BENIGN LUNG TUMOR I. INTRODUCTION Tumors are neoplasms in which an abnormal growth of new tissue.

This situation is caused by abnormal growth and differentiation genes that control the damage or apoptosis of cells. In medical term, a tumor known as neoplasia. Neo means new, plasia means growth / division, so neoplasia refers to the growth of new cells, which differs from surrounding cells those are normally grow. There are two main functions of our cells, namely implementing its functional activity and multiply by dividing. However, in tumor cells that occur, most of the cell's energy is used exclusively for proliferation. This proliferation function regulated by the nucleus of the cell (nucleus), resulting in tumor cells found that the cell nucleus is enlarged because of increased work demands. Lung is an elastic organ and is located inside the coneshaped chest cavity (cavum thoracis). Lung tumors are one type of tumor is difficult to cure. These tumors are caused by cells that divide and grow uncontrollably in the pulmonary organs. Lung tumors can be classified to two of the primary lung tumors and secondary lung tumors. Primary lung tumors can be divided into benign and malignant tumors. From the above definitions of tumors, the tumors were divided form the two major categories of benign tumors (benign) and malignant tumors (malignant) or popularly called as cancer. There are significant differences in the nature of them. Rare benign lung tumor usually found incidentally on routine examination because benign tumors are rarely giving a complaint and grow very slowly. Benign lung tumors that are often encountered is Hamartoma. Other types of benign tumor that is the fibroma, lipoma and others very rarely found. Solitary pulmonary nodules found on the level of 1-2 per 1000 chest radiography. Approximately 30% of the nodules proved to be malignant. From the remaining nodules, benign lung tumors makes about 2-5% of primary lung tumors. Benign lung tumors are a heterogeneous group of neoplastic lesions from lung structures. These tumors include bronchial adenomas, hamartomas, and unusual group of neoplasms (eg, chondromas, fibromas, lipomas, leiomyomas, hemangiomas, teratomas, pseudolymphomas, endometriosis, and bronchial glomus tumors). 1,2,3,4

Many of malignant lung tumors, are also found as carcinoma bronchogen because most of primary malignant tumor originating from the lower respiratory system are derived from epithelial and mucosal bronchial branching. Secondary lung tumors are more common than primary lung tumors. Travel or metastasis from elsewhere to the lung usually haematogenous, limfogen or directly. Usually tumors that metastasize to the lungs was already very advanced or in high stage. Malignant tumors of other organs that often metastasize to the lungs, among others osteosarkoma, breast carcinoma, breast carcinoma, carcinoma of the skin and womb. 1,2,3,4

II. INCIDENCE Benign lung tumors are rarely encountered that is only about 2-5% of all primary lung tumors. In America malignant lung tumors in the reported cause of death as many as 136 000 people a year (1987). Most of cases are occur with patient over 35 years old. The highest incidence occurred at the age of 55-65 years and men are more than women with a ratio of 4:1. Although benign lung tumors do not cause significant health problems, complications can result from obstructive lesions that can affect the patient's pneumonia, atelectasis, and hemoptysis. Exact incidence is unknown because these tumors are often asymptomatic and detected only during autopsy. 1,2,3,4

III. DIVISION Benign epithelial tumours Benign tumours arising from the submucosal glands Sclerosing pneumocytoma Alveolar adenoma Squamous papiloma Benign mesenchymal tumours Hamartoma Lipoma Leiomyoma Granular cell tumors

Benign tumors arising from submucosal glands Most tumours of the submucosal glands are of low grade malignancy and form a small subgroup of bronchopulmunary carcinoma. Benign tumours of the submucosal glands are even rarer than their malignant counterparts. They include mucous cell adenoma, pleomorphic adenoma and oncocytoma. All these tumours tend to affect young adults and even children and are unrelated to smoking. They often grow as an intrabronchial polyp. Pleomorphic adenoma shows a mixed pattern of differentiation with both connective tissue and epithelial components the former probably representing metaplasia of their myoeepithelial elements. Oncocytoma is an adenoma of unusual appearance due to cytoplasm being packed with large number of mitochondria which are apparently inactive. This is taken to represent a degenerative change. Similar large eosinophilic cells are sometimes found in the ducts of otherwise normal submucosal glands. In spite of their name, these tumours are quite benign. 8 Sclerosing pneumocytoma These benign tumours are found in the periphery of the lung. They are more common in women than in men and affect populations in the far East more than elsewhere. There is marked vascular and less evident epithelial component. Although originally believed to be angiomatous in nature or even mesothelial it is probable that these tumours arise from epithelial alveolar lining cells and the term sclerosing pneumocytoma is therefore preferred to the older one of sclerosing haemangioma.8

