Secondary Lung Tumors

History of Metastasectomy

During the 19th century, in the European literature there were sporadic reports of lung resections for metastatic tumors. The first of these reports was in 1855, by the French surgeon Sédillot, who removed a chest wall tumor and excised disease extending into the lung. The first case of a true pulmonary metastasectomy was described by Weinlechner in 1882 in a patient with a rib sarcoma, who was found to have two incidental pulmonary metastases at the time of the sarcoma resection. Kronlein reported the first long-term survivor after pulmonary metastasectomy in a patient with recurrent chest wall sarcoma and a metastatic lung nodule. The patient went on to survive 7 years, eventually succumbing to recurrent pulmonary disease.

The first, and perhaps most famous, report of a planned pulmonary metastasectomy in the United States was performed in 1933 by Barney and Churchill. Soon after resection of a renal cell carcinoma, they noted that the patient's pulmonary nodule, seen on a chest radiograph preoperatively and presumed to be tuberculosis, had doubled in size. The lesion, now thought to represent metastatic disease, was treated with radiation therapy. They noted a poor response and elected to resect the nodule. The patient went on to live 23 years, eventually dying of coronary artery disease with no evidence of tumor recurrence at autopsy. Despite the early discovery (in the late 1800s) that survival could be improved by resection of metastatic disease, it was not for another 40 years that metastasectomy was performed as a separate procedure by Divis in Europe. This was followed soon after by similar reports in the American literature by Torek and Tudor Edwards in the early 20th century.

These early reports, and others like them, paved the way toward general acceptance of pulmonary metastasectomy. Although initial indication for surgery was reserved for those with a solitary metastasis, with time and experience, surgeons began to perform more aggressive metastasectomies. In 1947, Alexander and Haight described the first case series of 24 patients who underwent pulmonary metastasectomy. In this series, they described a young woman with a spindle cell neurogenic sarcoma. She initially underwent a right lower lobectomy for metastatic disease in 1939. She had a recurrence in 1940 for which she underwent a left upper lobectomy. This article was the first to define criteria for resection of pulmonary metastases, including control of the primary tumor, absence of extrathoracic disease, and sufficient pulmonary reserve.

The largest effort aimed at evaluating patients undergoing pulmonary metastasectomy was undertaken by the International Registry of Lung Metastases (IRLM). Established in 1991, the IRLM accrued 5206 patients in North America and Europe. This landmark report demonstrated that complete resection, long disease-free interval, and single lesions were associated with better long-term survival. This and other studies have helped to develop current criteria for performing pulmonary metastasectomies and to define anticipated survival after resection.

Pathophysiology of Pulmonary Metastases

In 1889, British surgeon Stephen Paget observed that metastatic disease followed a nonrandom pattern. Using autopsy records of patients with a variety of primary tumors, he hypothesized that factors in certain tumors have an affinity for certain factors in target organs. Theories have subsequently evolved that attempt to explain the propensity for metastases to spread to specific organs. The “cascade spread” theory hypothesizes that a single organ represents the first site of spread, followed by systemic dissemination. This metastatic cascade is considered to be a complex series of events culminating in the generation of metastases. The initial phase of the cascade involves tumor growth via neovascularization, which is stimulated by growth factors secreted by the tumor cells and local host cells. The invasive phase of tumor growth involves the local production and activation of proteolytic enzymes (matrix metalloproteinases, collagenases, serine proteinases, cysteine proteinases) derived from both the host and tumor tissue. These enzymes decrease cell adhesiveness, stimulate cell migration, and enhance chemotaxis and subsequent tumor cell detachment.

Metastasis is most likely initiated after cell detachment from the primary tumor mass. Typically, epithelial cells undergo anoikis (apoptosis) because of the loss of cell-cell interactions once they are separated from parent tissue. Metastatic cells are thought to resist anoikis by forming cell-cell attachments with other tumor cells or host cells and through the overexpression of proteins that inhibit anoikis.

