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1 2 Hypertrophic osteoarthropathy (HOA) is a syndrome of clubbing of the digits, periostitis of the long (tubular) bones (swelling of the forearms and lower thighs), and arthritis. Although not entirely understood, it has become sign looked for in diagnostic circumstances with regards to lung cancer. Although no lesion could be seen, it is important to remember that that does not mean there was no lesion there. The possibility of it being a very small lesion that could have easily been lost or over looked – especially considering the year this particular patient was seen in (1945) – was extremely likely. 3 The damage smoking does on one’s lungs is subject to the amount smoked daily, the tendency of the patient to inhale and the duration of their smoking habit. There are 55 different carcinogens (including PAH (= polycyclic aromatic hydrocarbons - Bap (benzo[a]pyrene) being the most extensively studied) and NNK = 4 – (methylnitrosamino) – 1- (3 – pridyl) – 1 – butanone) in cigarette smoke for which “there is sufficient evidence of carcinogenicity”. During the metabolic processes of PAH and NNK, carcinogen metabolites are made and bind covalently to DNA in cells creating DNA adducts. If these adducts escape cellular repair mechanisms and persist, they can cause miscoding which can lead to permanent mutations. If this mutation occurs on the loci of oncogenes or tumour suppressor genes, it may cause activation or deactivation respectively. If this happens often enough, it will create abnormal cells that lose their growth control and consequently become cancer cells. There is also the possibility of DNA damage as a result of free radicals and reactive oxygen species. Reactive oxygen species and free radicals also inhibit the enzyme α1 antitrypsin, consequently allowing enzymes such as elastase released by neutrophils to break down the elastic fibers in the parenchyma of the lungs. Epithelial changes usually take the progressive course of squamous metaplasia, squamous dysplasia, carcinoma in situ and finally invasive carcinoma. 4 Bronchial carcinoma can be divided into primary or bronchogenic carcinoma (cancer that begins in the lungs or the lungs being the site of the primary carcinogenic lesion) or secondary carcinoma (cancer that started somewhere else in the body and metastasised to the lungs). Primary or Bronchogenic carcinoma can be further divided into Small cell carcinoma (which is can of the small round cells in the lungs) or non-small cell cancer (cancer of the all the rest of the cells that make up the lungs). Non-small cell carcinoma can then be classified as either: squamous cell carcinoma, adenocarcinoma or large cell carcinoma. The most important reason classification of carcinomas is done, is to determine treatment, different options for best prognosis in each subset; the faster the cancer can be identified, the better and more specific care the patient can receive, the better the prognosis. Small cell carcinoma is highly metastatic and has a high initial response to chemotherapy whereas Nonsmall cell is the less metastatic and less responsive. Small cell carcinoma Males (14%), Females (18%) and overall (20 – 25%) It is a cancer of the round cells within the lung Its strongest association is with cigarette smoking It is a highly malignant cancer Infiltrate widely; disseminate early; rarely resectable It is thought to originate from neuroendocrine cells (APUD cells) in the bronchus and are often associated with the ectopic production of hormones like ADH and ACTH that may result in paraneoplastic syndromes such as the syndrome of inappropriate ADH secretion (SIADH) or Cushing’s syndrome. Adenocarcinoma Males (37%), females (47%) and overall (25 – 40%) Most common type in North America; with women and non-smokers Affects bronchiolar or alveolar tissue of lung Peripherally located Poorer stage-to-stage prognosis than squamous cell carcinoma 5 Squamous cell carcinoma Males (32%), females (25%) and overall (25 – 40%) Most common in men with a smoking history Cancer linked most commonly with tobacco smoking Originates in central bronchi as an intraluminal growth Therefore, early detection through sputum sampling possible. Large Cell carcinoma Males (18%), females (10%) and overall (10 – 15%) Large Polygonal Cells – undifferentiated Highly anaplasitc neoplasms Peripherally located; invading segmental bronchi and larger airways Poor prognosis because of tendency to spread 6 Although seemingly uncomplicated, clarifying the stages of development of a cancer is very difficult – especially in the lungs where palpation is impossible and biopsies are difficult and dangerous. Classification of most neoplasms falls under grading and stages which are essential for management, determining prognosis and treatment and documenting results of therapy. Grading is assessed via: The degree of histological differentiation The amount of anaplasia Mitotic activity The TMN system of staging is used more widely: T – Tumour – representing the size of the tumour N – Nodal – whether or not it has spread the nearest nodes M – Metastasis – whether or not the cancer has disseminated to distant parts of the body Table showing the staging of