Bronchogenic carcinomas include small cell carcinoma, squamous cell carcinoma, adenocarcinoma, large-cell carcinoma and undifferentiated carcinoma. Bronchogenic carcinoma is clearly associated with tobacco smoking. Once the diagnosis of bronchogenic carcinoma is confirmed by a biopsy study, disease staging with CT or FDG-PET is indicated because treatment is stage-based. While stage I and II disease benefit from surgical lobectomy, chemotherapy is essential for patients with stage III and IV.

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large cell carcinoma of the lung

Image: “LOWER RESPIRATORY TRACT: LARGE CELL CARCINOMA The corresponding surgical resection shows neoplastic cells with abundant pale eosinophilic cytoplasm and a surrounding infiltrate of inflammatory cells which can also be seen among the tumor cells in the fine needle aspirate specimen. A histologic section shows a proliferation of atypical cells along the alveolar walls (A).” by The Armed Forces Institute of Pathology (AFIP) – PEIR Digital Library (Pathology image database). Image# 408049. Image and description are from the AFIP Atlas of Tumor Pathology. License: Public Domain


Definition of Bronchogenic Carcinoma

Bronchogenic carcinoma includes small and non-small cell lung cancer. These tumors arise from the bronchial and bronchiolar tree in the lungs and are considered as the most common malignancy in the developed world. Squamous-cell carcinoma, small-cell carcinoma, adenocarcinoma, large-cell carcinoma and undifferentiated carcinoma are all types of the bronchogenic carcinoma spectrum.

Epidemiology and Etiology of Bronchogenic Carcinoma

The incidence of bronchogenic carcinoma is estimated to be more than 200,000 cases per year, while bronchogenic carcinoma related deaths are about 160,000 per year in the United States. These figures put bronchogenic carcinoma as the most commonly diagnosed malignancy in the United States.

small cell carcinoma

Image: “Histopathologic image of small cell carcinoma of the lung. CT-guided core needle biopsy. H & E stain.” by KGH. License: CC BY-SA 3.0

All types of bronchogenic carcinoma are more common in males. Squamous cell and small cell carcinoma are clearly smoking related while adenocarcinoma can be identified in both smokers and non-smokers. Socioeconomic status is not an important epidemiological factor in bronchogenic carcinoma.

Tobacco smoking is the most important etiology and risk factor for bronchogenic carcinoma. Several carcinogens can be identified in cigarettes and include polycyclic aromatic hydrocarbons, aromatic amines, benzene, vinyl chloride, arsenic and chromium.

Another important category of smokers is called the never smokers. These are people who smoked less than 100 cigarettes in their lifetime. While small-cell lung cancer is rare in this group, adenocarcinoma is being increasingly identified. Environmental air pollution from fuel combustion has also been suggested as a possible etiological factor for bronchogenic carcinoma in non-smokers.

Classification of Bronchogenic Carcinoma

  • Adenocarcinomas represent 40% of the bronchogenic carcinomas and they are the most common type of bronchogenic carcinomas in non-smokers or never smokers.
  • Squamous cell carcinoma is usually found in the center of the lungs, while adenocarcinomas are peripheral. Squamous cell carcinoma is more closely associated with previous history of tobacco smoking.
Image: “This poorly differentiated (solid) adenocarcinoma shows many cells with mucin vacuoles stained with digested PAS. The vacuoles were difficult to see on routine sections, and the case had originally been classified as large cell carcinoma.” by The Armed Forces Institute of Pathology (AFIP). License: Public Domain

Image: “This poorly differentiated (solid) adenocarcinoma shows many cells with mucin vacuoles stained with digested PAS. The vacuoles were difficult to see on routine sections, and the case had originally been classified as large cell carcinoma.” by The Armed Forces Institute of Pathology (AFIP). License: Public Domain

  • Large-cell carcinoma is another type of bronchogenic carcinoma where the cells do not show gland formation as is the case with adenocarcinoma or keratinization as is found in squamous cell carcinoma. Again, this type of bronchogenic carcinoma is believed to be related to tobacco smoking.
  • Small-cell carcinoma is the most dangerous form of bronchogenic carcinoma. These tumors are more likely to metastasize to distant organs at the time of presentation and the prognosis is usually grim. Small-cell carcinoma is more common in smokers.

Pathophysiology  and Clinical Presentation of Bronchogenic Carcinoma

Carcinogens in tobacco smoke are responsible for the majority of the cases of bronchogenic carcinoma. Polycyclic aromatic hydrocarbons and nicotine-derived nitrosamine (NNK) are known to result in DNA damage. Occupational exposure to asbestos is associated with an increased risk of lung cancer.

The different carcinogens in tobacco smoke are believed to result in multiple insults to the cell DNA until DNA repair mechanisms fail to cope with the degree of repeated hits. Once this happens, patients develop bronchogenic carcinoma.

The clinical presentation of bronchogenic carcinoma is highly dependent on the location of the tumor and the histological type. Cough is the most common presenting symptom, hence any change in the character or severity of cough in a smoker is always a red alarm for possible lung cancer.

Patients can also complain of anorexia and weight loss, chest pain, shortness of breath and hemoptysis. Secondary bacterial infection of the lung tissue that is distal to an obstructed bronchiole can be a presentation of bronchogenic carcinoma.

