alpha particles. Underground uranium miners who were occupationally exposed to radon and its decay products have an increased risk of LC, and there is an interactive effect between radon exposure and cigarette smoking. Radon is present in soil, rock, and ground water, and it can accumulate in homes. In a meta-analysis, a linear relationship between the amount of radon detected in the home and the risk of developing LC, and radon exposure could be responsible for up to 2% of LC deaths (Darby et al, 2005).

III- Familial Risk

The role of hereditary factors is less well understood for LC than it is for many other human cancers. However, it was suggested that first-degree relatives have an increased risk of developing LC. A meta-analysis revealed that an increased LC risk was associated with having an affected relative. Moreover, the risk was greatest in relatives of patients diagnosed with LC at a young age and in those with multiple affected family members.

Although the molecular basis underlying any familial increase in risk is not well characterized, certain population subsets have a higher risk from certain environmental carcinogens, based upon both genetic and acquired susceptibility factors. However, because no single genetic factor is sufficiently predictive, it is not yet possible to assess a given individual's risk on a molecular level (Perera, 1996).

IV- Inflammation

Chronic inflammation is associated with LC. A retrospective cohort study of 10,474 patients with chronic obstructive pulmonary disease (COPD) found that the risk of LC was decreased among patients taking inhaled corticosteroids (ICS) at a dose 1200 mcg/day, compared to those not taking ICS or taking lower doses (Parimon et al, 2007).

V- Dietary Factors

Antioxidants

An extensive body of literature suggests that low serum concentrations of certain antioxidant compounds, especially derivatives of vitamins A and E, are associated with the development of LC. Epidemiologic surveys suggested that high levels of beta-carotene in the diet or in the blood were associated with a lower risk of cancer in general and LC in particular. In addition, an increased consumption of fruit, green and yellow vegetables, may be associated with a substantially lower risk of LC, both among cigarette smokers and non-smokers. However, large chemoprevention trials using supplementation with retinoids, beta-carotene, and/or alpha tocopherol have not reduced the incidence of LC (The Alpha-Tocopheral, B.-C.C.P.S.G., 1994)

Cruciferous vegetables

Cruciferous vegetables are rich in isothiocyanates which have preventative properties against LC in animals. Human observational studies suggest that vegetable consumption has a protective effect against lung cancer, with the best evidence for green cruciferous vegetables (eg, broccoli, cabbage).

VI- Benign Lung Disease

The coexistence of a number of benign lung diseases increases the risk of LC. Individuals with diffuse pulmonary fibrosis have an 8- to 14-fold increased risk for LC, even when age, gender, and smoking history are taken into consideration. Patients with prior asbestos exposure complicated by interstitial fibrosis (ie, asbestosis) are much more likely to develop LC than patients with asbestos exposure alone. COPD has been associated with a 2- to 4-fold increased frequency of primary LC (Turner et al, 2007).

VII- Oncogenic Viruses

A viral etiology for one variety of LC, bronchioloalveolar carcinoma (BAC), has been proposed in sheep, however, this has not been definitively linked to BAC in humans. Subsequently, a potential causal role for human papillomavirus (HPV) in squamous cell carcinoma of the lung has been hypothesized because of the presence of HPV DNA within SCCs of the cervix, anorectum, skin, esophagus, and upper airways. However, one study that tested 34 formalin-fixed specimens of SCC of the lung with the polymerase chain reaction detected HPV DNA in only two cases (Bohlmeyer et al, 1998).

Chapter 2: Pre-invasive Bronchial Lesions & Development of Lung Cancer

1-Historical View

In 1935, Lindberg observed that squamous metaplasia is a frequent finding in the bronchi of patients with lung cancer (Lindberg, 1935). Subsequent histologic studies supported this observation and squamous metaplasia was considered to be an important step in the genesis of bronchogenic squamous carcinoma.

Auerbach et al, 1961, systematically mapped epithelial changes in the bronchial tree of cigarette smokers at autopsy, and found varying degrees of cytologic abnormality in patchy areas of the bronchial epithelium. However, even in the most severely affected bronchi, large areas of normal or nearly normal respiratory epithelium were present. The epithelial abnormalities were most frequent and most severe in patients who had invasive squamous carcinoma.