Movement from the extracellular space into a vascular compartment is termed intravasation . Cancer cells have been shown to degrade basement membranes via local release of extracellular matrix-degrading proteins (matrix metalloproteinases), facilitating migration into the lymphatic and circulatory system. Once in the circulatory system, tumor cells must avoid recognition and destruction by the host immune system. Only 0.1% of tumors cells in circulation go on to generate metastases. Mechanisms that cancer cells use to survive include human leukocyte antigen (HLA) class I downregulation (mediator of immune cell recognition) and loss of immunogenic antigens. Cancer cells also downregulate the immune system via the production of immunosuppressive cytokines. Some evidence suggests that clots form around tumor cells that protect these cells from immunologic and physiologic stresses in the bloodstream.

Tumor cells bind to pulmonary vasculature, which, via a platelet-induced reaction, stimulates endothelial cell retraction. The lung is thought to play a role as the primary capillary filter for drainage of most organs, and its rich capillary network provides an ideal environment for deposition. Movement of tumor cells from the circulatory system into the interstitium is called extravasation . Basement membrane disruption is thought to occur in a manner similar to intravasation.

Once extravasated, tumor cells may remain quiescent or they may proliferate. Proliferation and local invasion require neovascularization, which is induced via a shift toward the intracellular and extracellular production of pro-angiogenic factors. Epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and transforming growth factor-α (TGF-α) foster tumor cell proliferation in the new environment. On the other hand, the host organ produces inhibitors, such as TGF-β, mammastatin, and amphiregulin, to prevent metastatic implantations. These compounds are under investigation to assess their ability to control metastatic disease.

Evaluation of the Patient with Secondary Pulmonary Tumors

Radiographic Evaluation

Most pulmonary metastases are detected by chest radiography ( Fig. 23-1 ) or computed tomography (CT) ( Fig. 23-2 ) during routine follow-up for the primary cancer. Radiologic testing is used to define the extent of the disease and to determine whether an individual is a candidate for pulmonary metastasectomy. A search for extrathoracic disease may involve imaging the original primary disease site as well as looking for distant disease. A new pulmonary nodule in a patient with a prior malignancy should be considered cancer until proven otherwise.

Because of its higher resolution, helical CT is the gold standard imaging modality for evaluation of the lungs and characterization of metastatic lesions. Lung metastases can be small (usually less than 1 cm), and they appear as multiple lesions in 75% of cases. Most metastatic lesions to the lung are found on the lung periphery, and they have a predilection for the basilar lung fields, probably because of increased blood flow to this region when the patient is in an upright position. Distinguishing between a metastatic lesion and other malignant or benign lung lesions can be difficult. CT characteristics of metastatic lesions include spherical shape with well-circumscribed, smooth borders. Lesions with irregular or spiculated borders with associated linear densities are more commonly associated with primary lung cancers, although this is not a universal finding. Calcifications in lung nodules are rarely seen in metastatic pulmonary disease. Metastases that may have associated calcifications include osteosarcomas, chondrosarcomas, and breast and ovarian cancer. Cavitation can occur in benign lesions such as those caused by lung abscess, aspergillosis, or tuberculosis. Malignant nodules that can cavitate include squamous cell carcinoma (primary lung or metastatic carcinomas), sarcoma, and testicular tumors.

Positron emission tomography (PET) is imperative when considering patients for metastasectomy. In a series of patients with melanoma, ¹⁸ F-fluorodeoxyglucose (FDG)-PET had a sensitivity of 92%, a specificity of 88%, and accuracy of 91%. PET is helpful in assessing extent of disease, including the primary disease site as well as thoracic and extrathoracic potential sites of metastases. However, PET positive findings should be interpreted with caution because of the low specificity of positive results. When considering surgical management of metastatic lung disease, all potential sites of metastatic disease identified on CT and PET should be thoroughly evaluated, particularly in the mediastinum, because tissue confirmation of multiple organ involvement will likely change management. Although CT is useful for identifying and characterizing pulmonary metastases, caution must be exercised because intraoperative pulmonary palpation may identify smaller parenchymal lesions not detected with imaging.