lung cancer as defined by the Radiological Society of North America http://radiographics.rsna.org/content/30/5/1163/F1.expansion.html 7 The macroscopic appearance of bronchial carcinoma is generally the same across the different types and subsets of carcinoma; there are, however, differences (as can be expected) that account for the differences in treatment and prognosis. For this student case, the slide focuses on the morphological appearance of the case at hand rather than covering all possibilities. Most lung cancers originate around the hilus of the lung although adenocarcinomas as a primary carcinoma appear more frequently around the periphery. Lesions are often described as cauliflower-like, grey-white, firm intraparenchymal masses; some fungate into bronchial lumens to produce intraluminal masses. Infiltration of surrounding areas is not uncommon: peribronchial spaces and tissues, pleural spaces; if the tumour grows large enough, haemorrhage, necrosis and cavitation may occur centrally. Extension to bronchial, tracheal and mediastinal lymph nodes is fairly common (50%); distant metastasis varying (liver 30-50%, brain 20%, bone 20%). SCC spread to the adrenals is disproportionately common. 8 The microscopic morphology of carcinomas is where most of the differentiation is seen. In the slide, the characteristics of Large cell carcinoma are highlighted because they relate directly to the case. Adenocarcinoma Malignant epithelial carcinoma with glandular differentiation (mucin production by cancer cells) Its subtype, bronchioalveolar adenocarcinoma is the most distinctive microscopically. Key feature: ability to grow into pre-existing structures without destroying the alveolar architecture. Growth pattern = lepidic, or like butterflies sitting on a fence. Squamous Cell Carcinoma Characterised by presence of keratinization and/or the presence of intracellular bridges. Moderately to well differentiated Small Cell Carcinoma Highly malignant epithelial cell, round with limited cytoplasm, ill-defined borders and “salt and pepper” or grainy chromatin network in absent or barely noticeable nuclei. High mitotic count; cells grow in clusters. Large Cell Carcinoma Detail on slide. Multinucleated, large, prominent nuclei Moderate amounts of cytoplasm Ill-defined borders Undifferentiated on light microscopy 9 Although common, in this case as well as others, lung cancer often presents and/or is diagnosed toward the end stages. Its signs are common and are – occasionally and unfortunately - misunderstood in clinical practice for symptoms of basic pulmonary disease; each symptom however, can be explained and rationalised with cancer in mind. Dyspnoea In the case of an infiltrative, intraluminal mass, an obstruction to an airway would result in difficulty breathing, manifesting as shortness of breath, gasping, inability to take in or let out deep breaths with coughing or pain. Chest Pain There may be many explanations for the sensation of pain in the chest for something such as bronchial carcinoma but one highlighted is one most applicable to the case – pleuritic chest pain. The likelihood was that the increase growth of the tumour pushed against the pleural causing a sharp or stabbing pain. Loss of Weight This is very briefly explained in the slide: because of the presence of the tumour, there is secretion of tumour necrosis factor (defence mechanism), the presence of TNF in the blood is sensed by the hypothalamus in the brain and this inhibits the centre of the brain responsible for creating a sense of hunger, so decreasing food intake. There is also the possibility that this patient’s loss of weight was as a result of an increased energy expenditure (↑basal metabolic rate) in attempts to combat the tumour (as well as to supply the cells of the tumour with nutrients). Clubbing Clubbing under any circumstance is difficult to explain, leaving all ideas of pathogenesis speculation. In this particular case, the idea of a paraneoplastic syndrome causing an increase in substance to stimulate the cellular growth in the nail bed. Clubbing can also occur secondary to bronchiectasis (bronchiectatic infection). Another important sign in lung cancer (not noted in our patient) is haemoptysis – the coughing up of blood due to erosion of the cancer into a blood vessel. 10 Paraneoplastic syndrome or ‘the great mimic’ is a condition that is borne from neoplasms in the body replicating the role of endocrine glands, secreting their substances (e.g. hormones) in excessive amounts or in places around the body where it isn’t needed and could possibly cause harm. Lung cancers are associated with several paraneoplastic syndromes (the syndromes sometimes leading to the discovery of the primary neoplastic lesion). Some of the hormones or hormone-like factors commonly produced include: > Antidiuretic Hormone (ADH) causing hyponatraemia as a result of inappropriate ADH secretion > Adrenocorticotropic hormone (ACTH) creating Cushing’s syndrome > Parathyroid Hormone, parathyroid releasing hormone, prostaglandin E and some cytokines – all leading to hypercalcaemia > Calcitonin causing hypocalcaemia > Serotonin and bradykinin which are associated with carcinoid syndrome > Gonadotropins causing gynaecomastia 11 12