It was generally assumed that the initial carcinogenic event was squamous metaplasia that progressed to atypical metaplsia. In the most severe of these epithelial changes, the entire thickness of the epithelium was occupied by abnormal cells resembling those of invasive carcinoma, and this lesion was termed carcinoma in situ (CIS).

Saccomanno et al, 1974 described their experience with long-term cytologic studies of a large population of uranium miners in comparison with cigarette smokers and non-smokers. They proposed a sequence of epithelial events in the development of bronchogenic epidermoid carcinoma (summarized in Fig. 1)

2- Terminology and Definitions

It is important to define some important terms that will be mentioned later as this will have its implications on the deeper understanding of the subject.

Metaplasia:

It is defined as complete transformation of one cell type, e.g. a cylindrical mucosa cell, into another cell type, e.g. a squamous cell type.

Metaplasia is most commonly seen in the lung, the endocervix and the pleura. Cytological metaplasia often coincides with some cellular dedifferentiation, e.g. some slight irregularity in nuclear, nucleolar or cytoplasmic shape or size, a somewhat enhanced Nuclear/Cytoplasmic Ratio (NCR).

Atypia:

Some loss of the typical features of a cell. Often atypia is accompanied by either metaplasia or some dyskaryosis

Dyskaryosis:

Some dedifferentiation of a cell and nucleus so that certain features of malignancy are suggested. lt can be induced by carcinogens, smoking, radiation therapy and/or cytostatic drugs.

Squamous dysplasia

It is defined as; a precursor lesion of squamous cell carcinoma arising in the bronchial epithelium. Synonyms include; squamous atypia, bronchial premalignancy, preinvasive squamous lesion, and early non-invasive cancer. Squamous dysplasia does not invade the stroma. The basement membrane remains intact and is variably thickened. There may be vascular budding into the epithelium, termed angiogenic squamous dysplasia. The latter lesion has also been previously reported as micropapillomatosis. (Franklin et al, 2004)

Carcinoma in-situ (CIS):

It is defined as malignant cellular changes in the full thickness of the mucosa but an intact basement membrane (Colby et al, 1998). CIS is usually squamous cell carcinoma. (Fig. 2)

Microinvasive carcinoma:

Is described as a few millimeters of basement membrane invasion but not involving the muscle or cartilage.

Early lung cancer:

It is defined as the limitation of the local infiltrating growth of tumor to the different layers of the bronchial wall, which means the tumor tissue must not exceed the outer tunica fibrocartilaginea and the adjacent lung tissue must not be infiltrated. Accordingly, an invasion of lymph vessels, pleura and lymph nodes must be excluded (Kennedy et al, 2007) (Fig. 3)

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Fig. 1 Sequence of epithelial events in the development of bronchogenic carcinoma

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Fig. 2 Carcinoma in situ. The bronchial mucosa is replaced with atypical squamous cells extending from the surface to the base of the epithelium. Note the severe nuclear polymorphism, hyperchromasia and enlarged nuclei (From Franklin et al, 2004)

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Fig. 3 Early Bronchial Cancer

3-Theories of lung carcinogenesis

There are two main theories

1) The Multi-step evolution theory

Most opinions for the development of squamous carcinoma of the lung agree that it begins with transformation of the columnar respiratory epithelium into benign squamous metaplasia, passing through various stages of metaplastic atypia, onto carcinoma in situ (Fig. 1 & 2), and then to frankly invasive carcinoma (Saccomanno et al, 1974).

2) The de novo evolution theory

The concept of squamous metaplasia as a precursor lesion of bronchogenic carcinoma was subsequently challenged by Melamed et al, 1977 . In their histologic study of the resected lobectomy specimens from patients with in situ, or invasive lung cancers, they found no transition from squamous metaplasia or basal hyperplasia to carcinoma. On the contrary, carcinomas seemed to arise de novo from transformed basal (reserve) cells of the bronchial epithelium. Furthermore, they observed that squamous metaplasia, which is a common finding in the absence of carcinoma, was seen predominantly in the mainstem and lobar bronchi, whereas the earliest in situ and focally invasive carcinomas were found to arise in more distal segmental and subsegmental bronchi. The authors concluded that neoplastic transformation of the bronchial epithelium induced by respired carcinogens (e.g. tobacco smoke) proceeds independently of squamous metaplasia and basal hyperplasia. The latter were believed to be a non-specific reaction to the irritating smoke. (Melamed et al, 1977).