Indications for Surgery

Reasons to perform surgery for secondary pulmonary malignancy include curative resection, tissue diagnosis, or evaluation of residual disease. Before proceeding with resection, a number of questions should be considered in the preoperative assessment of the patient.

Does the pulmonary nodule represent one site of multiorgan spread, thereby contraindicating resection? Pulmonary metastases are common in the advanced stages of cancer, with as many as one third of patients presenting with secondary nodules. Of these patients, however, most pulmonary nodules (75% to 85%) are a manifestation of widespread disease. Consequently, only 15% to 25% of patients have lesions confined to the lung and are appropriate candidates for curative resection ( Table 23-1 ). Preoperative evaluation, therefore, should exclude extrathoracic disease.

When pleural or pericardial effusion is present, thoracentesis or pericardiocentesis should be performed to evaluate for malignancy. Positive cytology contraindicates resection. Cytology may be falsely negative, however, in up to 40% to 60% of cases. Consequently, a negative cytology returned in the context of a high index of suspicion for malignant effusion warrants pericardial or pleural biopsy, or both. A VATS approach can be used to access the pleural space, and it offers a minimally invasive transthoracic approach to the pericardium. It also affords the option of visualizing and palpating the lung as well as sampling the mediastinal lymph nodes. Bronchoscopy should always be performed before thoracoscopy or thoracotomy, to evaluate for endobronchial lesions.

Is a nonsurgical therapeutic option available? Although surgical resection of secondary pulmonary malignancies may give patients a significant survival advantage, nonsurgical management may be more appropriate for certain cancers. For example, in the context of nonseminomatous germ cell tumors, great success has been obtained with chemotherapy, with cure rates approaching 90% (see “ Germ Cell Tumors ,” later). In addition, alternative therapies such as radiofrequency ablation or stereotactic body radiation may be appropriate in selected cases (see “ Alternative Treatment Options ,” later).

Will the patient tolerate the procedure? Risk factors associated with metastatic disease (e.g., smoking and advanced age) require that patients being considered for surgical resection receive a thorough medical assessment with particular attention to their pulmonary and cardiac status. Stress testing, echocardiograms, arterial blood gases, pulmonary function testing, and ventilation-perfusion scans may be necessary to assess patients' tolerance for a proposed resection or their ability to undergo single-lung ventilation. Also, previously administered chemotherapeutic agents such as bleomycin or mitomycin may result in additional compromise of pulmonary function, and doxorubicin may be associated with cardiac impairment. In addition, the thoracic surgeon expecting to perform a metastasectomy must always be prepared to perform a formal lobectomy should the pathology reveal a primary lung cancer or should wedge resection result in incomplete resection. Thus, performing the preoperative assessment with consideration for anatomic resection and its attendant risk is prudent.

Are the lesions resectable? Unresectability is defined as noncontiguous involvement beyond the visceral pleural envelope. This is best determined at operation. Preoperatively, imaging modalities can only provide an estimate of resectability. In addition, thoracoscopy can sometimes be useful to assess for disseminated disease or bulky tumors that involve major structures and preclude complete resection. If the pericardium or pleura is involved with neoplastic disease from direct extension of an underlying parenchymal lesion, but there is no associated effusion, they should be resected en bloc with the specimen. Direct metastases to the pleura or pericardium in a discontinuous manner (i.e., disseminated spread) and malignant pleural or pericardial effusions are generally contraindications for resection.

Is the primary tumor controlled? Efficacy of pulmonary metastasectomy depends on, among other factors, the ability to control the primary site of disease. The primary neoplasm should generally be addressed before resection of the pulmonary metastases. Therefore, thorough preoperative testing should be performed to rule out other possible metastatic sites or local recurrence of the primary tumor prior to pulmonary metastasectomy ( Box 23-3 ).

Alexander and Haight, in the 1940s, were the first to describe specific selection criteria for consideration of pulmonary metastasectomy. They realized that the benefits of surgical resection depended on primary tumor control, absence of extrathoracic spread, and adequate patient selection. Approximately one third of patients meet these selection criteria and can appropriately undergo metastatic resection.