Alveolar adenoma These will-circumscribed tumours arise in the periphery of the lung of elderly patient. They resemble lymphangiomas microscopically but the flattened cells that line their narrow spaces are epithelial rather than endothelial and they are possibly related to the sclerosing pneumocytoma described above. Their nature is generally only recognised once they are excised, following which they do not recur.8

Squamous papillomas Squamous papillomas may be solitary or multiple, the latter forming the condition known as juvenile papillomatosis. This condition most commonly affects the larynx but may extend into the trachea or large bronchi and very rarely into the distal lung. The onset is generally before the age of 11 years and most examples regress before puberty. However repeated laser therapy may first be required, because the lesions are prone or recur. Multiple laryngeal, tracheal and bronchial papillomas cause hoarseness, stridor, and respiratory obstruction, while the rare pulmonary lesions appear on chest radiographs as solid or cystic rounded nodules. The human papilloma virus is an aetiological factor and types 6 and 11 have been identified in the lesions. Solitary papillomas are generally found in elderly smokers with human papilloma virus again involved, although here the virus is of types 16 and 18 rather than 6 and 11. The epithelial covering can show the whole range of changes described in the development of squamous cell carcinoma in flat bronchial epithelium: squamous metaplasia, dysplasia, carcinoma in-situ and invasive tumours. In general, older patients are more likely to have premalignant lesions.

Figure 1 Figure 1 : shows multiple cysts of varying sizes in the right upper and mid-zone with ill defined opacities in the right lower zone silhouetting the raised right dome of diaphragm8

Hamartoma Hamartoma is the most common benign neoplasm of the lung, accounting for up to 8% of all primary tumours. In dorland`s hamartoma means a benign tumours-likes nodule composed of an over-growth of mature cells and tissue normally present in the affected part but with disorganization and often with one elements predominating. Its pathogenesis is currently believed to involve clonal proliferations of mesenchymal elements. Tumours are typically composed of cartilage, fibromyxoid stroma, and adipose tissue along with incorporated bronchiolar epithelium and less common diverse elements such as bone or hair. Incidence of Hamartomas occurs more frequently in men, and the mean age at presentation is the six decade, with only rare cases described before the third decade of life. Many cases of Hamartomas unrecognized and are found only at autopsy.9 Hamartoma typically present as a solitary pulmonary nodule, usually discovered incidentally on chest films or during the course of a surgical procedure for another indication. Most patient are completely asymptomatic. An exception is the endobronchial hamartoma, which represents fewer than 20% of cases. Patient with endobronchial hamartoma often complain of cough, dyspnea, wheezing, and occasionally hemoptysis.9 Radiographically, hamartoma are usually solitarybut multiple nodules have been reported in up to 3% of cases. The nodules are typically smooth, lobulated, peripheral lesions, approximately 0.5 to 3 cm in diameter. These tumours grow very slowly. Classically, hamartoma have an eccentric `popcorn` calcification pattern on plain chest radiographs. Calcification can be seen more frequently and to better advantage by CT-Scan. These scan may also reveal central fat within the lesion, a distinctive and characteristic finding in hamartoma. If a diagnostic workup is pursued, then transthoracic needle aspiration should be performed, as it has proven diagnostic yield of greater than 85%. Biopsy-proven hamartomas can be safely observed with out specific therapy. Excision is warranted when patients have symptoms or when lesions demonstrate significant growth. Lung-sparing surgical resection is the treatment of choice because hamartomas rarely recur. No additional adjuvant therapy is required for the typical case.9

Figure 2 : `popcorn` calcification pattern on plain chest radiographs

Figure 3 : computed tomography scan after intravenous contrast demonstrate the presense of calsification and fat within the hamartoma