4- Clinico-diagnostic Features of Preinvasive Squamous

Lesions

Squmous dysplasia and CIS are a continuum of recognizable histologic changes in the large airways. They can occur as single or multifocal lesions throughout the tracheobronchial tree. Dysplasia or CIS may exist as an isolated finding or as a bronchial surface lesion accompanying invasive carcinoma.

Clinical features :

Squamous dysplasia is nearly always asymptomatic but occurs in individuals with heavy tobacco exposure (more than 30 pack years of cigarette smoking) and with obstructive airway disease. Preinvasive squamous bronchial lesions are found more frequently in men than in women.

Relevant Diagnostic Procedures:

(1) Sputum cytology examination

Currently, the only non-invasive test that can detect preinvasive lesions is sputum cytology examination. Twenty percent of patients with greater than a 30 pack year history of cigarette smoking, airway obstruction with FEV1<70% of expected, have moderate dysplasia or worse by AFB. (Franklin et al, 2004)

Sputum atypia as an independent variable in predicting dysplasia at AFB has not yet been tested in a controlled trial evaluating high risk smokers with airway obstruction.

(2) White-light bronchoscopy

Approximately 40% of cases of CIS can be detected by WLB. About 75% of the detected CIS lesions appear as superficial or flat lesions; the remaining 25% have a nodular or polypoid appearance. Because nodular/polypoid lesions are elevated from the adjacent normal mucosa, lesions as small as 1-2 mm in diameter can be seen. Flat or superficially spreading lesions greater than 1-2 cm in surface diameter are generally visible as areas of focal thickening, increase in vascularity, or marked irregularity of the mucosa. (Lam et al, 1998)

Flat lesions 5-10 mm in diameter usually produce non-specific thickening, redness, fine roughening, loss of luster or a slight increase in granularity which are difficult to distinguish from inflammation or squamous metaplasia. Lesions <5mm are usually invisible on WLB. Bronchial dysplasia usually presents as non-specific mucosal swelling or thickening at a bronchial bifurcation. (Lam et al, 1998 and Franklin et al, 2004)

(3) Autofluorescence bronchoscopy

Preinvasive lesions that have subtle or no visible findings on WLB can be localized by autofluorescence imaging using a violet or blue light for illumination instead of white-light and special imaging sensors attached to a fiberoptic bronchoscope for detection of the abnormal autofluorescence.

Dysplastic and malignant tissues have a significant decrease in the green autofluorescence intensity relative to the red autofluorescence. These preinvasive lesions are identified by their brown or brownish-red autofluorescence. Lesions as small as 0.5 mm can be localized by this method. (Hirsch et al, 2001)

(4) Localization and macroscopy

Foci of CIS usually arise near bifurcations in the segmental bronchi, subsequently extending proximally into the adjacent lobar bronchus and distally into subsegmental branches. The lesions are less frequent in the trachea. Bronchoscopically and grossly there is often no macroscopical alteration. When gross abnormalities are present, focal or multi-focal plaque-like greyish lesions resembling leukoplakia, non-specific erythema and even nodular or polypoid lesions may be seen. (Franklin et al, 2004)

5- Cytological Criteria of Preneoplasia/Early Lung Cancer

Sputum cytological classification scheme for preneoplastic lesions have been published by Saccomanno et al, 1974 . This scheme consists of gradations of microscopic abnormality similsr to those observed in histological sections from lower airways of smokers. These cytological criteria include;

a) Regular metaplasia:

1- Cells are all of about same size.
2- Nuclei are of uniform size with normal Nuclear/Cytoplasm ratio (N/C ratio).
3- Nuclear material is fine and powdery with rare chromocenters which are
demonstrably smaller than nucleoli.
4- Cytoplasm is usually basophilic
5- Cells usually occur in sheets, but may be single.

b) Metaplasia, mild dysplasia :