Due to the overlap between the symptoms of chronic obstructive lung disease and bronchogenic carcinoma, the threshold to suspect lung cancer should be always low in a smoker.

nail clubbing

Image: “Clubbing fingers” by Desherinka – Own work. License: GNU Free Documentation License

Paraneoplastic syndromes are usually identified in bronchogenic carcinoma and each presentation can be clearly linked to certain histological subtypes. For instance, hypercalcemia is more common with squamous cell carcinoma, nail clubbing can be found in all types of bronchogenic carcinoma, and endocrine syndromes such as SIADH, ectopic ACTH production and Eaton-Lambert syndrome are associated with small-cell lung cancer.

Diagnostic Work-up and Staging of Bronchogenic Carcinoma

Any known smoker who presents with recent-onset cough or a change in their cough and respiratory function should have a chest x-ray. If the chest x-ray reveals a nodule, the location of the nodule is essential to determine the next diagnostic step.

For central nodules, sputum cytology can be useful to aid with the diagnosis as it can reveal malignant cells. Bronchoracic and transthoracic biopsies are also indicated to define the histological type of the bronchogenic carcinoma as this clearly affects the treatment plan and prognosis.

For patients with a peripheral nodule, computed tomography (CT) guided transthoracic biopsy is indicated to identify the histological type of the cancer.

Laboratory investigations in lung cancer can reveal hypercalcemia, an inappropriately elevated antidiuretic hormone level, or increased ACTH.

Computerized tomography of the chest is used for staging purposes. CT scan can also help to differentiate between small and non-small cell lung cancer as the former is more commonly associated with massive lymphadenopathy. The CT scan should also include the upper abdomen as early metastasis to the liver and adrenal glands is common and should be evaluated early in the disease for staging.

For patients with neurologic findings, a brain MRI is indicated to exclude possible brain metastasis.

Fluoro-18-2-deoxyglucose (FDG) positron emission tomography (PET) is commonly used in patients with bronchogenic carcinoma to identify possible mediastinal involvement.

large cell carcinoma of the lung

Image: “LOWER RESPIRATORY TRACT: LARGE CELL CARCINOMA The corresponding surgical resection shows neoplastic cells with abundant pale eosinophilic cytoplasm and a surrounding infiltrate of inflammatory cells which can also be seen among the tumor cells in the fine needle aspirate specimen. A histologic section shows a proliferation of atypical cells along the alveolar walls (A).” by The Armed Forces Institute of Pathology (AFIP) – PEIR Digital Library (Pathology image database). Image# 408049. Image and description are from the AFIP Atlas of Tumor Pathology. License: Public Domain

While the histological type of bronchogenic carcinoma plays a role in the determination of the prognosis, the most important prognostic factor is the extent of disease metastasis status and lymph node involvement.

The tumor, lymph node, metastasis (TNM) staging system is used in adenocarcinoma, squamous cell carcinoma and large-cell carcinoma but not in small-cell carcinoma.

The tumor could be confined to the lung without basement membrane invasiveness, Tis, 3 cm or less in diameter, T1, between 3 and 7 cm, T2, more than 7 cm but does not invade the mediastinum, T3 or invading the mediastinum T4. Several subtypes of the tumor status also exist.

The lymph node status could be clean without metastasis, N0, metastasis to ipsilateral peribronchial and hilar lymph nodes, N1, metastasis to ipsilateral mediastinal lymph nodes, N2 or metastasis to the contralateral lymph nodes N3.

Patients could have no metastasis, M0, or have distant metastasis, M1.

Stage 0 bronchogenic carcinoma is defined as a TisN0M0 disease. T1N0M0 is identified as Stage 1A disease. Stage 1B disease includes T2N0M0. Patients with T1N1M0 or T2N1M0 are considered as Stage IIA. T3N1M0 disease is stage IIB. Stage III includes all other disease stages but without metastasis. Stage IV disease is any bronchogenic carcinoma with metastasis (M1).

Treatment of Bronchogenic Carcinoma

The best management plan of bronchogenic carcinoma is one that is based on the stage of the disease.

Patients with stage I disease should undergo a surgical resection of the whole involved lobe. Patients with poor respiratory function where surgical resection is not feasible may be cured by radiotherapy alone. Adjuvant chemotherapy might be beneficial in patients with stage I disease.

Stage II disease can also be treated by surgical resection. If the patient is not a possible surgical candidate, he or she might benefit from curative radiotherapy. Adjuvant platinum-based chemotherapy is beneficial in these patients after resection.

Patients with stage III disease might or might not benefit from surgery. Chemoradiation therapy is recommended without surgical intervention in patients with stage III disease who also have mediastinal lymph node disease. Etoposide, a cisplatin-based chemotherapeutic, is usually recommended in these patients.

Patients with stage IV disease should be evaluated for possible surgical resection followed by chemotherapy when the metastatic lesion is single. Patients with stage IV disease might benefit from platinum-based chemotherapy, bevacizumab, carboplatin-paclitaxel combination therapy or other novel chemotherapeutics.

The American Society of Clinical Oncology recommends the use of two platinum-based cytotoxic drugs, followed by a switch to a single drug regimen if there was response. Non-responders might benefit from docetaxel, erlotinib, or pemetrexed as second line therapy.

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