Lipoma Lipomas are the most frequent tumors of the body, 'pulmonary' lipomas are very rare. Endobronchial lipomas have an incidence of 0.1 to 0.5% of all lung tumors. Lipomas, as benign pulmonary tumors, can be found endobronchially, intrapulmonary, and mediastinal. Lipomas may arise within a bronchus or the periphery of the lung. They are probably one-sided developments of the mixed mesenchymoma referred to hamartomas. They have no premalignant connotation. Computer tomography can suggest this diagnosis because the tumours have the radiolucency of fat. Cough as the most frequent complaint. The other symptoms include: increased sputum, hemoptysis, fever, and dyspnea. Eighty percent of patients have abnormalities on chest radiograph (e.g., atelectasis, consolidation, or mass). Management of lipoma are resection by bronchoscopy is the first choice of treatment.8

Figure 4 : showed a hilar mass on the right side, with the density of fat (-100 HU), identified as a hilar lipoma. There was also a large cystic structure in the right upper lobe, adjacent to the right hilus. Leiomyoma As with smooth muscle tumour elsewhere in the body the histological differentiation of benign leiomyoma from low-grade leiomyosarcoma is difficult. However, in the lung most smooth muscle are benign. They may be found in the trachea, bronchi, or in association with peripheral bronchioles. In all cases the possibility of metastasis from another site, such as a low grade leiomyosarcoma of the uterus should be considered. Pulmonary leiomyoma seem to to occur with about equel frequency in the proximal bronchi and parenchyme. 8

Granular cell tumour

Granular cell tumors (GCT) are uncommon, usually benign neoplasms, most frequently originating from tongue, skin, and breast. Granular cell tumour were originally believed to be

derived from smooth muscle but it is now accepted that they are benign lesions derived from schwann cells. As seen with nerve shealth tumours, they express the S100 neural marker but are composed of polygonal rather than spindle cells and have abundant eosinophilic cytoplasm . The lesions are usually small but may occasionally measure several centimetres in diameter. They occurs in the major airway present with obstructive symptoms. Histologically the outstanding feature is numerous fine, acidophilic, cytoplasmic granules, which appear similar to lysosomes under electron microscopy.8

Figure 5 : Chest radiograph showing a mass lesion (arrow) intimately associated with a segmental bronchus of the left lower lobe. Although Chest computed tomogram showing localized expansion of mass, which measured 2.8 2.0 cm in size. IV. ETIOLOGY The cause of benign lung tumors till now is not understood certainty. While pulmonary malignant tumors according to the ACS (the American Cancer Society) for more than eight out of 10 cases of lung cancer caused by smoking. And not only the cigarette as the cause but also the cigar and pipe smokers have a higher risk for lung cancer. The number of smokers each year, the number of smokers every day and how long the person inhaled smoke are at risk for developing lung cancer. The development of lung cancer through passive smoking also increases the exposed through the air when someone else smokes.1,4,5,7

A carcinogen is found in air is 3.4 benzpiren pollution. In certain circumstances bronchogenic carcinoma is a disease caused by work. From various industrial materials, one of the most dangerous is asbestos. The risk of cancer due to asbestos 10 times greater. There is also an increased risk among those who work with uranium, chromate, arsenic, iron and iron oxide. Lung cancer risk either due to contact with asbestos and uranium is greater if the person is smoking. 1,4,5,7 Other factors may also play a role in increasing the risk of lung cancer is diet and environment especially family. Some research shows that smokers of low vitamin A diets increase the risk of lung cancer. The loss of chromosomes (partial 11p, 13q, 17p, and 3p) tumor gene mutations suppressor (p53, Hap-1, ErbAb etc.) and others that implicate familial factors in the formation of lung cancer. The factors that have been in explaining this clearly states that although smoking plays a central role in increasing the incidence of lung cancer but also many guidelines that state that smoking is not the only factor. Chronic infection, caused by air marshals in motor vehicles and industrial work that led to contact with carcinogenic substances, dietary factors, family factors and perhaps other factors are not learned and is a predisposing the occurrence of lung cancer.6

V. ANATOMY AND PHYSIOLOGY The lungs are the essential organs of respiration; they are two in number, placed one on either side within the thorax, and separated from each other by the heart and other contents of the mediastinum. The substance of the lung is of a light, porous, spongy texture; it floats in water, and crepitates when handled, owing to the presence of air in the alveoli; it is also highly elastic; hence the retracted state of these organs when they are removed from the closed cavity of the thorax. The surface is smooth, shining, and marked out into numerous polyhedral areas, indicating the lobules of the organ: each of these areas is crossed by numerous lighter lines.10