1- Cells vary slightly in size.
2- Nuclei vary slightly in size; N/C ratio may vary slightly.
3- Nuclear material is fine and powdery with rare clusters of nuclear material
near the nuclear membrane.
4- Cytoplasm may be acidophlic.
5- Cells usually occur in sheets, but may be found singly.

c) Metaplasia, moderate atypia :

1- Cells vary moderately in size; some are smaller than in mild metaplaisa.
2- Nuclei vary significantly in size.
3- N/C ratio varies moderately. lt may be higher or lower than normal
4- Nuclear material is fine and powdery in most areas, but nuclear masses are
abundant, particularly along the nuclear membrane.
5- Nuclear lobulations, crevices, and nodules are present.
6- Cytoplasm may be basophlic, but acidophilia predominates.
7- Cells usually occur in sheets, but an increase in single cells is found.

d) Metaplasia, marked atypia

1- Cells vary markedly in size, but are generally larger than those in moderate atypia.
2- Nuclear pleomorphism is marked; nuclear material is coarse and sometimes
clustered about nuclear membrane.
3- N/C ratio varies markedly. lt may be higher or lower than normal.
4- Nucleoli are present, but are small and may be acidophilic.
5- Acidophilic cytoplasm predominates.
6- Single cells predominate.

e) Carcinoma in situ

1- Cells vary in size and may be double the size of those in metaplasia with marked atypia.
2- Single cells are present, but clusters are more common than in invasive carcinoma.
3- Nuclear material is coarse and accumulated in large masses, but concentrations are not usually accumulated near membrane. Chromocenters are large, simulate nucleoli, but are not always acidophilic.
4- N/C ratio varies markedly. lt may be higher or lower than normal.
5- Cannibalism and multinucleation may be present.
6- Acidophilic cytoplasm predominates.

f) Invasive carcinoma

1- Cells are usually larger than normal, but may be very pleomorphic and bizarre. They are
usually single, but clusters are found.
2- Nuclear material is coarse and accumulated in masses. lt is unevenly distributed adjacent to the nuclear membrane.
3- Nucleoli are large and acidophilic.
4- N/C ratio varies markedly. It may be higher or lower than normal.
5- Multinucleation is common.
6- Cytoplasm may be acidophilic and basophilic.

6- Histopathological Criteria of Preinvasive Squamous

Lesions

A variety of bronchial epithelial hyperplasias and metaplasias may occur that are not regarded as preneoplastic; including goblet cell hyperplasia, basal cell (reserve cell) hyperplasia, immature squamous metaplasia, and squamous metaplasia. The term preinvasive does not imply that progression to invasion will necessarily occur. These lesions represent a continuum of cytologic and histologic changes that may show some overlap between defined categories. (Franklin et al, 2004)

The histopathological criteria regarding cellular differentiation in preneoplasia and early lung cancer are basically the same as what mentioned before by Saccomanno et al, 1974. The difference is that by histopathology, it is possible to correlate the different types of cells in relation to the basement membrane and to each other. By lesions of squamous metaplasia, all types of dysplasia and carcinoma in situ, the basement membrane is always intact; whereas in microinvasive carcinoma and worse, the case is not so. (Franklin et al, 2004). The histopathologic criteria of preinvasive squamous lesions according to the WHO Classification of Tumors are shown in (Table 1) (Travis et al, 2004)

Table 1: The WHO histopathologic criteria of preinvasive squamous lesions*

Abbildung in dieser Leseprobe nicht enthalten

* From Travis et al, WHO Classification of Tumors, 2004

7 - Bronchoscopic Appearances of Early Lung Cancer

The Japan Lung Cancer Society Guidelines, 2000 gave description for the bronchoscopic findings of early lung cancer. (Classification of Lung Cancer, of The Japan Lung Cancer Society, 2000). These findings include;

(A) Standard findings

(1) Occult type:

Bronchoscopic findings are normal. Cytological examinations, such as bronchoscopic brushings, etc., show a localized carcinoma in the segmental or subsegmental branches. The category TX N0 M0, or occult carcinoma according to the stage grouping in the TNM classification should be excluded from this type.

