Adenocarcinoma of the lung is the most common type of lung cancer, and like other forms of lung cancer, it is characterized by distinct cellular and molecular features. It is classified as one of several non-small cell lung cancers (NSCLC), to distinguish it from small cell lung cancer which has a different behavior and prognosis. Lung adenocarcinoma is further classified into several subtypes and variants. The signs and symptoms of this specific type of lung cancer are similar to other forms of lung cancer, and patients most commonly complain of persistent cough and shortness of breath.

Adenocarcinoma is more common in patients with a history of cigarette smoking, and is the most common form of lung cancer in younger women and Asian populations. The pathophysiology of adenocarcinoma is complicated, but generally follows a histologic progression from cells found in healthy lungs to distinctly dysmorphic, or irregular cells. There are several distinct molecular and genetic pathways that contribute to this progression. Like many lung cancers, adenocarcinoma of the lung is often advanced by the time of diagnosis. Once a lesion or tumor is identified with various imaging modalities, such as computed tomography (CT) or X-ray, a biopsy is required to confirm the diagnosis.

Treatment of this lung cancer is based upon the specific subtype and the extent of spread from the primary tumor. Surgical resection, chemotherapy, radiotherapy, targeted therapy and immunotherapy are used in attempt to eradicate the cancerous cells based upon these factors.

Signs and symptoms The majority of patients who are diagnosed with lung cancer usually present with locally advanced or metastatic disease. Only about one third of patients have stage I disease when diagnosed. The symptoms that the patient exhibits usually reflect the extent of the cancer's spread. Lung cancers that are discovered early may cause symptoms localized to the respiratory system. However, lung cancer that is advanced will cause patients to experience additional signs and symptoms secondary to the cancer spreading to other organ systems. In order of highest frequency, the most common signs of lung cancer include: Cough that does not go away or gets worse Weight loss Dyspnea (shortness of breath or difficulty breathing) Chest pain, which may be aggravated by deep breathing, coughing, or laughing Hemoptysis (coughing up blood or rust-colored phlegm) Bone pain Clubbing Fever Generally feeling tired or weak Superior vena cava obstruction- facial, neck, upper torso swelling. This is caused by compression of vasculature by the lung tumor that restricts blood return from the upper body. Dysphagia (trouble swallowing or the sensation that something is caught in the throat) and hoarseness New onset of wheezing without history of asthma

Clinicians should have a high level of suspicion for lung cancer, especially in patients with a smoking history. Patients with recurring or unresolving lung infections (e.g. bronchitis and pneumonia) that are unresponsive to antibiotics should also be further evaluated for lung cancer. In nonsmokers, women and East Asians are more likely to present with symptoms of an underlying lung cancer at younger ages. Importantly, many of these signs are commonly due to other causes that are not cancer.

Extrapulmonary manifestations The most common paraneoplastic syndromes associated with adenocarcinoma of the lung are described below: Hypercalcemia of malignancy is more common in squamous cell carcinoma of the lung, but can occur in adenocarcinoma as well. Parathyroid hormone-related peptide (PTHrP) is produced by tumor cells and functions similarly to parathyroid hormone (PTH). The production of this hormonally active peptide by cancer cells causes increased bone resorption via upregulation of osteoclasts, one of the cells responsible for bone remodeling. When bone is broken down, calcium is released into the bloodstream, resulting in hypercalcemia. The signs and symptoms of elevated calcium in the blood include: thirst, fatigue, constipation, polyuria (increased urination), and nausea. It is important to rule out boney metastases in patients with NSCLC because they also present with hypercalcemia. Hypertrophic pulmonary osteoarthropathy (HPO) is fairly rare in adenocarcinoma. Less than 1% of patients with adenocarcinoma of the lung will exhibit this finding, but when it does occur, it is a poor prognostic factor. The exact mechanism of HPO is unknown but it is thought to be hormonal or neurogenic in etiology. The triad of HPO includes distal clubbing, arthritis, and bilateral symmetrical periosteal formation.

Causes

Risk factors According to the Nurses' Health Study, the risk of pulmonary adenocarcinoma increases substantially after a long duration of tobacco smoking: smokers with a previous smoking duration of 30–40 years are more than twice as likely to develop lung adenocarcinoma compared to never-smokers (relative risk of approximately 2.4); a duration of more than 40 years increases relative risk to 5.

This cancer usually is seen peripherally in the lungs, as opposed to small cell lung cancer and squamous cell lung cancer, which both tend to be more centrally located, although it may also occur as central lesions. For unknown reasons, it often arises in relation to peripheral lung scars. The current theory is that the scar probably occurred secondary to the tumor, rather than causing the tumor. The adenocarcinoma has an increased incidence in smokers, and is the most common type of lung cancer seen in non-smokers and women. Deeper inhalation of cigarette smoke results in peripheral lesions that are often the case in adenocarcinomas of the lung. Generally, adenocarcinoma grows more slowly and forms smaller masses than the other subtypes. However, it tends to metastasize at an early stage.