Figure 6 : Front view of the lungs

Each lung is conical in shape, and presents for examination an apex, a base, three borders, and two surfaces. The apex (apex pulmonis) is rounded, and extends into the root of the neck, reaching from 2.5 to 4 cm. above the level of the sternal end of the first rib. A sulcus produced by the subclavian artery as it curves in front of the pleura runs upward and lateral ward immediately below the apex. The base (basis pulmonis) is broad, concave, and rests upon the convex surface of the diaphragm, which separates the right lung from the right lobe of the liver, and the left lung from the left lobe of the liver, the stomach, and the spleen. Since the diaphragm extends higher on the right than on the left side, the concavity on the base of the right lung is deeper than that on the left. Laterally and behind, the base is bounded by a thin, sharp margin which projects for some distance into the phrenicocostal sinus of the pleura, between the lower ribs and the costal attachment of the diaphragm. The base of the lung descends during inspiration and ascends during expiration.10

Figure 7 : Anatomy of lungs Both lungs are filling most of the thorax cavity of each is wrapped by two membrane called the pleura. Larger right lung and has three lobes while the left lung has two lobes. Each lobe is further towards bronkhopulmuner segments each have segment bronchus. Tracheal branching will end up with two main branches of lung bronchi of the right bronchus and left bronchi. In the lungs there are branching bronchi again to form secondary and tertiary bronchi. Furthermore, a small bronkhiolus and ends with bronkhiolus terminalis. The final part of bronkhiolus terminalis called alveoli. Alveoli sacs in the form of thematic clusters of alveoli at the end of the bronchial terminalis. Each lung consists of 300 million alveoli with a surface area of 40-80m2. The alveoli are lined by a delicate layer of simple squamous epithelium, the cells of which are united at their edges by cement substance. Between the squames are here and there smaller, polygonal, nucleated cells. Outside the epithelial lining is a little delicate connective tissue containing numerous elastic fibers and a close net-work of blood capillaries, and forming a common wall to adjacent alveoli. Inoxygenate of blood in the heart are taken into the lungs through the arteries to the bronchi will pulmunalis and bronkhiolus. Oxygenate blood of the system will pass through the capillary-venule venule pulmuner who will unite to form veana pulmunalis. Lymph channels in the lungs is a closed channel which is located between alveolar cells and on arterial pulmunalis endhothelium. Lymphatic fluid carry proteins, lipids, dead cells and foreign particles away from the lungs intersisiel space which plays an important role in lung defense system from disease. 10

Contraction and relaxation of muscles in the chest and diaphragm occur if done inspiration and expiration. As inspiration, the diaphragm and intercostal muscles will contract. In expiration, the diaphragm and intercostal muscles relax. Respiration center located at the brain stem controls breathing. Oxygen is obtained from the process of inspiration, through the alveoli into the blood vessels,then will then be taken to the left side of the heart through pulmonary veins to be pumped to the entire body. Deoxygenated blood from the body will flow to the right side of heart to be pumped back into the lungs through the pulmonary artery. Carbon dioxide from the capillaries will enter into the alveoli and then flow into the alveolar space and will be released through the expiration process. 10

VI. PATHOPHYSIOLOGY Pathogenesis of primary lung tumors either benign or malignant is less understandable. Nomenclature of benign and malignant lung tumors based on histological. Neoplastic lesions is a proliferative lesion of autonomous cells without the normal control mechanisms of their growth. Neoplastic lesion characterized by the proliferation of autonomous cells with no response to normal control mechanisms that regulate their growth. An additional characteristic of benign tumors is an extension without an invasive local tissue or spread to other sites. 3

For secondary lung tumors, there are two prominent mechanisms of cancer spread to the lungs those are direct extension and true metastatic. Usually a direct extension of primary tumors involving other organs (such as thyroid, esophagus, and thymus) or derived from the tumor metastases to other intrathoracal structure (eg mediastinal lymph glands), which generally causes obstructive abnormalities in the trachea or bronchus. Direct extension can also occur through blood flow, like the spread of cancer cells from the kidney or testis as thrombus that is carried within vascular into the lungs via the inferior vena cava and the right heart. True metastatic occurs through the pulmonary artery, bronchial arteries or lymphatic system or the lungs, pleural cavity or through the airway passage.3 VII. CLINICAL SYMPTOMS Most of primary lung tumors are already found in an advanced stage. In the advanced stage there is no lung cancer patients who do not have any complaints and clinical symptoms. Conversely in the early stages of this disease is sometimes a long time does not cause significant complaints or clinical symptoms. Complaints and symptoms of lung cancer originating from airway disorders, the emphasis into the surrounding organs and metastases. Disturbances in the respiratory tract causing symptoms such as cough and haemoptysis. Tumors in the central region generally give symptoms of cough because intrabronchial irritation. Shortness of breath may caused by bronchial obstruction. Pressure and infiltration of surrounding organs can lead to dysphagia, pain, dyspnoea so that it can happen intrabronkial tumor capillary rupture. Metastasis via the bloodstream can attack and organ systems as far as the other lymph glands and liver most frequently in children and kidney, brain, bone and kidney rarest.7,8,9