(2) Thickened type:

The mucosal epithelium is superficially elevated, frequently at the bifurcation. (Figure 4)

(3) Nodular type:

The distinctive sessile lesion has a large base and elevated mucosa epithelium. The height of the elevated mucosa epithelium should be more than 2 cm. (Figure 5, a)

(4) Polypoid type:

The tumor is pedunculated. Movement on respiration is useful for distinguishing between this type and the nodular type. (Figure 5, b) Combination of some features may be present

(B) Associated findings

1. Changes in the surface of the mucosal epithelium: irregularity, granulation, or corrugation.
2. Bleeding.
3. Abnormal folds.
4. Necrosis.
5. Dilatation and/or hyperplasia of blood vessels.
6. Indistinct cartilage ring.

Abbildung in dieser Leseprobe nicht enthalten Abbildung in dieser Leseprobe nicht enthalten

Fig. 4 Examples for thickened type bronchial cancer

Abbildung in dieser Leseprobe nicht enthalten Abbildung in dieser Leseprobe nicht enthalten

Fig 5 (a) Nodular type (b) Polypoid type

8- Natural History of Preinvasive Bronchial Lesions

Currently, there is a great deal of interest in understanding the development of cancer and developing therapeutic interventions to halt or reverse the progression of lung cancer. As early forms of neoplasia are being recognized more frequently in patients, there is a need to have a sufficient understanding of the biology of these lesions to make reasonable treatment decisions.

Lung cancers are believed to arise after a series of progressive pathological changes (preneoplastic or precursor lesions) in the respiratory mucosa. While the sequential preneoplastic changes have been defined for centrally arising squamous carcinomas, they have been poorly documented for large-cell carcinomas, adenocarcinomas, and SCLCs.

Mucosal changes in the large airways that may precede or accompany invasive squamous cell carcinoma include hyperplasia (basal cell hyperplasia and goblet cell hyperplasia), squamous metaplasia, squamous dysplasia, and carcinoma in situ. While hyperplasia and squamous metaplasia are considered reactive and reversible changes, dysplasia and carcinoma in situ are the changes most frequently associated with the development of squamous cell lung carcinomas. Adenocarcinomas may be accompanied by changes including atypical adenomatous hyperplasia (AAH) in peripheral airway cells, although the malignant potential of these lesions has not been demonstrated. For SCLC, no specific preneoplastic changes have been described in the respiratory epithelium. (Colby et al., 1998)

Currently available information suggests that lung preneoplastic lesions frequently are extensive and multifocal throughout the lung, indicating a field effect “field cancerization” by which much of the respiratory epithelium has been mutagenized, presumably from exposure to carcinogens. (Franklin et al, 2004)

The concept of the development of squamous cell carcinoma through a sequence of epithelial events, have been dated since a long time (Saccomanno et al, 1974). It is assumed that the main theory for lung carcinogenesis; is the multi-step evolution theory, In this theory; it is believed that development of squamous carcinoma of the lung begins with transformation of the columnar respiratory epithelium into benign squamous metaplasia, passing through various stages of metaplastic atypia, onto carcinoma in situ, and then to frankly invasive carcinoma (Saccomanno et al, 1974). Even, it is believed that intraepithelial (preinvasive) neoplasia starts with a molecular phase, in which the epithelium is morphologically normal but is undergoing genomic instability, followed by a morphologic phase, in which aberrant proliferative foci with nuclear and cytologic changes, termed dysplasia, and carcinoma in situ. This morphological phase form the basis for the microscopic diagnosis of preinvasive or intraepithelial neoplasia.

However, the natural course of preinvasive bronchial lesions, the time to progression, their prevention, then when and how to treat such lesions; are not easy to be interpreted, despite a relatively large number of studies reported for these issues (Melamed et al, 2006, and Kennedy et al, 2007 )

Carcinoma in situ squamous cell cancers (and dysplastic lesions) do not present with radiographically detectable lesions, but squamous dysplasia or carcinoma in situ can often be detected during endoscopic examination of bronchi, particularly when fluorescent lighting is used (Kennedy et al, 2007 ).