Mechanism

Pathogenesis

Large scale studies such as The Cancer Genome Atlas (TCGA) have systematically characterized recurrent somatic alterations likely driving lung adenocarcinoma initiation and development.

Gene mutations and copy number alterations Since smoking is a strong mutagenic factor, lung adenocarcinoma is one of the tumor types with the highest number of mutations. Common somatic mutations in lung adenocarcinoma affect many oncogenes and tumor suppressor genes, including TP53 (mutated in 46% of cases), EGFR (27%), KRAS (32%), KEAP1, STK11 and NF1. EGFR and KRAS mutations tend to appear in a mutually exclusive fashion. KRAS mutations are associated with smoking habits, whereas EGFR mutations occur more frequently in females, people of Asian ethnicity and never-smokers.

Copy number amplifications in oncogenes such as TERT, Mdm2, EGFR, MET, and Myc have been reported, as well as deletions of tumor suppressor genes such as CDKN2A.

Frequent alterations occur in genes belonging to the receptor tyrosine kinase pathway, of which EGFR is the most prominent example. This pathway is involved in cell proliferation and survival and it is often deregulated in cancer. As a consequence, targeted therapies have been developed to inhibit mutant pathway components.

Chromosomal rearrangements Three membrane associated tyrosine kinase receptors are recurrently involved in fusions or rearrangements in adenocarcinomas: ALK, ROS1, and RET, and more than eighty other translocations have also been reported in adenocarcinomas of the lung.

In ALK rearrangements, the most common partner gene is EML4.

Pathophysiology The respiratory tract can be divided into two main components: the conducting airways and the gas exchange airways. The gas exchange airways are made of alveoli, small microscopic air sacs that are responsible for the exchange of oxygen and carbon dioxide during normal breathing. Alveoli are composed of two cell types, type I and type II pneumocytes. Type I pneumocytes cover 95% of alveolar surfaces, and are not able to regenerate. Type II pneumocytes are more common, making up 60% of the cells within alveolar epithelium, but constitute only 3% of the alveolar surface.

There are several factors that contribute to the transformation of normal alveolar epithelium into dysplastic, or pre-cancerous, lesions. Adenocarcinoma of the lung develops in a step-wise progression as type II pneumocytes undergo consecutive molecular changes that disrupt normal cell regulation and turnover. Atypical adenomatous hyperplasia (AAH) is considered a pre-cancerous lesion, and is thought to further progress to adenocarcinoma in situ and invasive adenocarcinoma of the lung. The lesions of AAH are <5 mm, can be single or multiple, and have a ground glass appearance on CT imaging. As more genetic mutations and dysregulation of normal cell signaling pathways accumulate, AAH can progress to adenocarcinoma in situ (AIS). AIS lesions are classified as small tumors <3 cm with abnormal type II pneumocyte cell growth that is limited to the alveolar spaces i.e. without invasion into the stroma, pleura, or vasculature. This type of growth is termed "lepidic" and is characteristic of adenocarcinoma of the lung in its earliest stages.

Diagnosis A diagnosis of lung cancer may be suspected on the basis of typical symptoms, particularly in a person with smoking history. Symptoms such as coughing up blood and unintentional weight loss may prompt further investigation, such as medical imaging.

Classification

The majority of lung cancers can be characterized as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Lung adenocarcinoma is one of the three major subtypes of NSCLC, which also include squamous carcinoma and large cell carcinoma.

Historically, there has been much debate in the most accurate method of describing adenocarcinoma of the lung and several revisions of classification systems have been published. Most recently, the International Multidisciplinary Classification of Lung Adenocarcinoma was published in 2011 and represents the consensus of several organizations to more accurately describe this specific type of lung cancer. The current classification system aims to more reliably predict prognosis and determination of therapeutic management.

The tumor size, pattern of cell growth, and depth of cell invasion into normal lung tissue are considered in determining classification. The following names represent a step-wise pathologic progression in the natural course of adenocarcinoma development; Adenocarcinoma in situ (AIS), Minimally invasive adenocarcinoma (MIA), and Invasive adenocarcinoma. Invasive adenocarcinoma of the lung includes a heterogenous mixture of subtypes and variants.

The 2011 consensus describes five subtypes of invasive adenocarcinomas based on the cell pattern that is most predominant. These subtypes are described below:

lepidic predominant acinar predominant papillary predominant micropapillary predominant solid predominant with mucin production

Cell patterns identifying subtypes are associated with prognosis, ranging from favorable (lepidic) to intermediate (acinar and papillary) to poor (micropapillary and solid).

Four discrete variants of invasive adenocarcinomas not assignable to these five subtypes are also included in the current classification: invasive mucinous adenocarcinoma colloid adenocarcinoma fetal adenocarcinoma primary pulmonary enteric adenocarcinoma

Imaging