VIII. DIAGNOSIS Diagnosis of lung tumors can be decided through the anamnesis of the major complaints and other complaint that was followed at the same time of chief complaint. Also asked about smoking habits, how stem spent each day, how long these habits and when to stop. Also related to air pollution in the workplace or home environment.10

On physical examination noted a general state of patients according to Karnofsky scale, deformities and thoracic movement, voice change, enlargement of lymph glands, especially in the area of supraclavicular. Investigations including routine laboratory examinations of blood, sputum cytology, liver function, kidney function, and others. Thoracic radiology examination is an absolute must to determine the exact location of the tumor. Bonchoscopy inspection is also important to be done. Transthoracal biopsy or transthoracic needle aspiration biopsy is useful to determine the histological or cytological diagnosis, by taking material directly from the tumor. In addition to lung cancer TNM classificationthere is also UICC & AICC 1987 staging. 7

Primary tumor

TX Primary tumor can not be assessed T0 The tumor did not appear Tis Carcinoma in situ T1 Tumor 3 cm T2 Tumors> 3 cm invasion into the pleural visceralis followed by atelectasis or obstructive pneumonitis T3 Tumors of various sizes which infiltrated the thoracic wall, diaphragm, mediastinal pleura, parietal pericardium Tumors of various sizes which infiltrated the mediastinum, heart, great vessels, trachea, T4 esophagus, spinal

Regional lymph nodes

NX Regional lymph nodes can not be assessed N0 There was no metastasis to regional lymph nodes N1 Metastases in the lymph glands on the same side or same side of the hilum N2 Mediastinal metastases the same side and / or glandular subkarina N3 Contralateral mediastinal metastases, contralateral hilum lymph nodes M Distant metastases MX Can not be in the assessed of distant metastases M0 No distant metastasis M1 There are distant metastases

IX. MANAGEMENT Benign lung tumors were best treated by surgical resection of the tumor. The extent of surgery may be simple endoscopic resection, thoracotomy with bronchotomy/local excision, segmental resection, lobectomy, sleeve resection, or pneumonectomy. The extent is usually determined at surgery and is as conservative as possible. Endoscopic resection using the rigid bronchoscope is readily used to resect endobronchial benign lung tumors except for bronchial adenomas. Recently, bronchoscopic resection offers an alternative to surgical resection. At 1 and 10 years, respectively, 100% and 94% of completely resected carcinoids were free of disease. Commonly, surgical resection is recommended for bronchial adenomas because of the potential for malignancy. The surgical approach should include complete resection, sparing of as much lung as possible, and lymph node dissection. Endoscopic resection with neodymium: yttriumaluminum-garnet (Nd:YAG) laser can be used for adenoma in high-risk or elderly patients.7,9,10

Treatment of malignant lung tumors or lung cancer based on histopathological type, degree (stage, stage) and appearance (performance status) patients. In general, this treatment is a combination of surgery, radiation or chemotherapy and consumption of cytostatic Lung carcinoma surgery called as curative treatment if the tumor was carried out and the perfect gland dissection accompanied by pathological examination found no metastasis to the gland that was lifted. Patients with extensive-stage disease was handled with only chemotherapy. Several combination chemotherapy regimens were often used consisted of cyclophosphamide and doxorubicin. 7,9,10 X. PROGNOSIS Prognosis of benign lung tumors such as bronchial adenoma which has been operated is good. Reported 5 years survival rates after resection reached 95% and will decrease to 70% if regional lymph nodes are affected. Overall prognosis for patients with carcinoma bronkogenik is bad. If there are any symptoms or signs of disease were 75% was not able to recover again. For patients who had made the diagnosis, one-year survival reached 20%, 5 years survival rates less than 10% and only slightly increased in recent years. 4