Although it is clear that many, and probably most, CIS lesions will never progress to invasive cancer, it is not possible to predict in which lesions, or even in which individuals, will invasive cancer develop. Previous studies reported that approximately 11% of moderate dysplasia (Frost et al, 1986), 46% of severe dysplasia (Risse et al, 1988), and 78% of carcinoma in situ (Venmans et a l, 2000); will progress to invasive cancer if left untreated. On the contrary, it was reported that squamous metaplasia and mild dysplasia regress after smoking cessation and treatment of inflammation (Band et al, 1986).

Thus, it seems that the natural history of these preinvasive bronchial lesions remains largely unknown (Melamed et al, 2006 )

On the other hand, although our knowledge of the molecular events in invasive lung cancer is relatively extensive, a relatively little that is known about the sequence of genetic events in preneoplastic lesions. A few studies have provided suggestions that molecular lesions can be identified at early stages of the pathogenesis of lung cancer. (Ahrendt et al, 1999 )

Moreover, despite advancement in molecular biology techniques, as yet there are no accurate predictions of risk of malignant progression. In their evaluation for 134 preneoplastic lesions among 52 individuals of high-risk groups for lung cancer, Breuer et al, 2005; found a nonstepwise histologic changes, that were unrelated to the initial histologic grading. Moreover, the authors concluded that one can not differentiate the potentially more malignant preneoplastic lesions among the many prenoplastic lesions present in the bronchial mucosa. The value of localizing intraepithelial neoplasia is related to the natural history of these lesions, with the possibility of their presence being a marker of malignant risk and the potential for cure by local intervention when malignancy is detected at the earliest possible stage.

Moreover, initial chemoprevention attempts for lung cancer have also been unsuccessful in decreasing lung cancer incidence (and possibly even increased lung cancer incidence) and thus it is not clear that the chemopreventative agents with favorable activity in the squamous mucosa of the upper aerodigestive tract will help prevent the progression of squamous cell cancer in the lung. (The Alpha-Tocopheral, B.-C.C.P.S.G., 1994).

Furthermore, the recognition of CIS squamous cell cancers poses some complex patient management dilemmas. Logically, treatment of CIS lesions should result in a decreased frequency of invasive squamous cell cancer in treated individuals. However, because individuals who have these lesions usually have multiple lesions, surgical resection of some early stage tumors may be not validated. Even more, up to 10% of successfully resected patients with lung cancer subsequently develop a second primary lung neoplasm, and a second operation may not be feasible at that point. (Kennedy et al, 2007)

However, there remains hope that more specific interventions of lung cancer development will be found, and monitoring these in situ squamous lesions is likely to become important in the clinical management of pulmonary neoplasia. The value of localizing intraepithelial neoplasia is related to the natural history of these lesions, with the possibility of their presence being a marker of malignant risk and the potential for cure by local intervention when malignancy is detected at the earliest possible stage.

In light of the continuing prevalence of lung cancer and the modest yet significant advances in the field, the American College of Chest Physicians (ACCP) through the Health and Science Policy Committee commissioned the development of this Second Edition of the Diagnosis and Management of Lung Cancer: ACCP Evidence-Based Clinical Practice Guidelines. This project was launched in the hope that a systematic review, evaluation, and synthesis of the published literature, along with expert opinion and consensus when necessary, would lead to a series of recommendations that would assist physicians in achieving the best possible outcome for their patients given the knowledge and capabilities available at this time.

The Second Edition of the Guidelines has employed a new grading system that classifies recommendations as strong (grade 1) or weak (grade 2) according to the balance among benefits, risks, burdens, and possibly cost, and the degree of confidence in estimates of benefits, risks, and burdens. The system classifies the quality of evidence as high (grade A), moderate (grade B), or low (grade C) according to factors that include the study design, the consistency of the results, and the directness of the evidence. For selecting such recommendations; two considerations were taken into account. First, the evidence and benefits need to be sufficiently strong for the recommendations to have a 1A grade. Secondly, these criteria should be considered; (1) practicality for ACCP members and their patients, (2) importance, (3) scientific acceptability, (4) usability, and (5) feasibility. (Alberts, 2007 )

These guidelines recommends that; For patients with known severe dysplasia or CIS in the central airways, standard WLB is recommended at periodic intervals (3 to 6 months) for follow-up. AFB should be used when available. Grade of recommendation, 2C (Kennedy et al., 2007).

Chapter 3: Screening of Lung Cancer

Appropriate cancer screening should lead to early detection of asymptomatic or unrecognized disease by the application of acceptable, inexpensive tests or examinations in a large number of persons. The main objective of cancer screening is to reduce morbidity and mortality from a particular cancer among persons screened.

Screening for disease implies that tests for disease are applied to asymptomatic individuals. The goal of screening is to identify patients with unrecognized disease (pulmonary nodule) and to identify patients at increased risk (smoking, family, and occupational history). The ideal screening test would have high sensitivity for detecting disease prior to development of advanced disease; high specificity; relative safety; acceptability to patients and physicians; relative low cost; and, most importantly, would either reduce mortality, improve quality of life, or both. Ideally, the effectiveness of a screening test will be evaluated in randomized controlled trials to minimize methodological biases. (Patz et al, 2000)

Unfortunately, 75% of patients with lung cancer present with symptoms due to advanced local or metastatic disease that is not amenable to cure. Despite advances in therapy, five-year survival rates average less than 15% for all individuals with lung cancer (American Cancer Society, 2007). Prevention, rather than screening, is the most effective strategy for reducing the burden of lung cancer. The promotion of smoking cessation is essential, as cigarette smoking is felt to be causal in almost 90 percent of all lung cancer. (Wingo et al, 1999)

I- Role of Sputum Cytology

It has been appreciated since the publication of postmortem studies in the 1950s that preinvasive changes involving the bronchial epithelium may occur over wide areas of the tracheobronchial tree, and that such changes are particularly common in individuals who have smoked heavily and/or developed other sites of invasive lung cancer (Auerbach et al, 1961).

These observations underlie the widely held belief that lung cancer, particularly squamous cell carcinoma, develops through a series of morphological stages from metaplasia, to dysplasia, to carcinoma in situ, and then to invasive disease.

Cytologic analysis of exfoliated cells in sputum is a rapid, relatively inexpensive means to establish a tissue diagnosis in an individual with an apparent pulmonary carcinoma. Sputum can be either spontaneously collected or induced with hypertonic saline. Pooling of three daily specimens increases the diagnostic yield. Sputum samples are considered representative if alveolar macrophages as well as bronchial epithelial cells are present. (Petty, 2003 )

The possibility of detecting preinvasive and early invasive carcinoma was raised by a longitudinal study of sputum obtained from uranium miners in whom abnormal epithelial cells were found several years before a clinical diagnosis of lung cancer was established. (Saccomanno et al, 1974) However, large trials sponsored by the National Cancer Institute subsequently failed to demonstrate a significant reduction in lung cancer mortality in patients who had undergone intensive screening with sputum cytology.

Although sputum cytology failed to detect the majority of lung cancers and influence overall mortality in screened versus unscreened groups, it succeeded in identifying a small number of patients with carcinoma in situ and radiologically occult squamous cell carcinoma involving the central airways. The bronchoscopic localization of these early lesions proved particularly difficult but was ultimately judged to be worthwhile because surgical resection was associated with excellent 5-year survival in the range of 90%. (Patz et al, 2000)

Overall, the sensitivity of sputum cytology is 65% (range, 22% to 98%) in the setting of established cancers. The diagnostic yield of sputum cytology is enhanced for centrally located lesions, squamous cell carcinomas, and large tumors, particularly if multiple sputum samples are examined. (Petty, 2003)

Screening with sputum cytology is not currently recommended by any major advisory organization (Bach et al, 2007-b); however, interest in its use is returning because of technical advances that could enhance the sensitivity of the technique.

Automated Image Cytometry (AIC) technique is used for quantitative measurement of DNA content and texture features of nuclei of exfoliated respiratory tract cells in sputum and bronchial wash. Up to 100 nuclear features such as the size, shape, and DNA content of the nucleus can be measured, as well as features describing the distribution of chromatin within the nucleus (Farouk et al, 2002). Moreover, the combined use of AIC and bronchoscopic evaluation (WLB+AFB, using LIFE system) was reported to yield a 100% detection rate of all diagnosed preneoplasias in high-risk populations (Farouk et al, 2002).

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